Essential of Special Patholog by DR Zair Hassan: December 2015

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Essential Special Pathology
Chapter One BLOOD VESSELS
Arteriosclerosis:
 The term arteriosclerosis means “hardening of arteries” which reflects arterial wall thickening and
loss of elasticity.
Morphologically:
The following morphologic entities are included in arteriosclerosis:
 Atherosclerosis
 Senile arteriosclerosis
 Monckeberg’s medial sclerosis(Medial calcific sclerosis)
 Characterized by the presence of calcification in the media of muscular arteries
 Typically seen in person older than 50 years
 Hypertensive Arteriosclerosis:
a. Hyaline Arteriosclerosis is associated with benign hypertension.
Pathogenesis:
 Injured endothelium
 Leakage of plasma components across injured endothelial cells.
 Increase smooth muscle thickening and ECM production in response to hemodynamic stress.
b. Hyperplastic Arteriosclerosis is more typically seen in severe hypertension. Vessels exhibit
characteristic“onionskin” concentric laminated thickening of arteriolar walls and luminal
narrowing.
In malignant hypertension these changes are accompanied by fibrinoid deposits and vessel
wall necrosis (necrotizing arteriolitis), which are particularly prominent in the kidney
(Nephrosclerosis).
Atherosclerosis
Definition:
Atherosclerosis is a term characterized by initial lesion called ‘’atheroma’’ that protrudes into
vascular lamina. An atheromatous plaque consists of a raised lesion with a soft yellow, grumous core of
lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap. Besides obstructing
blood flow, atherosclerotic plaques weaken the underlying media andcausing rupture followed by
catastrophic vessel thrombosis.
Morphology of Atherosclerosis:
 Fatty streaks are thin flat, yellow streak in the intima of artery, 1cm in diameter. They are composed
of lipid filled foamy macrophages whose cytoplasm has become distended with lipid
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Essential Special Pathology Chapter 1:
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 Atheromatous plaques grossly appear white to yellow, vary 0.3cm to1.5 cm in diameter
Fatty Streak → Atheroma → Atheromatous plaques
 Abdominal aorta is involved more than thoracic aorta. In descending order the vessels involved are:
 Lower abdominal aorta
 Coronary arteries
 Popliteal arteries
 Descending thoracic aorta
 Internal carotid artery
 Vessels of circle of Willis
Note: Vessels of upper arm and kidneysare spared
Principal cells/components of plaque:
 Cells including SMCs, macrophages, and T cells
 ECM(Extracellular matrix) including collagen, elastic fibers, and proteoglycans
 Intracellular and extracellularlipid
Fibrous cap:
 Smooth Muscle Cells
 Macrophages
 Lymphocytes
 Connective Tissue
 Neovascularization
Necrotic Center:
 Cell Debris
 Cholesterol Crystals
 Calcification
Figure: Components of Atheromatous Plaque

Pathogenesis of atherosclerosis
Endothelial Damage:
 Endothelial cell damage of muscular and elastic arteries
 Causes of endothelial cell injury (hypertension, smoking, tobacco andLDL)
Cell response to the endothelial injury:
 Macrophages and platelets adhere to damaged endothelium
 Release cytokines causes hyperplasia of medial smooth muscle cells
 Smooth muscle cells migrate to the tunica media
 Cholesterol enters smooth muscle cells and macrophages, called foam cell
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Essential Pathology
Special Pathology Chapter 1:
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 Smooth muscle cells release cytokines that produce extracellular matrix

 Matrix components include collagen, proteoglycans and elastin
Development of fibrous cap:
 Components of fibrous cap: (smooth muscle, foam cells, inflammatory cells, ECM)
 Fibrous cap overlies a necrotic center
 Disrupted plaques may extrude underlying necrotic material leading to thrombosis.
Fibrous plaque becomes dystrophically calcified and ulcerated
Role of Monocyte in Generation of Atheroma:
 Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL.
Monocytes recruitment and differentiation into macrophages and ultimately into foam cells is
theoretically protective, since these cells remove potentially harmful lipid particles. However,
progressive accumulation of oxidized LDL drives lesion progression. Thus, macrophages activation
results in cytokines production (TNF) and reactive oxygen species thus aggravating LDL oxidation.
Role of Hypercholesterolemia in Atherosclerosis:
 Chronic hyperlipidemia particularly hypercholesterolemia, can directly impair EC function by
increasing local production of reactive oxygen species. Among these effects, oxygen free radicals
accelerate nitric oxide decay, damping its vasodilator activity and thereby increasing the local stress
on the vessel’s wall.
 With chronic hyperlipidemia, lipoproteins accumulate with in the intima. These lipids are oxidized to
through the action of oxygen free radicals locally generated by macrophages or ECs. Oxidized LDL is
ingested by macrophages through scavenger receptors, distinct from the LDL receptors resulting in
foam cell formation.
 In addition, oxidized LDL stimulates the release of growth factors, cytokines and chemokine by ECs
and macrophages that increase monocytes recruitment into lesion. Finally oxidized LDLs are cytotoxic
to the ECs and SMCs, can induce extra cellular dysfunction
 The importance of oxidized LDL in atherogenesis is suggested by its accumulation with in
macrophages at all stages of accumulation. Moreover, antioxidant therapy (β-carotenes and Vit E)
protects against atherosclerosis.
Clinical consequences of atherosclerosis:
 Occlusion of smaller vessels can compromise tissue perfusion.
 Plaque rupture causes exposure of atherosclerotic debris, leading to acute vascular thrombosis or
distal embolization
 Destruction of the underlying vessel wall can lead to aneurysm formation with secondary rupture and
thrombosis
Risk Factors for Atherosclerosis:
Major risks Minor risks
Non modifiable Obesity
Increasing age Physical inactivity
Male gender Stress (type A personality)
Family history Postmenopausal estrogen deficiency
Genetic abnormality High carbohydrates intake
Modifiable Lipoprotein
Hyperlipidemia Hardened trans unsaturated fat intake
Hypertension Chlamydia pneumoniae infection
Cigarette smoking Homocystinuria
Diabetes
C- reactive proteins
Complications of Atherosclerosis:
 Vessels weakness: (abdominal aortic aneurysm)
 Vesselsthrombosis:
 Acute MI (coronary artery)
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 Stroke (internal carotid and middle cerebral artery)
 Small bowel infarction ( superior mesenteric artery)
 Hypertension:
 Renal artery atherosclerosis may activate the Rennin Angiotensin system.
 Peripheralvasculardisease:
 increased risk of gangrene
 pain in buttock and when walking (claudication)
 Cerebralatrophy:
 Atherosclerosis involving Circle of Willis or Internal Carotid Artery
Diagnosis:
 Measurement of Resting Ankle-Brachial Index (ABI):
If it is less than 0.9, it is highly suggestive of peripheral arterial disease.
 Angiography
 Duplex Ultrasonography
Bad cholesterol:
 The major component of the serum cholesterol associated increased risk is LDL (bad cholesterol). It
delivers cholesterol to the peripheral tissues
Good cholesterol:
 In contrast, HDL (good cholesterol) mobilizes cholesterol from developing and existing atheroma and
transports it to the liver for excretion in the bile. So higher level of HDL correlate with reduced risk
Aneurysm
Definition:
It is the localized abnormal dilation of the blood vessels or heart.
Common causes Key Point
 Atherosclerosis Surgical repair can be
 Hypertension done if the Abdominal
 Trauma Aneurysm is 5-5.4 cm
 Hereditary Disorders (Marfan’s Syndrome)
Classification of aneurysm:
Based On Pathogenic Mechanism:
 Atherosclerotic (arteriosclerotic) aneurysm
 Mycotic aneurysm
 Berry aneurysm of cerebral artery
 Syphilitic (luteic) aneurysm
 Dissecting aneurysm (Dissecting hematoma)
Depending Upon the Composition ofThe Wall:
 True aneurysm(involve all 3 layers of the artery intima, media and adventitia)
 False aneurysm (pseudoaneurysm when a wall defect leads to hematoma formation)
Depending Upon the Shape:
 Saccular aneurysm has large spherical shaped dilatation.
 Fusiform aneurysm having slow spindle shaped dilatation.
 Cylindrical with a continuous parallel dilatation
 Serpentine or varicose which has tortuous dilatation of the vessel.
 Racemose or cricoid having mass of intercommunicating small arteries and vein
Pathogenesis:
Inadequate or abnormal connective tissue synthesis:
 Marfan syndrome-defect in type IV collagen synthesis
 Ehlers-Danlos syndrome-defective collagen iii synthesis
 Vitamin C deficiency causes alteration in collagen cross linking
 Leoysdietz Syndrome-Mutation In TGF Β Receptors
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Excessive connective tissue degradation
 Collagen degradation with altered synthesis by inflammatory infiltrate and destructuctive proteolytic
enzymes
 ↑MMP production especially by macrophages
 ↓ tissue inhibitor of metalloproteinase(TIMP) expression
Loss of vascular smooth muscle cells or inappropriate collagen or non-elastic ECM
 Systemic hypertension causes luminal narrowing of the aortic vasa vasorum leading to ischemia of
the outer media. With degenerative changes, which include fibrosis, inadequate ECM synthesis and
accumulation of increase, amount of amorphous proteoglycans. Histologically these changes are
called Cystic MedialDegeneration(CMD)
Note: Abdominal aorta is the favored site of atherosclerotic aneurysm
Clinical consequences:
 Rupture (Most common complication) into the peritoneal cavity or retroperitoneal tissue leading to
massive often-fatalhemorrhage cause shock and sudden death
 Occlusion of the renal, iliac vertebral, mesenteric resulting in distal ischemia of the Kidneys, legs,
spinal cord and GIT, respectively
 Embolism from atheroma or mural thrombus
 Impingement on adjacent structures e.g. compression of ureter or erosion of vertebrae by the
expanding aneurysm
 An abdominal mass (often palpably pulsating) that simulates a tumor
Aortic Dissection
Definition:
rd rd
It is defined as ‘’an intimal tear in the vessel wall which separate the inner 2/3 from the outer 1/3 .
Pathogenesis:
Cystic medial degeneration (CMD):
 Elastic tissue fragmentation
 Matrix material collects in the area of fragmentation in the tunica media.
Risk factors for CMD:
 Increase in wall stress: hypertension, pregnancy, and Coarctation
 Defect in connective tissue: Marfan syndrome, Ehlers-Danlos syndrome, Vitamin C deficiency,
copper metabolic defects.
 Skeletal abnormalities: elongated axial bones
 Ocular findings: Lens subluxation
Intimal tear:
 Due to hypertension or underlying structural weakness in the media
 Usually occur within 10cm of aortic valve.
 Blood dissects under arterial pressure through area of weakness
 Blood dissect proximally and distally or blood dissects the vessel wall in both directions often forming
a double barrel lumen
Morphology:
 The intimal tear marking the point of origin of the dissection is found in the ascending aorta, usually
with in 10cm of aortic wall. Such tears are usually transverse or oblique and 1-5 cm in length with
sharp, jagged edge.
 Dissection can extend along the aorta retrograde toward the heart as well as distally Sometimes all
the way into the iliac and femoral Arteries.
 Dissecting hematoma spreads along the laminar plane of aorta b/w middle and outer 3rd
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 It often ruptures out through the adventitia causing massive hemorrhage.

 Sometimes hematoma reenters the lumen of the aorta, producing second distal intimal tear and new
vascular channel with in the media of aortic wall “Double Barreled Aorta”
 Cystic medial degeneration (CMD)
 Inflammation is absent
Clinical course:
 Sudden onset of severe excruciating chest pain radiating to the back, whereas pain of MI radiates to
inner arm
 Type A dissection: (proximal lesion) involving either ascending aorta or both ascending and
descending aorta (type I and II of the DeBakey classification)
 Type B: (distal lesion): not involving ascending part and usually beginning distal to the subclavian
artery called type B or DeBakey III)
 Sudden onset of excruciating pain in the chest radiating to back b/w scapulae
 Rupture: usually into pericardial sac, pleural cavity or peritoneal cavity
 Cardiac temponade
 Aortic insufficiency
 Myocardial infarction
 Extension of the dissection into the great artery of the neck
 Loss of upper extremity pulse (due to compression of subclavian artery)
 Aortic valve regurgitations
 X-ray chest shows widening of the AV root
Classification of Aortic Dissection:
DeBakey classification:
 DeBakey I include Ascending aorta, Descending aorta and Arch of aorta
 DeBakey II include Ascending aorta
 DeBakey III include Descending aorta
Figure: DeBakey Classification of Aortic Dissection
Stanford’s classification:
 Stanford’s type A Ascending aorta
 Stanford’s type B Descending aorta
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Q. A 63-year-old woman has the sudden onset of “knife-like” pain in the chest radiating to the back. She has
previous history of poorly controlled hypertension. On examination, she has blood pressure of 150/100 mmHg.A
chest radiograph reveals a widened mediastinum. Laboratory findings include normal serum creatinine kinase MB.
a) Which one of the following three is the most likely diagnosis?
1-Aortic Dissection 2-Infective endocarditis 3-Myocardial infarction
b) Write the important morphological points to the lesion
c) Give two important risk factors related to the diagnosis
Diagnosis:
Aortic Dissection
Morphology:
 The intimal tear marking the point of origin of the dissection is found in the ascending aorta, usually
with in 10cm of aortic wall. Such tears are usually transverse or oblique and 1-5 cm in length with
sharp, jagged edge.
 Dissection can extend along the aorta retrograde toward the heart as well as distally sometimes
all the way into the iliac and femoral Artery.
 dissecting hematoma spreads along the laminar plane of aorta b/w middle and outer 3rd
 It often ruptures out through the adventitia causing massive hemorrhage.
 sometimes hematoma reenters the lumen of the aorta, producing second distal intimal tear and new
vascular channel with in the media of aortic wall so forming “double barreled aorta “Cystic medial
degeneration (CMD)
Risk Factor:
 Hypertension (mostly in older people)
 Defect in connective tissue:Marfan syndrome, Ehlers-Danlos syndrome (mostly in younger people)
 Nutritional Deficiency: Vitamin C deficiency,Copper metabolic defects
Vasculitis
Giant cell arteritis (Temporalis arteritis)
General Description:
 The most common form of chronic vasculitis
 An old-age disease—rare before the age of 50 years
 Granulomatous arteritis with giant cells involving short segments of head arteries, most
ofteninvolving temporal arteries but also ophthalmic or vertebral arteries
 Palpable nodularity of tortuous temporal arteries is typical
 Symptoms include headaches, visual symptoms and constitutional symptoms such as fever,fatigue
and weight loss
 Diagnosis requires biopsy of the affected blood vessel
 Because of the segmental nature of inflammation, biopsy is negative in 30% cases
Q.A 55 years old man presents with left sided facial pain, with palpable left temporal artery. Biopsy of the artery
reveals fragmentation of internal elastic lamina, with granulomas containing multinucleated body giant cells.
a) What is the diagnosis?
b) Which other condition should be considered in the differential diagnosis if a granulomatous Vasculitis
involves the aorta?
c) List the three pathogenic mechanisms involved in non-infectious Vasculitis.
d) Classify Vasculitis
Diagnosis:
Giant cell arteritis (Temporalis arteritis)
Differential Diagnosis:
Takayasu’s arteritis
Pathogenesis:
 Immune complex associated Vasculitis.
 Anti-neutrophil cytoplasmic antibodies.(ANCA)
 Anti-endothelial cell antibodies
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Classification of Vasculitis:
Vessel size Vasculitis
Large vessels(GT) Giant cell arteritis(G), Takayasu’s arteritis(T)
Medium vessels(KP) Polyarthritis nodosa(P), Kawasaki’s disease(K)
Small vessels(WMC) Wegner’s granulomatosis(W), Microscopic polyangitis(M),

Churg- Strauss syndrome(C), Henoch-schonlein purpura, etc.
Takayasu’s arteritis (Pulseless disease)
 Takayasu’s arteritis is a chronic granulomatous Vasculitis of the medium sized and large arteries
 Characterized principally by ocular disturbances and marked weakening of the pulses in the upper
extremities, hence the alternate name, Pulseless disease
 Transmural scarring and thickening of the aorta, particularly the aortic arch and great vessels, with
severe luminal narrowing of the major branched vessels
Morphology
 Classically affects the aortic arch and arch vessels
 Pulmonary artery are involved in 50 % patients, and renal and coronary arteries can also be affected
 Histologically, mononuclear infiltrate (Chronic inflammation) and perivascular cuffing of the vasa
vasorum, intense Transmural mononuclear inflammation with giant cells and patchy medial necrosis
Clinical features
 Nonspecific symptoms include fever, fatigue and weight loss
 Reduced upper extremity blood pressure and pulse strength; neurological deficits
 Ocular disturbances include visual defects, retinal hemorrhage and total blindness
 Distal aorta disease can manifest as leg claudication and pulmonary artery hypertension
 Narrowing of the coronary Ostia can lead to myocardial infarction and involvement of the renal
arteries causes systemic hypertension
Polyarteritis Nodosa:
Polyarteritis nodosa (PAN or c-PAN) is a systemic Vasculitis characterized by necrotizing inflammatory
lesions that affect medium-sized and small muscular arteries, preferentially at vessel bifurcations,
resulting in microaneurysm formation, aneurysmal rupture with hemorrhage, thrombosis, and,
consequently, organ ischemia or infarction
People with active hepatitis B or hepatitis C may develop this disease
Types:
 Hepatitis B related PAN
 Hepatitis B unrelated
Morphology:
 Vascular lesions in medium-sized muscular arteries occur mainly at bifurcations and branch points.
 Inflammation is not continuous but it is segmental transmural necrotizing Inflammation which may
start in the vessel intima and progress to include the entire arterial wall, destroying the internal and
external elastic lamina, resulting in ‘’Fibrinoid Necrosis’’
 Aneurysms develop in the weakened vessel, carrying a subsequent risk for rupture and hemorrhage.
Thrombi may develop at the site of the lesions. As lesions progress, proliferation of the intima or
media may result in obstruction and subsequent tissue ischemia or infarction. Polyarteritis nodosa
(PAN) spares large vessels (the aorta and its major branches), the smallest vessels (capillaries and
small arterioles), and the venous system
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Clinical features:
Nerve
 Peripheral neuropathies are very common (50 to 70%). This includes tingling, numbness and/or pain
in the hands, arms, feet, and legs.
 Predominantly affect motor neurons
Skin
 Skin abnormalities are very common in PAN and may include purpura, livedo reticularis, ulcers,
nodules or gangrene.
 Skin involvement occurs most often on the legs and is very painful.
Kidney
 Renal artery vasculitis may lead to protein in the urine, impaired kidney function, and hypertension.
 Small percentage of patients goes on to require dialysis.
Gastrointestinal Tract
 Abdominal pain, gastrointestinal bleeding (occasionally is mistaken for inflammatory bowel disease)
 Hemorrhage, bowel infarction, and perforation are rare, but very serious
Heart
 Clinical involvement of the heart does not usually cause symptoms.
 However, some patients develop myocardial infarctions (heart attacks) or congestive heart failure.
Eye
 Sclerotic or inflammation in the sclera (white part of the eye)
Genitals
 Testicular infarction
Note:Characteristically spares pulmonary vessels.
Laboratory investigation:
No specific lab tests exist for diagnosing Polyarteritis nodosa. Diagnosis is generally based on the physical
examination and a few laboratory studies that help confirm the diagnosis:
 CBC (may demonstrate an elevated white blood count)
 ESR (elevated)
 Perinuclear pattern of ant neutrophil cytoplasmic antibodies (p-ANCA) - not associated with "classic"
Polyarteritis nodosa, but is present in a form of the disease affecting smaller blood vessels, known
as microscopic polyangitis or leukocytoclastic angiitis
 Tissue biopsy (reveals inflammation in small arteries, called arteritis)
 C-reactive protein elevated
 Angiography: Showing beading pattern
Kawasaki Disease:
Kawasaki disease (KD) is an acute febrile vasculitis syndrome of early childhood that, although it has a
good prognosis with treatment, can lead to death from coronary artery aneurysm (CAA) in a very small
percentage of patients.
Clinical features
 Irritability
 No exudative bilateral conjunctivitis (90%)
 Anterior uveitis (70%)
 Perianal erythema (70%)
 Sterile pyuria
 Erythema and edema on the hands and feet; the latter impedes ambulation
 Strawberry tongue and lip fissures
 Hepatic, renal, and GI dysfunction
 Myocarditis and pericarditis
 Myocardial infarction in children is mostly caused by Kawasaki disease.
 Lymphadenopathy (75%); generally, a single, enlarged, nonsuppurative cervical node measuring
approximately 1.5 cm
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Lab investigations:
 Erythrocyte sedimentation rate (ESR)
 C-reactive protein (CRP)
 Alpha1-antitrypsin
 Echocardiography useful to detect coronary artery dilatation
Wegner Granulomatosis
 Characterized by specific triad of
 Granuloma of the lung/ upper respiratory tract(ear, nose , sinuses , throat )
 Vasculitis of small to medium sized vessels, most prominently in the lung and upper respiratory
tract e.g. sinusitis, rhinitis etc.
 Glomerulonephritis
 Wegner granulomatosis is likely to be initiated as a cell-mediated hypersensitivity reaction directed
against inhaled infectious or environmental antigens.
Note: Wegner granulomatosis is C-ANCA whereas microscopic polyangitis and Churg-Strauss syndrome is
P-ANCA (antineutrophilic cytoplasmic antibody)
Churg-Strauss Syndrome
 Also called allergic granulomatosis and angiitis is a small vessel necrotizing vasculitis classically
associated with asthma, allergic rhinitis, lung infiltrates, peripheral eosinophilia, extravascular
necrotizing granulomas and a prominent infiltration of vessels and perivascular tissue by eosinophils.
 Churg-Strauss is C-ANCA
Microscopic Polyangitis
 It is also called hypersensitivity vasculitis or leukocytoclastic vasculitis
 Necrotizing glomerulonephritis (in 90 % patients) and pulmonary capillaritis are particularly common
 In some cases, antibody responses to antigens such as drugs(e.g. penicillin), microorganism(e.g.
streptococci)or tumors protein have been implicated
Morphology
 Characterized by segmental fibrinoid necrosis of the media with focal transmural necrotizing lesions,
granulomatous inflammation is absent
 Only infiltration neutrophils that frequently fragmentation are seen , giving rise to the term
leukocytoclastic vasculitis
Clinical features
 Major features include hemoptysis, hematuria, proteinuria, abdominal pain, bleeding, muscle pain,
weakness, or palpable cutaneous purpura etc.
Thrombangitis Obliterans (TAO)
 Thrombangitis Obliterans (TAO), an inflammatoryvasculopathy also known as Buergers disease, is
characterized byan inflammatory endarteritis that causes prothrombic state and subsequent Vaso-
occlusive phenomena. The inflammatory process is initiated within the tunica intima. It
characteristically affects small and medium sized arteries as well as vein of the upper and lower
extremities
 The condition is strongly associated withuseof tobacco, and disease progression is closely linked to
continue use
 Genetic factors an association with HLA-A9 and HLA-B5
Clinical presentation:
 Patients often present with moderate to severe claudication that can quickly progress to critical limb
ischemia, featuring rest pain or tissue loss
 Feature of acute limb ischemia ( e.g. pain, parasthesia, pallor, mottling, paresis and uselessness) are
common signs and symptoms encountered in the emergency setting
Treatment:
 Pharmacological therapy is generally ineffective.
 Abstinence from tobacco is the only measure known to prevent disease progression.
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Thrombophlebitis:
Definition:
Thrombophlebitisis vein inflammation related to a thrombus(blood clot). When it occurs repeatedly in
different locations, it is known as "Thrombophlebitis migrans", "migrating thrombophlebitis"
or Trousseau's syndrome.
Types
There are two main types of thrombophlebitis:
 Deep venous thrombophlebitis (affects deeper, larger veins)
 Superficial thrombophlebitis (affects veins near the skin surface)
Causes
Risk factors include disorders related to increased tendency for blood clotting, injury to vein wall and
reduced speed of blood in the veins such as varices and prolonged immobility. Prolonged traveling by car
or airplane may promote a blood clot leading to thrombophlebitis but this occurs relatively rarely. Specific
disorders associated with thrombophlebitis include superficial thrombophlebitis (affects veins near the
skin surface) and deep venous thrombosis (affects deeper, larger veins). Thrombophlebitiscan be found in
people with Behcet's disease. Thrombophlebitis migrans can be a non-metastaticmanifestation of
malignancies such as pancreatic carcinoma (Trousseau sign of malignancy).
Clinical features:
The following symptoms are often (but not always) associated with thrombophlebitis:
 Pain in the affected part of the body
 Skin redness or inflammation (not always present)
 Swelling (edema) of the extremities (ankle and foot)
 Palpable cord-like veins
 Localized warmth and tenderness of the leg
 Forced and painful dorsiflexion of the foot (Homan sign)
 Cancers of the head of the pancreas cause superficial migratory thrombophlebitis because of release
of procoagulant from the tumor (Trousseau's syndrome)
Venous Thrombosis (Phlebothrombosis):
Venous thrombosis affects veins of the lower extremity in 90% of cases. It can be dividedinto superficial and deep
vein thrombosis:
1. Superficial venous thrombosis:
 Usually occurs in great saphenous venous system, particularly when there are varicosities.
 Rarely embolizes
 Causes local edema, pain, and tenderness (i.e. it is symptomatic)
 Local edema due to impaired venous drainage predisposes the involved overlying skin to infection
after slight trauma leading to a condition known as varicose ulcer.
2. Deep venous thrombosis (DVT):
 May embolizes, hence, is more serious.
 Usually starts in deep veins within the calf muscles.
 Although they may cause local pain and edema, unlike superficial veinous thrombosis, they are
entirely asymptomatic in approximately 50% of patients. This is because deep venous obstruction is
rapidly offset or released by collateral bypass channels
 Has higher incidence in middle aged and elderly people due to increased platelet aggregation and
reduced PGI2production by the endothelium
Predisposing factors:
 Trauma, surgery, burns which usually result in:-
 Reduced physical activity leading to stasis
 Injury to vessels
 Release of procoagulant substance from the tissue
 Reduced t-PA activity (fibrinolysis)
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 Pregnancy and puerperal states increase coagulation factors and reduce the synthesis of
antithrombotic substances. Myocardial infarction and heart failure cause venous stasis to the left
side.
 Malnutrition, debilitating conditions and wasting diseases such as cancer. DVT due to these
conditions is known as marantic thrombosis
 Inflammation of veins (thrombophlebitis) also predisposes to thrombosis.
 Migratory thrombophlebitis is a condition that affects various veins throughout the body and is
usually of obscure etiology, but sometimes it is associated with cancer, particularly pancreatic cancer.
Migratory thrombophlebitis is also known as Trousseau's syndrome.
Note: pulmonary embolism is a common and serious clinical complication of deep vein thrombosis(DVT).
In many cases, the first manifestation of thrombophlebitis is a pulmonary embolus.
Raynaud’s Disease and Raynaud’s phenomenon:
Raynaud’s disease:
It is not a vasculitis but is a functional vasospastic disorder affecting chiefly small arteries and arterioles of the
extremities, occurring in otherwise young healthy females. The disease affects most commonly the fingers and
hands. The ischemic effect is provoked primarily by cold but other stimuli such as emotions, trauma, hormones and
drugs also play a role. Clinically, the affected digits show pallor, followed by cyanosis, and then redness,
corresponding to arterial ischemia, venostasis and hyperemia, respectively. Long-standing cases may develop
ulceration and necrosis of digits but occurrence of true gangrene is rare. The cause of the disease is unknown but
probably occurs due to vasoconstriction mediated by autonomic stimulation of the affected vessels. Though
usually no pathologic changes are observed in the affected vessels, long-standing cases may show endothelial
proliferation and intimal thickening. In Raynaud’s disease, there is symmetrical involvement of the affected part of
the body while in Raynaud’s phenomena there may be unilateral involvement.
Raynaud’s phenomenon:
Differs from Raynaud’s disease in having an underlying cause e.g. secondary to atherosclerosis, connective tissue
diseases like scleroderma and SLE, Buerger’s disease, multiple myeloma, pulmonary hypertension and ingestion of
ergot group of drugs. Raynaud’s phenomenon like Raynaud’s disease also shows cold sensitivity but differs from
the latter in having structural abnormalities in the affected vessels. These changes include segmental inflammation
and fibrinoid change in the walls of capillaries.
Superior and Inferior Vena Cava Syndrome:

Superior Vena Cava Syndrome
 Caused by neoplasms that compress or invade the superior vena cava
 Such as bronchogenic carcinoma or
 Mediastinal lymphoma
 Obstruction produces a characteristic clinical complex that includes marked dilation of the vein of the
head, neck, and arms and cyanosis.
 Pemberton’s sign: It is reddish discoloration of the face on raising both the hands above the
shoulder.
Inferior vena cava syndrome
 Caused by neoplasms that compress or invade the inferior vena cava (IVC) or by a thrombus from the
hepatic, renal, or lower extremity veins
 Certain neoplasms— particularly hepatocellular carcinoma and renal cell carcinoma
 Show a striking tendency to grow within veins, and occlude the IVC.
12
Blood Vessels
Vascular Tumor
Classification of Vascular Tumor and Tumor like Conditions
1. Benign Neoplasm, Developmental or Acquired condition
Hemangioma
 Capillary hemangioma
 Cavernous hemangioma
 Pyogenic granuloma
Lymphangioma
 Simple(capillary) Lymphangioma
 Cavernous Lymphangioma(cystic hygroma)
Glomus tumor
Vascular ecstasies
 Nevus flammeus (Sturge Webber Syndrome)
 Spider telangiectasia(Arterial Spider)
 Hereditary hemorrhagic telangiectasia(Osler-Weber-Rend disease)
Reactive vascular proliferations
 Bacillary angiomatosis
2. Intermediate Grade Neoplasms
 Kaposi sarcoma
 Hemangioendothelioma
3. Malignant Neoplasms
 Angiosarcoma
 Hemangiopericytoma
Kaposi Sarcoma
Q. A 56 old male presents with raised plaques over his legs andis found to be HIV positive. A biopsy of the lesion
revealed a vascular neoplasm. Further investigation revealed lesion with similar histology involving multiple
abdominal viscera.
a) Name the likely tumor?
b) List three other forms of the same disease?
c) Give the pathogenesis of Kaposi sarcoma
Diagnosis:
Kaposi sarcoma
Types of Kaposi Sarcoma:
 Classic or chronic KS (European KS)
 Lymphadenopathy KS (African KS)
 Transplant associated KS
 AIDS associated (epidemic) KS
Pathogenesis:
 Human herpesvirus-8 (HHV-8) or KS-associated herpes virus (KSHV)
 95% of KS lesions have subsequently been shown to be KSHV-infected
Capillary Hemangioma:
Most common variant
 Occur in the skin, subcutaneous tissues, and mucous membranes of the oral cavities and lips, as well
as in the liver, spleen, and kidneys
 The “strawberry type” or Juvenile Hemangioma of the skin of newborns is extremely common (1 in
200 births)
 Grows rapidly in the first few months but then disappears at 1 to 3 years of age and completely
regresses by age 7 in 75% to 90% of cases
13
Blood Vessels
Morphology
 Capillary Hemangioma are bright red to blue and vary from a few millimeters to several centimeters
in diameter
Histologically,
 These are benign un-encapsulated aggregates of closely packed, thin-walled capillaries, usually blood-
filled and lined by flattened endothelium.
Complications:
 Cosmetic Disfigurement
 Rupture and Fatal Hemorrhage
 Thrombocytopenia
Glomus Tumor
 Glomus tumors are benign, exquisitely painful tumors arising from modified smooth muscle cells of
the Glomus body, a specialized arteriovenous structure involved in thermoregulation
 Although they can resemble cavernous hemangiomas, Glomus tumors constitute a distinct entity by
virtue of their constituent cells
 Most commonly found in the distal portion of the digits, especially under the fingernails. Excision is
curative
Morphology
 Glomus tumor lesions are round, slightly elevated, red-blue, firm nodules (usually <1 cm in diameter)
that initially resemble a minute focus of hemorrhage
 Histologically, these are aggregates, nests and masses of specialized Glomus cells intimately
associated with branching vascular channels, all within a connective tissue stroma
 Individual tumor cells are small, uniform, and round or cuboidal, with scant cytoplasm
14
Chapter Two HEART
Myocardial Infarction
Q.A 50 years old male presented in emergency room with sever, crushing sub sternal chest pain radiating to the
neck and jaw with discomfort in the epigastrium. The pain had been there for the last 20 minutes and was not
significantly relieved by nitroglycerin or rest. He was found to be a heavy smoker for last 20 years with strong
family history of hypercholesterolemia. Electrocardiographic abnormalities such as ST segment abnormalities and
T-wave inversion are noted. His blood chemistry is ordered. The patient went into cardiogenic shock and could not
come out of it.
a) What are morphologic changes seen in myocardial infarction?
b) Give the laboratory evaluation a patient with MI.
Morphological Changes Seen in Myocardial Infarction:
Reversible injury:
Time Gross features Light microscopy Electron microscopy
0-1/2 hour None None Relaxation of myofibrils:
glycogen loss.
Mitochondrial swelling
Irreversible injury:
Time Gross Microscopy
½-4 hours None Waviness of fiber at border
4-12 hours Occasionally dark mottling Beginning of coagulation necrosis; edema,
hemorrhage
12-24 hours Dark mottling Necrosis continues, Pyknosis of nuclei, Myocyte
Hypereosinophila, Marginal contraction band
necrosis
1-3 days Mottling with yellow tan Coagulation necrosis, with loss of nuclei and
infarct center striations, interstitial infiltrate of neutrophils
3-7 days Hyperemic border, central Beginning disintegration of dead myofibers with
yellow tan softening dying neutrophils. Early phagocytosis by
macrophages
7-10 days Maximally yellow tan and Well-developed phagocytosis of dead cells
soft with red tan margins Granulation tissue formation
10-14 Red gray depressed infract Well established granulation tissue with collagen
Days border deposition
2-8 week Gray white scar Increase collagen deposition
>2 months Scarring complete Dense collagen scar
Laboratory Diagnosis
 Cardiac troponin T and I: Detectable after 2 to 4 hours and peak at 48 hours. Their levels remain
elevated for 7 to 10 days.
 CK-MB: rise within 2-4 hours, peak at 24-48 hoursand return to normal with in 72hrs.
 Detection of myoglobin is the first cardiac marker to become elevated after MI. Its lack cardiac
specificity and is excreted in urine rapidly. Its level returns to normal within 24 hours of MI.
 Detection of lactate dehydrogenase is non-specific .LDH begins to rise after 24 hours,reaches peak
in3-6 days andreturns to normal in 14 days.
15
Heart
Myocardial Response to Ischemia:
 Biochemical Response:
Cessation of aerobic glycolysis within seconds
↓
Inadequate production of high-energy phosphates….ATP, andCreatinine phosphate
accumulation of noxious breakdown products (lactic acid)
 Functional Response:
Loss of contractility, Electrical instability….Arrhythmia, ventricular Fibrillation, sudden death
 Morphological Response:
Coagulative necrosis (initially subendocardial zone, progressively increase transmurally….dependent
upon duration and severity of ischemia
All transmural infarcts involve at least portion of the left ventricular septum
Involvement of Left anterior descending artery (LAD):40-50%
 Infarct area
 Anterior wall of left ventricle near apex
 Septum (⅓ ant)
 Apex (Entire circumference)
Involvement of Right coronary artery (RCA): 30-40 %
 Infarcted area:
 Left ventricle (post+ inferior part)
 Post part of the septum 2/3
 Right ventricular (inferior / post wall)
Complication of Myocardial Infarction:
 Contractile dysfunction
 Arrhythmias
 Myocardial rupture
 Papillary muscle dysfunction
 Heart Block
 Pericarditis (Dressler Syndrome; Post MI Pericarditis)
 Infarct expansion
 Mural thrombus
 Ventricular aneurysm
 Progressive late heart failure
Q. A 65 years old male presented with left sided chest pain radiating to left arm and jaw. He was taken to hospital
where ECG showed ST elevation. (KMU past Question)
a) What is your diagnosis and define it.
b) Which tests are helpful for the diagnosis?
c) What are the pathological findings in a typical myocardial infarction?
Diagnosis:
Myocardial infarction: myocardial infraction is the necrosis of heart muscle resulting from ischemia
Test helpful for diagnosing:
ECG changes are found in most (85%) but often they are nonspecific .Diagnostic ECG changes are found in
50 to 65 % of cases during the first 2 days of onset of theInfarction. Characteristics changes include ST
segment elevation, T wave inversionand appearance of wide deep Q waves.
Laboratory finding in serum that become positive after occlusion of coronary artery are
 Cardiac Troponin T and I: detectable after 2 to 4 hours and peak at 48 hours. Their levels remain
elevated for 7 to 10 days
 Creatine Kinase Level:CK-MB: rise within 2-4 hours, peak at 24-48 hours and return to normal with in
72hrs.
 Myoglobin Level:Detection of myoglobin is the first cardiac marker to become elevated after MI. It
lack cardiac specificity and is excreted in urine rapidly. Its level return to normal within 24 hours of MI
16
Heart
 Lactate Dehydrogenase: Detection of Lactate dehydrogenase is nonspecific .LDH begins to rise after
24 hours, reaches peak in 3-6 days andreturns to normal in 14 days.
 Homocysteine Levels: Increased in the level of Homocysteine is also a risk factor of MI
Figure:Enzymes Changes following Acute Myocardial Infarction

Echocardiography
 Useful for demonstrating abnormally contracting part of ventricular myocardium and visualizing
thrombi or rupture in the wall of myocardium
Pathological findings in Myocardium in MI
 First day: myocardium is pale on gross examination .No histological changes are seen but there may
be some eosinophilia of necrotic fibers
 Second day: necrotic myocardial cells are surrounded by few neutrophils
 Third day: fragmentation of necrotic myocytes and numerous neutrophils are seen
 Fourth day: Macrophages appear which slowly replace the neutrophil and remove the dead
myocardial cells
 End of first week: ingrowth of angioblasts mark the beginning of granulation tissue formation
 Second week: granulation tissue has begun to replace the necrotic myocardium
 Third week: granulation tissue slowly transform into a fibrous scar
 Six week: a fibrous scar has formed
Acute Coronary Syndrome
Acute coronary syndrome include the following
 Ischemic heart disease-unstable angina
 Acute MI
 Sudden cardiac death
Pathogenesis of Ischemic Heart Disease
 Decrease Tissue Perfusion
 Ischemic heart disease is a consequence of inadequate coronary perfusion relative to myocardial
demand,this imbalance occurs as a consequence of the combination of preexisting (fixed)
atherosclerotic occlusion of coronary arteries and newly superimposed thrombosis
 Ischemic heart disease become symptomatic when there is more than 70 % occlusion of a vessel
of a lumen resulting in so called critical stenosis
 Increased oxygen demand
 Increase in oxygen demand in condition such as exercise or physical exertion, excitement and
anxiety in the presence of coronary atherosclerosis
 Superimposed lesions: Various superimposed lesion play an important role in the development of
myocardial ischemia. They include
17
Heart
 Acute plaque changes:

 Rupturing, fissuring, or ulceration of plaque can expose highly thrombogenic sub-
endothelium. This local disruption of plaque increases the risk of platelets aggregation and
thrombosis at that time. Platelets aggregations lead to mechanical occlusion of small blood
vessel by releasing mediators and may contribute to myocardial ischemia.
 Thrombosis associated with a disrupted plaque often triggers the acute coronary syndrome
 Coronary artery spasm usually occurs with at least some preexisting atherosclerosis.
Angina pectoris:
Definition:
Angina pectoris is a chest pain or pressure produced by myocardial ischemia.
• Angina pain is often precipitated by exertion. Other factors that increase myocardial oxygen demand
(e.g. emotional stress, eating meal, sexual intercourse) may also precipitate angina.
• The chest pain in angina is squeezing in type or a feeling of pressure or tightness in the chest.
Sometimes it can be burning in nature or felt as epigastric discomfort.
Pathogenesis:
The pain probably is the consequences of ischemia; induce by the release of Adenosine, Bradykinin and
other molecules that stimulate autonomic afferent nerves.
Types of Angina:
Chronic stable Angina (Crescendo Angina):This is the most common pattern. Stable or typical anginais
characterized by attacks of pain following physical exertion or emotional excitement and is relieved by
rest. ECG including stress ECG can detect this episode. Such episodes are less severe in nature and shorter
in duration.
Unstable Angina: This term applied to angina when a change in status occurs, so that angina will also
occur at rest and is of increased duration. It may be progressive and it can be a feature of imminent
myocardial infarction. Therefore, physicians and patients should be aware that close observation and
intensive therapy are required. It represents a more serious situation than chronic stable angina.
New onset angina is an angina that progresses in severity, duration or frequency over 1-or 2 months
Variant (Prinzmetal’s) Angina:This is a type of angina resulting from transient coronary spasm, which
usually but not always associated with fixed atherosclerotic lesion. The spasm produces total but transient
coronary occlusion.
It usually occurs at rest (often at night) and episodes are frequently complicated with ventricular
arrhythmias.
Laboratory investigations:
 Electrocardiography:
 Resting ECG:
ECG taken when the patient is not in pain may be normal. The presence of new horizontal or down
sloping of ST segment depression and new T-wave inversion are suggestive of myocardial ischemia.
ST segment elevation associated with pain that returns to normal as the pain wanes suggest variant
angina.
 Stress ECG (ETT):
Recording ECG during exercise increases the sensitivity and specificity of ECG. This helps to quantify
the patient’s exercise tolerance. The presence of new horizontal or down sloping of ST segment
depression has sensitivity of 70% and specificity of 90%.
 Radiologic/Imaging:
Chest X-ray in patients with symptoms and signs of congestive heart failure
Stress radionuclide ventriculography
Stress echocardiography
Cardiac catheterization
 Other Laboratory Tests:
Hemoglobin or CBC, fasting blood glucose,
Serum lipid profile
18
Heart
Rheumatic Fever
Definition:
An acute immune mediated multisystem inflammatory disorder, which occurs few weeks after an episode
ofGroup AStreptococcus Pharyngitis.
Pathogenesis:
It is Type II hypersensitivity reaction in which host antibodies are produced against M protein of the
Group A Streptococci, that cross react with glycoprotein of self-antigen in the heart, joint and other
tissues. Because of this, complications develop.
Complications:
 Thromboembolism
 Infective endocarditis
 Arrhythmias
 Cardiac hypertrophy
 Fibrosis
 Pericarditis and pericardial effusion
 Congestive heart failure
Laboratory Diagnosis:
Non-Specific Investigation:
 ESR is increased
 Leukocytosis is present
 C-Reactive proteins are present in serum
 Serum gamma globulins are also increased
 Anemia due to suppression of erythropoiesis
Throat Swab:
 It can be positive for streptococci in 50% cases
Changes in Serological Investigation:
 ASO (Antistreptolysin O) titer is markedly increased
 It rises in 1-2 weeks and maximum level is reached in 3-5weeks after infection
ECG Changes:
 P-R interval isprolonged
 Q-T interval is prolonged
Jones Criteria for Rheumatic Fever:
Major criteria Minor criteria
Carditis Fever
Migratory polyarthritis Arthralgia
Chorea (Sydenham’s chorea) Previous rheumatic fever
Erythema Marginatum Raised ESR or C- reactive protein
Subcutaneous nodules ECG show prolonged PR Interval
Q.A 11 years old child presents with fever, joint painand swelling along with shortness of breath. He has a history
of sore throat few weeks back. On examination, he has a mid-diastolic murmur and his left knee is swollen and
tender. Lab work up raised ESR and raised ASO titer. Echo shows mitral stenosis. (KMU 2014)
a) What is the most likely diagnosis?
b) Name the distinctive histological lesions in the heart in this condition and briefly write its
morphology
c) Enumerate at least four complication of the above condition
d) Briefly describe the pathogenesis of acute rheumatic heart disease
Diagnosis:
Rheumatic fever
19
Heart
Morphology:
Aschoff bodies
 Distinctive lesions occur in the heart, called Aschoff bodies, which consist of foci of lymphocyte
(primarily T cells), occasional plasma cells, and plump activated macrophages called Anitschkow cells
(pathognomonic for RF).
 Aschoff body macrophages have abundant cytoplasm and central round-to ovoid nuclei in which the
chromatin is disposed in a central, slender, wavy ribbon (Hence the designation “caterpillar cells”),
and may become multinucleated.
 It give an important ‘’Fish mouth’’ deformity of mitral valves.
Complication:
 Thromboembolism
 Infective Carditis
 Arrhythmias
 Cardiac hypertrophy
 Fibrosis
 Pericarditis and pericardial effusion
 Congestive heart failure and rheumatic heart disease
Pathogenesis:
It is Type II hypersensitivity reaction in which host antibodies are produced against M protein of the
Group A Streptococci, that cross react with glycoprotein of self-antigen in the heart, joint and other
tissues. Because of this, complications develop.
Infective Endocarditis
Definition:
 Infective endocarditis is the colonization of heart valves (or mural endocardium) by a microbiological
agent. This leads to local formation of friable, infected vegetation that frequently cause valvular
injury.
 Infective endocarditis may be acute or subacute.
Types:
1) Acute Infective Endocarditis:
 It is caused by organism of high virulence such as Staphylococcus aureus
 Usually occur on previously normal valves
 Rapidly progressive course
 High fever with rigor, malaise and weakness are the characteristic features
 Embolic and valve perforation complications are common
2) Subacute Infective Endocarditis:
 It is caused by organism of low virulence such as streptococcus viridans
 Mostly underlying cardiac disease is present
 Insidious course
 Low fever, malaise and weight loss are the presenting feature
 Embolic and valve perforation complications are less common
Etiology
Factors usually operative in Infective Endocarditis are:
Bacteria, Septicemia and Pyemia Following
 Oral surgery (tooth extraction)
 I.V. drug abuse
 Severe infections
Abnormality of Heart Endocardium:
 Chronic rheumatic heart disease
 Prosthetic cardiac valves
 Cardiac surgery
20
Heart
Impaired Defense Mechanisms
 Immune deficiency
 Immune suppression
 Organ transplantation
 Cancer chemotherapy
 Steroid therapy
 Cardiac surgery
Pathogenesis of Infective Endocarditis:
Causative Organism
 50% of acute cases are caused by Staph.aureus
 50% of subacute cases are caused by Streptococcusviridans
Portal of Entry of Organisms:
 Surgery
 Iv drug abuse
 Bladder catheterization
Formation of Infective Vegetation
 Formation of sterile platelet–fibrin deposits at the sites of eddy currents or jet streams, produced by
stenotic or incompetent valves
 Agglutinating antibodies that produce bacterial clumps become attached to the developing
vegetations
 Adhesion factors on endocardium have specific receptors for bacterial attachment and implantation
and so on, favor the bacterial attachment
Morphology:
Gross Examination
 Irregular friable bulky and microbe laden vegetations are found attached along the line of closure of
valvular leaflets
 They may be single or multiple in number
 In acute IE, vegetation is bulky and may cause perforation of the valves
The distributions of vegetations in IE are as follows
 Commonly occur on left side
 In cardiac prostheses, they occur on the margin of the sewing ring
 In RHD, their distribution is Mitral>Aortic>Tricuspid
Microscopically:
 Vegetations constitute tangled masses of fibrin, blood cells, platelets and usually colonies of
organisms with scanty polymorphs
 In healed endocarditis, vegetations become sterile,fibrosed and calcified
Complications
 Embolism
 Cardiac
 Renal
 Metastatic Infection
Major criteria Minor criteria
Sustained Bacteremia (HACEK group)* Any Predisposing Condition
Endocardial Involvement Fever
Vascular Phenomena
Immune Phenomena
Definitive: 2 Major, 1 Major + 3 Minor or 5 Minor
Possible: 1 Major + 1 Minor or 3 Minor
* H. Influenza, Actinobacillus, Cardiobacterium, Eikenella, Kingella
21
Heart
Libman-Sacks Endocarditis
Libman-Sacks endocarditis (Non-Infective) is characterized by the presence of sterile vegetations on the
valves of patients with systemic lupus erythematosis (SLE). The lesions probably develop because of
immune complex deposition and thus exhibit associated inflammation, often with fibrinoid necrosis of the
valve substance adjacent to the vegetation, subsequent fibrosis and serious deformity can result in lesions
that resemble chronic rheumatic heart disease. Similar lesions can occur in the setting of antiphospholipid
antibody syndrome.
Myocarditis
 Myocarditis is an inflammation of the myocardium often resulting from infectious process, which
subsequently leads to myocardial destruction andcardiomyopathies. The acute picture is nonspecific
unless overt congestive heart failure develops. Although the causes of myocarditis are numerous, the
most common association is an antecedent viral syndrome.
Causes of myocarditis
Infections:
 Viruses: Coxsackie A and B virus, mumps, chlamydia and rickettsia, influenza etc.
 Fungi: Candida
 Bacteria:Borrelia burgdorferi, Coryneabacterium diphtheria, Meningococcal specie
 Parasites: Trypanosoma cruzi, ToxoplasmaGondi
Immune mediated reaction:
 Rheumatic fever, SLE, Rheumatoid arthritis, Progressive Systemic Sclerosis
Chemicals:
 Alcohol, Drug like Doxorubicin, cyclophosphamide, TCAs (Tricyclic Antidepressants) etc.
Pathogenesis:
 Myocarditisis defined as inflammatory changes in the heart muscle and is characterized by an
interstitial mononuclear cell infiltrate with myocytes necrosis.
 It is not known whether the infiltrate is caused by a direct invasion of the infective agents or by a
systemic immune response. In the chronic stage, cytotoxic T lymphocytes infiltrate the myocardium
and mediate an autoimmune response with myocardial autoantibody activity directed against cardiac
myosin. This autoimmune process persists, after the viral particles are no longer detected. Coronary
artery thrombus formation, luminal obstruction, ischemia, and dysrhythmias compound the
deleterious effects of the inflammatory response.
Morphology of Myocarditis:
 Acute myocarditis:The heart is dilated, flabby and often mottled and pale hemorrhage present.
Microscopically the myocardium is edematous, interstitial inflammatory infiltrates and myocytes
injury
 Chronic myocarditis: It is characterized by cardiac failure, the presence of lymphocyte and plasma
cells in the Interstitium
Pericarditis
Definition:
Pericarditis is an inflammation of the pericardium surrounding the heart. Pericarditis and cardiac
temponade are clinical problems involving the potential space surrounding the heart or pericardium.
Pericarditis is a cause of fluid accumulation in this potential space whereas; cardiac temponade is the
hemodynamic result of fluid accumulation in the pericardial cavity.
Pathogenesis:
The pericardium consists of an outer fibrous layer (parietal pericardium) and an inner serous layer
(visceral pericardium).Normally the two layers are separated by a small quantity of fluid (15-50 ml).The
pericardium serves as a protective barrier from the spread of infection or inflammation from adjacent
structures. It also prevents sudden dilatation of the cardiac chambers during exercise and hypervolemia. It
restricts the anatomic position of the heart and minimizes friction with the surrounding structures.
Approximately 120 cc of additional fluid can accumulate in the pericardium without an increase in
pressure. Further fluid accumulation can result in marked increases in pericardial pressure, eliciting
22
Heart
decreased cardiac output and hypotension (cardiac temponade). The rapidity of fluid accumulation
influences the hemodynamic effect.
Clinical Features:
 Pericardial Friction Rub
 Muffling of the Heart Sounds
 Decrease in cardiac Output
 Kussmaul sign: Some blood reflexes back into the Jugular vein causing distension on inspiration
 Hypotension Associated with Pulsus Paradoxus
 Chest X-ray Shows ‘’Water bottle sign’’
 ECG: Changes in the PR, ST and T-Wave
Causes of Primary Pericarditis:
Viruses: Coxsackie virus, Adenovirus, Epstein Barr virus etc.
Bacteria: Streptococcus pneumonia, staphylococci, mycobacterium tuberculosis, etc.
Causes of secondary pericarditis
 Myocardial infarction, cardiac surgery, exposure of mediastinum to radiation, SLE, rheumatic
fever
 Uremia (most common systemic disease), metastatic malignancies
Classification of Pericarditis:
Clinical classification Etiologic Classification
I. Acute pericarditis (<6 weeks) I. Infectious Pericarditis
a. Fibrinoid a. Viral
b. Effusive (serous or sanguineous) b. Pyogenic
II. Subacute pericarditis (6 weeks to 6 c. Tuberculosis
months) d. Fungal
a. Effusive-constrictive II. Noninfectious Pericarditis
b. Constrictive a. Uremia
III. Chronic pericarditis (over 6 months) b. Acute myocardial infraction
a. Constrictive c. Neoplasm
b. Effusive d. Idiopathic
c. Adhesive (no constrictive) III. Hypersensitivity/autoimmune
a. Rheumatic fever
b. Rheumatoid arthritis
c. SLE
d. Posttraumatic
Heart failure
Definition:
It is the inability of the heart to handle the volume of blood returned to its which under normal conditions
it should handle, and inability to meet the metabolic requirements of the body tissue.
Types of heart failure
Systolic heart failure
 Left heart failure
Diastolic heart failure
 Right heart failure
 Biventricular heart failure
 High output cardiac failure
Pathophysiology
 The heart failure in heart is both forward and backwards, i.e. inability of heart to properly profuse the
kidneys (forward failure) leading to increased sodium reabsorption and congestion and the
complication which result from it (backward failure).
23
Heart
 Increased fluid content,translates into increased work load on heart, which leads to cardiac
hypertrophy (starts obeying the frank starling law),this happens to a certain extent, after which the
heart is unable to cover the increased workload (stops obeying the frank starling law ).
 Molecular mechanism include binding of ligands like angiotensin 2, endothelin-1,norepinephrine,IGF-
1,TGF-beta activate various intracellular pathways 1 mitogen activated protein kinases and phospho-
inositol kinases, beta adrenergic coupled protein kinases-2 Calcium Calmodulin coupled protein
kinases (these chemicals make the myocardial cells undergo the various changes like hypertrophy etc.
 Various genes like c-jun are involved in the remodeling of the heartFetal genes and protein are
expressed e.g. ANF and BNP expressed in fetal hearts are seen in heart failure. The fast beta myosin
with high ATPase activity is replaced by slow beta myosin with low ATPase activity
 Galaectin-3 is a serum marker for the severity of the heart failure, it is a molecule produced by the
macrophages to stimulate the fibroblasts to make collagen.
Batista Partial Left Cardiac asthma?

Ventriculectomy?
Causes of heart failure

 Either heart cannot pump blood because of failure of the pump action
 Because of the blood flowing the wrong way
 The heart has to pump against increased resistance
 The heart has to pump a very large amount of blood.
Morphology of Left Sided Heart Failure:
 Due to backpressure, the lung is heavy and boggy. The most important histological feature is the
presence of ‘’Heart failure cells’’ which are RBC laden Macrophages, which are formed due to
leakage of RBC into alveolar spaces, which are taken up by alveolar macrophages, which are
phagocytized to give hemosiderin laden alveolar macrophages.
 Cardiac chambers: Dilated and hypertrophied.
 Brown induration of lung: The fibrosis of the alveolar walls due to chronic septal edema and the
accumulation of the hemosiderin together are designated as brown induration of the lung.
 Pulmonary edema: Pulmonary alveolar capillaries are congested. There is transudation of fluid, which
overflows into alveoli called pulmonary edema.
Morphology of Right heart failure
 Hepatic congestion, may lead to painful hepatomegaly
 Nutmeg liver, the central region of hepatocytes become congested appearing red while the
peripheral region is uncongested appearing yellow. This red and yellow mottling gives a
characteristics appearance called nutmeg liver.
 Centrilobular hemorrhagic necrosis: due to inability of the right ventricle to pump blood ,the
systemic blood backs up into the hepatic vein ,then into the hepatic venules, which ultimately expand
and result in the necrosis of the region of liver near the portal tract which is least profuse with blood
and hence at increased risk of necrosis (zone 3).
 Cardiac cirrhosiswhen severe and longstanding, hepatic congestion can lead to fibrosis; if congestion
is due to right heart failure, it is called cardiac cirrhosis
 Compression of the liver increases the jugular vein neck distention
24
Heart
Figure: Gross and Microscopic Appearance of Nutmeg Liver

Clinical Manifestations
 Progressive dyspnea, which initially occurs with exertion and later occurs at rest
 Dyspnea on exertion has been found to be the most sensitive complaint, yet the specificity for
dyspnea is less than 60%.
 Orthopnea and paroxysmal nocturnal dyspnea (PND) are symptoms that are more specific; however,
sensitivity for orthopnea and PND is only 20-30%.
 Cough productive of pink, frothy sputum is highly suggestive of CHF. Wheezing may also occur.
 Peripheral edema and ascites
 Nonspecific complaints include the following: easy fatigability, light-headedness, malaise anxiety
abdominal pain, nausea etc.
 Past medical history may include the following: rheumatic fever, alcohol use, hypertension , angina ,
previous history of myocardial infarction and familial history of heart disease
LaboratoryInvestigation:
 Chest X-Ray:
The main findings are cardiomegaly, pulmonary edema, and pleural effusion.
 Echocardiography:
May help identify valvular abnormalities, ventricular dysfunction, cardiac temponade, pericardial
constriction, and pulmonary embolus
 Electrocardiogram (ECG):
Is a nonspecific tool but may be useful in diagnosis of concomitant cardiac ischemia, prior myocardial
infarction (MI), cardiac dysrhythmias, chronic hypertension and other causes of left ventricular
hypertrophy
 Other Laboratory Tests: Hemoglobin, Urinalysis, BUN, Creatinine
Congenital Anomalies of Heart
Classification of Congenital Heart Disease:
With Shunt Without Shunt
 Acyanotic  Right Sided
 Atrial Septal Defect  Pulmonary Stenosis
 Ventricular Septal Defect  Ebstein’s Anomaly
 Patent Ductus Arteriosus  Left Sided
 Cyanotic  Coarctation of Aorta
 Tetralogy of Fallot  Aortic Stenosis
 Transposition of Great Vessels  Dextrocardia
 Truncus Arteriosus
25
Heart
Ventricular septal defect (VSD):

 Most common congenital heart disease at birth or in children
 50% of the congenital heart diseases close spontaneously
Morphology
 90% of the VSDs are in the membranous septum, whereas 10% are in the muscular part
 VSD IN TOF (tetralogy of Fellot) there can be multiple VSDs in TOF
 VSDs are most common in the superior portion of the septum below the pulmonary artery
outﬂow tract,bundle of his is located below and may effect it
Clinical features:
 Small defects may close spontaneously, either by hypertrophy of muscles or by attachment of the
tricuspid valve tot eh margins of the defect
 If the defect fails to close it may result in ‘’Eisenmenger Syndrome’’ shunting of blood into the right
ventricle leads to increased blood in the pulmonary vasculature,which causes thickening of the
vessels which causes an increased resistance in pulmonary vessels,this may increase so much that it
causes reverse blood shunt so instead of a left to right shunt it becomes a right to left shunt So
patient present with hypertrophy of right ventricle and cyanosis
Atrial Septal Defect (ASD)
 Most common congenital heart disease in adults
 It’s the inability of the atrial septum to close down properly
 Most of the ASDs occur in the Ostium Secundum
Pathogenesis:
 15% of familial ASDs and 3% of sporadic ASDs are associated with coding errors inNKX2.5.
 Deletion of the T-box gene TBX1 in the DiGeorge syndrome (chromosome 22Q11 deletion) has been
implicated in ASD formation
 Holt-Oram syndrome in which large secundum-Type ASDs typically occur
Morphology:
 Failure of closure of septum secundum: It is a true deﬁciency of atrial septum and this defect occurs
in the middle portion of the septum, in larger defects it may cause the hypertrophy of the right atria
 Sinus venosus defect in 5% cases near the superior vena cava
 Ostium primum it includes 7% of cases and involves the region near the endocardial cushions
 Atrioventricular canal defects
 Coronary sinus associated: it is associated with persistent left superior vena cava and is located at the
posterior part of interatrial septum at the location point of coronary Ostium site
 Patent foramen ovale
Clinical features:
 Children usually are asymptomatic, may present with dyspnea on exertion and easy
fatigabilityEisenmenger syndrome may result
Patent Ductus Arteriosus (PDA):
Patent Ductus Arteriosus:It is the patent Ductus Arteriosus, normally in fetal life because the lungs of
fetus are not fully developed,the blood is short circuited by connecting the pulmonary trunk to the aorta
called as Ductus Arteriosus,in adult life the duct usually is replaced by a ligament, called ligamentum
arteriosum,if it persists it is called as Patent Ductus Arteriosus
 It gives rise to 10% of all congenital heart disease
 PDA is associated with 1.Congenital rubella 2.Tetralogy of Fallot 3. respiratory distress syndrome
 Some conditions it is good to keep the PDA open, e.g. pulmonic stenosis/ Tetralogy of
Fallot,transposition of great vessels and hypo-plastic right heart syndrome
 The open PDA is prone to infections (bacterial in general) and is associated with a machine like
murmur
Differential
So when the pulmonary tree pressure increases the left to right shunt in the PDA will be reversed and
26
Heart
"cyanosed" desaturated blood from the pulmonary circulation will shunt through the PDA to the
descending aorta causing the cyanosis to be seen in the lower limbs only. (Sometimes the PDA connects
before the left subclavian artery and in this case, the cyanosis can be seen in the left hand nails).
Tetralogy of Fallot:
 5% of all congenital cardiac malformations, Tetralogy
Key Point:
of Fallot Eisenmenger Syndrome
 Most common cause of cyanotic congenital heart st
Remember, the shunting in PDA is 1 left to
disease right and then right to left as Pulmonary
 The four features of the tetralogy are: Hypertension develops
 VSD
 Obstruction to the right ventricular outflow tract (sub pulmonic stenosis)
 An aorta that overrides the VSD
 Right ventricular hypertrophy
All of the features result from anterosuperior displacement of the infundibular septum, so that there is
abnormal division into the pulmonary trunk and aortic root.
Even untreated, some tetralogy patients can survive into adult life Clinical severity largely depends on the
degree of the pulmonary outflow obstruction.
Morphology:
The heart is large and "boot shaped" in tetralogy of Fellot because of:
 Right ventricular hypertrophy
 The proximal aorta is typically larger than normal, with a diminished pulmonary trunk.
 The left-sided cardiac chambers are normal sized, while the right ventricular wall is markedly
thickened and may even exceed that of the left
 The VSD lies in the vicinity of the membranous portion of the interventricular septum, and the aortic
valve lies immediately over the VSD
 The pulmonary outflow tract is narrowed, and, in a few cases, the pulmonic valve may be stenosis.
Chances of survival is inversely related to degree of sub pulmonic stenosis
 Additional abnormalities are present in many cases, including PDA or ASD
 Actually beneficial in many respects, because they permit pulmonary blood flow
Q. A male infant presents with the cyanosis and digital clubbing.His cyanosis does not improve with 100 %
oxygenation. His chest x-ray show decrease vascular markings and Boot shaped cardiac shadow. Echocardiography
confirmed his diagnosis to be one of congenital of heart disease.
a) What is the probable diagnosis?
b) What are the structural abnormalities in this condition? Key Point:
c) What is the hemodynamic consequence in this condition? Lutembacher syndrome:
d) Why pulmonary hypertension does not develop in this condition? Affects more specifically
e) Why ASD and PDA are beneficial in this condition? the atria of the heart
f) Give a brief account of pathophysiology of this condition. andthe mitral or bicuspid valve.
Diagnosis: The disorder itself is known
Tetralogy of Fallot more specifically as
Structural abnormalities both congenital atrial septal
 Ventricular septal defect defect (ASD) and acquired
 Overriding of aorta mitral stenosis (MS).Congenital
 Pulmonary outflow obstruction (at birth) atrial septal defect
 Right ventricular hypertrophy refers to a hole being in the
Hemodynamic consequences septum or wall that separates
 Right to left shunting the two atria; this condition is
 Decrease pulmonary blood flow usually seen in fetuses and
infants
 Increased aortic volume
Pulmonary hypertension does not develop in this condition because of reduced pulmonary circulation
due to pulmonary outflow obstruction
27
Heart
PDA and ASD are beneficial in this condition to provide pulmonary circulation
Pathophysiology:
The marked narrowing of the pulmonary outflow tract results in a right to left shunt through the
ventricular septal defect, resulting in central cyanosis. The right ventricle is hypertrophied
Ventricular Septal Defect Atrial Septal Defect Patent Ductus Arteriosus Tetralogy of Fellot
Cardiomyopathy:
Definition:
The term cardiomyopathy (literally, heart muscle disease) is used to describe heart disease resulting
from an abnormality in the myocardium.
Types of cardiomyopathy
Dilated cardiomyopathy:
 The term dilated cardiomyopathy (DCM) is applied to a form of cardiomyopathy characterized by
progressive cardiac dilation and contractile (systolic) dysfunction, usually with concomitant
hypertrophy. It is sometimes called congestive cardiomyopathy.
 The histologic abnormalities in DCM are nonspecific and usually do not point to a specific etiologic
agent
Pathophysiology:
 Dilated cardiomyopathy represents the final common morphologic outcome of a variety of biological
insults. It is a combination of myocyte apoptosis and necrosis with increased myocardial fibrosis,
producing reduced mechanical function. Many causes are a result of direct toxicity (e.g., alcohol) or
mechanical insults (e.g. chronic volume overload in mitral valvular regurgitation), infection (e.g.
myocarditis).
Hypertrophic cardiomyopathy:
 Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy, poorly compliant
left ventricular myocardium leading to abnormal diastolic filling, and in about one third of cases,
intermittent ventricular outflow obstruction. It is the leading cause of left ventricular hypertrophy
unexplained by other clinical or pathologic causes.
Pathophysiology:
 Generally, ventricular hypertrophy involves the proximal portion of the interventricular septum.as
the septum thickens, it may narrow the outflow tract. In addition, systolic anterior motion of the
mitral valve may occur and result in left ventricular outflow tract obstruction and mitral regurgitation.
When systolic anterior motion occurs, the mitral valve leaflets are pulled or dragged anteriorly
toward the ventricular septum, producing the obstruction. Consequently, the left ventricle has to
generate much higher pressures to overcome the out flow obstruction and to pump blood to the
systemic circulation. Premature closure of the aortic valve may occur and is caused by the decline in
pressure distal to the left ventricular outflow obstruction
 Genetic Predisposition:
HCM is the most common genetic cardiovascular disease. About half of patients’ with HCM have a
positive family history with autosomal dominant transmission.
Clinical Features
 The clinical course of HCM is variable. Most patients with HCM are asymptomatic.
 The most common symptom of HCM is dyspnea on exertion.
28
Heart
 Patients may also complain of chest pain with exertion, syncope or palpitation.
 Unfortunately, the first clinical manifestation of the diseases may be sudden cardiac death frequently
occurring in young children and young adults, often during or after physical exertion.
Restrictive cardiomyopathy
 Restrictive cardiomyopathy is a disorder characterized by a primary decrease in ventricular
compliance, resulting in impaired ventricular filling during diastole
Pathophysiology:
 These conditions result in impaired ventricular filling and primarily diastolic heart failure. They
present with a clinical heart failure syndrome that is frequently indistinguishable from that caused by
systolic dysfunction. Atrial fibrillation is poorly tolerated. It simulates other right side heart failure like
cor pulmonale and diastolic dysfunction of constricted pericarditis.
Causes of Sudden Cardiac Death:
 Congenital coronary arterial abnormalities
 Aortic valve stenosis
 Mitral valve prolapse
 Myocarditis or sarcoidosis
 Dilated or hypertrophied cardiomyopathy
 Pulmonary hypertension
 Congenital acquired abnormality of cardiac conducting system
Cor pulmonale:
Definition: Cor pulmonale is a disease of the right sided cardiac chambers caused by
pulmonary.Hypertension from primary disease within the lung substance within its vessel
Causes of Cor pulmonale
Lung disease Thoracic cage abnormality
 COPD  Kyphosis
 Pulmonary fibrosis  Scoliosis
 Severe chronic asthma  Thoracoplasty
 Lung resection  Neuromuscular disease
Pulmonary vascular disease  Myasthenia gravis
 Pulmonary emboli  Poliomyelitis
 Pulmonary vasculitis  Motor neuron disease
 Primary pulmonary hypertension Hypoventilation
 ARDS  Sleep apnea
 Sickle-cell disease  Enlarged adenoids in children
 Parasite infestation Cerebrovascular disease
Valvular HeartDisease:
Stenosis:
Failure of a valve to open completely, thereby preventing forward flow is called valvular stenosis
Regurgitation:
Failure of a valve to close completely thereby allowing reversed flow is called valvular regurgitation
Mitral stenosis:
Important Features:
 Mitral stenosis is sequelae of rheumatic heart disease primarily affecting women.
 Mitral stenosis has a progressive, lifelong course that is slow and stable in the early years, with rapid
acceleration later in life.
 It is very common in the developing countries manifesting below the age of 20 whereas there is
generally a latent period of 20 to 40 years between the occurrence of rheumatic fever and of mitral
stenosis in developed countries.
 The most common cause of mitral stenosis is senilecalcification.
29
Heart
 Elevated left atrial pressure eventually causes pulmonary vasoconstriction, pulmonary hypertension
and compromise of right ventricular function
 Many patients remain asymptomatic until atrial fibrillation develops or until pregnancy occurs, when
there is increased demand on the heart
 Symptoms are generally those of left-sided heart failure: dyspnea on exertion, orthopnea and
paroxysmal nocturnal dyspnea. Patients may also present with hemoptysis, signs of right-sided heart
failure, and embolic phenomena like stroke
Complication of Mitral Stenosis:
 Atrial fibrillation
 Thromboembolism
 Right sided heart failure
Echocardiography
Echocardiography is the study of choice for diagnosis and to assess the severity of mitral stenosis
Chest X-ray may show left atrial enlargement and sign of pulmonary congestions
ASO Titer
Anti DNAse
Mitral regurgitation
Causes:
 Rheumatic fever
 Infective endocarditis
 Degenerative valvular disease (mitral valve prolapsed).
 Myocardial infarction affecting papillary muscles
Pathophysiology:
Chronic mitral regurgitation is a state of volume overload leading to the development of left ventricular
hypertrophy. The left atrium also enlarges to accommodate the regurgitate volume. This compensated
phase of mitral regurgitation varies in duration but may last many years. The prolonged state of volume
overload may eventually lead to decompensate mitral regurgitation.
This phase is characterized by impaired left ventricular function, decreased ejection fraction and
pulmonary congestion.
Clinical Features:
Fatigue, Exertional dyspnea and orthopnea are the most common complaints.
Right-sided heart failure with painful hepatic congestion, peripheral edema may occur in patients with MR
who have associated pulmonary hypertension.
Lab Investigation
Echocardiography
Echocardiography can be used to determine the etiology and morphology of mitral regurgitation, which
are important in determine suitability for mitral valve repair
Chest X-ray:
Enlargement of LA and LV, Pulmonary venous congestion and interstitial edema and Kerley-B lines
Tricuspid Regurgitation (TR)
TR is functional and secondary to marked dilatation of tricuspid annulus. The most common cause of TR is
pulmonary hypertension as result of left sided cardiac failure or pulmonary parenchymal/vascular disease.
Less common causes include rheumatic HD, right sides myocardial infarction, and endocarditis in IV drug
abusers.
Clinical features:
 In patients with pulmonary HTN, symptoms of pulmonary congestion diminish, but the symptoms of
right sided heart failure are intensified such as peripheral edema and ascites
 Patients will have prominent jagular venous distention
 Holosystolic murmur at the left lower sternal border
 Pulsatile liver more prominent ascites than edema is a common finding
30
Heart
Laboratory Investigation:
Echocardiography
It is a very useful study, and it differentiates primary from secondary TR
Mitral Valve Prolapse (MVP):
Mitral valve prolapse occurs when varying portions of one or both leaflets of the mitral valve extend or
protrude abnormally above the mitral annulus into the left atrium.
Causes:
 Redundant or excessive mitral valve tissue
 Congenital diseases such as Marfan’s syndrome, Osteogenesis imperfecta
Clinical futures:
 MVP is more common in females and more common in the age group of 14-30.
 The clinical course is often benign
 Most patients are asymptomatic and may remain so for their entire lives.
 Some patients may manifest with features of Mitral regurgitation
 Arrhythmias like premature ventricular contractions and ventricular tachycardia may occur as
complications.
 The mid-systolic click, often accompanied by a late systolic murmur, is the auscultatory hallmark of
mitral valve prolapse.
Aortic Stenosis (AS):
Aortic stenosis could be caused by:
 Rheumatic Carditis
 Congenital stenosis of aortic valve or
 Senile/calcific aortic stenosis most common cause, which is idiopathic, results in calcification and
degeneration of the aortic leaflets
 Persons born with a bicuspid aortic valve are predisposed to develop aortic stenosis
Clinical features
Initially the patient is asymptomatic during an extended latent period. This is followed by the classic
symptoms of Aortic stenosis:
 Angina, exertional syncope and dyspnea
Laboratory Investigation:
Echocardiography
Echocardiography with Doppler provides an accurate assessment of aortic valve area and transvalvular
gradient and can be used to estimate left ventricular hypertrophy and ejection fraction.
Chest X-ray: may demonstrate valve calcification
Aortic Regurgitation (AR):
Aortic regurgitation results from disease affecting the aortic root or aortic leaflets, preventing their
normal closure.
Causes:
 Endocarditis
 Rheumatic fever
 Collagen vascular diseases
 Aortic dissection
 Syphilis
Bicuspid aortic valves are also prone to regurgitation
 In chronic aortic regurgitation, the stroke volume increased, which in turn causes systolic
hypertension, high pulse pressure and increased afterload. The afterload in aortic regurgitation may
be as high as that occurring in aortic stenosis
 Patients may be asymptomatic until severe left ventricular dysfunction has developed. The initial
signs of aortic regurgitation are subtle and may include decreased functional capacity or fatigue. As
31
Heart
the disease progresses, the typical presentation is that of left-sided heart failure: orthopnea, dyspnea
and fatigue
 Systolic dysfunction is initially reversible, with full recovery of left ventricular size and function after
aortic valve replacement. Over time, however, progressive chamber enlargement with decreased
contractility make recovery of left ventricular function and improved survival impossible, even with
surgery
 Wide Pulse Pressure: Due to increased stroke volume and hyperdynamicpulse
 Water Hammer Pulse:Rapid rise and fall or distension or collapse
 Austin Flint Murmur:Because the aortic valves are incompetent, blood regurgitate from the aorta
into the ventricle. The incompetent aortic valve strikes the leaflets of the mitral valve producing a
diastolic murmur called Austin Flint Murmur
Lab Investigation:
 Echocardiography
Echocardiography with Doppler ultrasonography provides information about aortic valve morphology
and aortic root size, and a semi quantitative estimate of the severity of aortic regurgitation .It
provides valuable information about left ventricular size and function
Cardiac Tumors:
Primary Neoplasm:
 Primary cardiac tumors are uncommon
Other cardiac tumors:
 Lipoma are localized, masses of adipose tissue, create ball valve obstruction(with Myxoma) or
produce arrhythmia
 Papillary fibroelastomas usually are only incidentally identified lesions, although they can be
embolizes
Cardiac Angiosarcoma and other sarcoma
Myxoma:
 Benign mesenchymal tumor with a gelatinous appearance and abundant ground Substance on
histology
 Most common primary cardiac tumor in adults
 Usually forms a pedunculated mass in the left atrium that cause syncope due to obstruction of the
mitral valve
Rhabdomyoma:
 Benign hematoma of cardiac muscle
 Most common primary cardiac tumor in children; associated with tuberous sclerosis caused by
mutation in the TSC1 or TSC2 tumor suppressor gene
 Usually arises in the ventricle
Metastasis:
 Metastatic tumors constitute the most common malignancy of the heart than primary tumors
 Common metastases to the heart include breast and lung carcinoma, melanoma, and lymphoma
 Most commonly involves the pericardium, resulting in a pericardial effusion
32
Chapter Three
Disorders of the Hematopoietic and Lymphoid Systems
General Description
Components of blood
1. Cellular parts
 Red blood cells, white blood cells, platelets
2. Plasma
 Fluid, electrolytes, proteinand lipids etc.
White blood cells
Granules
 Primary (azurophilic) seen at the myeloblast and promyelocyte stage,and contain the enzyme
Myeloperoxidase
 Secondary: these appear at the myelocyte stage. They are neutral staining in the neutrophil, red-
orange in the eosinophil and blue in the basophil
Neutrophil
 Number 2.5 – 7.5x10 /L
9
 Neutrophils have a multi lobe nucleus

 Neutrophil size is 9-15 micrometer in size
 Migrates to the site of infection or inflammation
 It is a phagocyte
 Kill microorganisms by oxygen dependent mechanisms. This involves the production of hydrogen
peroxide and the superoxide anion by the enzyme NADPH oxidase
 Killing microorganisms by oxygen independent mechanisms – intracellular acid pH, or enzymes
lysozyme and lactoferrin that are contents of the secondary granules
 Lifespan of neutrophils in the marrow is 11 days. When neutrophils enter the peripheral pool, they
only survive for hours (Half-life of 6-8 hours). Survival in tissues for 1-2 days
Causes of Neutrophilia:
 Physiological
 Vigorous exercise
 Pregnancy
 Newborn
 Pathological
 Bacterial infections
 Inflammation or necrosis
 Metabolic disorders e.g. diabetic ketoacidosis, uremia and eclampsia
 Steroid therapy
 Acute hemorrhage or hemolysis
Neutropenia
9 9
Defined as a neutrophil count of less than 2.5 x 10 /L. Usually symptomatic at <1.0 x 10 /L, with recurrent
9
infections, oral ulcers. Serious or life-threatening reactions occur at < 0.2 x10 /L.
Classification of Neutropenia:
 Benign familial
 Cyclic: neutrophil counts fall at 21-day intervals and remain low for 5-7 days.Due to failure of normal
humoral feedback mechanism
 Secondary:Due to viral infections, autoimmune disease or drug induced–most common adult cause
of isolated neutropenia, associated with anti-inflammatory, anti-thyroid, antihypertensive and oral
hypoglycemic agents
33
Hematopoietic and
Lymphoid System
Eosinophilia
 Defined as an absolute eosinophil count > 0.7 x 10 /L
9
Causes
 Parasitic infestation, especially by organisms which invade tissues
 Allergic disorders: Bronchial Asthma, Urticarial andHay fever
 Drug reactions
 Hematologic diseases: Chronic myeloid leukemia, Pernicious anemia
 Hodgkin disease
Basophils
 Similar to mast cells found in tissues
 Involved in IgE mediated hypersensitivity reactions, subsequent to reaction between allergen and
IgE the release of basophil granule contents e.g. histamine, lead to the recognized clinical
features of allergy or hypersensitivity
Causes of Basophilia
 Hypothyroidism
 Myeloproliferative diseases
 Chicken pox
Mononuclear Cells: (Lymphocytes, monocytes, plasma cells and macrophages)
Lymphocytes: Produced in the bone marrow from pluripotent stem cells
 T lymphocytes: account for 65-80% of peripheral blood lymphocytes and are functionally divided
into T helper cells (predominate in blood) and T suppressor cells (predominate in marrow)
 B-lymphocytes: These have endogenously produced Immunoglobulin molecules on the cell
surface, which act as receptors for specific antigens
9
Lymphocytosis: absolute lymphocyte count >4.0x 10 /L. Levels are higher in infancy and gradually
decrease toward adult levels.
Causes of Lymphocytosis
 Acute infections : pertussis, hepatitis, infectious mononucleosis
 Chronic infections : tuberculosis , congenital syphilis
 Lymphoma or leukemia
 Morphologic variations in lymphocytes in reactive states
 increased size
 increase in cytoplasm of to the nucleus
Monocytes
 Bone marrow monocytes arise from the same precursor cell as granulocytes. Bone marrow
monocytes give rise to peripheral blood monocytes and tissue macrophages
 Tissue macrophages constitute part of the mononuclear phagocyte system
Morphology of monocytes
 Variable size
 Abundant gray cytoplasm, often vacuolated
 Larger than lymphocytes
 Indented nuclei
 May combine to form giant cells
Monocytosis: Causes
 Bacterial infections ( most cause Neutrophillia) syphilis, bacterial endocarditis
 Recovery from acute infections
 Protozoan infections
 Collagen vascular diseases
 chronic steroid therapy
 Granulomatous diseases: Sarcoidosis, Ulcerative Colitis
34
Hematopoietic and
Lymphoid System
Platelets:
 Platelets are produced from fragmentation of megakaryocytes in the bone marrow results in platelets
of which 1/3 sequestered in the spleen, 2/3 circulates for 7-10 days
 Platelet count in a normal adult ranges from 150,000 – 450,000/ml
 When platelet count is reduced there will be reactive marrow megakaryocytosis
 Platelet count varies during menstruation i.e. rises during ovulation and failing during theonset of
menses
 It is also Influenced by nutritional state: decreased in sever Fe2+, folic acid, or vitamin B12deficiency
 Platelets are acute phase reactants hence may be increased in patients with systemic inflammation,
tumors, bleeding and mild iron deficiency hence the term secondary or reactive thrombocytosis is
used. Cytokines IL-3, 6, and 11 mediate it
Peripheral blood films with Different Disorders:
 Many hematological (and other) diagnoses are made by careful examination of the peripheral blood
film. It is also necessary for interpretation of the full blood count indices
 Anisocytosis: Is variation in RBC size, e.g. megaloblastic anemia, and thalassemia
 Acanthocytes: Spicules on RBC (unstable RBC membrane lipid structure); causes: splenectomy;
alcoholic liver disease; Abetalipoproteinemia; spherocytosis
 Poikilocytosis:Variation in shape of RBCe.g. Thalassemia, Myelofibrosis
 Reticulocytes: These are peripheral nucleated RBCs(normal range: 0.8–2%; or <85×10 /L). Young,
9
larger RBCs (contain RNA) signifying active erythropoiesis. Increased in hemolysis, hemorrhage, and
ifB12, iron or Folate is given to marrow that lack these
 Blasts: Nucleated precursor cells. They are not normally in peripheral blood, but are seen in
myelofibrosis, leukemia and malignant infiltration by carcinoma
 Right shift: Hypermature white cells: hypersegmented polymorphs (>5lobes to nucleus) seen in
megaloblastic anemia, uremia, and liver disease
 Left shift: Immature myeloid cells are seenin the peripheral blood, e.g. in infection
 Rouleaux formation: Red cells stack on each other (it causes a raised ESR, Seen with chronic
inflammation, paraproteinemia and myeloma
 Target cells: (also known as Mexican hat cells. These are RBCS with central staining, a ring of pallor,
and an outer rim of staining seen in liver disease, hyposplenism, thalassemia—and, in small numbers,
in iron deficiency anemia (IDA)
 Teardrop RBCS: Seen in extramedullary hemopoiesis; seen in Leucoerythoblastic film i.e.
Myelofibrosis
 Cabot rings: Seen in: pernicious anemia; lead poisoning
 Schistocytes: Fragmented RBCS sliced by fibrin bands, in intravascular hemolysis. Look for
Microangiopathic anemia, e.g. DIC, hemolytic uremic syndrome, thrombotic thrombocytopenic
purpura (TTP)
 Hypochromia: Less dense staining of RBCS due to ↓Hb synthesis, seen in IDA, thalassemia, and
Sideroblastic anemia (iron stores unusable)
 Polychromasia: RBCS of different ages stain unevenly (young are bluer). This is a response to
bleeding, hematinic replacement (ferrous sulfate, B12, Folate), hemolysis, or marrow infiltration.
Reticulocyte count is raised
Red Blood Cells Disorders
Anemia:
Definition:
 Functional definition: A significant reduction in red cell mass and a corresponding decrease in the
02carrying capacity of the blood
OR
 Laboratory definition: A reduction of the Hemoglobin concentration (12 g/dl, red cell mass or
Hematocrit, to below normal levels according to age or gender
35
Hematopoietic and
Lymphoid System
OR
 Qualitative and quantitative deficiency of the hemoglobin or RBCs with respect to age sex and
ethnicity
Classification of anemia on the Basis of Morphology:
3
Microcytic anemia’s: MCV<80 μm
 Iron deficiency anemia
 Anemia of chronic disease in later stages
 Thalassemia
 Sideroblastic anemia
3
Macrocytic anemia: MCV>100 μm
 Folate deficiency
 Vit B12 deficiency
 Liver disease
 Pernicious Anemia
3
Normocytic anemia: MCV 80-100μm
 Blood loss and aplastic anemia, Anemia of chronic disorder in initial stages, Mixed Deficiency Anemia
 Intrinsic RBCs defect:
 Hereditary spherocytosis
 Hereditary ellipocytosis
 Paroxysmal nocturnal hemoglobinuria
 Sickle cell anemia
 G6PD deficiency
 Extrinsic RBCs defect:
 Immune hemolytic anemia
 Microangiopathic hemolytic anemia
 Malaria
Classification of anemia on the Bases of Etiological (Pathological):
 Decrease RBC,s production
 Increase RBCs degradation
 Chronic blood loss
Iron deficiency anemia:
Common causes of iron deficiency anemia:
 Pathological blood loss
Peptic ulcer, stomach carcinoma, colon carcinoma, chronic aspirin ingestion esophageal varices,
hematuria, uterine bleeding, hookworm infestation
 Increased physiological demand
E.g. growing children, women in reproductive age
 Inadequate intake
Nutritional deficiencies etc.
 Malabsorption
Impaired absorption (Gatrectomy, tropical sprue, celiac disease etc.)
 Intravascular Hemolysis: Chronic intravascular hemolysis cause hemoglobin loss in urine
(hemoglobinuria) which causes iron deficiency anemia
Laboratory Diagnosis of Iron Deficiency
Complete Blood Count
 Hemoglobin ↓
 RBC count↓
 RBC indices (MCV, MCH, MCHC ↓)
 WBC-normal
 Platelets count normal or increased
36
Hematopoietic and
Lymphoid System
 RDW (red cell distribution width) ↑
 Reticulocyte count normal or decrease
Peripheral smear
Hypochromic microcytic anemia, anisocytosis, poikilocytosis-elliptocytes,
Pencil shaped cells
Figure: Peripheral Smear of Iron Deficiency Anemia

Bone marrow
 Erythroid hyperplasia-micro Normoblasts seen
 Prussian blue stain –Decrease/absent iron stores
Biochemical finding
 Serum iron decrease
 Serum ferritin less or <12 mg/dl
 TIBC (total iron binding capacity) ↑
 Transferrin saturation decrease or low
Clinical features of iron deficiency anemia:
Features of anemia:
Fatigue, palpitation, faintness, dyspnea, pallor
Feature of epithelial changes:
Koilonychias (concavity of fingernail), Atrophic Glossitis (atrophy of mucus membrane of tongue)
Plummer- Vinson syndrome: A triad characterized by:
 Iron deficiency anemia
 Dysphagia
 Glossitis
Iron metabolism:
 Daily 10-30mg iron ingested, 5-10% absorbed to balance precisely the amount lost (1mg) under
physiologic condition
 Amount absorbed can increases up to five fold if body iron store are depleted or erythropoiesis is
accelerated
 Absorbed as hem and non-heme iron in the duodenum and proximal jejunum
Iron absorption:
 Is facilitated by: Stomach acidity, Ascorbic acid, citrates, while
 Is limited/reduced by : Phosphates, Oxalates, Tannates (tea) and pyrates (plant food)
 Transferrin is the transport protein that carries iron in the plasma and ECF
Thalassemia:
Definition
The thalassemia is a heterogeneous group of inherited disorders caused by mutation that decreases the
rate of synthesis of α or β-globin chains
Pathogenesis of thalassemia
37
Hematopoietic and
Lymphoid System
 Thalassemia α or β Autosomal recessive disease
 Alpha thalassemia is due to α globin chain deletion on chromosome 16.one gene deletion produce a
silent carrier. Combination of two-gene deletion is called α Thalassemia trait. The combination of
three-gene deletion is called HbH. The combination of four gene is called Hb Bart or hydrop fetalis
 β Thalassemia is major, minor and intermediate
 Mutation leading to RNA splicing are the most common cause of β thalassemia who’s genes are
located on chromosome 11 OR Removes the Exon which is coding part of DNA or frame shift
mutation or non-sense mutation which stop codon
 α chain ↑,β chain↓ so α chain deposited in RBCs. Blood cells destroyed in bone marrow Called as
ineffective erythropoiesis (most erythroblast die in bone marrow)
 Extravascular hemolysis
Destruction of aggregate containing in RBCs in spleen
 Extra medullary hematopoiesis
 Blood cells are formed by lymph node, liver, spleen
Blood cells ↓ so compensated by Erythroid precursor hyperplasia peripheral smear→↑ (Reticulocyte
is a nucleated)
Laboratory investigation of thalassemia
 Complete Blood Count:
Hb↓, (MCV, MCH ↓) show hypochromic microcytic anemia, ↑ reticulocyte count
 Peripheral smear
Microcytosis, Hypochromasia, Poikilocytosis, Anisocytosis andTarget cells
Fragmented RBCs. basophil stippling may be present.Howell jolly bodies may be present in the RBCs.
 Bone marrow findings
Erythroid hyperplasia
 Hemoglobin electrophoresis
Reveals reduced or almost absent HbA1, an excess of HbF and low, normal or ↑level of HbA2
 Specific Investigation: α or β globin chain synthesis studies on reticulocytes show in increased α: β
with reduced or absent β chain
 High performance liquid chromatography is now a day used to diagnose Hb disorder
 PCR is also used to detect Hb abnormality
 X ray skull show “hair on end” appearance
 Serum ferritin is high after treatment and serum iron binding capacity is saturated
(Patient is at increased risk of hemochromatosis)
Figure: peripheral Smear of Thalassemia (Arrows showing Target Cells)
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Hematopoietic and
Lymphoid System
Prevention of Thalassemia
 The disease can be prevented at prenatal level by screening the carrier males and females before
marriage (especially if disease runs in family) and if found carrier of the disease then can be offered
genetic counseling. Similarly, males and females can be screened after marriages and if found carrier
they can be offered genetic counseling at that time
 Moreover, during early fetal life by DNA analysis, the presence of the disease can be diagnosed and
the fetus can be aborted at early stage
 screening of school going children
Figure: Pathophysiology of Thalassemia
Sideroblastic anemia:
 Refractory anemia with hypochromic with ↑marrow iron
 Many pathological ring sideroblasts are found in the bone marrow
 Is caused by defect in heme synthesis
Classification:
 Hereditary (sex linked recessive trait)
 Acquired
Primary: Myelodysplasia
Secondary:
 Malignant diseases of the marrow
 Drugs e.g. cycloserin alcohol, lead
 Others: hemolytic anemia, megaloblastic anemia, Malabsorption
 15% of marrow erythroblasts are ring sideroblasts in hereditary and 1% acquired form
Lead poisoning
 Inhibits both hem and globin synthesis
 Interferes with breakdown of RNA by inhibiting the enzyme pyrimidine-5 nucleotidase→accumulation
of denatured RNA in red cells giving rise to Basophilic stippling
 Hypo chromic/Hemolytic anemia with bone marrow ring sideroblasts
 Free erythrocyte protoporphyrin is raised
39
Hematopoietic and
Lymphoid System
Figure: Sideroblastic cells

Megaloblastic anemia:
Etiologies of megaloblastic anemia
 Vitamin B12deficiency
 Folate deficiency
 Abnormalities of vitamin B12or Folate metabolism, transcobalamine deficiency, antifolate-drugs
 Other defects of DNA synthesis: congenital enzyme deficiency, alcohol, treatment with
hydroxyurea, etc.
Cells primarily affected are those with rapid turnover:
 Hematopoietic cells (RBCs, granulocytes, megakaryocytes)
 Cells derived from Respiratory tract and GIT etc.
 Macrocytic RBCs appear before the onset of anemia
Pathogenesis of megaloblastic anemia
 It is a descriptive morphologic term in which maturation of the nucleus is delayed relative to that of
cytoplasm. The delay in maturation of the nucleus is attributed to defective DNA synthesis. This
condition leads to Megaloblastic marrow and ineffective erythropoiesis. The immature erythroblasts
are destroyed within the bone marrow leading (Intramedullary hemolysis) which results
Megaloblastic anemia
Laboratory Diagnosis of Megaloblastic Anemia
 (↓RBCs, Hb↓, ↓ WBCs and platelets): (↑MCV, ↑RDW, ↑MCHC)
 Peripheral Blood Picture:
 Myeloid mass will be decreased
 Macrocytosis (oval macrocyte)
 Anisocytosis
 Poikilocytosis
 Hypersegmentation of neutrophil
 Low platelets and WBCs
 Bone Marrow Examination:
 Hypercellular fragments
 Megaloblast
 Myeloid series shift to lift with giant myelocyte and giant metamyelocyte
 Serum Bilirubin Level Increased.
 Raised LDH
 Decreased Hepatoglobin
 Decreased Serum Vitamin B12 level
 Schilling Test: To rule out the cause of Vit B12 deficiency (Pernicious Anemia)
 FIGLO Test: Differentiate either the anemia is due to Vitamin B12 or Folic acid
40
Essential
Essential
Special
Special
Pathology
Pathology Chapter3:3:
Chapter
Hematopoietic
Hematopoietic and
and
Lymphoid
Lymphoid System
System
Figure: Peripheral Smear of Megaloblastic Anemia (Arrow showing Hypersegmented Neutrophil

Clinical features of megaloblastic anemia:
 Pallor and jaundice (“lemon yellow”)
 Loss of papillae of tongue (“beefy red”)
 Neurological deficit (due to demyelination) only in Vitamin B12 Deficiency
 Neurological abnormality in pernicious anemia is subacute combine degeneration of the spinal cord,
demyelination of the posterior and lateral column of the spinal cord presenting with
 ↓ Vibration sense + Romberg /spastic paraparesis, ataxia etc.)
 Can also cause dementia, behavior change and depression
 Signs of associated conditions: Vitiligo (depigmentation of skin), thyroid disease etc.
Causes of Macrocytic Anemia:
 Vitamin B12 deficiency
 Folic acid deficiency
 Aplastic anemia
 Myelodysplastic syndromes
 Cytotoxic drugs
 Liver disease
 Myeloma and paraproteinemia
Aplastic anemia
Definition:
 peripheral blood pancytopenia (low RBCS, WBCs and platelets) with aplasia(inability to produce blood
cells ) of the bone marrow
Causes of aplastic anemia:
 Congenital:
 Familial Aplastic Anemia, Fanconi’s anemia, Dyskeratosis Congenital, Pearson’s syndrome
 Acquired:
 Idiopathic: 50-70%
 drugs: alkylating agent and antimetabolites
 Idiosyncratic reaction to mylotoxic (chloramphenicol, sulphonamides)
 Infections: EBV, CMV, parvovirus and heap A,B,C are not culprit
 Physical agents: ionizing radiation ( therapeutic or nuclear accident)
 Miscellaneous: thymoma
Pathogenesis of aplastic anemia
 Aplastic anemia is not a single disorder but comprises of a group of pathogenically distinct entities. It
can result from
 Defective or deficient hematopoietic stem cells
 A defect in bone marrow stroma that enables it to support normal stem cell functions
 Suppression of marrow stem cells by immune mechanisms
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Hematopoietic and
Lymphoid System
 Auto reactive T cell destroy myeloid stem cells
 Mutation in Telomerase gene
Laboratory diagnosis of aplastic anemia
 Complete Blood Count
 Hb ↓10 g/dl, RBCs low, WBC low, Platelets very low, marked neutropenia
 Peripheral Smear
 Anemiais normochromic normocytic type/ may be of macrocytic type
 Bone marrow findings or trephine biopsy
 Hypocellular bone marrow
 90% intertrabecular space being occupied by fat
 The limited cellurity often consists of only lymphocytes and plasma cells
 Reticulocytopenia
 Pancytopenia
 Erythropoiesis is depressed
 Increased fat stasis
 Both the serum iron and TIBC are reduced; serum transferrin levels are normal
 The serum ferritin is normal or raised.
 Bone marrow storage (reticuloendothelial) iron is normal
 Screening for paroxysmal nocturnal hemoglobinuria (PNH)
 Virology profile
 Liver function test
Hemolytic anemia:
Definition:
Anemia caused by accelerated red cells destruction is termed as hemolytic anemia
Classification of Hemolytic Anemia:
Intrinsic (Intrascapsular) Hemolytic Anemia
Hereditary
Membrane Membrane skeleton protein: spherocytosis; ellipocytosis
abnormality Membrane lipids : Abetalipoproteinemia
Enzymes Enzymes of HMP Shunt Pathway : G6PD, Glutathione Synthetase
deficiencies Glycolytic Enzymes: Pyruvate Kinase , Hexokinase
Disorders of Structurally Hemoglobin Synthesis: Sickle Cell Anemia, Unstable Hemoglobin
Hb synthesis Deficient Globin Synthesis: Thalassemia Syndrome
Acquired Membrane defect : paroxysmal nocturnal hemoglobinuria (PNH)
Extrinsic (Extra Corpuscular)
Anti-body Transfusion Reaction, Rh Disease of the Newborn
Mediated
Mechanical Microangiopathic Hemolytic Anemia, Disseminated Intravascular
Trauma to Coagulation, Defective Cardiac Valves
RBCs
Infection Malaria
Classification of Immune Hemolytic Anemia:
Warm Antibody Type
Primary (Idiopathic)
Secondary B cell Neoplasm CLL, Autoimmune Disorders (SLE), Drug Induced
Cold Anti-Body Type
Acute Mycoplasma Infection, Infectious Mononucleosis
Chronic Idiopathic; B-cell Lymphoid Neoplasm
42
Hematopoietic and
Differentiate between warm and cold antibodies immuno hemolytic anemia

Lymphoid System
Warm antibody immuno hemolytic anemia Cold antibody immuno hemolytic anemia
Anemia are cause by immunoglobulin IgG Caused by IgM antibodies
Active at 37 C at body temperature Active at temperature below 30 C
Mechanisms Of Hemolysis:
 Intravascular
 Extravascular
Intravascular Hemolysis:
 Red cells destruction occurs in vascular space
 In intravascular hemolysis pathology lies in the RBCs
Clinical states associated with Intravascular hemolysis:
 Acute hemolytic transfusion reactions
 Severe and extensive burns
 Paroxysmal nocturnal hemoglobinuria
 Severe microangiopathic hemolysis
 Physical trauma
 Bacterial infections and parasitic infections (sepsis)
Extravascular hemolysis:
 Red cells destruction occurs in reticuloendothelial system
 In extravascular hemolysis pathology causing hemolysis is outsideRBCs
Clinical states associated with extravascular hemolysis:
 Autoimmune hemolysis
 delayed hemolytic transfusion reactions
 Hemoglobinopathies
 Hereditary spherocytosis
 Hypersplenism
 Hemolysis with liver disease
 Laboratory findings sugestive of extravascular hemolysis
Signs of hemolytic anemia: Physical:
 Symptoms of anemia
 Jaundice
 Pallor
 Splenomegaly / hepatosplenomegaly
 Increased temperature
 Rapid pulse
Laboratory investigation
 CBC: Anemia, Hb decrease
 Peripheral smears
 Fragments of the red blood cells ("schistocytes") can be present
 Some red blood cells may appear smaller and rounder than usual (Spherocyte)
 Reticulocytes are present in elevated numbers
 Erytroblasts can be present
 Bone marrow
 Erythroid hyperplasia (Megaloblast)
 Biochemical Investigations:
 The level of unconjuncated bilirubin in the blood is elevated
 The level of lactate dehydrogenase (LDH) in the blood is elevated
 Hepatoglobin level are decreased
 Iron level in the blood is elevated
 Increased excretion of urobilinogen in the urine and stercobilinogen in stool
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Hematopoietic and
Lymphoid System
 Coomb’s Test:
 The direct Coomb’s test is positive if an immune process causes hemolysis
 Osmotic Fragility Test: Sometimes-abnormal result of osmotic fragility test
Hereditary Spherocytosis:
Definition:
It is a group of disorders characterized by a defect in the RBCs cytoskeleton, most commonly ,it occurs
because of mutations in, spectrin, or other mutations like ankyrin or band3,and protein 4.2.
Pathogenesis:
 The mutations in the RBC membrane leads to, uncoupling of the bi-lipid layer under the cytoskeleton,
which leads to loss of the membrane in form of vesicles, the loss of membrane leads to a change in
shape of the RBC, which changes into spherical shaped cell, instead of the biconcave it usually is
 In hereditary spherocytosis, biconcave erythrocytes are released from the marrow but they rapidly
lose membrane and therefore assume a spherical shape
 The Spherocyte have reduced deformability, so their ability to withstand changes in PH, glucose etc.
and impedes their course through the splenic microcirculation. The cells are retained for long periods
in the splenic cords they are ultimately phagocytized
 Increased osmotic fragility (RBCs lyse under normal osmotic stress, which normal RBCs withstand)
Figure: Pathogenesis of Hereditary Spherocytosis

Morphology:
rd
On peripheral smear, the Spherocyte look round, with loss of the central 2/3 of pallor and more of round
than biconcave with an increased surface to volume ratio.
Clinical Features:
Features are variable and are those of chronic
Extravascular hemolysis (Pigment gallstones commonly Develop in 40 to 50 % patients)
Laboratory Findings:
 CBC:
 Normocytic normochromic anemia
 MCHC is increased
 Increased RDW (means increased more RBCs with weird shapes and sizes)
 Peripheral Smear:
 Spherocytosis and Polychromasia seen on peripheral smear (Reticulocytosis)
 Serum bilirubin and urinary urobilinogen are raised (due to hemolysis of sickle cell)
 Osmotic fragility:
 When cells are placed in a solution of increasing hypotonicity, they take water, swells up and
eventually lyse. Spherocyte rupture early than normal
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Hematopoietic and
Lymphoid System
Note: Howell jolly body is present in any disease in which splenectomy is needed so in hereditary
spherocytosis splenectomy required so Howell jolly body is present in hereditary spherocytosis
Sickle cell anemia:
Q. Peripheral blood film of a 23 years old female with history of jaundice and severe anemia shows the numerous
Sickles shaped red cells.
a) What is the diagnosis and the type of hemoglobin would the Hb electrophoresis?
b) Outline the mechanism of sickling of red cells in this patient.
c) List the laboratory investigation.
d) What are the Complications?
Diagnosis:
Sickle cell anemia and Hemoglobin S (HbS) would be found on Hb electrophoresis.
Mechanism of Sickling:
1. Predominantly extravascular hemolysis of sickle cells
2. Miss sense point mutation (replacement of glutamic acid by Valine at 6 position of β globin chain)
3. Causes of sickling:
 HbS molecules aggregate and polymerize into long needle like fibers RBCs assumes sickle or
boat like shape
 HbS concentration greater than 60% is the most important factor for sickling.
 Increase in deoxyhemoglobin increase the risk for sickling
 Acidosis
 Volume depletion
 Hypoxemia
Investigations:
 CBC: Anemia.
 Peripheral smear: Sickle shaped red cells, or Boat Shaped polychromatophilia, Reticulocytosis and
Howell-Jolly bodies.
 Hb –electrophoresis or high-performance liquid chromatography (HPLC).
 X-ray skull will show ‘’crew cut’’ appearance.
 Bone marrow show Compensatory hyperplasia of Erythroid progenitor.
 Biochemical analysis show increase breakdown of Heme to Bilirubin.
Complication:
 Acute Chest Syndrome
 Vaso-occlusion in the episode can involve many sites but occur most commonly in the Bone marrow
resulting in Aplastic Crisis
 Sickle cell Disease patients are more prone to infections
Paroxysmal Nocturnal Hemoglobinuria (PNH):
Definition:
Acquired membrane defect in multi potent myeloid stem cell in which intravascular complement
mediated lists of RBCs, neutrophils and platelets occurs at night time, because respiratory acidosis
enhance complement attachment to these cells
Pathogenesis:
 An acquired clonal disease, arising from a somatic mutation in a single abnormal stem cell. PNH
involves the PIG-A gene (short arm of the X chromsome). The mutation results of glycosyl-
phosphatidyl-inositol (GPI) anchor abnormality
 Deficiency of the GPI anchored membrane proteins (DAF=decay-accelerating factor CD55, MIRL=a
membrane inhibitor of reactive lysis, C8BP=C8 binding protein)
 The defective synthesis of GPI affects all hematopoietic cells (anemia, neutropenia and
thrombocythopenia, or they may have complete BM failure)
 Red cells are more sensitive to the lytic effect of complement
 Intravascular hemolysis
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Hematopoietic and
Lymphoid System
Symptoms:
 Passage of dark brown urine in the morning, severe pain in he abdomen and recurrent
thromboembolism (ie vena cava inf., portal mesenteric system).
 Episodic hemoglobinuria (may cause iron deficiency)
 Increased incidence of vessel thrombosis (hepatic vein)
 Increased risk for developing acute myelogeneous leukemia
It screen sucrose hemolysis test: confirm acidified serum Lysis test (Ham’s Test)
Laboratory Findings:
 Decrease Hb, Anemia
 Peripheral Smear:
 Sometimes Pancytopenia.
 Biochemical Findings:
 Serum iron concentration decreased
 Hemoglobinuria
 Hemosiderinuria
 Acidified Serum Lysis Test (Ham’s test): PNH cells lyse due to complement activation in acidified
serum
 Sugar Water (Sucrose Hemolysis) Test: RBCs sensitive to complement will lyse in sucrose and serum
 Flow Cytometry: Lack of CD59 on RBCs, or Lack of CD59 or CD55 on granulocytes
Glucose 6-Phosphate Dehydrogenase:
Definition:
It is an inherited disease characterized by hemolytic anemia(destruction of RBCs) caused by the inability
to detoxify oxidizing agents. G6PDH (or G6PD) deficiency is the most common enzymatic disorder in
humans.
Functions:
 Regenerates NADPH, allowing regeneration of glutathione
 Protects against oxidative stress
 Lack of G6PD leads to hemolysis during oxidative stress
 Infection
 Medications
 Fava beans
 Oxidative stress leads to Heinz body formation, increase extravascular hemolysis
Laboratory diagnosis
 Complete Blood Count: low Hemoglobin, anemia
 Direct Measurement of G6PD activity in RBCs by spectrophotometer
 Screening G6PD Fluorescent Spot Test
 Blood Smear with Stains for Heinz Bodies blood film may show contracted and fragmented cells; bite
cells and blister cells.
 Fractionated Serum Bilirubin; TSB (total serum bilirubin) ↑, DSB (direct or conjugated serum bilirubin
N), and In DSB (indirect or unconjugated serum bilirubin) ↑
 Genetic test for variant
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Chapter 3:
Hematopoietic and
Lymphoid System
Figure: Peripheral Smear of G6PD (Arrow showing Bite cell)

Laboratory Diagnosis of Hypochromic Anemia:
Test Iron Deficiency Chronic Disorders Thalassemia Sideroblastic
Anemia Anemia
MCV, MCH, MCHC Reduced Low normal to Very Low Very Low
Reduced
Serum Irun Reduced Reduced Normal Raised
TIBC Raised Reduced Normal Normal
Serum Ferritin Reduced Raised Normal Raised
Marrow Iron Stores Absent Present Present Present
Iron in Normoblasts Absent Absent Present Ring Sideroblasts
Hb Electrophoresis Normal Normal Abnormal Normal
Polycythemia:
Definition
Polycythemia is defined as an elevation of the packed cell volume; and may be:
 Absolute Polycythemia: the red cell mass is actually increased; this increase may be:
 Primary absolute polycythemia : ↑in Red cells due to autonomous proliferation of the myeloid
stem cells polycythemia Rubra Vera
 Secondary absolute polycythemia: to underlying diseases which produce increased EPO
 Hypoxic states e g. Cyanotic heart disease, chronic lung disease
 Inappropriate EPO production e g. Renal cysts, renal cancer, pheochromocytoma
 Relative polycythemia:There is no increase of red cell mass, but a relative decrease in plasma volume
causes an increased PCV due to loss of plasma volume
Primary Polycythemia
Peak incidence in the 6th decade, but may be seen in young adults
Common signs and symptoms
 Plethoric skin
 Splenomegaly
 Headache and dizziness
 Venous or arterial thrombosis
 Pruritus due to histamine release from basophils
Criteria for Diagnosis
 Increased PCV > 0.55
 Arterial oxygen saturation > 92 %
 Splenomegaly
 Leukocytosis / thrombocytosis
Complication of blood transfusion:
Transfusion reaction are generally classified into 2 i.e. Immune and Non-immune Transfusion reaction
Immunologic Transfusion Reaction:
 Hemolytic Transfusion Reaction:
47
Hematopoietic and
Lymphoid System
 Intravascular hemolysis (ABO incompatibility)
 Extravascular hemolysis (RH system)
 Transfusion related acute lung injury (TRALI):
 Transfusion of donor plasma containing high level of anti HLA antibodies which bind to
leukocytes of recipient and reaction occur
 Allergies:
 Febrile reaction
 Anaphylactic reaction
 Urticarial reaction
 Graft versus host reaction
Non-Immune Transfusion Reaction:

 Circulatory overload
 Massive transfusion
 Transmission of infection
 Air embolism
 Thrombophlebitis
 Transfusion haemosiderosis (as in thalassemia major)
Indication of Packed Cells Transfusion:
 In a person with normochromic anemia without any underling cardiac disease can be given packed
RBCs since it will increase oxygen carrying capacity of blood and will help the patient
 Platelets transfusion are indicated in patients with thrombocytopenia and hemorrhagic condition
 Fresh frozen plasma indication in patient of coagulation failure and TTP
 Cryoprecipitate contain plasma protein, fibrinogen, factor8 and vWF.
White Blood Cells Disorders
Figure: Origin of Different Blood Lineages

Infectious Mononucleosis:
Caused by infection with Epstein-Barr virus (EBV) and characterized by:
 Fever and pharyngitis
 Lymphadenopathy and mild splenomegaly
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Hematopoietic and
Lymphoid System
 Increased circulating atypical mononuclear cells
 High titers of Heterophile antibodies
 Peak incidence at ages 15 –25 years
Clinical features:
 Incubation period of 5-8 weeks
 Pharyngitis with edema and adenoidal hypertrophy
 Lymphadenopathy – tender, bilateral and symmetrical
 Mild to moderate splenomegaly in 50-75 %
 Atypical features include skin rash, hepatitis and encephalitis
Differential diagnosis:
 Acute viral pharyngitis caused by other organisms - serological tests are negative
 Acute leukemia – usually significant anemia and /or thrombocytopenia; also peripheral blood
lymphoid cells are blasts (with nucleoli). Peripheral blood picture will be the same or worse after 10-
14 days (will show improvement in IM)
Hematological features:
 Leukocytosis of 12-18 x10/l with atypical mononuclear cells. The majority of these are activated T
lymphocytes
 Anemia and thrombocytopenia are uncommon and usually autoimmune in nature
Serological Features:
 EBV- specific antibodies:
 Antibodies to Viral Capsid Antigen (VCA): IgM antibodies produced during incubation period and
peak after 2-3 weeks then decline. IgG antibodies subsequently appear and persist for life
 Antibodies to Nuclear antigen (EBNA) begin weeks after onset of illness and persist indefinitely
 Autoantibodies: Uncommon, may cause autoimmune anemia or thrombocytopenia
 Heterophile antibodies:
 These non-specific serum agglutinins will agglutinate sheep or horse red cells. This is the basis of
the ‘‘Monospot’’ test.
Lymphadenopathy
Definition: Lymph node enlargement
Clinical features:
 Patient may complain of swollen glands or mass. Systemic illness with enlarged lymph nodes can have
a variety of constitutional symptoms such as weight loss, fevers, night sweats, fatigue and malaise
Etiology:
Viral (most common cause of mild, transient lymphadenopathy lasting < 6 weeks):
 EBV, CMV, HSV, VZV, hepatitis, measles
 HIV: usually see generalized or local lymph node enlargement when patient is symptomatic from HIV
itself. Enlarged lymph nodes can also be a sign of HIV related illness such as tuberculosis,
histoplasmosis, CMV infection, Kaposi’s sarcoma, lymphoma, dermatological conditions such as
seborrhoeic dermatitis. Persistent generalized lymphadenopathy is common in HIV positive patients
and is often due to HIV alone.
Bacterial (2ndmost common):
 Generalized lymphadenopathy (tuberculosis, atypical mycobacteria)
 TB adenitis (scrofula) is common in our setting and typically causes unilateral cervical
lymphadenopathy with discharging sinuses in patients without HIV infection; in the setting of HIV
infection, the lymphadenopathy is often diffuse and bilateral and may indicated disseminated disease
localized lymphadenopathy = local adenitis (streptococci, staphylococci) tends to be severe and acute
in onset
Neoplasm (3rdmost common):
 Lymphoma, leukemia, metastatic carcinoma
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Hematopoietic and
Lymphoid System
Fungal and parasitic:
 Toxoplasmosis, histoplasmosis
Immunologic:
 Drug hypersensitivity (phenytoin), serum sickness, collagen vascular disease
Lymphoma:
Definition:
Lymphomas are the malignant tumors of lymphoid cells native to the lymphoid tissue (i.e. lymphocytes,
histocytes and their derivatives)
Types of lymphoma
 Non Hodgkin lymphoma
 Hodgkin lymphoma
Non-Hodgkin lymphoma:
Classification of Non-Hodgkin lymphoma
B-cell lymphoma:
 Burkitt’s lymphoma
 Diffuse large B-cell lymphoma
 Extranodal marginal zone lymphoma
 Follicular lymphoma
 Small lymphocytic lymphoma
T-cell lymphoma:
 Precursor T-cell lymphoblastic leukemia
 T-cell Prolymphocytic Leukemia
 T-cell Granular Lymphocytic Leukemia
 Enteropathy Type T-cell Lymphoma
 Mycosis fungoides and sezary syndrome
Burkitt lymphoma:
Q. an 8 year old boys present with a pain large, hard fix and non-tender mass involving the Lower jaw. Smear of
autopsy reveals malignant cells having low N/C ratio, deeply basophilic cytoplasm with vacuolation.
b) What are the various form/types?
c) List the salient features of morphology, immunological markers, chromosomal translocation and viral
agent involved
Diagnosis:
Burkitt lymphoma
Types:
Sporadic (American) type: It involve GIT and Paraaortic Lymph Nodes
Endemic (African) Type: It Involve Mandibular Region
Morphology of Burkitt lymphoma:
 The tumor cell have oval nucleoli containing 2-5 prominent nucleoli
 Very high rates of proliferation and apoptosis are characteristic findings
 Macrophages show “Starry sky appearance”
 Diffuse intermediate cells
 Cytoplasm has basophilic appearance
Immune markers: CD10, CD19, CD20
Pathogenesis:
Chromosomal translocation: Translocation involving the MYC gene on chromosome 8 and IgH on
chromosome 14 t(8; 14)
Viral agent: Epstein bar virus (EBV)
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Figure: Burkitt Lymphoma Macrophages surrounded by Clear Space (Starry Sky Appearances)
HodgkinLymphoma
Q. A 32 years old female presents with bilateral cervical and supraclavicular Lymphadenopathy. The lymphnodes
are free movable and non-tender. Theperipheralbloodshows eosinophilia.Biopsy of lymph node reveals variant RS
cells and collagen bands.
b) What are the sub types?
c) What are the salient features of Etiology and pathogenesis
d) Describe morphological appearance of Reed Sternberg cell
Diagnosis:
Hodgkin lymphoma
Types of Hodgkin lymphoma:
 Nodular Sclerosis Hodgkin Lymphoma
 Mixed Cellularity Hodgkin Lymphoma
 Lymphocyte Predominance Hodgkin Lymphoma(It is negative for CD15, 30 usual markers of Hodgkin
Lymphoma but positive for B- Cell markers CD 19, 20, 22 and 45)
 Lymphocyte Rich Hodgkin Lymphoma
 Lymphocyte Depletion Hodgkin Lymphoma
Etiology and pathogenesis:
 RS cells
 Epstein bar virus(EBV) episomes frequently present in RS cells
 EBV DNA is the same in all tumor cells indicating that infection occur beforecellular transformation
 EBV positive tumor cells express LMP-1(a protein have transforming activity).
 LMP-1 transmit signals that upregulateNF-KB(a transcription factor of broad importance in
lymphocytic activation)
 Activation of NF-ҡB also occur in EBV negative tumors
 Thus inappropriate activation of NF-KB to be a common event in clinical HL
 Activation of NF-KB by EBV or other mechanisms rescues these cells from apoptosis, sometime
resulting the stage for acquisition of other unknown mutants that collaborate to produce RS cells
Morphology of Hodgkin lymphoma
Classic RS cell:
 It is a type of neoplastic giant cell whichhas two mirror image nuclei or nuclear lobes, each containing
a large (inclusion like) acidophilic nucleolus surrounded by a distinctive Clear zone, together they
impart an “owl eye” appearance.
 Nuclear membrane is distinct.
Neoplastic cell of Hodgkin lymphoma
 In most cases it is a transformed germinal center B cells
 CD15, CD30 positive
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Reed Sternberg Cells:

Reed Sternberg Cell:
It is a type of neoplastic giant cell which is the pathognomonic of Hodgkin Lymphoma and which has
specific characteristic shape
1. Classic RS cell:
It is a large cell, which has characteristically a bilobed nucleus, appearing as mirror image of each
other. Each lobe of the nucleus contains a prominent, eosinophilic, inclusion like nucleolus with a
clear halo around it, giving an owl-eye appearance.
2. Lacunar type RS cell:
Is smaller and in addition to above features has a pericellular space or lacuna in which it lies, which is
due to artefactual shrinkage of the cell cytoplasm. It is characteristically found in nodular sclerosis
variety.
3. Polyploid type (or popcorn or lymphocytic Histiocytic i.e. L and H) RS cells:
Are seen in lymphocyte predominance type of HD. This type of RS cell is larger with lobulated nucleus
in the shape of popcorn.
4. Pleomorphic RS cells:Are a feature of lymphocyte depletion type. These cells have pleomorphic and
atypical nuclei.
Morphology of mixed cellularity:
 Most common form of Hodgkin lymphoma in patient older than 50, comprises 25%
 There is male predominance
 Classic RS cells are plentiful with in a distinctive heterogeneous cellular infiltrate which includes
lymphocytes, eosinophil, plasma cells and benign histocytes.
 Compared with other subtype it has disseminated disease andsystemic manifestation.
Figure: Morphology of Mixed Cellularity

Clinical Features of Hodgkin Lymphoma
 Fever, unexplained weight loss, night sweats
 Pruritus
 Epstein Bar Virus: uncommon variant of fever
 Hematologic findings:
 Normocytic anemia
 painless enlargement of single group of lymph nodes
 Main factors determining prognosis :
 Clinical stage is more important than the type Hodgkin
 Majority have lymphadenopathy above the diaphragm( stage 1 and 11)
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 Usually involves supraclavicular nodes and anterior mediastinal nodes
 Increase risk for second malignancy :
 Acute myelogeneous leukemia or NHL
 Complication of treatment with radiation and alkylating agents
LaboratoryInvestigation of Hodgkin Lymphoma
 Biopsy “Gold standard”
 FNAC for staging
 C reactive protein, LFT
 Radiography X ray chest, CT scan thorax and pelvis
 Magnetic resonance imaging MRI
 PET scan
 Bone scan
Differences b/w Hodgkin and Non- Hodgkin Lymphomas
Hodgkin lymphoma Non-Hodgkin lymphoma
1. More often localized to single axial Group More frequent involvement of multiple peripheral
lymph nodes (cervical, mediastinal) nodes
2. Contagious spread Noncontiguous spread
3. mesenteric nodes Waldyer ring rarely Involved Mesenteric nodes and Waldyer ring commonly
involved
4. extra-nodal involvement uncommon Extra- nodal involvement common
Ann Arbor Staging of Hodgkin Lymphoma
Stage Distribution of disease
I Involvement of single lymph node region (I) or involvement of single
Extra lymphatic organ or tissue (Ie)
II Involvement of two or more lymph node region on the same side of diaphragm alone (II). Or
involvement of limited contiguous extra lymphatic organ (IIe)
III Involvement of lymph node region on both side of the diaphragm (III) which may include the
spleen (IIIs) limited contiguous extra lymphatic organ (IIIe) or both (IIIes)
IV Multiple or disseminated foci of involvement of one or more extra lymphatic organ or tissue
with or without lymphatic involvement
Leukemia
Definition of leukemia
 Leukemias are neoplasms of hematopoietic cells proliferating in the bone marrow initiallyand then
disseminate to peripheral blood, lymph nodes, spleen, liver etc.
 Lymphomas differ from leukemias in that, lymphomas arise primarily from lymph nodesbut spread to
blood and bone marrow only in "leukemic phase” of the diseases.
Note: Malignant WBCs in blood = Leukemia whereas Malignant WBCs in Lymphoid tissue =Lymphoma
Classification of leukemias: is based on
Cell of origin: there are two types of leukemias
 Lymphoid leukemias
 Myeloid leukemias
Clinical course of the disease- two forms of presentation of leukemias
 Acute leukemias
 Chronic leukemias
Thus, combining the above two criteria, there are have 4 main types of leukemias
 Acute lymphoblastic leukemia (ALL)
 Chronic lymphoid leukemia (CLL)
 Acute myelogeneous leukemia (AML)
 Chronic myeloid leukemia (CML)
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Acute Lymphoblastic Leukemia (ALL)

Q. A young adult was diagnosed as a case of acute lymphoblastic leukemia on bone Marrow biopsy
a) Briefly describe it morphological findings on bone marrow biopsy.
b) Give Immunophenotypemarkers for B and T acute lymphoblastic leukemia.
Ans: a. Morphology of Acute Lymphoblastic Leukemia (ALL)
 Increased no. of lymphoblast
 Depressed myelopoiesis
 Depressed erythropoiesis
b. Immunophenotype markers for B ALL: CD10, CD19, CD20 positive
Immunophenotype markersfor T ALL: CD1, CD2, CD5, CD7 positive
Q.
a) Which leukemia is more common in children?
b) Write its subtypes according to FAB classification.
c) Write the blood finding along with the cytochemistry, immunological markers and chromosomal
abnormalities.
Acute Lymphoblastic Leukemia
FAB classification of ALL
L1 Blasts are small,homogenous, indistinct nucleoli,monomorphic, N/C ↑
L2 Blast are large, heterogenous, nucleated,N/C ↓
L3 Burkitt type, cytoplasmic basophilia, vacuolation
 Peripheral Blood findings: Pancytopenia or increase blast cells
 Bone Marrow: Blasts more than 20% and 30% according to WHO and FAB, respectively
 Cytochemistry: Periodic acidic Schiff (PAS) positive, TdT (Terminal Deoxy Nucleotidyl transferase)
Positive in 95% of cases
 Immunohistochemistry: CD2, 3, 5, 7,10,19,20
 Chromosomal abnormality: t (12; 21), t (9; 22) etc.
Acute Myelobloastic Leukemia (AML)
FAB classification of AML:
M0 Minimally Differentiated AML
M1 AMLWithout Differentiation
M2 AML With Differentiation
M3 Acute Promyelocytic Leukemia( Mostly DIC Occur In Patients)
M4 Acute Myelomonocytic Leukemia
M5 Acute Monocytic Leukemia
M6 Acute Erythroleukemia
M7 Acute Megakaryocytic Leukemia
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Differences b/w AML and ALL:
Features ALL AML
Age Children Adults
Hepatosplenomegaly/lymphadenopathy Prominent 50-75% cases Less common
Blasts Lymphoblast smaller Myeloblast larger
N/C ratio High Low
Chromatin Clumped Spongy sieve like
Nucleoli <2 indistinct 2-5 distinct
Auer rods Not present Present in 10-20 %
Terminal deoxynucleotidyl trasferase Often present Negative
(TdT)
Cyto chemical stain PAS + MPO, SB, Non-Specific Esterase
Immunological markers T-CD 2,3,5,7 .B-CD 19,20 CD 13,33,34
Chromosomal abnormalities Hyperdiploidy t( 9;22) Translocation t(8;21),t(15;17),
Inversion(16)
Prognosis Good Bad/ not so good
Chronic myeloid leukemia (CML):
Q. A 45-year-old female come to the OPD complaining of weakness, easy fatigability and weight loss .she also
noticed swelling in left side of the abdomen. On palpation, marked splenomegalywas observed with dragging
sensation in the abdomen. On full blood count; TLC was 300,000, platelets 400,000and peripheral smear
examination showed a predominance of myelocyte,metamyelocyte and neutrophils.
a. What is your provisional diagnosis?
b. Describe the salient features of pathophysiology of this order.
c. What other investigation would you do?
d. What transformation occurs in this disease?
e. How can we distinguish CML from Leukemoid reaction
Diagnosis:
Chronic myeloid leukemia (CML)
Pathophysiology:
 In >90% cases of CML,karyotyping reveals Philadelphia chromosome t(9;22)
 On FISH (Fluorescence in situ Hybridization), RT-PCR-BCR-ABL fusion gene which diverts synthesis of
210-kDa fusion Protein with intrinsictyrosine kinase activity
 Role of Philadelphia Chromosome in pathogenesis of CML
Genetic sequences on Chromosome 22 (BCR gene) are fused with sequences translocated from
chromosome 9 ABL gene). This fusion gene codes for an abnormal protein with Tyrosine Kinase activity.
This Tyrosine Kinase is involved in signal transduction and activates pathways within the affected cells
leading to malignant transformation. Tyrosine kinases work by transferring a phosphate group from ATP
to intracellular proteins that regulate cell division.
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Figure: Pathogenesis of CML

Laboratory Investigations:
 WBC counts increased,Platelets increased, left shift on peripheral smear, basophilia
 Bone marrow aspiration and trephine biopsy
 Hypercellular marrow predominance of myelocyte, neutrophils and increase reticulin
 Cytogenetic
 Philadelphia chromosome t (9;22) on karyotyping
 BCR-ABL fusion gene (FISH, RT-PCR)
 Leukocyte alkaline phosphatase (LAP)/NAP score
 Decrease or absent in chronic phase
Transformation of CML
 Transformation to Acute leukemia
 70% cases of CML transform to AML
 30% cases of CML transform to ALL
CML can be DistinguishedFrom Leukemoid Reaction By:
 No clinical history of infection or inflammation etc.
 The presence of significant splenomegaly
 The low LAP score
 The WBC differential
 The presence of Phi chromosome
Stages of CML:
 Chronic Phase: asymptomatic, weight loss, fatigue, and splenomegaly. Blasts are <10%
 Accelerated Phase: Marked Splenomegaly, leukocytosis, thrombocytopenia, worsening fever,
infection. Blasts 10-20% and basophils >20%, increased LAP score
 Blast Crisis: Acute leukemia, bleeding and severe constitutional symptoms like fever, malaise. Blasts
>20%
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Figure: Peripheral Smear of AML Figure: Peripheral Smear of CML

Chronic Lymphocytic Leukemia (CLL)
Q. A 70-year-old male during a visit to a physician complaining only of increased fatigue is found to have a multiple
enlarged non-tender cervical and Axillary lymph nodes along with the enlarged liver and spleen. Laboratory
Examination of peripheral blood reveals absolute lymphocytosis. Most of these Lymphocytes are mature looking
and there are smudge cells present.
b) What cell markers are expressed by the tumor cell (immunophenotype)?
c) What immune function abnormality is seen in this disorder?
d) Any transformation to more aggressive lymphoid neoplasms?
e) What is the difference between SLL and CLL
f) Give the lab diagnosis and Differential diagnosis
Diagnosis:
Chronic lymphocytic leukemia (CLL)
Immune markers
Pan B-cell markers i.e. CD19, CD20, CD23 and T-cell marker CD5
Immune function abnormality
Hypogammaglobulinemia due to failure of transformation of B- cell into plasma cell
Autoimmune hemolytic anemia (Warm or Cold Antibody) and thrombocytopenia
Transformation
Prolymphocytic leukemia (PLL)
Diffuse large B cell lymphoma (DL-BC lymphoma)(Richter syndrome)
Difference between SLL and CLL
If the peripheral blood lymphocyte count exceeds 4000 cells/microliter, thepatient is diagnosed with CLL,
if it does not;a diagnosis of SLL is made
 Complete Blood Count: Hb normal or decrease, TLC is always raised
 Peripheral smear:Smudge cells, severe lymphocytosis etc.
 Cytogenetic:11, 17 and 13q deletion
 Immunophenotype:Pan B-cell markers i.e. CD19, CD20, CD23 and T-cell marker CD5
 Serum immunoglobulin is low or normal
 Coomb's test is positive in the presence of hemolysis
Differential Diagnosis
Small lymphocytic leukemia (SLL), follicular lymphoma (FLL)
Viral infection (infectious mononucleosis, cytomegalo virus)
Prolymphocytic leukemia (PLL), ALL
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Figure: Peripheral Smear of CLL

Clinical features of acute leukemia:
Due to organ infiltration
 Bone pain
 Lymphadenopathy or Hepatosplenomegaly
Bone marrow failure
 Anemia – dyspnea, fatigue, palpitations
 Neutropenia – fever, infections
 Thrombocytopenia – bleeding from skin or mucosa
Hypermetabolic state
 Fever and Drenching night sweats
Differences between Acute and Chronic Leukemia:
Features Acute leukemia Chronic leukemia
Age All ages Usually adult
Clinical onset Sudden Insidious
Course(untreated) 6 month or less 2-6 years
Leukemic cells Immature >30% blast More mature cells
Anemia Prominent Mild
Thrombocytopenia Prominent Mild
WBC count Variable Increase
Lymphadenopathy Mild Present, often
Splenomegaly Mild Present,often prominent
Leukemoid reaction:
Definition: Extremely high leukocyte counts seen in a non- leukemic state and may be lymphoid or
granulocytic in nature.
Causes:
 Severe infections
 Malignancies with bone marrow infiltration
 Severe hemorrhage
 Lymphoid reactions seen usually in children in response to viral infections
Differentiation from Leukemia by the Following Features:
 Presence of an appropriate underlying condition
 Morphology of white blood cells: reactive e.g. toxic changes vs. neoplastic
 No evidence of bone marrow failure (anemia or thrombocytopenia)
 High LAP score in granulocytic reactions
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Leukocyte Alkaline Phosphatase (LAP) Test:

 This is a semi quantitative assessment of the level of functional alkaline phosphatase in the cytoplasm
of neutrophils
 It is used to differentiate between CML and Leukemoid reaction
Method: Film is made from freshly collected blood, and immediately fixed
Incubate in a phosphate solution, then rinse and counterstain
Interpretation: assess the number and intensity of blue cytoplasmic granules in 100 cells
For each cell score 0-4. Maximum score is 400. Normal 35 -100
0: No stained granules
1: few granules
2: moderate staining
3: Numerous granules, strongly positive
4: Numerous intensely stained granules
Myeloproliferative Disease
Definition: These are a group of chronic marrow diseases, which have the hyperplasia of cellular and or
stromal bone marrow components causing increase in RBCs, Platelets or WBCs. They are classified based
on the nature of the predominant proliferating cell line:
 Primary polycythemiaVera (Erythroid)
 Essential thrombocythemia (megakaryocytic)
 Chronic myeloid leukemia (granulocytes)
 Primary myelofibrosis (fibrous tissue)
Clinical features:
 Non-specific features common to all, due to a Hypermetabolic state
 Fever, weight loss and drenching night sweats
 Splenomegaly: most prominent in MF and CML
 Specific features such as bleeding or thrombosis in PRV and ET
 All may be incidentally discovered on routine physical or laboratory tests
Diagnosis:
 Exclude a secondary or reactive state that can mimic the primary disorder. There are four such
reactive conditions
 Secondary polycythemia (vs. PRV)
 Reactive thrombocytosis (vs. ET)
 Leukemoid reaction (vs. CML)
 Secondary myelofibrosis (vs. MF)
Identify the specific MPD by the presence of diagnostic criteria e.g.
 Increased red cell mass or packed cell volume
 Platelet count above 600x 109 /l
 Philadelphia chromosome
 Bone marrow fibrosis > 1/3
Multiple myeloma:
Q.A 60 years old female complaining of aches and pains, on blood Cp showsNormocytic,normochromic anemia.Hb
8 gm/dl, ESR 110 mm at the end of One hour. The peripheral blood smear also showsrouleux formation. The X- Ray
spine show lytic lesions.
a) What is your provisional diagnosis?
b) Write the salient feature of etiology and pathophysiology of the above disease.
c) Write the complication of this disease
d) What investigation would you do to confirm the diagnosis
Diagnosis:Multiple myeloma(MM)-diagnosis requires at least 2 of the following;
 Monoclonal IgG or light chain in blood/urine
 Osteolytic bone lesion
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 Bone marrow plasmocytosis>10 %
Etiology:
 Radiation exposure Key Point:
 Exposure to petrochemical product It is rare under 40 years of Age
 Farmers, wood and leather workers are more prone
Pathophysiology:
 The Ig genes in myeloma cells always show evidence of somatic hypermutations
 Osteolytic lesions are caused by osteoclastic activation resulting from highserum RANK L(receptor
activation of NF-ҡB) produced by plasma cells and bone marrow stroma which binds to activating
RANK receptors on the osteoclast surface. When this receptors binds to RANK L, osteoclastogenesis is
initiated
 The action of RANK L,can be blocked by osteoprotegrin that act as a decay receptors that bind to
RANK L,thus preventing interaction of RANK with RANK L, therefore inhibit osteoclastogenesis
 The proliferation andsurvival of myeloma cells are dependent on several cytokines most notably IL-
1,6and TNF.it is produced by neoplastic plasma cells and normal stromal cells in the bone marrow
 Factors produced by neoplastic plasma cells also mediate bone destruction
 Cytokines produced by tumor cells, particularly MIPα receptorsactivation of NF-ҡB legend, RANK L
serve as osteoclast activating factor.
 Dysregulation of D cyclins is a common feature
 The other most frequent karyotypic abnormalities are deletions of 13q
 Common translocation partners include FGFR3 (fibroblast growth factor receptor 3) on chromosome
4p16
Complication:
 Bone pain and Hypercalcemia due to increased osteoclastic activity and microfractures
 Anemia due to crowding of bone marrow by proliferating plasma cells
 Renal insufficiency resulting from Bence jones protein or amyloidosis
 Susceptibility to infection due to Hypogammaglobulinemia because normalIg synthesis is suppressed
LaboratoryInvestigationof multiple myeloma:
 Complete Blood Count: Decrease Hb, decrease TLC, decrease platelets and increase ESR
 Peripheral smear: Rouleux formation
 Bone Marrow Aspiration And TrephineBiopsy: Increase plasma cells, multinucleated plasma Cells,
flamecells, Mottle cells, Russel bodies(globular inclusion in cytoplasm of plasma Cells),
Ductcherbodies(globular inclusion in nucleus of plasma cells)
 Radiological finding: show Lytic lesion on CT and X ray bone
 Plasma electrophoresis: monoclonal elevation of IgG(60%)or IgA(M band)
 Urine electrophoresis: free light chain to be excreted in urine and these light chain are excreted in
urine called Bence jones protein
 Renal Function Test: Urea andCreatinine raised
 SERUM calcium and uric acid raised
 Total protein increase, albumin decrease, globulin markedly increased
 SERUM B2 microglobulin: high level indicate poor prognosis
Morphological changes in kidney in multiple myeloma
 Myeloma nephrosis is associated with proteinaceous casts in DCT
 Multinucleated giant cells surround the casts
 Epithelial cells adjacent to the casts may become atrophic
 Metastatic calcification
 Light chain amyloidosis
 Bacterial pyelonephritis
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Clinical features(CRAB) of multiple myeloma
 C = Calcium (elevated)
 R = Renal failure
 A = Anemia
 B = Bone lesions
Difference between Myeloma Cell and Plasma Cell:
Plasma cells have Eccentric Nuclei with Cartwheel appearance
Myeloma cell have no Cartwheel appearance and contain Russel bodies and Ductcher bodies
Figure: Peripheral Smear of Multiple Myeloma

Myelofibrosis (MF):
Q.A 60 year old male with complaints of weight loss, anorexia, fever, fatigability and with abdominal discomfort
presents in the OPD. Blood CP shows a leucoerythoblastic blood Picture with “tear drop” poikilocytes.
a. What is the provisional diagnosis?
b. Write the salient features of pathogenesis.
c. What is the main complication?
d. What investigations are required for confirmation of the diagnosis?
Diagnosis:
Myelofibrosis with myeloid metaplasia/idiopathic myelofibrosis
Pathogenesis of Myelofibrosis
 Myelofibrosis –a clonal stem cell disease
 Hyperplasia of abnormal megakaryocytes
 Marrow fibrosis is characteristics secondary to platelets derived growth factor (PDGF) and
Transforming growth factor B (TGF B) released from neoplastic megakaryocytes Stimulate marrow
fibroblastic proliferation –mitogenic for fibroblast
 Due to fibrotic marrow, hematopoiesis shifts to extramedullary, sites tends to beDisordered and
ineffective, together with marrow fibrosis leading to anemia and Thrombocytopenia
Complication
 Transformation to AML
 Infections, thromboticandhemorrhagic episodes
Investigation
 Bone marrow aspiration –dry tap
 Bone marrow trephine biopsy-fibrotic hypocellular marrow, increased megakaryocytes, reticulin stain
 JAK 2 kinase mutation
 NAP increased
 Philadelphia chromosome absent
 S.urate and LDH increased
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Myelodysplastic Syndromes (MDS)

Definition: Heterogenous group of clonal disorders characterized by:
 Peripheral blood cytopenias with normal or increased marrow cellularity
 Morphological and functional abnormalities
 Peak incidence in the elderly
Causes
 Most are idiopathic
 Exposure to alkylating agents
 Ionizing radiation
Clinical features
 Anemia
 Recurrent infections
 Abnormal bleeding
Dysplastic changes in peripheral blood or marrow
 Macrocytic anemia
 Megaloblastoid erythropoiesis
 Agranular neutrophils
 Ringed sideroblasts
 monocytosis
Outcome
 Outcome is variable; 25-45% transform to AML
Bleeding disorders:
Idiopathic /Immunologic Thrombocytopenic Purpura:
 Immunologic thrombocytopeniais dividedbased on the pathologic mechanism, the inciting agent, and
the duration of the illness. Accordingly, they are classified as acute and chronic.
Acute ITP:
 Usually follows viral upper respiratory infection common in children aged 2-6 years (accounts for 90%
of pediatric cases)
 60% recovers in 4 to 6 week and >90% recover within 3 to 6 months.
Chronic ITP:
 It is common in adults and run a more indolent course.
 Women age 20 – 40 are afflicted most commonly and outnumber men by a ratio of 3:1.
 It presents acutely or more often with prior history of easy bruising and mennometrorhagia.
 There is immune mediated platelet destruction as well as functional platelet dysfunction.
Investigation
 Platelet count, complete blood count, serology for HIV, screening for SLE
 Bone marrow aspirate to look for reactive thrombocytosis ( increased megakaryocytes)
 Ultrasonography of the abdomen to look for splenomegaly
Coagulation Disorders (Secondary Hemostatic Disorders):
1. Hemophilia A
2. Hemophilia B (Factor IX deficiency)
3. Von-Willi brand’s disease
Hemophilia A (hemophilia)
Definition:
X linked recessive bleeding disorder caused by reduction in factor VIII activity,commonest hereditary
disorder, but 33% may not have family history and results from spontaneous mutations.
Defect: Absence or low level of plasma factor VIII
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Clinical feature
 Profuse post circumcision hemorrhage in infants;
 Recurrent painful hemarthroses and muscle hematomas
 Spontaneous intracerebral hemorrhage is important cause of death
 Transfusion related disorders: Hepatitis (HBV, HCV) and HIV infection are frequent
 Complications of repeated Coagulation factor transfusions
Complications:
 Massive hemorrhage after trauma
 Spontaneous bleeding
 Hemarthrosis (bleeding in joints)
 Prolonged PTT
Investigations:
 Activated partial Thromboplastin time (aPTT) is prolonged
 Normal bleeding time, platelets counts and PT
 Decrease factor VIII:C while normal factor VII:vWF
 Factor VIII clotting assay
Von Willi brand’s disease
 Has both functional platelet abnormality (abnormal platelet adhesion) and low factor VIII activity
 Inheritance is autosomal dominant with variable degree of penetrance.
 Defect is reduced synthesis of VWF, which facilitates platelet aggregation, and carrierof factor VIII
(protecting it from premature destruction).
Comparison between Different Coagulation Disorders:
Features Hemophilia Factor IX deficiency VonWilli brands
disease
Inheritance Sex linked recessive Sex linked recessive Autosomal dominant
Site of bleeding Body cavities, joint Body cavities, joint and Both mucocutaneous
and intramuscular intramuscular spaces and other sites
spaces
Platelet count Normal Normal Normal
Bleeding time Normal Normal Prolonged
Prothrombin tine (PT) Normal Normal Normal
Activated Prolonged Prolonged Prolonged
PartialThromboplastin
time(aPTT)
VIII Low Normal Low
VWF Normal Normal Low
Factor Normal Low Normal
Disseminated Intravascular Coagulation (DIC):
Definition: -DIC is an acute or chronic thrombohemorrhagic disorder occurring because of progressive
activation of coagulation pathway beyond physiologic set point secondary to a variety of diseases
resulting in failure of all components of hemostasis. Hence, the other term for DIC is consumption
coagulopathy.
Etiology andPathogenesis:
 It must be emphasized that DIC is not a primary disease. A coagulopathy occurs in the course of
variety of clinical conditions. DIC follows massive or prolonged release of soluble tissue factors and
/or endothelial-derived Thromboplastin into the circulation with generalized (pathologic) activation
of coagulation system.
 Therefore, DIC results from pathologic activation of the extrinsic and/or intrinsic pathways of
coagulation or impairment of clot inhibiting influences by different causes. Two major mechanisms
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activating the coagulation pathway to cause DIC are: (1) release of tissue factor or thromboplastic
substance into the circulation (2) widespread injury to the endothelial cells.
Tissue Thromboplastin substance may be derived from a variety of sources such as:
 Massive trauma, severe burns and extensive surgery. The major mechanism of DIC isbelieved to be
auto infusion of Thromboplastin from the tissues
 Obstetric conditions in which Thromboplastin derived from the placenta, dead retained fetus, or
amniotic fluid may enter the circulation
 Cancers such as acute promyelocytic leukemia, adenocarcinoma of the lung in which a variety of
Thromboplastin substances like mucus are released which directly activate factor X, VII, and
proteolytic enzymes
 Gram negative sepsis (an important cause of DIC) in which bacterial endotoxins cause increased
synthesis, membrane exposure, and release of tissue factor from monocytes. Furthermore, activated
monocytes release intereukin-1 (IL-I), TNF-α, both of which:
 Increase expression of tissue factor in endothelial membrane
 Decrease expression of thrombmodulin which is a potent activator of protein C- an anti-
coagulant
 TNF-α, an extremely important mediator of septic shock, in addition to the above, up regulates
the expression of adhesion molecules on endothelial cells and favors adhesion of leukocytes,
with subsequent damage of endothelial cells by free radicals and preformed proteases
Endothelial injury: Widespread endothelial injury may result from:
 Deposition of antigen-antibody complexes as it occurs in systemic lupus erythematous
 Extreme temperature e.g. Heat stroke, burns
 Hypoxia, acidosis, shock
Clinical Features:
Few clinical presentations include
 Microangiopathic hemolytic anemia
 Dyspnea
 Cyanosis
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Essential
Essential Special
Special Pathology
Chapter
Hematopoietic and
Hematopoietic and
Lymphoid System
Lymphoid System
 Respiratory failure
 Convulsions and coma
 Oliguria and acute renal failure
 Sudden or progressive circulatory failure andShock
 Complete Blood Count: Anemia, thrombocytopenia
 Peripheral smear: fragmented RBCs, thrombocytopenia
 Bleeding time: prolonged
 PT: prolonged
 APTT: prolonged
 Fibrinogen levels: reduced
 FDPs: raised
 D-dimers raised (more specific as compared to FDPs)
Clinical Disorders of Splenomegaly
Massive Splenomegaly Moderate Splenomegaly Mild Splenomegaly
Chronic Myeloid Leukemia Chronic Congestive Splenomegaly Acute Splenitis
Chronic Lymphocytic Leukemia Acute Leukemia Acute Splenic Congestion
Hairy Cell Leukemia Hereditary Spherocytosis Infectious Mononucleosis
Lymphoma Thalassemia Acute Febrile Disorders
Malaria Autoimmune Hemolytic Leukemia Septicemia
Gaucher Disease Amyloidosis, TB
Primary Tumor Of Spleen NiemenPick Disease
Thrombocytopenia:
Definition:
Thrombocytopenia is a blood disease characterized by an abnormally low number of platelets in the blood
stream .The normal amount of platelets is usually between 150,000 and 450,000 cells/µl of blood .When
the platelet number drop below 150,000 cells per microliter of blood this person is said to be
thrombocytopenic.
Mechanism of Thrombocytopenia
 Decreased production of platelets (e.g., aplastic anemia, leukemias, VitaminB12and Folate deficiency)
 Decreased platelet survival (e.g., due to immunologic and nonimmunologic destruction)
 Increased splenic sequestration (e.g., hypersplenism syndrome, but also in any splenomegaly)
 Dilutional (e.g., massive transfusions may produce a dilutional thrombocytopenia)
Level of thrombocytopenia
 Greater than 100,000/mm = thrombocytopenia (laboratory finding—usually asymptomatic)
3
 20,000 to 50,000/mm3= posttraumatic bleeding

 Less than 20,000/mm3= spontaneous bleeding
65
Chapter Four LUNG
Pulmonary Infections
Pneumonia
Definition:
Pneumonia is an acute inflammation of lung parenchyma resulting from infection of alveoli and
respiratory bronchioles. It is characterized pathologically by consolidation of lung parenchyma and
clinically by fever, cough, and dyspnea and chest pain.
Pathogenesis of Pneumonia:
 Micro Aspiration of oropharyngeal contents
 Inhalation of aerosol droplets ranging from 0.5-1 µm
 Blood stream infection
Classification of Pneumonia:
1. Community acquired acute pneumonia:
 Commonest cause: Streptococcus  Staphylococcus Aureus
Pneumoniae or Pneumococcal  Legionella Pneumophila
Pneumonia  Enterobacteriaceae
 H. influenza
 Moraxella Catarrhalis
2. Community acquired atypical pneumonia
 Mycoplasma pneumoniae  Influenza virus
 Chlamydia  Respiratory syncytial virus
 Coxiella Burnetti  Adenovirus
3. Nosocomial pneumonia:
 Gram negative rods  Pseudomonas
 Enterobacteriaceae (Klebsiella,  S. aureus
Serratia, E. coli)
4. Aspiration pneumonia:
Anaerobes oral flora (Bacteroides, Provetella) Admixed with aerobes
5. Chronic pneumonia:
 Nocardia  Histoplasma
 Actinomyces  Coccidioides immitis
 Mycobacterium
6. Necrotizing pneumonia and lung abscess:
 S. Aureus  Pseudomonas
 Strep. Pyogenes  Anaerobes (Prevotella, Bacteroides,)
 K.Pneumoniae  Type 3 pneumococcus
7. Pneumonia in the compromised host:
 Cytomegalovirus  Invasive Aspergilosis
 Pneumocystitis Jiroveci  Invasive candidiasis
 M. Avium intracellulare
Brief description of Different Pneumonias
Community acquired acute pneumonia:
Community acquired pneumonia can have typical or atypical presentation. This classification is less
distinct but it may have diagnostic value. More commonly, patients have “typical” presentation and
‘’Streptococcus Pneumoniae’’is the most common cause. However, other organisms like H. influenza and
oral flora can be causes. Pneumoniais often preceded by a URTI(Upper respiratory tract infection)
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Lung
The “typical” Community acquired pneumonia is characterized by:

 Sudden onset with a single shaking chills. This is followed by high grade fever (upto 40 C)
0
 Cough is productive with purulent, blood streaked or rusty sputum

 Pleurtic chest pain on the involved side is worsened during inspiration and coughing
 Dyspnea (shortness of Breath)
 Headache,myalgia, arthralgia and fatigue etc.
The “atypical” pneumonia present with:
 Atypical” pneumonia is usually caused by M. pneumoniae, K.pneumoniae, oral anaerobes and P.
Carinii (usually in HIV patients), as well as S. Pneumoniae. Some viruses like influenza virus, Varicella
zoster virus and cytomegalovirus may cause “atypical” pneumonia. Tuberculosismay also be present
in this form
 More gradual onset of symptoms, dry cough, shortness of breath
 Prominence of systemic symptoms like headache, malaise, fatigue, nausea, vomiting and diarrhea
 Chest findings on physical examination are minimal even though X-ray changes are marked.
Complications:
 Local: Para pneumonic effusion or pus in the pleural space (empyema)
 Distant complications: include septic arthritis and meningitis. Pneumonia can progress to sepsis,
sometimes with septic shock.
Laboratory findings:
 CBC: leukocytosis with increased neutrophils is seen in most cases
 Gram stains from sputum may show a predominant pathogen like Gram-positive diplococcic
 Chest x-ray shows pulmonary infiltrates or homogeneous opacity indicating lobar pneumonia. Very
early in the course, it may be normal
Aspiration pneumonia:
This occurs when large amount of Oro-pharyngeal or gastric contents are aspirated into the lower
respiratory tract. Aspiration occurs more frequently in patients with:
 Decreased level of consciousness (alcoholism, seizure, strokes or general anesthesia)
 Neurologic dysfunction of oropharynx and swallowing disorders
 People with periodontal disease are affected more
Common Etiologic agents of Aspiration pneumonia are often polymicrobial
 Anaerobic organisms in the oral cavity
 Enterobacteriaceae
 S. Pneumoniae
 S. Aureus
Patients present with cough and foul smelling sputum. The cough may be chronic forming lung abscess
and may resemble TB. There will be signs of cavity on physical exam and CXR. It is treated with crystalline
penicillin and metronidazole IV for several weeks if lung abscess develops.
Community acquired Pneumonia in Immunocompromised hosts:
Immunocompromised hosts such as transplant recipients, HIV infected patients, and patients on
Chemotherapy etc. are prone to develop pneumonia. The etiologic agents are
 Common bacterial causes of CAP: Strep. Pneumoniae, H.influenzae, Mycoplasma
 Gram-negative organisms: Enterobacteriaceae
 Fungi such as Pneumocystis Carinii (Jiroveci), C. neoformans, Histoplasmosis, Aspergillus
 Mycobacterium tuberculosis
 Viruses : HSV, CMV
Hospital-acquired pneumonia:
 A patient is said to have hospital-acquired pneumonia if the symptoms begin 48 hours after hospital
admission and not incubating at the time of admission. Common organisms that cause hospital-
acquired pneumonia are:
 Gram-negative bacilli including Pseudomonas aeroginosa, K.pneumoniae
 Staphylococcus aureus andOral anaerobes
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Essential Special
Essential Pathology
Special Pathology Chapter
Chapter 4:4:
Lung
Lobar Pneumonia:
Morphology and microscopy of lobar pneumonia:
 Stage of Congestion:Vascular congestion, scattered neutrophils
 Stage of Red Hepatization:Lung lobe has liver like consistency
 Stage of Gray Hepatization:The lung is dry, gray, and firm because the red cells arelysed
 Stage of Resolution:Exudates within the alveoli are enzymatically digested
Fate: resolution
Note: Lobar pneumonia are mostly caused by Pneumococci
Lung abscess:
Definition:
Lung abscess is defined as collection of pus within a destroyed portion of the Lung. It may develop
following necrotizing infections of the lung (bacterial pneumonia, TB, fungal infection),loss of blood supply
to a part of the lung causing cavitary infarction due to septic or bland embolism, obstruction to airways or
cavitations of malignancy. The anaerobic abscess is the commonest and usually follows periodontal
diseases (gingivitis, pyorrhea) or aspiration of oropharyngeal/gastric contents.
Etiology:
 Pyogenic bacteria like Staph. Aureus, Klebsiella pneumoniae, Pseudomonas, mixed anaerobes, and
Nocardia commonly cause lung abscess
 Common risk factors include alcoholism, immunodeficiency, loss of consciousness and periodontal
diseases
Clinical features:
 In the early stage, manifestations of lung abscess may resemble that of pneumonia
 Lung abscess develops after 1-2 week of bacterial Pneumonia which may cause aspiration or
bronchial obstruction
 Patients will have cough with sudden expectoration of massive purulent and foul smelling sputum,
high-grade fever, and sweating with occasional hemoptysis
Diagnosis:
 It should be confirmed by chest x-ray by demonstrating parenchymal infiltrates with cavity containing
‘’air-fluid level’’. Gram stain and culture of the sputum help to make etiologic diagnosis
Complications:
 Metastatic brain abscess  Pneumothorax
 Fatal hemoptysis  Bronchopleural fistulas
 Empyema  Meningitis
 Secondary amyloidosis  Septic embolism
Tuberculosis
 It is a communicable chronic granulomatous disease caused by mycobacterium Tuberculosis.
 It usually affects the lungs but may involve any organ or tissue in the body.
Etiology
Acid-fast bacilli causing T.B. namely are:
 Mycobacterium tuberculosis
 Mycobacterium Bovis
Predisposing factors
 Poverty
 Overcrowding
 Chronic debilitating illness
 Old age
 Poor housing with poor ventilation
 Malnutrition
 Alcoholism
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Lung
Primary Tuberculosis
It is a form of T.B that develops in previously unexposed and therefore un-sensitized persons. The source
of organisms is exoganisms i.e. Mycobacterium tuberculosis..
Pathogenesis:
Morphology
Gross Examination:
 After inhalation, the mycobacteria implant in the distal air spaces of the lower part of the upper lobe
or the upper part of the lower lobe, usually close to the pleura.
 At implantation site, a 1-1.5 cm area of grey –white inflammatory consolidation emerges called
‘’Ghon Focus’’. It is a chronic granulomatous tuberculotic lung parenchyma inflammatory lesion.
Ghon Complex: it is the tuberculotic lung parenchyma and the draining Hilar lymph nodes together.
Microscopically:
 At the active site of involvement, there are both non-caseating(hard) and caseating(soft) tubercles.
 Soft Tubercle: appear as
 Central caseation
 Epithelioid cells derived from macrophages (Langhan type of giant cells) surrounding collar of
lymphocytes with few plasma cells, enclosing rim of fibroblasts and connective tissue
Figure: Tubercular Granuloma
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Lung
Secondary Tuberculosis
It is form of T.B. that arises in a previously sensitized host, it is caused by:
 Reactivation of dormant primary lesions especially in those with weakened host defenses
 Exogenous reinfection because of large inoculum of virulent bacilli
Morphology:
Gross Examination
 Mostly found within 1-2 cm of apical pleura where oxygen tension is high
 Firm, grey-white to yellow areas of consolidation with formation of tubercles, variable central
caseation and peripheral fibrous induration
 Regional lymph nodes are less prominently involved early in the developing disease than they are in
primary T.B.
Microscopically
 At the site of lesions, there are coalescent tubercles with central caseation.
Clinical Features
Patient may present with
 Fever (low-grade,remittent, appear late each afternoon and then subside)
 Night sweats
 Malaise, anorexia and fever
 Cough
 Pleurtic pain
Complications:
 Hemoptysis
 Military T.B
 Tuberculosis bronchopneumonia
 Cavitation of lungs
 Scarring of lungs
 Obliterative fibrous pleurities
 Secondary amyloidosis
 Blood Examination
 ESR is increased
 TLC increase in miliary T.B lymphocytes
 Sputum Examination
 Sputum Culture
 Chest X-ray shows
 Patchy consolidation in the post apical region
 Lung cavitation
 Areas of increased density suggesting caseation
 Scar tissue produce sharp margins and tends to contract
 Hilar lymphadenopathy
 Unilateral pleural effusion
 Millary spread may be evident
 Fibreoptic Bronchoscopy
 Biopsies of Pleura, Lymph Nodes and Lung Lesions
 Montoux (Tuberculin test)
 Serodiagnosis(Recently PCR and ELISA are also in use to diagnose tuberculosis)
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Lung
Q. Following bone marrow transplantation, a patient develops high-grade fever with chills; chest X-ray shows
pulmonary infiltrates.
a) List three major causes of pulmonary infiltrates in such patients with two examples for each.
b) What pulmonary infections are likely to occur in an AIDS patient at CD4+ count> 200 cells/mm3?
 Virus: cytomegalovirus
 Bacteria: gram negative bacteriaand S. aureus
 Fungi: Cryptococcus, Pneumocystitis, Aspergillus
 Drug reactions
 Malignancy
 Pulmonary Infection in AIDS Patients:
 200: bacterial + tubercular infections
 < 200: Pneumocystitis pneumonia
 <50: M. Avium + Cytomegalovirus
Chronic Obstructive Pulmonary Diseases (COPD)
Definition:
Chronic obstructive pulmonary diseases are conditions characterized by chronic irreversible airway
obstruction causing an increased resistance to outflow of air due to chronic bronchitis and emphysema.
Both these diseases occur together in the same individual in a variable proportion but the manifestations
of one often predominates the clinical picture.
 Pulmonary Emphysema
 Chronic bronchitis
 Asthma
 Bronchiectasis
Pulmonary emphysema:
 Pulmonary emphysema: is distension of the airspaces distal to the terminal bronchioles,
accompanied by destructive changes of the alveolar septa.
Types:
 Centriacinar (Centrilobular) emphysema: Common type, involve proximal acini
 Panacinar (panlobular) emphysema: Uniformly enlarged acini from the level of respiratory
bronchioles, alveolar duct to alveoli
 Distal acinar emphysema: Distal part is involved, this type is the common cause of spontaneous
pneumothorax in young adults
 Irregular emphysema: Involvement is irregular, seen surrounding scars due to any cause, usually
asymptomatic
Pathogenesis of Emphysema
 Smoking: → reactive oxygen species (free radicals) → inactivation of antiproteases (functional alpha-1
AT deficiency → neutrophil elastase increases → tissue damage → emphysema
 Congenital alpha-1 antitrypsin deficiency → increases neutrophil elastase → tissue damage →
emphysema
 Protease-Antiproteases Imbalance
 Oxidant-Antioxidants Imbalance
Morphology of emphysema:
Gross:
 Pale and voluminous lungs in ‘’Panacinar emphysema’’
 Deeper pink and less voluminous in ‘‘Centriacinar emphysema’’
Microscopically:
 Enlarged air spaced due to destruction of alveolar wall without fibrosis
 Loss of elastic tissue in alveolar septa >causing smaller airway collapse duringexpiration
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Lung
Differences b/w Panacinar and Centriacinar emphysema:
Centriacinar Panacinar
Most commonly seen in smokers Associated with alpha-1 antitrypsin deficiency
Apical segments involve Lower lobe is effected
Distal alveoli are spared Involves uniformly all levels
Acquired Genetic or acquired
Chronic bronchitis
Definition:
A chronic obstructive pulmonary diseaseis said to be present when there is a persistent productive cough
for at least three consecutive months in at least two consecutive years.
Types:
 Simple chronic bronchitis
 Chronic mucopurulent bronchitis
 Chronic obstructive bronchitis
 Chronic asthmatic bronchitis
Etiology
 Smoking most important
 Air pollutant such as Sulphur dioxide and nitrogen dioxide
Pathogenesis of Chronic Bronchitis:
Hypersecretion of mucus secreting glands
Cause:
 Most important cause is smoking. Air pollutants like sulfur dioxide or nitrogen dioxide
 Hypertrophy of mucous glands
 Increase in number of goblet cells in surface epithelium of smaller bronchi and bronchioles
 Inflammation with infiltration of CD+8 Lymphocytes, Macrophages and Neutrophils
NOTE:No eosinophil is present except in Asthma)
 Peripheral airflow obstruction is due to either ‘’small airway disease (chronic bronchiolitis) or co-
existent emphysema
 Tobacco smoke causes increase in ‘Transcription of mucin gene (MUC5AC) and production of
neutrophil elastase
 Local mucus hyper secretion is mediated by cytokine (IL-13)
Morphology of Chronic Bronchitis
Gross:
 Mucosal lining is Hyperemic and swollen
 Mucosal lining is often covered by mucinous or mucopurulent secretions
Microscopic:
 Enlargement of mucus secreting glands
 The magnitude of increase in size is assessed by ‘’Reid index= thickness of sub mucosal
layer/thickness of bronchial wall” (normal value=0.4)
 Inflammatory cells are largely mononuclear
 Chronic bronchiolitis characterized by goblet cell metaplasia, mucous plugging, inflammation and
fibrosis.In severe cases, complete obstruction of lumen occurs due to fibrosis which is known as
‘’bronchiolitis Obliterans”
 Changes of emphysema co-exist
. Reid index:
A ratio between the thickness of sub mucosal mucous secreting glands and that of the bronchial wall
Calculation: RI= gland/wall. Normal value: less than 0.4
Clinical features:
 A mild "smoker's cough" is often present many years before onset of exertional dyspnea. Gradual
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Lung
progressive exertional dyspnea is the most common presenting complaint.
 Cough, wheezing, recurrent respiratory infections, occasionally weakness, weight loss, or reduced
libido may also be initial manifestations.
Complication:
 Bronchopneumonia
 Bronchiectasis
 Cor pulmonale
Differences between chronic bronchitis and emphysema
Character Chronic bronchitis Emphysema
Age(year) 40-45 years 60-75
Dyspnea Mild ,late Severe, early
Cough Early, copious sputum Late, scanty
Infection Common Occasional
Respiratory insufficiency Repeated Terminal
Cor pulmonale Common Rare, terminal
Air way resistance Increased Normal, slight increase
Elastic recoil Normal Low
Chest radiography Prominent vessel, large heart Hyperinflation, small heart
Appearance Blue Pink
Asthma:
Definition:
Asthmais characterized by episodic, reversible bronchospasm resulting from an exaggerated
brochoconstrictor response to various stimuli. Clinically it presents with dyspnea, chest tightness and
wheezing)
Types:
 Extrinsic or atopic asthma
 Intrinsic or nonspecific asthma
Comparison of the two major types of asthma:
Character Allergic (atopic) asthma Non allergic (idiosyncratic)
Age of onset Early in life Late in life
Family or personal history of Present Absent
allergy: rhinitis, utricaria
Skin test with intradermal Positive wheal and flare skin test Negative skin test
injection of allergens
Serum IgE level Elevated Normal
Response to inhalation of Positive Negative
provocation test
Pathogenesis of asthma:
Type I hypersensitivity reaction with exposure to extrinsic allergens
Initial sensitization to an inhaled allergen:
 Stimulate induction of subtype 2 helper T cell that release IL-4, IL-5 andIL-13
 IL-4 stimulates IgE production
 IL-5 stimulates eosinophil
 IL-13 (induces mucous and IgE production)
Re-exposure of Inhaled Antigen Cross-Links IgE Antibodies: On mast cells present on mucosal surfaces
 Release of histamine and other preformed mediators
 Functions of these mediators Stimulate bronchoconstriction, mucous production and leukocytes
influx
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Lung
Late phase: (4-8 hours later):
 Exotoxin is produced
 Chemotactic for eosinophil and activates eosinophil
 Eosinophil release major basic protein and cationic proteins damage epithelial cells and produce
airway obstructions
Chemical mediators:
 1 group (putative): IL, leukotriene’s C4, D4, E4 and acetylcholine
st
 2 group: histamines, PG-D2, PAF (Platelets activating factor)

nd
 3 group: IL-1, IL-6 and TNF

rd
Morphology of asthma:
Gross:
Occlusion of bronchi and bronchioles by thick, tenacious mucus plug
Microscopy:
Histological changes in bronchi:
 Thickening of the basement membrane
 Edema and mixed inflammatory infiltrate
 Hypertrophy of sub mucosal glands
 Hypertrophy/ hyperplasia of smooth muscles cells
Histological changes in the terminal bronchioles:
 Formation of spiral shaped mucous plugs
 Contains sheded epithelial cells called Curshmann spirals
 Pathologic effect of major basic protein and cationic protein
 Crystalline granules in eosinophils coalesce to form Charcot Leyden crystals.
 Patchy loss of epithelial cells, goblet cells metaplasia
 Increase thickness of basement membrane
Investigations of asthma:
 Oxygen saturation – <93% indicates hypoxia
 Peak flow rate (PFR) – ideally should be compared to patient’s personal best measured at time when
patient is asymptomatic. If personal best is not known PFR should be compared to predict PFR by age
and weight. If >80% obstruction is minimal, if 50-80% obstructions is moderate, if < 50% obstruction
is severe. In asthma, PFR should improve by 15% after dose of beta agonist.
 Chest X-ray – typically will show hyperexpansion with flattening of the diaphragms and clear lungs.
Streaky atelectasis often also present
 HIV test
 Sputum for culture and sensitivity – if fever and sputum
 Sputum for Acid Fast Bacilli(AFB x 3 months) – if productive cough > 2wk with fever, night sweats or
weight loss
 Methacholine Exacerbation Test
Complications:
 Airway infection
 Pneumothorax
 Cor pulmonale
Bronchiectasis:
Definition:
“Bronchiectasis is the abnormal and irreversible dilatation of bronchi and bronchioles due to destruction
of their muscles and elastic supporting tissue”
It results from chronic necrotizing infections of bronchi and bronchioles.
Morphology of bronchiectasis:
 Bronchiectasis usually involves lower lobes with visceral passages
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Lung
 Airways may be dilated four time their normal size and can be traced on lung surface
 Bronchi may dilate in fusiform or Saccular pattern
 Dilatation may produce a cystic pattern on the cut surface of the lung
Microscopically:
 There is an intense inflammatory exudate within the walls of the bronchi and bronchioles
 Pseudo stratification of columnar epithelium and squamous metaplasia of the remaining Epithelium
are commonly seen
 Lung abscess, fibrosis and scarring are other commonly found features
Pathogenesis of Bronchiectasis:
 Cystic fibrosis, bronchial obstruction and infection due to abnormally thick mucous which plug the
smaller Bronchi
 Infections: T.B, adenovirus, Staphylococcus Aureus, H. influenza
 Bronchial obstructions: proximally located bronchogenic carcinoma occludes lumen.
 Primary Ciliary dyskinesia (Kartagener’s syndrome):
 Absent dynein arm in cilia
 Dynein arm contain ATPase for movement of the cilia
 Allergic bronchopulmonary Aspergilosis
Restrictive lung disease
 Fibrosing Disease: Pneumoconiosis, Idiopathic Pulmonary Fibrosis
 Granulomatous: Sarcoidosis, Hypersensitivity Pneumonitis
 Eosinophilia
 Smoking Related.
 Other: Pulmonary Alveolar Proteinosis
Sarcoidosis:
Definition:
It is a multisystem disease of unknown etiology characterized by non-caseating granuloma in many tissues
and organs.
Morphology
Microscopically
 Non-caseating granuloma present in sarcoidosis irrespective of the organ involved.
 Compact collection of epithelioid cells rimmed by an outer zone of largely CD4+ T cells.
 The epithelioid cells are derived from macrophages and are characterized by abundant eosinophilic
cytoplasm and vesicular nuclei.
 Schaumann bodies, laminated concretion composed of calcium and proteins
 Asteroid bodies, stellate inclusion within giant cells. Their presence is not required for diagnosis of
sarcoidosis
Etiology and Pathogenesis
 Etiology remains unknown, several lines of evidence suggest that it is a disease of disorder immune
regulation in genetically predisposed persons exposed to certain environmental agents.
 Immune disorders/abnormalities driven by CD4+ T cells in the lung that secrete TH-1 dependent
cytokines such as IFN and IL2 locally
 Polyclonal Hypogammaglobulinemia, another manifestation of TH cell Dysreglation
 Genetic predisposition class I HLA-AI and HLA-B8
Clinical features
Pulmonary manifestation:
 Patient may be asymptomatic and first time diagnosed when routine chest X ray is performed that
show bilateral Hilar lymphadenopathy and paratracheal lymphadenopathy
 Localization to the lungs is by far the most common manifestation of sarcoidosis. Overall, about 50%
develop permanent pulmonary abnormalities, and 5 to 15% have progressive fibrosis of the
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Lung
lung parenchyma. Sarcoidosis of the lung is primarily an interstitial lung disease. In which the
inflammatory process involves the alveoli, small bronchi and small blood vessels
Extra pulmonary manifestation:
Lymph nodes
 Hilar, paratracheal, mediastinal, cervical, axillary, inguinal and mesenteric lymph nodes are enlarged
Skin lesions
 Sarcoidosis involves the skin in between 9 and 37% of persons. The skin is the second most commonly
affected organ, after the lungs. The most common lesions are erythema nodosum,
plaques, maculopapular, eruptions, subcutaneous nodules, and lupus pernio
Heart
 Conduction abnormalities are the most common cardiac manifestations of sarcoidosis among persons
and can include complete heart block
 Ventricular arrhythmias occur in about 23% of persons with cardiac involvement. Sudden cardiac
death, either due to ventricular arrhythmias or complete heart block is a rare complication of cardiac
sarcoidosis
 Cardiac sarcoidosis can cause fibrosis, granuloma formation or the accumulation of fluid in the
interstitum of the heart
Eye
 Eye involvement occurs in about 10–90% of cases. Manifestations in the eye include:
 Uveitis, choroiditis, retinitis, uveoparotitis andretinal inflammation, which may result in loss of visual
acuity or blindness. The most common ophthalmologic manifestation of sarcoidosis is uveitis.
 Mikulicz syndrome: The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever
is called uveoparotid fever. It may also have xerostomia (dry mouth).
Nervous system
 The central nervous system involvement is present in 10–25% of sarcoidosis cases. Other common
manifestations of neurosarcoid include optic nerve dysfunction, papilledema, palate dysfunction,
neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic
meningitis, and peripheral neuropathy.
Endocrine
 Prolactin is frequently increased in sarcoidosis, between 3% and 32% of cases
have hyperprolactinemia, and this frequently leads to amenorrhea, galactorrhea, or nonpuerperal
mastitis in women. Diabetes insipidus,pituitary dysfunction
Spleen
 Splenomegaly occurs in 30-40% cases.
Liver
 Hepatomegaly occurs in 20 % cases.
Complication:
 Progressive lung fibrosis
 Lung cavitation
 Hemoptysis
 Heart block, cardiac arrhythmia
Laboratoryinvestigation:
 X ray chest:Chest X-ray changes are divided into four stages:
Stage 1: bilateral Hilar lymphadenopathy
Stage 2: bilateral Hilar lymphadenopathy and reticulonodular infiltrates
Stage 3: bilateral pulmonary infiltrates
Stage 4: fibrocystic sarcoidosis typically with upward Hilar retraction, cystic and bullous changes
 Serum markers: Serum markers of sarcoidosis, include: serum amyloid-A, soluble interleukin-2
receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6
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 Serum angiotensin converting enzyme (ACE) levels: Angiotensin-converting enzyme blood levels are
used in the monitoring of sarcoidosis. Serum ACE levels are mostly elevated in sarcoidosis
 CD4/CD8 T cell ratio: A bronchoalveolar lavage, can show an elevated (of at least 3.5) CD4/CD8 T cell
ratio, which is indicative (but not proof) of pulmonary sarcoidosis. In at least one study, the induced
sputum ratio of CD4/CD8 and level of TNF was correlated to those in the lavage fluid.
 CT scan of chest, PET scan, CT-guided biopsy:
 Endoscopic ultrasound with FNA of mediastinal lymph node (EBUS FNA)
 Biopsy: Of superficial lymph node,biopsy of lymph nodes is subjected to both flows Cytometry to rule
out cancer
 Serum calcium: Hypercalcemia occur in some cases of sarcoidosis
 Tuberculin test: It is negative almost
 ESR: ESR is elevated/raised
Environmental Disease
Pneumoconiosis:
Definition:
Pneumoconiosis is a group of non-neoplastic pulmonary disease, which is due to inhalation of organic and
inorganic particulates. The mineral dust pneumoconiosis, which is due to coal dust, asbestos, silicon and
beryllium, usually occur from exposure in work places.
Pathogenesis:
Pneumoconiosis is a result of lung reactions towards offending inhaled substances. The reaction depends
on the size, shape, solubility and reactivity of the particles. Particles greater than 10μm are not harmful
because they are filtered out before reaching distal airways. When they are less than 1μm in diameter,
they tend to move in and out of alveoli like gases so that they will not deposit and result in an injury.
Silica, asbestos and beryllium are more reactive than coal dust bringing about fibrotic reaction, while coal
dust has to be deposited in huge amounts if it has to result in reaction because it is relatively inert. Most
inhaled dust is removed out through the ciliary movement after being trapped in the mucus linings. When
particles reach the alveoli, they are engulfed by macrophages. The more reactive particles activate
macrophages to release fibrogenic factors, toxic factors and proinflammatory factors. The cumulative
effect becomes lung injury and fibrosis. The important mediators released by macrophages are grouped in
to three:
 Freeradicals: reactive oxygen and reactive nitrogen species that induce lipid peroxidation and tissue
damage.
 Chemotactic factors: leukotriene B4 (LTB4) interleukin 8 (IL-8) IL-6, and TNF which recruit and
activate inflammatory cells and which in turn release damaging oxidants (free radicals).
 Fibrogenic cytokines: IL-1, TNF, Fibronectin, platelet derived growth factor (PDGF), and insulin like
growth factor (IG F-1), which recruit fibroblasts.
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Lung
Classification of Pneumoconiosis:
Pneumoconiosis can be classified according to the substance incriminated
 Coal workers Pneumoconiosis: Due to coal dust
 Silicosis: Due to silica
 Asbestosis: Due to asbestos
Coal workers pneumoconiosis:
Since earlier times of industrialization, it has been noticedthat coal miners were drying of “black lung”
complicated by tuberculosis. Coal dust mainly contains carbon but has a variety of trace metals inorganic
mineral and crystalline silica. Anthracite (hard) coal contains significantly more quartz than bituminous
(soft) coal. Anthracite (hard) coal is more frequently associated with lesions in the lungs; hence, the name
pulmonary anthracosis is coined for coal induced pulmonary lesions.
The disease has three distinct pathological entities:
 Anthracosis:- Where pigments are accumulated without cellular reaction and symptoms
 Simple coal workers pneumoconiosis with minimal cellular reaction and little or no pulmonary
dysfunction
 Progressive massive fibrosis with extensive fibrosis and compromised pulmonary function
Morphology:
 Pulmonary anthracosis-Macrophages in the alveoli and interstitum are found laden with carbon
pigments. These macrophages are also seen along the lymphatics including pleural lymphatics or
lymphoid tissue along bronchi and lung hilus
 Simple Coal workers pneumoconiosis (CWP) characterized by Coal macules and Coal nodules
 Coal macules constitutes of carbon-laden macrophages aggregated
 Coal nodule is when the macule additionally contains collagen fibers
 Complicated CWP - progressive Massive fibrosis (PMF) - occurring in the background of CWP after
many years by coalescence of coal nodules. It is characterized by coal nodules intermingled with
collagen fibers with central necrosis, size ranging from 2cm to 10cm
Clinicalcourse:
Pulmonary anthracosis and simple CWP result in no abnormalities in lung functions. When it progress to
progressive massive fibrosis in minority of cases it results in pulmonary hypertension and cor pulmonale.
Progression from simple CWP to PMF has been linked to amount and duration of exposure to coal dust.
Smoking also has been shown to have the same effects. Sometimes of course, the progression does not
need factors mentioned above
Asbestos Related Disease:
Asbestos is a generic name that embraces the silicate minerals that occur as long, thin fibers. Asbestosis
refers to the pneumoconiosis those results from the inhalation of asbestos fibers
Pathogenesis:
Asbestos fibers are thin and long so that they can reach the bifurcations of bronchioles and alveoli. There,
they are engulfed by macrophages to induce the cascade of inflammatory process, which finally result in
interstitial pulmonary fibrosis.
Morphology:
Asbestosis:Is an interstitial fibrosis of the lung. At early stages, fibrosis is in and around the alveoli and
terminal bronchioles. When disease progresses, gross examination of the lungs show gray streaks of
fibrous tissue, which accentuate the interlobular septa, together with diffuse thickening of the visceral
pleura. The asbestos body is the diagnostic structure seen under the microscope, consisting of asbestos
fiber beaded with aggregates of iron along its length.
Pleural plagues:After a period of many years, the inhalation of asbestos fibers will result in the
appearance of plaques on the partial pleura. They are 2 to 3 mm thick, and microscopically they are
densely collagenous and hyalinized and sometimes calcified.
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Mesothelioma:A clear-cut relationship between asbestos exposure and a malignant mesothelioma is now
firmly established
Other malignancies:Like lung and bladder, cancers can also result from asbestos exposure
Idiopathic Pulmonary fibrosis (IPF):
General Description: It is also known as ‘’Cryptogenenic Fibrosing alveolitis’’, where there is Fibrosis of
lung interstitum of unknown etiology.
Pathogenesis:
 IPF is triggered by unknown agent due to repeated cycles, which result in the Epithelial activation or
injury, that causes stimulation if TH2 helper T-cell. This causes inflammation. Which then generate
TGF-β1 → fibroblasts and myofibroblasts → deposition of Collagen and extra cellular matrix → that
causes pulmonary fibrosis.
 Secondary causes of interstitial fibrosis such as drugs(e.g. Bleomycinan, Amiodarone etc.) and
radiation therapy must be excluded.
Clinical Features:
Progressive dyspnea and cough
Fibrosis on lung Connective tissue ;initially seen in sub pleural patches, but eventually results in Diffuse
fibrosis with end-stage “honeycomb “lung
Pulmonary Vascular Diseases
Pulmonary Embolism (PE):
Definition:
Pulmonary embolism is an obstruction of the pulmonary artery or one of its branches by material that
originated elsewhere in the body. One of the most common causes of a PE is a thrombus that has traveled
to the lung from deep vein thrombosis, especially of the lower limbs.
Subtypes:
 Massive: causes hypotension (systolic blood pressure < 90mm Hg or a drop in the systolic of >40mm
Hg from baseline) for >15 minutes.
 Submassive:Not all PE’s meeting the definition of massive.
 Saddle PE: lodges at the bifurcation of the main pulmonary artery into the left and right.
Pathogenesis/Pathophysiology
Most thrombotic PE’s come from DVT’s. The majority of DVT has come from the lower extremities,
although they can come from other deep veins. Once a thrombus travels to the lung, it causes
hemodynamic changes (increased pulmonary vascular resistance decreased cardiac output),
inflammation, impaired gas exchange and sometimes infection. Untreated PE has a mortality rate of 30%.
Risk Factors
 Immobilization  Malignancy
 Surgery within the past three months  Chronic heart disease
 Stroke  Autoimmune disease
 Paresis  History of venous thromboembolism
 Paralysis  Obesity
 Central venous instrumentation in the past  Cigarette smoking
three months
Clinical Presentation:
Symptoms:
 Dyspnea at rest or with exertion
 Pleuritic chest pain
 Cough
 Orthopnea
 Calf or thigh pain
 Calf or thigh swelling
 Wheezing
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 Hemoptysis
Signs:
 Tachypnea
 Tachycardia
 Decreased breath sounds
 Fourth heart sound
 Accentuated pulmonic component of the second heart sound
 Jugular venous distention
 Signs of lower extremity DVT (edema, erythema, tenderness, palpable cord)
Investigations:
 CT scan of the chest if available
 CXR
 Ultrasound of the lower extremities
 Full blood picture
 D-dimmer
 ECG
Pulmonary hypertension:
Definition:
 It is defined as the elevated mean arterial pulmonary pressure of 25mm of Hg at rest
 Heath and Edward grading system was devised to grade the, pulmonary hypertension according to
the fact that the arterial changes induced by the pulmonary hypertension could be reduced by
corrective cardiac surgery or not.
 The grades range from grade 1 to 6, in which grade 1 to 3 are reversible, and grade 4 and above are
usually not.
 The microscopic and gross pathology depends on the cause which is causing pulmonary hypertension
 Pulmonary hypertension may be one of the following :
 Pre-capillary, e.g. pulmonary emboli, left-to-right shunts, primary pulmonary hypertension
 Capillary, e.g. chronic obstructive airways disease
 Post-capillary, e.g. left ventricular failure, mitral stenosis
 Chronic hypoxemia, e.g. Pickwickian syndrome, Kyphoscoliosis, Poliomyelitis
Precapillary:
 Many small emboli in the pulmonary capillaries cause obliteration of the vascular bed.
 Left to right shunts.
 Primary or of unknowncause: this disease tends to affect young women. The cause of primary
pulmonary hypertension is uncertain, but may include ingestion of drugs and toxins.
Capillary:
 It mostly is due to disease in the pulmonary vascular bed. E.g., honeycomb lung from any cause.
Severe chronic obstructive airways disease may also cause pulmonary hypertension and ‘’cor
pulmonale’’
Post capillary:
 It is due to high pressure in the pulmonary venous system causing secondary backpressure into the
arterial tree, e.g. mitral stenosis, left ventricular failure from any cause, and the rare pulmonary veno
occlusive disease
Chronic hypoxemia:
 From any cause may eventually cause pulmonary hypertension, it could result from being at very high
altitude or even gross obesity as it causes poor respiration
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Atelectasis (Collapse Alveoli)

Definition:
Loss of lung volume caused by inadequate expansion of air spaces
Types:
 Atelectasis Neonatorum
Primary and Secondary
 Acquired
 Resorption atelectasis: It is a consequence of complete obstruction of airways. Air already
present is absorbed resulting in collapse. Causes include mucous plug, foreign body, clots etc.
 Compressionatelectasis: Occur when pleural cavity is partially or completely filled by fluid
 Contraction atelectasis: Occur when fibrotic changes in lung or pleura prevent expansion
 Patchy Atelectasis: It is non-obstructive atelectasis in which there is loss of surfactant
Note: Atelectasis is potentially reversible except contraction atelectasis
Pleural Diseases
Pleural effusion:
Definition:
Pleural effusion is the presence of excess fluid in the pleural space. Normally 10– 20 ml of fluid is spread in
a thin layer between the two layers of pleurae. Pleural effusions are classified as transudates and
exudates based on laboratory analysis of the fluid.
Transudative effusion:
Results from elevations in hydrostatic pressure or decrease in oncotic pressure. The following are some of
the causes:
 Heart failure
 Cirrhosis of the liver
 Nephrotic syndrome
 Myxedema
 Hypoproteinemia
Exudative effusion:
It isdue to pleural inflammation (pleurisy) with an increased permeability of the pleural surface to protein.
Pleurisy commonly occurs in infections such as pneumonia, infections of the esophagus, mediastinum or
sub-diaphragmatic areas, traumatic injuries, and extension of infections from adjacent organs. Initially
pleurisy tends to be dry but fluid starts to collect subsequently. Itis found in association with:
 Para pneumonic effusions
 Empyema
 Pulmonary embolism
 Neoplasms
 Systemic lupus erythematosis and rheumatoid pleural effusion
 Sub-diaphragmatic abscess
 Pancreatitis
 Uremic pleural effusion
 Hemothorax
 Chylothorax (thoracic duct injury)
 Radiation and drugs
Clinical findings
 Pleuritic chest pain and dyspnea are the most common symptoms, but many pleural effusions are
asymptomatic and discovered on physical examination or chest x-ray
 Underlying causes should be suspected from the history
 Physical examination on the affected side discloses the presence of decreased chest motion, absent
tactile fremitus, percussion dullness, and decreased or absent breathes sounds
Diagnosis and Laboratory findings:
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 The diagnosis of pleural effusion can be suspected from a properly done physical examination
 Chest x-ray is the most precise way to confirm the physical findings. It demonstrates the presence of
pleural fluid as homogenous opacity with a Meniscus-sign and obliteration/blunting of the
costophrenic angle. Large pleural effusions may result in complete opacification of the hemithorax
and mediastinal shift to the opposite side. The best way to identify and localize a loculated pleural
effusion is with ultrasonography
 Ultrasound: Ultrasound is more sensitive than CXR for detecting pleural effusion
 Pleural Thoracenthesis: (aspiration of fluid) should be performed to confirm the presence of fluid and
to determine its characteristics, including color and consistency
 Clear yellow fluid is described as serous
 Bloody or blood-tinged fluid as sanguineous or serosanguineous. Some of the causes include
pulmonary infarction and pleural carcinomatosis
 Translucent or opaque, thick fluid as purulent
 Microscopic examination: of the fluid is important including Gram stain and culture (if possible).
 Total and differential cell counts should be obtained
 The predominance of polymorphonuclear leukocytes suggests an underlying pneumonia with a
parapneumonic effusion
 The presence of many small mature lymphocytes, particularly with few mesothelial cells, strongly
suggests tuberculosis
Pneumothorax:
Definition:
Refers to Accumulation of air or gas in the pleural sac
Etiology:
 Tension Pneumothoraxfrequently caused by trauma. Can also be iatrogenic from a procedure like
Thoracenthesis or lung biopsy
 Primary spontaneous pneumothorax occurs in patients without an apparent underlying disease.
Chest pain on the affected side with dyspnea is the typical presenting complaint. This often occurs at
rest and is rarely life threatening. It occurs more frequently in med than women, and especially in
young men (20-40 years old)
 Secondary spontaneous pneumothorax occurs in association with underlying lung disease.Although
it most commonly occurs secondary to COPD, many other conditions are associated such as
tuberculosis, Pneumocystis carini pneumonia, malignancy, fibrosis.
Clinical features and diagnosis:
 The major symptoms are chest pain and dyspnea.
 Physical exam reveals hyperresonance and decreased breath sounds over the involved side. If the
pneumothorax is large enough to impair right heart filling/function, then there will jugular venous
distension and a pulsus paradoxus and you may find deviation of the trachea to the contralateral side
 Chest x-ray shows an absence of lung markings beyond the distinctly white line of the visceral pleura.
If the patient is upright, air rises to the apex. When the patient is supine, air rises to the anterior
chest. May see a deep sulcus sign: anterior costophrenic angle is sharply delineated. On a lateral
decubitus film, place the suspected side up (whereas it should be down for fluid). 5 ml of air is
detectable.
Acute Lung Injury
Adult Respiratory Distress Syndrome (ARDS):
Q. A 32 years old male comes to ER with rapid onset of respiratory insufficiency, cyanosis and severe arterial
hypoxemia that is refractory to oxygen therapy and progressive multisystem organ failure. He is diagnosed to have
ARDS.
a) What clinical disorders are associated with the development of ARDS.
b) Give pathogenesis of ARDS.
Clinical Disorders Associated with ARDS:
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Direct lung injury Indirect lung injury

Common causes
1. pneumonia Sepsis
2. aspiration of gastric content Sever trauma with sock
Uncommon causes
Pulmonary contusion Cardiopulmonary bypass
Fat embolism Acute pancreatitis
Near drowning Drug overdose
Inhalational injury Transfusion of blood products
Reperfusion injury after lung implantation Uremia
Pathogenesis of Adult Respiratory Distress Syndrome(ARDS):
 Acute damage to alveolar capillary walls and epithelial cell
 Alveolar macrophages and other cells release cytokines
 Cytokines are chemotactic to neutrophils
 Neutrophils transmigrate into alveoli through pulmonary capillaries
 Capillary damage causes leakage of a protein rich exudate producing hyaline membraneby the action
of different mediator
 Neutrophils damage type 1 and type 2 Pneumocytes decrease in surfactant causes Atelectasis with
intrapulmonary shunting
 Late findings
 Repair by type 2 Pneumocytes
 Progressive interstitial fibrosis
Lung tumor
Classification of lung tumor:
Epithelial:
Benign:
Papilloma
Adenoma
Malignant:
Small Cell Carcinoma:
Small cell carcinoma (oat cell carcinoma): combined small cell carcinoma
Non-Small Cell Carcinoma:
Squamous cell carcinoma
Adenocarcinoma
Large cell carcinoma: large cell neuroendocrine carcinoma
Adenosquamous carcinoma
Soft Tissue Tumors:
(Fibroma, Fibrosarcoma; Leiomyoma, Leiomyosarcoma; Lipoma, Chondroma, Hemangioma,
Lymphangioma, Granular Cell Myoblastoma
Tumors of Pleura
Primary Mesothelioma
Secondary Mesothelioma
Carcinoid tumors: (typical, atypical)
Carcinoma of Salivary Gland Type
Unclassified tumor
Metastatic tumors
Morphology of lung carcinoma:
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Initiation:Small mucosal lesions, which are firm and grey-white
Form: i) intraluminal masses ii) invasion into bronchial mucosa iii) bulky masses pushing into
lungparenchyma
Spread: i) pleura ii) pleural cavity iii) intrathoracic structures iv) distant metastasis through lymphatic or
Hematogenous route
Types:
Squamous cell carcinoma:
 Common in smokers especially men
 Centrally located
 Spread to Hilar nodes common
 Parathyroid Hormone-related peptide production (PTH-rp)
 TP53 and RAS mutation
Microscopy:
 Squamous metaplasia → squamous dysplasia (loss of nuclear polarity, nuclear hyperchromasia,
pleomorphism, mitotic figures) → Carcinoma in situ → invasive cancer
Points of Identification:
 Keratin pearls
 Intercellular bridges
Adenocarcinoma:
 Common in women and nonsmokers
 Located in periphery
 K-RAS mutations
Histological forms:
 Acinar adenocarcinoma
 Papillary adenocarcinoma
 Mucinous (manifest as pneumonia-like consolidation)
 Solid adenocarcinoma
Microscopy:
 Atypical adenomatous hyperplasia characterized by (i) nuclear hyperchromasia, ii) pleomorphism and
iii) prominent nucleoli→ Adenocarcinoma in situ characterized by i) less than 3cm diameter ii) growth
on preexisting structures iii) preservation of alveolar architecture → Invasive adenocarcinoma
Large cell carcinoma:
Microscopy:
Characterized by:
 Moderate cytoplasm
 Large nuclei
 Prominent nucleoli
 No glandular or squamous differentiation
Small cell lung carcinomas (SCLCs):
 Pale gray
 Centrally located
 Spread to Hilar or mediastinal nodes
 Express neuroendocrine markers
 Paraneoplastic syndrome (production of ACTH, ADH, gastrin-releasing peptide, calcitonin)
 Rb mutations, 3p deletions, p53 mutations, p16 mutations
Microscopy:
 Diffuse sheet of cells
 Scant cytoplasm
 Small hyperchromatic nuclei and Indistinct nucleoli
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Sites of metastasis for all lung carcinoma:
 Hilar nodes
 Supraclavicular node (Virchow node)
 Nodes in neck (Scalene nodes)
Complications:
 Extension into pleural or cavities causing inflammation and effusion
 Compression of Superior vena cava causing venous congestion or vena caval syndrome
 Pancoast Tumors: Those apical tumors, which invade brachial or cervical sympathetic plexus to cause
pain along ulnar nerve distribution or to produce Horner syndrome characterized by
 Ipsilateral exophthalmos
 Ptosis
 Mitosis
 Anhidrosis (loss of sweating especially on forehead)
Laboratory Diagnosis of Lung Carcinoma:
Chest X-Ray
 This is the most valuable screening test.
 Enlarged Hilar lymph nodes, pleural effusion and streaky shadowing throughout the lung point to
metastatic cancer.
Sputum Cytology
 It may contain malignant cells
Fiber optic Bronchoscopy
 Cytology specimens from peripheral lesions and biopsy specimens are taken with this technique and
then examined for carcinoma
Transthoracic Fine-Needle Aspiration Biopsy
 With this technique, specimens can be obtained from lesions that are more peripheral
Computed Tomography
Magnetic Resonance Imaging
 It also helps to localize the tumor.
Differences between Squamous Cell Carcinoma and Adenocarcinoma:
Features Squamous cell carcinoma Adenocarcinoma
Gender frequency Mostly males More in females
Association with smoking Mostly Less frequently
Size Large ,firm growth Smaller
Site Centrally located Peripherally located
Growth rate Rapid Slowly
Subtypes Nil 05
Histology Keratinizationand intercellular Glandular formation
bridges
Premalignant lesions Dysplasia, metaplasia and in situ Atypical adenomatous hyperplasia
lesion
Extent of metastasis Narrow range Widely spread
Metastasis Late Early
Mutation P53 k-RAS
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Differences B/W Small Cell Lung Carcinoma and Non-Small Cell Lung Carcinoma:
Features SCLC NSCLC
Histology Scant cytoplasm, small Abundant Cytoplasm,

hyperchromatic nuclei, fine pleomorphic nuclei with
chromatin, nucleoli of coarse chromatin
Indistinct patternNucleoli prominent
Neuroendocrine markers Usually present Usually absent

Epithelial markers Present Present
Mucin Absent Present
Peptide hormones production ACTH, ADH, calcitonin PTH
Tumor suppressor gene
abnormalities:
RB mutations 90% 20%
p53 mutations >90% >50%
Dominant oncogene
abnormalities
KRAS mutations Rare 30%
EGFR mutations Absent 20%
Response to chemotherapy Often complete response Uncommonly complete

and but recur invariably Response
Radiotherapy
Squamous Cell Caof Lung Adenocarcinoma of Lung
Small (Oat) Cell Ca of Lung
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Para Neoplastic Syndrome:

Definition:
Para neoplastic syndrome is an aggregate of symptom complexes in cancer - bearing patients that cannot
readily be explained by the local or distant spread either of the tumor or by the elaboration of hormones
indigenous to the tissue from which the tumor arose
Para neoplastic syndrome occurs in about 10% of patients with malignant disease
Despite its infrequency, the syndrome is important for three reasons:
 They be the earliest manifestation of an occult neoplasm
 In affected patients, they may represent significant clinical problems and may even be lethal
 They may mimic metastatic disease and, therefore, confound treatment
Classification of Para neoplastic syndromes:
Hormone Disease Type of Lung Cancer
ACTH And ACTH Like
Cushing Syndrome Small Lung Ca, Pancreatic Ca
Substances
ADH Or Atrial Natriuretic
SIADH* Secretion Small Cell Lung Ca
Hormones
Parathyroid Hormone Related SCC Of Lungs, Breast Ca, Renal Ca,
Hypercalcemia
Peptide TGF, TNF , IL1 Adult T-Cell Leukemia, Ovarian Cancers
Insulin Or Insulin Like Fibrosarcoma Other Sarcomas
Hypoglycemia
Substances HCC
Serotonins, Bradykinin, Bronchial Adenoma, Pancreatic Ca,
Carcinoid Syndrome
Histamine Gastric Ca
Renal Ca, Cerebellar Hemangioma, Liver
Erythropoietin Polycythemia
Cancer
Mucin That Activate Clotting Venous Thrombosis Pancreatic And Bronchogenic Ca
Nonbacterial Thrombotic
Hypercoagulability Advanced Cancers
Endocarditis
*Syndrome of Inappropriate Antidiuretic hormone
Note: Hypercalcemia is probably the most common Paraneoplastic Syndrome and among
endocrinopathies, Cushing syndrome is the most common variety of paraneoplastic effect.
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Chapt
Chapter Five KIDNEY AND ITS COLLECTING SYSTEM
General Features of Kidney:

Components of Glomerular Capillaries:
 Endothelial cells
 Basement membrane
 Lamina Rara Interna
 Lamina Densa
 Lamina Externa
 Podocytes (Epithelium folded in the form of podocytes)
Note: Electron microscopy reveals the immune complexes between the endothelial cells and the GBM is
calledsubendothelial deposit, whereas between the outer surface of the GBM and the podocytes is called
subepithelial deposits.
Azotemia
 Azotemia is a biochemical abnormality that refers to increased blood urea and serum creatinine due
to decrease glomerular filtration rate
 Retention of nitrogenous waste products either through their failure to be delivered to the kidney
such as in chronic heart failure, shock, or failure of the kidney to excrete them is called azotemia
Uremia
 It is a clinical syndrome characterized by failure of renal excretory function and metabolic and
endocrine alteration resulting from renal damage
Types of uremia:
Classified into 3 types
 Pre Renal: uremia resulting from hypo perfusion of the kidneys in condition such as Shock, CHF etc.
 Renal: uremia resulting from renal disease such as glomerulonephritis, Pyelonephritis and tubular
necrosis
 Post renal: uremia resulting from obstruction in the urinary tract caused by calculi, Fibrosis, tumor
etc.
Glomerulonephritis is characterized by 4 basic tissue reaction:
 Hyper cellularity
 Basement membrane thickening
 Hyalinosis (protein balls)
 Sclerosing
Renal Casts and the various diseases in which they are present
Cast Disease associated with it
Hyaline cast No specific disease ,insignificant in absence of proteinuria

RBC cast Glomerulonephritis
WBC Acute pyelonephritis,Tubulointerstitial nephritis
Fatty cast Nephrotic syndrome
Waxy cast Chronic renal failure
Renal tubular cell cast Acute tubular necrosis
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Kidney and its Collecting System
NephroticSyndrome
Definition:
The Nephrotic syndrome refers to a clinical complex that includes:
 Massive proteinuria, with daily protein loss in the urine of 3.5 gm/day or more in adults
 Hypoalbuminemia, with plasma albumin level less than 3gm/dl
 Generalized edema, the most obvious clinical manifestation
 Hyperlipidemia and Lipiduria
Causes of Nephrotic syndrome:
Primary glomerular disease:
 Minimal change disease(Common in children)
 Membranous Glomerulonephritis (common in adults)
 Focal segmental Glomerulosclerosis
 Membranoproliferative Glomerulonephritis
 IgA nephropathy
Secondary/Systemic diseases with renal manifestations:
 Diabetes mellitus
 Amyloidosis
 Systemic lupus erythematous
 Ingestion of drugs ( gold, pencillamine, street heroin)
 Infections: (malaria, syphilis, hepatitis B and HIV)
 Malignancy ( carcinoma, melanoma)
 Good Pasture’s Syndrome, Wegner’s granulomatosis
 Polyarteritis nodosa, Henoch Schonlein purpura etc.
Hereditary Disorders:
 Alport’s syndrome (defect in type IV collagen)
 Fabry’s disease
Minimal change disease:
Q. A 4 years old girl presents with generalized edema and laboratory results show proteinuria in excess of 3.5gm
per day with Hypoalbuminemia. The patient improved dramatically on corticosteroid administration.
b) What are the light microscopic and ultra-structural and immunofluorescence findings for this
disease?
c) What is the likely pathogenic mechanism?
Diagnosis:
Minimal change disease (Lipoid Nephrosis):
Light Microscopic Findings:
 Glomeruli appear normal
 The cells of the proximal convoluted tubules are often heavily laden with protein droplets and Lipids
but this is secondary to the tubular reabsorption of the lipoproteins passing through the diseased
glomeruli
 This appearance of PCT is the basis for the older term for this disorder, Lipoid Nephrosis
Ultrastructure and Immunofluorescence Findings:
 Even with the electron microscope, the GBM appears normal
 The only obvious abnormality is the uniform and diffuse effacement of the foot processes of
Podocyte
 The cytoplasm of the Podocyte appears flattened over the external aspect of the GBM obliterating
the network of arcades b/w Podocyte and GBM
 There is also epithelial cell vacuolization, microvillus formation and focal detachment
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Pathogenesis:
The exact mechanism is unknown but, possibly T cell–derived, factor that causes Podocyte damage and
effacement of foot processes resulting in the loss of negative charge on the GBM, that cause the loss of
proteins in the urine
Membranous Nephropathy/Glomerulonephritis:
Morphology of Membranous Nephropathy:
Light Microscope:
 Diffuse thickening of GBM
Electron Microscope:
 Subepithelial deposits separated by small spikes of GBM matrix (spike anddome pattern) → deposits
are incorporated into GBM, giving its double layered appearance with spikes → deposits are later
catabolized and disappear leaving behind cavities with in GBM→ which are filled with progressive
deposition of GBM matrix→ ultimately as disease progress → glomeruli become sclerosed and
hyalinized.There is loss of foot process of podocytes
Immunofluorescence microscope:
 Show granular deposits of immunoglobulin’s and complement along the GBM
Minimal Change Disease Membranous Nephropathy

Focal Segmental Glomerulosclerosis (FSGS)
 FSGS as one of the most common causes of primary glomerular diseases in adults and the incidence
of FSGS has been increasing in recent year
 FSGS causes asymptomatic proteinuria or Nephrotic syndrome with or without renal insufficiency in
adults
 FSGS is a progressive form of kidney disease, accounting for 2-3 % of patients with end stage renal
disease (ESRD)
Histological Types:
 Collapsing (HIV Associated)
 Tip (Heroin/Steroid Use)
 SLE Associated
 Hereditary
Etiology
Primary (idiopathic) include the following
 FSGS with Hyalinosis
 Progression from minimal change disease
 Progression from immunoglobulin M (IgM) nephropathy
 Progression from Mesangial proliferative glomerulonephritis
Secondary
Drug associated with FSGS include the following
 Intravenous heroin
 Analgesics and anabolic steroids
 Lithium
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Viruses associated with FSGS include the following

 Hepatitis B
 HIV
 Parvovirus
Pathophysiology
 Mechanism that initiate glomerular injury which leads to glomerulosclerosis are largely unknown
 The primary pathophysiologic process in FSGS is an injury inherited within or directed to podocytes
 Foot process effacement , proliferation of Mesangial, endothelial, and epithelial cells in the early
stages, followed by shrinkage/collapse of glomerular capillaries all leading to scarring
(Glomerulosclerosis)
Morphology
 In FSGS, the disease affecting only some of the glomeruli (hence the term focal) and lesion involving
only a part of glomerulus, sparing the others (hence the term segmental).Thus, the involvement is
both segmental and focal
 On light microscopyThe affected glomeruli exhibit increased Mesangial matrix, obliterated capillary
Lumina, and deposition of hyaline masses (Hyalinosis) and lipid droplets
 Immunofluorescence microscopy often reveals nonspecific trapping of immunoglobulin’s usually
IgM, and complement in the area of Hyalinosis
 Onelectron microscopy, the podocytes exhibit effacement of foot processes
Membranoproliferative Glomerulonephritis (MPGN):
Morphology of Membranoproliferative Glomerulonephritis:
Under Light Microscope:
 Glomeruli are enlarged with proliferation of mesangial cells and leukocytic infiltration is prominent.
 GBM is thickened and glomerular capillary wall shows a double contour or“tram-track” appearance
especially evident in PAS staining
 This is caused by splitting of the basement as processes of mesangial cells extend into the peripheral
capillary loops .This is called mesangial interposition
Ultrastructure And Immunofluorescence features:
 Type I MPGN is characterized by electron dense subendothelialdeposits, which are mostly C3 and
IgG
 Type II MPGN, (Dense Deposit Disease): The lamina Densa of GBM is transformed into an irregular,
ribbon like extremely electron dense structure. There is only C3 deposit in this type. So this type II is
also called dense deposit disease
Pathogenesis:
 Most cases of type I MPGN appear to be caused by chronic immune complex reaction but the
initiating agent is unknown
 Type I MPGN also occurs in association with hepatitis B and C, SLE and secondary infection. The
fundamental abnormality in dense deposit disease appears to be excessive complement activation
 Since C3 nephritic factor is an autoantibody, it is consider that, there is a genetic Predisposition to
development of type II MPGN in some person as well
 Mutation in the gene encoding the complement regulatory protein factor H in some patient as well
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Figure: Membranoproliferative GN
IgA nephropathy:
 IgA nephropathy begin as an episode of gross hematuria that occur within 1 or 2 days of a
nonspecific upper respiratory tract infection
 Usually affects children and young adults
 IgA nephropathy is the of the most common causes of recurrent microscopic or gross
hematuria and is the most common glomerular disease revealed by renal biopsy worldwide
 The hallmark of the disease is the deposition of IgA in the mesangium
Pathophysiology
 Exact mechanism is unknown but IgA antibodies are increased in serum of patients with IgA
nephropathy
Morphology
 Histologically the glomeruli may be normal or there is Mesangial deposition of IgA
antibodies
 Immunofluorescence picture is of Mesangial deposition of IgA, often with C3 and smaller
amount of IgG or IgM
 Electron microscopy confirm the presence of electron dense deposit in the mesangium
Nephritic syndrome
 Nephritic syndrome: this is clinical complex characterized by:
 Hematuria with Dysmorphic red cells and red blood cell casts in the urine
 Oliguria and azotemia
 Hypertension
 Proteinuria less than 3.5 gm/day
Causes:
 Immunologically mediated glomerular injury
 Genetic
 Systemic diseases e.g. SLE
 Primary glomerular disease
 Inflammatory reactions
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Acute Post Infectious (Post Streptococcal) Glomerulonephritis:

Q. A young male presents with nephritic syndrome. He is HCV positive on serology. Renal biopsy was carried out
which revealed on light microscopy an accentuation the lobular arrangement of glomerular tuft and double
contour of GBM.
a) What will be the Morphologic (electron and light microscopic)clinical picture of this biopsy?
b) Describe the clinical course of this disease.
c) Give the pathogenesis of acute proliferative post streptococcal glomerulonephritis.
d) Laboratory Diagnosis.
Light Microscopic picture:
The most characteristic change in the post infectious GN isuniform increase Cellularity of the glomerular
tuft that affects nearly all glomeruli, hence term “diffuse”.
The increased cellularity is caused by both proliferation and swelling of endothelial and Mesangial cells
and by neutrophilic and monocytic infiltrate. There is necrosis of the capillary wall. May be crescents with
in the urinary space in response to sever inflammatory injury.
Electron microscopy:
Shows deposited immune complexes arrayed as sub endothelial, intramembranous or most often sub
epithelial humps nested against the GBM.
Mesangial deposit are also occasionally present
Immunofluorescence findings:
This study reveals scattered granular deposited of IgG and complement with in the capillary wall
Clinical course:
 Malaise
 Nausea
 Nephritic syndrome
 Oliguria
 Azotemia
 Hypertension
 Gross hematuria
 Smoky brown urine / cola colored urine
 Serum Antistreptolysin o antibodies elevated
 End stage renal disease.
Pathogenesis:
 Group Abeta hemolytic streptococcus have some nephritogenic strains (Types 1, 4, 12, typing based
on M protein of cell wall)
 Immune complexes formed by combination of specific antibodies against Streptococcal antigens
(exotoxin B and Streptococcal GADPH), localize on the glomerular capillary wall and activate the
Complement system
 The immunologic system may be activated by streptococcal antigens that adhere to the glomerular
structures and act as ‘planted antigen’ as well as by altered endogenous antigens
 Glomerular deposition of immune complexes leads to diffuse proliferation and swelling of glomerular
cells
 Urine routine examination ( R/E)
 Urine culture
 Biopsy of kidney
 BUN (Blood Urea and Nitrogen)
 ASO titer (Anti-Streptomycin O)
 Immunofluorescence
 Electron microscopy
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Rapidly Progressive (Crescentric) Glomerulonephritis (RPGN):

 It is characterized by progressive loss of renal function laboratory finding typically of nephritic
syndrome
 It is associated with severe oliguria and lead to death from acute renal failure within a period of
weeks to months
 Crescents are formed due to proliferation of parietal cells
Types:It has the following three types
 Anti-GBM Antibody-Mediated Crescentric Glomerulonephritis
 It is characterized by linear deposits of IgG, and in many cases C3 on the GBM
 In some patients, the anti GBM antibodies also bind to pulmonary alveolar capillary basement
membrane to produce a clinical picture of pulmonary hemorrhage associated with renal failure
(GoodPasture syndrome).
 It is associated with HLA-DR2.
 Immune Complex-Mediated Crescentric Glomerulonephritis
 Crescent can be a complication of any of the immune complex nephritis including Post
streptococcal GN, SLE, IgA nephropathy and Henoch Schonlein purpura.
 Characteristics granular (lumpy bumpy) pattern of staining of the GBM/mesangium for
immunoglobulin/complement on immunofluorescence study
 Pauci-Immune Crescentric Glomerulonephritis
 It is characterized by the lack of anti-GBM antibodies or immune complex deposition by
immunofluorescence and electron microscope
 Most of these patients have antineutrophilic antibody (ANCA) in their serum.RPGN is associated
with systemic vasculitis such as Polyarteritis nodosa, microscopic polyangitis , Wegner
granulomatosis
Morphology
 Kidneys are enlarge, pale with petechial hemorrhages
 Crescents are formed by proliferation of parietal cells and by migration of monocyte/macrophages
into the Bowman’s space
 Focal necrosis, Mesangial proliferation
 Electron microscopy may show distinct ruptures in the GBM
 The crescents eventually obliterate Bowman’s space and compress the glomeruli resulting in severe
oliguria
Post-Streptococcal GN Rapidly Progressive GN
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Diabetic Nephropathy
Q.A 62 years old female from Hayatabad Peshawar presents with generalized body edema. Labs show
Hypoalbuminemia and micro albuminuria. Fasting blood sugar levels are more than 200mg/dl on two consecutive
days. The patient gives history of “fainting episodes” for which she had been consulting the local Hakeem Zahir
Shah. What spectrum of changes would you expect to find on renal biopsy from this patient?
Glomerular lesion:
 Thickening of GBM
 Diffuse glomerulosclerosis
 Nodular glomerulosclerosis
 Exudates lesion (capsular drops)
Renal vascular lesion:
 Arteriosclerosis
 Hyaline arteriosclerosis of both afferent and efferent arterioles
 Acute and chronic pyelonephritis
 Diffuse mesangial sclerosis
 Necrotizing papillitis
 Tubular lesion: glycogen infiltrate, glycogen nephrosis or “Armani Ebstein’s cells”
Vascular Diseases of Kidney
Hypertension:
Definition:
According to the WHO hypertension is defined as the blood pressure systolic above 160mmHg or diastolic
above 90mmHg
Types:
Primary hypertension:Also called as essential hypertension, there is no secondary cause known
Secondary hypertension: It is hypertension, whichis causedbecause of some secondary disease or
pathology; it can occur because of diseases in various organs and organ systems e.g. diseases of adrenals,
e.g. Cushing syndrome, and pheochromocytoma cause secondary hypertension
Coarctation of aorta, primary hyperparathyroidism, atherosclerosis of the renal vessels, preeclampsia and
Graves’ disease
Classification of Hypertension on the Bases of Types and Causes:
 Essential hypertension: (90-95%)
 Secondary hypertension
Renal:
 Acute glomerulonephritis
 Chronic renal disease
 Polycystic disease
 Renal artery stenosis
 Renal vasculitis
 Rennin producing tumors
Endocrinal:
 Adrenocortical hyperfunctioning ( Cushing syndrome)
 Pheochromocytoma
 Acromegaly
 Hypothyroidism (myxedema)
 Hyperthyroidism (thyrotoxicosis)
 Pregnancy induced
Cardiovascular:
 Coarctation of aorta
 Polyarteritis nodosa
 Increased intravascular volume
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 Increased cardiac output

 Rigidity of the aorta
Neurologic hypertension:
 Psychogenic
 Increased intracranial pressure
 Sleep apnea
Pathogenesis:
Genetic factor play a role in essential hypertension
 Gluco-corticoid remediable Aldosteronism (GRA):
It’s an autosomal dominant genetic defect that leads to congenital hypertension, it produces excess
aldosterone (mineralocorticoid) which under the control of the corticotrophin hormone a mutation in
chromosome 8,allows mutation in the aldosterone synthase and 11beta –hydroxylase with ectopic
hormone production
 Syndrome of apparent mineralocorticoid excess (SAME):
Mutations occur in gene for enzyme 11 beta hydroxysteroid ,which normally diminishes the
mineralocorticoid like effect of Gluco-corticoids so (when this is inactivated) there is increased stimulation
of mineralocorticoid receptors even though the plasma level of mineralocorticoids is normal
 Liddle Syndrome:
Figure: Pathophysiology of Hypertension

Hypertensive Renal Disease:
Morphology of Benign Hypertension (Nephrosclerosis):
Gross:
 The kidneys are symmetrically atrophic
 Renal surface shows diffuse, fine granularity that resembles grain leather
Microscopically:
 Hyaline thickening of the walls of the small arteries and arterioles, known as hyaline arteriosclerosis.
This appears as a homogenous, pink hyaline thickening, at the expense of the vessel lumen, with loss
of underlying cellular details
 The narrowing of the lumen results in markedly decreased blood flow through the affected vessels,
with consequent ischemia in the organ served
 Diffuse tubular atrophy and interstitial fibrosis are present
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Morphology of Malignant Hypertension:

Gross:
 The kidney may be normal in size or slightly shrunken, depending on the duration and severity of the
hypertensive disease
 Small pinpoint hemorrhages may appear on the cortical surfaces from rupture of arterioles or
glomerular capillaries, giving the kidney a ‘’flea-bitten appearance’’
Microscopically:
 Damage to the small vessels is manifested as fibrinoid necrosis
 In large arteries and arterioles, proliferation of the intimal cells after acute injury produces an “onion
skin appearance” .This hyperplastic arteriosclerosis causes marked narrowing of arterioles and small
arteries to the point of total obliteration
Urinary Bladder Carcinoma
Etiological factors
 Cigarette Smoking, Various Occupational Carcinogens
 Arylamines
 Schistosoma Haematobium
 Long Term Analgesic Use
 Heavy Dose Of Analgesic
 Radiation
 Deletion Of Chromosome 9p and 9q
 Specific Cytogenetic Abnormality
Classification of Urinary Bladder Carcinoma
A. Urothelial (transitional) tumors (90%):
 Papilloma
 Exophytic papilloma (to be distinguished from inverted Urothelial papilloma)
This is entirely benign and not associated with ↑ risk for subsequent carcinoma
 Inverted papilloma
 Papillary Urothelial neoplasms of low malignant potential (PUNLMP)
 Low grade and high grade papillary Urothelial cancers
 Carcinoma in situ (CIS, or flat non-invasive Urothelial carcinoma)
 Invasive carcinoma
B. Carcinomas and others (10%):
 Mixed carcinoma
 Squamous cell carcinoma
 Adenocarcinoma
 Small-cell carcinoma Sarcomas
 Sarcomas (5 %)
Pathogenesis of urinary bladder carcinoma
 More in men than in women. 80% between 50 and 80 years
 Some of important contributors include
 Cigarette smoking
 Industrial exposure to arylamines, particularly 2naphthylamine
 Schistosoma Haematobium in endemic areas (Egypt, Sudan) are an established risk for Squamous Cell
Carcinoma
 Deletions in 9p, which contains tumor-suppressor gene p16, are found in low grade papillary tumors
and flat carcinomas in situ
 Deletions in 17p, the site of the p53 gene, are often found in invasive bladder cancers
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Morphology of transition cell carcinoma:

Gross and microscopic findings:
 Low grade cancer: (usually papillary and are not invasive)
 High grade cancer: (papillary or flat and are usually invasive)
 Most common sites: lateral or posterior walls at the base of the bladder
 Significance of blood group antigens (A, B or H)
Laboratory diagnosis:
 Cystoscopy
 Biopsy
 Cytology for cancer cells
 Urine R/E for cancerous epithelial cells
Q. Sections from transurethral resection of a bladder tumor reveal lamina propria invasion by a papillary Urothelial
carcinoma.
a) What is pathologic stage T (primary tumor) for this tumor?
b) Illustrate the four gross morphologic types of bladder cancer.
c) Give the American Joint Commission on cancer (AGCC) TNM staging for Urothelial carcinoma of
urinary bladder.
Stage T1 (T1)
Gross morphological types of bladder carcinoma
 Papilloma papillary carcinoma
 Invasive papillary carcinoma
 Flat non-invasive carcinoma
 Flat invasive carcinoma
TNM staging for urinary bladder carcinoma:

Ta Noninvasive, papillary
Tis Carcinoma in situ (noninvasive, flat)
T1 Lamina propria invasion
T2 Muscularis propria invasion
T3a Microscopic extra-vesicle invasion
T3b Grossly apparent extra-vesicle invasion
T4 Invades adjacent structures
N0 No nodal involvement
N1, N2 Single node involvement
N3 More nodal involvement
M0 No metastasis
M1 Distant metastasis
Classify Diseases Affecting Tubules and Interstitium

A. Tubulointerstitial nephritis:
Causes of Tubulointerstitial Nephritis:
 Infections: (acute bacterial pyelonephritis, chronic pyelonephritis)
 Toxins: (drugs, analgesic, heavy metals)
 Metabolic diseases (urate nephropathy, acute phosphate nephropathy)
 Physical factors ( chronic urinary tract obstruction)
 Neoplasms (multiple myeloma)
 Immunologic reactions (Transplant Rejection, Sjogren’s Syndrome, Sarcoidosis)
 Vascular disease
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Tubulointerstitial nephritis types:

 Acute pyelonephritis
 Chronic pyelonephritis
 Drug induced interstitial nephritis
B. Acute tubular necrosis
C. Diffuse cortical sclerosis
Acute Pyelonephritis:
Definition:
It is an acute suppurative inflammation of the kidney caused by bacterial infection.
Etiology:
 Gram-negative bacilli e.g. E.coli (commonest one), Proteus, Klebsiella Pneumoniae and Pseudomonas
 Streptococcus fecalis and staphylococcus are uncommon
Pathogenesis of acute pyelonephritis:
 Adhesion of bacteria to the mucosal surfaces:
 Hematogenous infection: (E.coli, staphylococcus)
 Ascending infection: (E.coli, Proteus, Enterobactor, Pseudomonas, Klebsiella)
 Instrumentation: catheterization and cystoscopy
 Urinary obstruction: congenital or acquired, (in the stasis of urine bacteria multiply)
 Increased vesicoureteral reflex
 Pregnancy
 Preexisting renal lesion
 Patient’s sex and age: male and advancing age
 Immunosuppression and immunodeficiency
Morphology:
Gross:
 Discrete, yellowish, raised abscesses are grossly apparent on the renal surface
 They may coalesce to form a single large area of suppuration
Microscopically:
 Characteristic histologic feature of acute pyelonephritis is liquefactive necrosis with abscess
formation within the renal parenchyma
 In the early stages pus formation (suppuration) is limited to the interstitial tissue, but later abscesses
rupture into tubules
 Large masses of intratubular neutrophils frequently extend within involved nephrons into the
collecting ducts, giving rise to the characteristic white cell casts found in the urine
Papillary Necrosis:
 It is a second form of pyelonephritis where there is necrosis of the renal papillae. There are three
predisposing conditions for this: Diabetes, Urinary tract obstruction, and Analgesic abuse
 This lesion consists of a combination of ischemic and suppurative necrosis of the tips of the renal
pyramids (renal papillae)
 The pathognomonic gross feature of papillary necrosis is sharply defined gray-white to yellow
necrosis of the apical two thirds of the pyramids. One papilla or several or all papillae may be
affected
 Microscopically, the papillary tips show characteristic coagulative necrosis, with surrounding
neutrophilic infiltrate
 Urine Examination
 Urine culture is done to isolate the organism
 Hematuria is commonly seen in acute pyelonephritis
 Pus cells and white cell cast are also seen
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 Blood
 TLC ↑, ESR↑, creatinine level slightly raised
 Intravenous Pyelogram
 Asymmetry between the kidneys is evident
 Patchy lesion of the kidney can also be seen
Complication
 Chronic pyelonephritis
 Perinephric abscess
 Recurrence
Chronic Pyelonephritis:
Morphology:
Gross:
 One or both the kidneys may be involved, either diffusely or patchily
 kidneys are irregularly contracted and scarred but their involvement is asymmetrical
 Pelvic and calyceal walls are thickened and distorted
 Papillary blunting is a common feature
 Their mucosa is granular or atrophied
Microscopically
 Dilatation or contraction of the tubules with atrophy of lining epithelium is observed
 pink to blue glassy colloid cast is seen in dilated tubule and it is called ‘’thyroidization’’of the kidney
 Glomerular lesion and hyalinization are commonly seen
 Chronic inflammatory infiltration and fibrosis also involve the calyceal mucosa and the wall
Acute Tubular Necrosis (ATN):
 ATN is characterized morphologically by destruction of tubular epithelial cells and clinically by acute
suppression of renal function.
Types of ATN
 Ischemic ATN
 Nephrotoxic ATN
Pathogenesis:
Figure: Pathophysiology of ATN

Clinical features of ATN
 1 phase decline in urine output due to decrease in renal blood flow
st
 2 Oliguric phase: marked oliguria and uremia

nd
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
rd
3 Diuretic phase: damage tubular epithelium is replaced by a simple type which has not yet
developed concentrating activity, so large volume of dilute urine is passed, resulting in dehydration,
electrolyte imbalance and acidosis
 4 recovery phase: Progressive return to normal function
th
Differences between ischemic and nephrotoxic ATN:

Ischemic ATN Nephrotoxic ATN
Causes: acute pancreatitis, mismatch transfusion, Causes: metals, contrast media, gentamycin like
septicemia, hemolytic crisis,shock drugs, organic solvent etc.
Involve proximal convoluted tubule and ascending limb Only proximal convoluted tubule involve
Oliguria is present Oliguria absent
Blebbing and shedding of brush border, basement Basement membrane is intact
membrane rupture
Cast: eosinophilicbrown granular cast are seen in urine Cast: nonspecific CCL4 lipoid cast
pigment granular cast consisting of Tamm-Horsfall protein,
Hb and myoglobin
Hematuria:
Hematuria is defined as ‘’the Presence of blood or blood cells castes in urine’’
Causes of hematuria:
 Upper urinary tract (kidney, ureter)
 Renal stone
 Glomerulonephritis
 Renal cell carcinoma
 Lower urinary tract (bladder, urethra, prostate)
 Infection
 Transitional cell carcinoma
 Benign prostatic hyperplasia
 Drugs associated with hematuria
 Anticoagulant (warfarin and heparin)
 Cyclophosphamide (hemorrhagic cystitis)
Cause of painless hematuria:
 Benign Papilloma
 Urothelial (Transitional Cell Carcinoma)
 Squamous Cell Carcinoma
 Papilloma Papillary Carcinoma
 Invasive Papillary Carcinoma
 Flat Non-Invasive Carcinoma
 Renal Cell Carcinoma
Renal Tumors
Classification of kidney tumors:
A. Epithelial tumors of renal parenchyma:
 Adenoma
 Renal cell carcinoma
B. Epithelial tumors of renal pelvis:
 Transitional cell papilloma
 Squamous cell carcinoma
 Adenocarcinoma of renal pelvis
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C. Nephroblastic (Embryonal)Tumors:
 Nephroblastoma: (Wilm’s tumor)
 Mesoblastic nephroma
 Multicystic nephroma
D. Non-epithelial tumors:
 Angiomyolipoma
 Fibroma
 Sarcoma
 Oncocytoma
E. Metastatic tumors
F. Un-classified tumors
G. Tumors like lesion:
 Renal blastema
 Renal dysgenesis
 Renal cysts
 Hemorrhagic fluid
Renal Cell Carcinoma (RCC):
Classification of renal cell carcinomas:
A. Clear cell carcinoma
B. Papillary renal cell carcinoma
C. Chromophobe renal cell carcinoma
Risk factor for renal cell carcinoma
 Smoking
 Genetics factor positive family history
 Cystic disease of the kidney
 Exposure to asbestos, heavy metal and petrochemical product
 In women obesity and estrogen therapy
 Analgesic nephropathy
 Tuberous sclerosis
Pathogenesis of Renal cell carcinoma
 Involve loss of VHL (von Hippel Lindau) (3p) tumor suppressor gene is a key step in the development
of RCC
 The VHL protein causes the degradation of hypoxia-induced factors (HIFs) and in the Absence of VHL,
HIFS is stabilized. HIFs are transcription factor that contribute to Carcinogenesis by stimulating the
expression of vascular endothelial growth factor(VEGF) as well as number of other genes that drive
tumor cell growth
Morphology of Renal cell carcinoma:
Gross:
These tumors are large, spherical masses. On Cut section: yellow gray white with area of cystic softening
or hemorrhage
Microscopically:
Microscopically, there are two distinct types of cells in the RCC i.e.
Clear cells: they are vacuolated lipid laden cells in which nucleoli are usuallypushed basally
Granular cells/solid cells: with granular pink cytoplasm and round small regular nuclei
Clinical Feature
Renal Features
 Hematuria
 Dull flank pain
Extra Renal Features
 Fever
 Polycythemia due to increased erythropoietin
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 Hormone like substance release causing hypertension, Cushing syndrome, feminization or

masculinization
Note: The triad of painless hematuria, long standing fever and dull flan pain is characteristics for renal cell
carcinoma
Laboratory diagnosis of renal cell carcinoma:
 Urine examination shows pus cells, malignant cells i.e. clear vacuolated cells
 I.V pyelography show filling defect, elongation or compression of calyces etc.
 Renal ultrasonography to localize the tumor
 Renal scan to localize the tumor
 Renal biopsy to confirm the diagnosis
 Chest X ray to see the metastasis
 Bone scans to see the metastasis
 Bone marrow aspiration to see neoplastic cells
 Nonspecific tests: CBC, ESR etc.
Wilm’s Tumor:
Pathogenesis of Wilm’s tumor:
 A defect in chromosome 11, including tumor suppressor gene WT-1 result in abnormal growth of
metanephric blastema
 In the inherited form of the disease, one allele is inherited in a defective form and the other suffers
an acquired mutation. This show that both the normal alleles should be lost to acquire Wilm’s tumor
 Associated with WAGR syndrome and beckwith wiedermann
Morphology of Wilm’s tumor (Nephroblastoma):
Gross:
 Unilateral palpable mass in a child with hypertension. Hypertension is due to rennin secreting tumor
 Large necrotic gray tan tumor
 Derived from mesonephric mesoderm
 Lungs are the most common site of the metastasis
Microscopic:
 Contain abortive glomeruli and tubules, primitive blastema cells and rhabdomyoblasts
 Shows nests and sheets of primitive blastema with intervening mesenchyme
 Foci of muscles, bones, cartilage containing cholesterol crystals and lipid macrophages may be seen
 Degree of anaplasia in the stromal component correlate with prognosis
Cystic Diseases of Kidney
Classificationof cystic diseases of the kidney:
 Multicystic renal dysplasia
 Polycystic kidney disease:
 Autosomal dominant (adult) polycystic disease
 Autosomal recessive (childhood) polycystic disease
 Medullary cystic disease: a. Medullary sponge kidney b. Nephronophthisis
 Acquired ( dialysis associated) cystic disease
 Localized ( simple) renal cyst
 Renal cyst in hereditary malformation syndrome
 Glomerulocystic disease
 Extraparenchymal renal cysts
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Hydronephrosis
Definition:
Refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma caused
by obstruction to the outflow of urine
Causes:
 Congenital anomalies:
 Uretharal Stricture, Meatal Stenosis, Bladder Neck Obstruction
 Acquired:
 Urinary calculi
 Benign prostatic hypertrophy (BPH)
 Tumors: (carcinoma of prostate, bladder tumors)
 Inflammation: (prostatitis, urethritis)
 Sloughed papillae or blood clots
 Pregnancy
 Uterine prolapse and cystocele
 Functional disorders: (neurogenic)
Renal Stones:
Main Types Urolithiasis With Prevalence.
 Calcium oxalate and phosphate: 70%
 Magnesium ammonium phosphate: 15-20%
 Uric acid: 5-10%
 Cysteine: 1-2%
 Xanthine
Pathogenesis:
 Calcium Stones:
Calcium stones develop with hypercalciuria that is not associated with Hypercalcemia. Most in this
group absorb calcium from the gut in excessive amounts (absorptive hypercalciuria) and promptly
excrete it in the urine, and some have a primary renal defect of calcium reabsorption (renal
hypercalciuria). It occurs in alkaline pH
 Magnesium Stones (Triple Phosphate):
Magnesium ammonium phosphate (struvite) stones almost, always occur in persons with persistently
alkaline urine resulting from UTIs. In particular, infections with urea-splitting bacteria, such as
Proteus vulgaris and staphylococci
 Uric Acid Stones:
Occurs in cases where there is increase turnover of cells like leukemia etc. where there is more
increase amount of uric acid in urine (hyperuriceamia). It occurs in acidic pH
 Cysteine Stones:
Cysteine stones are almost invariably associated with a genetically determined defect in the renal
transport of certain amino acids, including cysteine
Note: Staghorn calculus occurs in alkaline urine in which the phosphate stone enlarge rapidly and often fill
the calyces, taking branching shape and therefore called Staghorn calculus
Complications:
 Recurrent infections
 Hydronephrosis
 Pyelonephrosis
 Urinary retention
 Renal failure
 Malignant transformation
Laboratory diagnosis of kidney stones:
 Ultrasound (the most important initial test conducted)
104
 X ray
 Showing opaque stones in case of Calcium and magnesium stones. Whereas radiolucent stones
such as uric acid, Xanthine and cysteine
 Urine R/E
 Cystoscopy
 Intravenous Pyelogram
Adult polycystic kidney disease
Genetics and pathogenesis of polycystic kidney disease
 The PKD1 gene encodes a large integral membrane protein named Polycystin-1
 It has been localized to tubular epithelial cells, particularly to those of the distal nephron
 Its precise function is not known but it contains a domains that are usually involved in Cell-cell
interaction and cell-matrix interactions
 The PKD2 gene product is Polycystin-2 is an integral membrane product
 It has been localized to all segments of renal tubules and is expressed in many extra adrenal tissues
 Some evidence indicates thatPolycystin-2 act as Ca permeable cation channel and that a basic
2+
defect in Adult polycystic kidney disease is a disruption in the regulation of intracellular Ca2+ levels
Morphology of adult polycystic kidney disease:
Gross appearance:
 The kidneys are usually bilaterally enlarged and may achieve enormous sizes; weights up to 4 kg for
each kidney have been reported.
 The external surface appears to be composed solely of a mass of cysts, up to 3 to 4 cm in diameter,
with no intervening parenchyma.
Microscopic examination:
 Reveals functioning nephrons dispersed between the cysts.
 The cysts may be filled with a clear, serous fluid or, more usually, with turbid, red to brown,
sometimes.
Acute renal failure
Definition:
Acute renal failure is a syndrome characterized by:
 Rapid decline in glomerular filtration rate (hours to days )
 Retention of nitrogenous wastes due to failure of excretion
 Disturbance in extracellular fluid volume and
 Disturbance in electrolyte and acid base homeostasis
Based on the amount of urine output acute renal failure may be classified as
 Anuric: If urine volume is less than 100 ml/day
 Oliguric: If urine volume is less than 400 ml/day
 Non-oligouric: If urine volume is greater than or equal 400 ml/day
Etiologic classification of acute renal failure
Prerenal ARF: account for nearly 55 % of all cases of acute renal failure
Hypovolemia
 Hemorrhage, burns, dehydration
 Gastrointestinal fluid loss: vomiting, surgical drainage, diarrhea
 Renal fluid loss: diuretics, osmotic diuresis (e.g., diabetes mellitus), hypoadrenalism
 Sequestration in extravascular space: pancreatitis, peritonitis, trauma, burns, severe
Hypoalbuminemia
Low cardiac output
 Diseases of myocardium, valves, and pericardium; arrhythmias; tamponed
 Other: pulmonary hypertension, massive pulmonary embolus
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Altered renal systemic vascular resistance ratio

 Systemic vasodilatation: sepsis, anaphylaxis IV. Renal hypoperfusion with impairment of renal
autoregulatory responses
 NSAIDS, angiotensin-converting enzyme inhibition
Renal ARF: account for nearly 40% of all ARF
 Renovascular obstruction(bilateral or unilateral in the setting of one functioning kidney)
 Disease of glomeruli or renal microvasculature
 Acute tubular necrosis:
 Ischemia: as for prerenal ARF (hypovolemia, low cardiac output, renal vasoconstriction,
systemic vasodilatation), obstetric complications (abruptio placentae, postpartum
hemorrhage)
 Toxins
 Exogenous: radio contrast, cyclosporine, antibiotics (e.g. aminoglycosides), chemotherapy
(e.g., cisplatin), organic solvents (e.g. ethylene glycol), acetaminophen, illegal abortifacients
 Endogenous: rhabdomyolysis, hemolysis, uric acid, oxalate, plasma cell dyscrasia (e.g.,
myeloma)
 Interstitial nephritis
Post renal ARF (OBSTRUCTION): account for 5% of ARF.
Ureteric:
 Calculi, blood clot, sloughed papillae, cancer, external compression (e.g. retroperitoneal fibrosis)
Bladder neck:
 Neurogenic bladder, prostatic hypertrophy, calculi, cancer, blood clot
Urethra:
 Stricture, congenital valve, phimosis
Pathophysiology:
 Hypovolemia leads to glomerular hypoperfusion, but filtration rate are preserved during mild
hypoperfusion through several compensatory mechanisms. During states of more severe
hypoperfusion, these compensatory responses are overwhelmed and GFR falls, leading to prerenal
ARF
 Drugs that interfere with adaptive responses in the renal microcirculation may convert compensated
renal hypoperfusion into overt prerenal ARF or trigger progression of prerenal ARF to ischemic
intrinsic renal ARF (ACE-inhibitors, NSAIDS)
Intrinsic ARF:
 Intrinsic renal ARF can complicate many diverse diseases of the renal parenchyma.
 Most intrinsic renal ARF is triggered by ischemia (ischemic ARF) or nephrotoxins (nephrotoxic ARF),
insults that classically induce acute tubular necrosis (ATN).
Complications of ARF:
 Intravascular overload: may be recognized by weight gain , hypertension , elevated central venous
pressure ( raise JVP) , Pulmonary edema
 Electrolyte disturbance:
 Hyperkalemia: (serum K >5.5 mEq/L) develops as a result of decreased renal excretion combined
+
with tissue necrosis or hemolysis.

 Hyponitremia: ( serum Na concentration < 135 mEq/L ) results from excessive water intake in
+
the face of excretory failure

 Hyperphosphatemia : ( serum Phosphate concentration of > 5.5 mg /dl ) results from failure of
excretion or tissue necrosis
 Hypocalcaemia: ( serum Ca < 8.5 mg/dl ) results from decreased Active Vit-D ,
++
Hyperphosphatemia , or Hypoalbuminemia
 Hypercalcemia: (serum Ca > 10.5 mg /dl) may occur during the recovery phase following
++
rhabdomyolysis induced acute renal failure.

 Metabolic acidosis: ( arterial blood PH < 7.35 ) is associated with sepsis or sever heart failure
106
 Hyperuriceamia: due to decreased uric acid excretion

 Bleeding tendency:May occur due to platelet dysfunction and coagulopathy associated with sepsis
 Seizure:May occur related to uremia
Urinalysis: Microscopic evaluation of urinary sediment
 Presence of few formed elements or hyaline casts is suggestive of prerenal or postrenal azotemia
 Many RBCs may suggest calculi, trauma, infection or tumor
 Eosinophilia: occurs in 95 % of patients with acute allergic nephritis
 Brownish pigmented cellular casts and many renal epithelia cells are seen in patients with acute
tubular necrosis (ATN)
 Pigmented casts without erythrocytes in the sediment from urine but with positive dipstick for occult
blood indicates hemoglobinuria or myoglobinuria
 RBCs and RBC casts in glomerular diseases
 Crystals RBCs and WBCs in post-renal ARF-
Urine and blood Chemistry: most of these tests help to differentiate prerenal azotemia, in which tubular
reabsorption function is preserved from acute tubular necrosis where tubular reabsorption is severely
disturbed
Radiography/imaging
 Ultrasonography:Helps to see the presence of two kidneys, for evaluating kidney size, shape and for
detecting Hydronephrosis or hydroureter. It also helps to see renal calculi, and renal vein thrombosis
 Retrogradepyelography: is done when obstructive uropathy is suspected
Chronic renal failure
Definitions:
Chronic Renal failure : progressive and irreversible reduction of the renal function, over aperiod of more
than 6 months, to a level less than 20 % of the normal, as a result of destruction of significant number of
nephrons.
Etiologies
Prerenalcauses:
 Sever long standing renal artery stenosis
 Bilateral renal artery embolism
Renalcauses:
 Chronic glomerulonephritis: Primary or secondary forms (30%)
 Chronic Tubulointerstitial disease:vesicoureteral reflux, and chronic pyelonephritis (in adolescents)
 Vascular disease:- hypertensive nephrosclerosis
 Diabetic nephropathy
 Connective tissue diseases: SLE, scleroderma
 Hereditary disease:-polycystic kidney disease
Post renal causes:
 Obstructive nephropathy: Urolithiasis, Benign Prostatic Hypertrophy, Chronic Glomerulonephritis,
Hypertension and diabetic nephropathy are the commonest causes for ESRD
Pathophysiology:
 Uremic manifestations occur mainly due to accumulation of nitrogenous wastes and the reason for
accumulation of these wastes is decreased renal excretion and reduced catabolizing capacity of the
kidney
 Most toxins in uremia are by products of proteins and amino acid metabolism, because unlike
carbohydrates and fats, which are metabolized to CO2and H2O, which can be excreted through the
lungs and skin, by products of protein are non-volatile organic acids
107
Clinical Manifestations and Complications of Chronic Renal Failure:

1. Fluid, electrolyte and acid base disturbance
 Volume expansion and contraction (edema, dehydration)
 Patients with CRF also have impaired renal mechanisms for conserving Na and H2O. When an
+
extra renal cause for fluid loss is present (e.g., vomiting, diarrhea, sweating, fever), these patients
are prone to volume depletion and dehydration
 In the face of Sodium intake patients may retain Na and water which may lead to congestive
+
heart failure, peripheral edema and ascites

 Potassium Homeostasis:-
 Most commonly, clinically significant hyperkalemia does not occur until the GFR falls to below 10
mL/min
 Factors that contribute to increased serum K level are
+
 Endogenous a K load (e.g., hemolysis, trauma, infection) or

+
 Exogenous K e.g., administration of stored blood, K+-containing medications, K+-containing

+(
dietary salt substitute)

 Acidosis: facilitates influx of K+ form ICF to ECF
 Drugs: potassium sparing diuretics, ACE inhibitors
 Metabolic Acidosis:-
 Acidosis is a common disturbance during the advanced stages of CRF. With advancing renal
failure, total urinary net daily acid excretion is usually reduced markedly
2. Renal Osteodetrophy and Metabolic Bone Disease:
 Is due to disturbance in bone phosphate and calcium metabolism
 Hyperphosphatemia is a feature of advanced renal failure. The serum phosphate concentration rises
in patients with a GFR < 20 mL/min
 Calcium: The total plasma Ca concentration in patients with CRF is often significantly lower than
2+
normal. Patients with CRF tolerate the hypocalcaemia quite well; rarely is a patient symptomatic from
2+ ++
the decreased Ca concentration. Note that the low serum level of Ca is attributed to secondary
hyperparathyroidism
 Reduced synthesis of vitamin D play a key role in the pathogenesis of hyperparathyroidism, both
directly and through hypocalcaemia
 Some of the resulting bony abnormalities are:
 Ostitis fibrosa cystica: is due to osteoclastic bone resorption of specially terminal phalanges , long
bones and distal end of clavicle
 Renal rickets (Osteomalacia)
 Osteosclerosis: enhanced bone density in the upper and lower margins of vertebrae
3. Cardiovascular complications
 Congestive heart failure and/or pulmonary edema: it may be due to
 Volume over load
 Increase pulmonary capillary permeability
 Hypertension:
 Is the most common complication of end stage renal disease
 It results from fluid overload
 Sometimes sever form of hypertension may occur
 Pericarditis: metabolic toxins are responsible for pericarditis:
 The finding of a multicomponent friction rub strongly supports the diagnosis
 The pericardial effusion is often hemorrhagic
4. Hematologic abnormalities :
 Normocytic normochromic anemia: which may be severe ( Hb 4-6 gm/dl)
 The cause of anemia is multifactorial
 Decreased synthesis of erythropoietin (the most important factor)
 Toxins suppressing bone marrow function
108
 Bleeding tendency: attributed to platelet dysfunction

 Patients may manifest with bleeding and easily bruiseability
 GI bleeding
 Intracranial hemorrhage
 Susceptibility to infection: is due to
 Change in leukocyte formation and function
 Serum creatinine and blood urea nitrogen measurement
 Hemoglobin
 Electrolytes: calcium, phosphate, and alkaline phosphates to assess metabolic bone disease
 Urinalysis:
 May be helpful in assessing the presence of ongoing activity of the underlying inflammatory or
proteinuric disease process, and when indicated should be supplemented by a 24 hour urine
collection for quantifying protein excretion
 The presence of broad casts on examination of the urinary sediment is a nonspecific finding seen
with all diverse etiologies and reflects an advanced stage of CRF
 Ultrasonography of kidneys:
 An ultrasound examination of the kidneys verifies the presence of two symmetric kidneys,
provides an estimate of kidney size, and rules out renal masses and obstructive uropathy
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Chapter Six ORAL CAVITY AND GASTROINTESTINAL TRACT
Diseases of Oral Cavity

Leukoplakia:
 Normally refers to a condition where areas of keratosis appear as firmly attached white patches or
plaque on the mucous membranes of the oral cavity
Sites
 Most often on the lower lip, buccal mucosa and soft palate
Etiology
 Exact cause unknown
 Strong association with use of tobacco
 Less commonly associated with alcohol abuse, ill-fitting dentures and irritant food
Complication
 About 5-15% ofthe cases leads to squamous cell carcinoma of oral cavity
Biopsy
 Biopsy of the lesion should be performed as it is considered as a premalignant condition
Erythroplakia:
 Any lesion of the oral mucosa that presents as bright red velvety plaques, which cannot be,
characterized clinically or pathologically as any other recognizable condition. Erythroplakia is a
premalignant lesion
Sites
 Most common area in the mouth where erythroplakia is found are the floor of the mouth , buccal
vestibule, the tongue and the soft palate . It also occur on the laryngeal mucosa
Etiology
 It is found in elderly men around the ages of 65-74
 It is commonly associated with smoking
 Alcohol and tobacco use have been described as risk factor
Complication
 Squamous cell carcinoma is found in almost 40 % of erythroplakia
Note: Erythroplakia is a much greater risk factor of malignant transformation than leukoplakia
Ulcerative lesion of the oral cavity:
 Herpetic Ulcer
 Aphthous Ulcer (Canker Sores)
 Candidiasis Ulcer
 Ulcer of Glossitis
 Ulcer of Necrotizing Ulcer Gingivitis (Fusospirochetal Infection)
 Ulcer Associated With Xerostomia (Sjogren’s Syndrome)
 Malignant Ulcer
 Ulcer Associated With Systemic Diseases(Syphilis, Measles, HIV andPemphigus)
 Ulcer Associated With Hematological Disease (Pancytopenia, Aplastic Anemiaetc.)
 Bechet’s Disease
Oral Cancer:
Q. A 60 years old female comes for consultation in your clinic with history of local pain at the base of tongue and
difficulty in chewing. Previously she has been asymptomatic and that recently she has noticed ulceration at
mentioned site. She has suspected to have a neoplastic lesion.
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Oral Cavity and
a) What are the risk factors that makes her a candidate for an oral cancer?
b) Give the morphological details of squamous cell carcinoma.
c) Enumerate the risk factors for carcinoma of the esophagus.
Risk factors for Oral Cancer:
Factors Comments
Leukoplakia, erythroplakia 3-25% in leukoplakia, more than 50% in Erythroplakia

Tobacco use Best established influence, particularly pipe smoking
Human papilloma virus type 16 and 30-50% chances
18
Alcohol abuse Weaker influence than tobacco use
Protracted irritation Weakly associated
Morphology:
Location:
 Vermilion border of the lateral margins of the lower lip
 Floor of the mouth
 Lateral borders of the mobile tongue
Early lesions appear as pearly white to gray circumscribed thickening of the mucosa. Closely resembling
Late lesions may grow in an Exophytic fashion to produce readily visible and palpable Nodular and
fungating lesions.
Eventually the lesions may assume an endophytic, invasive pattern with central Necrosis to produce
cancerous ulcer.
Microscopy:
 Moderately to well differentiated keratinizing tumors
 Epithelial Atypia
 Dysplasia
 Carcinoma in situ in the margin
 Metastasis rarely with lip cancers
Salivary Gland:
Classifications Salivary Gland Tumors
Benign Malignant
Pleomorphic adenoma Mucoepidermiod carcinoma
Warthin tumor Adenocarcinoma
Oncocytoma Acinic cell carcinoma
Basal cell adenoma Adenoid cystic carcinoma
Squamous cell carcinoma
Ductal papilloma Malignant mixed tumor
Adenoid Cystic Adenoma:
Relatively uncommon 5%. Recurrence is common
Morphology:
Gross appearance:
 Generally small, poorly encapsulated, infiltrative, gray pink lesion
Histologically:
 Composed of small cell having dark, compact nuclei and scant cytoplasm. The spaces b/w tumor cells
are filled by hyaline material
 Perineural involvement
 Cribriform pattern
111
Oral Cavity and
Esophagus:
Esophageal varices:
 The abnormal dilatation of the esophageal veins and venous plexus is called esophageal varices
Etiology and pathogenesis:
 The basic cause of esophageal varices is the portal hypertension that results in liver cirrhosis, during
which bypass develops and the blood flows from the portal circulation into the systemic circulation
especially at the lower end of the esophagus.
 The increased pressure in the esophageal plexus produces dilatation called varices. Varices occur in
approximately 2/3 of all cirrhotic patients. The varices may rupture and result in hematemesis.
Clinical features:
 Varices produced no symptom until they rupture
 Rupture of varices produced massive hemorrhage
 Most common cause of death in cirrhotic patients
Barret esophagus:
 Barrett esophagus refers to an abnormal change (metaplasia) in the cells of lower portion of
esophagus.
 The normal stratified squamous epithelial lining of the esophagus is replaced by simple Columnar
epithelium with goblet cells.
 Premalignant condition increases the risk of esophageal adenocarcinoma
CAUSE: adaption to chronic acid exposure from Reflux Esophagitis
DIAGNOSIS: Biopsy, Endoscopy
 Typically present b/w 40-60 years of age
 Frequent, longstanding heartburns
Complications include:
 Ulceration
 Distal adenocarcinoma
Esophageal Carcinoma:
Q. A 65-year-old writer with history of 45 packs develops progressive dysphagia to solid and liquids. An endoscopy
reveals a 5cm ulcerated mass in the middle esophagus. The esophageal function is normal.
Risk factors for esophageal carcinoma:
Esophageal disorders:
 Long-standing esophagitis
 Achalasia
 Plummer Vinson syndrome
Life style:
 Alcohol consumption
 Tobacco abuse
Dietary:
 Deficiency of vitamin A, C, riboflavin
 Deficiency of trace metals (zinc, molybdenum)
 Fungal contamination of food stuffs
 High contents of nitrites
Genetic predisposition:
 Tylosis ( hyperkeratosis of palm and sole)
112
Oral Cavity and
Risk Factor for Esophagus Carcinoma:
Alcohol Familial
Barret Esophagus Obesity
Esophagitis Esophageal Web
GERD(Gastro Esophageal Reflux Disease) Achalasia
Smoking Hot Liquid Intake
PlummerVinson Syndrome Deficiency Of Vitamins
Diverticula(Zenker’s Diverticula) Deficiency Of Trace Elements (Iron, Zn etc.)
Location
 Middle third 50-60 %
 Lower third 30-40%
 Upper third 10-20 %
Pathology
 Squamous cell carcinoma in 80 -90 %
 Adenocarcinoma in 10-20 %
 Undifferentiated carcinoma in 5-10 %
Squamous cell carcinoma (SCC)
 SCC is preceded by epithelial dysplasia and carcinoma in situ
 3 pattern of squamous cell carcinoma
 Fungating Polypoid lesion –protrude into the lumen
 Ulcerating lesions –extends deeply into the surrounding structure
 Diffuse infiltrating lesions-spread in the wall of esophagus
 ↑ Production of Vascular Endothelial Growth Factor (VEGF) in squamous cell esophageal neoplasm
Adenocarcinoma
 Typically arising in Barrett’s esophagus = abnormal change (metaplasia, most common in obese
persons) incells of lower end of esophagus caused by chronic acid exposure (reflux esophagitis), with
normal lining of esophagus (squamous epithelium) replaced by intestinal - type glandular epithelium
of three different types:
 Metaplastic columnar epithelium;
 Metaplastic parietal cell glandular epithelium within esophageal wall;
 Metaplastic intestinal epithelium with typical goblet cells (columnar epithelial cells whose function is
to secrete mucin), where dysplasia more likely develops
Pathogenesis
 p53 mutation (early event in carcinogenesis) in advanced dysplasia and carcinoma in situ in
adenocarcinoma
 with G1 cell having low level of DNA damage,p53 protein hampers entering S phase and copy its DNA
(→abnormal G1 cells undergo programmed cell death, i.e. apoptosis or growth arrest and DNA
repair); with G1 cell having high level of DNA damage and mutant p53 → cell dividesand undergoes
clonal expansion, evolution and cancerization.
 Overexpression of Cyclin D1 gene: Cyclin activates Cyclin -dependent kinases (CDK), leading to pRB
(retinoblastoma protein, a tumor suppressor) phosphorylation in adenocarcinoma.
Clinical features
 Initial symptoms: progressive dysphagia (difficulty in swallowing, initially with solid foods and
gradually with semisolids and liquids);by the time these symptoms develop disease is usually
incurable (dysphagia occurs when > 60% of esophageal circumference infiltrated by cancer)
 Dysphagia may be associated with pain on swallowing (odynophagia), pain radiating to chest and or
back, regurgitation or vomiting, aspiration pneumonia and weight loss
Spread
Disease most commonly spreads to adjacent and supraclavicular lymph nodes, liver, lungs, pleura and
bones.
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Oral Cavity and
Diagnosis
 Endoscopy
 Biopsy
 Esophagoscopy
 Double contrast radiographs
 Barium swallow
Esophageal Pathologies:
Gastroesophageal reflux Commonly presents as heartburn and regurgitation upon lying down. May also
disease (GERD) present with nocturnal cough and dyspnea, adult onset asthma. Decrease in
lower esophageal sphincter tone
Esophageal varices Painless bleeding of dilated Submucosal vein in lower 1/3 of esophagus
secondary to portal hypertension
Esophagitis Associated with reflux, infection (Candida: white pseudomembrane; HSV-1:
punched out ulcers; CMV: linear ulcers), or chemical ingestion
Mallory Weiss syndrome Mucosal lacerations at the Gastroesophageal junction due to sever vomiting,
lead to hematemesis. Usually found in alcoholic and bulimics
Boerhaave syndrome Transmural esophageal rupture due to violent stretching or retching
Esophageal stricture Associated with lye ingestion
Plummer Vinson syndrome Triad of Dysphagia, Glossitis and Iron deficiency anemia
Stomach:
Gastritis:
It is an inflammation of the Gastric mucosa, resulting in multiple clinical disorders
Acute Gastritis
 Acute gastritis is a transient mucosal inflammatory process that may be asymptomatic or cause
variable degrees of epigastric pain, nausea, and vomiting
 In more severe cases there may be mucosal erosion, ulceration, hemorrhage, hematemesis, melena,
or, rarely, massive blood loss
Morphology and its course
 Mild acute gastritis may be difficult to recognize, since the lamina propria shows only edema and
slight vascular congestion
 The surface epithelium is intact, although scattered neutrophils may be present among the epithelial
cells or within mucosal glands. The presence of neutrophils above the basement membrane in direct
contact with epithelial cells signifies active inflammation
 Acute superficial gastritis cause inflammation of superficial gastric mucosa
 Erosive gastritis cause destruction of multiple small zones of superficial mucosa
 Acute gastric ulceration cause destruction of full thickness of mucosa
 Hemorrhage may occur and cause dark punctae in a hyperemic mucosa
 Concurrent erosion and hemorrhage is termed acute erosive hemorrhagic gastritis
Pathogenesis:
 Exact cause unknown, following are the predisposing factors
 Prolonged use of NSAID particularly aspirin
 Staphylococcal food poisoning
 Heavy smoking and excessive use of alcohol
 Severe stress and shock
Complication of Acute gastritis:
 Acute gastric ulceration
 Perforation
 Hemorrhage
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Oral Cavity and
Chronic gastritis:
Definition:
It is a histological demonstration of lymphocytic and plasma cell infiltration of gastric mucosa.
Course:
 Superficial gastritis is followed by atrophic gastritis (characterized by distortion and destruction of
gastric glands) progressing to gastric atrophy (with loss of gastric glands), which then undergo
intestinal metaplasia (replacement of gastric mucosal cells by intestinal epithelial cells) and finally
progressing to gastric carcinoma
Chronic Gastritis is classifiedinto two types:
Type A-Gastritis (Autoimmune Gastritis)
 The inflammation is limited to gastric fundus and body with Antral sparing
 Associated with pernicious anemia, with circulating autoantibodies to parietal cells, which is why it is
also known as autoimmune gastritis
Type B- Gastritis (Chronic Antral Gastritis)
 It is more common than type A gastritis
 It commonly involves the antrum and mostly associated with H. pylori infection. However, the
inflammation may progress to involve the gastric fundus and body causing pangastritis usually after
15 - 20 years
Pathophysiology type B chronic gastritis:
 H. pylori infection is virtually associated with chronic active gastritis, but only 10-15% of the infected
individuals develop frank peptic ulcerations. The basis for this difference is unknown. The end
results are dependent upon the interplay between bacterial and host factors
 H. pylori infection is present in 90 - 100% of duodenal ulcers and 75 - 85% of gastric ulcers
 The end results of H. pylori infection are:
 Gastritis
 Mucosa associated lymphoid tissue lymphoma (MALT lymphoma)
 Peptic ulcer diseases
 Gastric cancer
Complication of chronic gastritis:
 Peptic ulcer disease
 Mucosal atrophy and intestinal metaplasia
 Dysplasia and gastritis cystica
 Perforation and hemorrhage
Laboratory Diagnosis of Gastritis:
 Endoscopy withBiopsy
 Test for H pylori
 Antibody testing IgG
 Urea breath test
Differences between H pylori and autoimmune associated gastritis
Character H. Pylori Associated gastritis Autoimmune Associated gastritis
Location Antrum (favorite site) Body
Inflammatory Neutrophils, plasma cells Lymphocyte ,macrophages
infiltration
Acid production Increase to slightly decrease Decrease
Other lesions Hyperplastic inflammatory polyp Neuroendocrine hyperplasia
Gastrin Normal to decrease Increase
Serology Antibody to H .pylori Antibodies to parietal cells
Sequelae Peptic ulcer ,adenocarcinoma Atrophy,Pernicious Anemia, Adenocarcinoma,
Carcinoid Tumor
Associations Low socioeconomic Autoimmune Disease, Thyroiditis, D.M, Grave
status,poverty,reside in rural area Disease
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Oral Cavity and
Peptic ulcers:
Definition:
 The chronic, most often solitary lesion that occurs in any portion of the GIT exposed to aggressive
action of acidic peptic juices
 About 90-95%, peptic ulcers occur in either first part of duodenum or stomach
Pathogenesis:
 Imbalance between the aggressive factors and the normal defenses of the gastroduodenal mucosa
Defense factor of mucosa
 Secretion of mucus by surface by surface epithelial cells
 Bicarbonate secretion into the surface, to create a buffered surface environment
 Rapid gastric epithelial regeneration
 Vigorous mucosal blood flow to sweep away hydrogen ions that have diffused back into the mucosa
from the lumen and to sustain the high cellular, metabolic and regenerative activity
 Mucosal secretion of prostaglandins (PGs), which may help to maintain mucosal blood flow
Aggravating factors
 H pylori infection: Gram negative bacteria secrete urease and protease. The organism also secretes
phospholipases which damage surface epithelial cells. It also attracts neutrophils that release
myeloperoxidase that can destroy the epithelial cells.
 Smoking exerts its effect by stimulating acid secretion and impairing mucosal defenses by mean of
decreased blood flow and reduced prostaglandin synthesis
 Ischemia decrease mucosal blood flow and delayed gastric emptying, thus aggravate peptic ulcer
 Duodenogastric reflex incompetence result in reflex of bile acid which diffuse back into the stomach,
damage the mucosal barrier and thus lead to chronic gastritis
Morphology of Peptic ulcer:
Gross:
Most favored sites are anterior and posterior wall of the first portion of the duodenum.
a) Clean, sharply demarcated and slightly elevated around the edges.
b) Most gastric ulcers are benign.
Histology:
1. Necrotic debris
2. Inflammation with predominance of neutrophils
3. Granulation tissue
4. Fibrosis
Laboratory Diagnosis of Peptic Ulcer Disease (PUD)
 Barium examinationof upper gastrointestinal tract, sensitivity ranges from 70 to 90%
 Endoscopy the most sensitive and specific method for the diagnosis
 Tests for H. pylori: There are two categories of tests for the diagnosis of this bacterium:
Invasive tests (endoscopy required)
 Rapid urease test
 Biopsy
 Culture
Non-invasive tests:
 Urea breath test - simple, rapid; useful for early follow up, false negative with recent therapy
 Serology: It is an inexpensive, convenient, not useful for early follow-up
 X ray studies: Presence of gas bubbles below the diaphragm is diagnostic of perforation
Differences between acute and chronic ulcers
Acute ulcer Chronic ulcer
Multiple ulcers Solitary
Base is hemorrhagic Base is clear
No granulation tissue Present
No thickening and scarring of blood vessel present Present
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Differences between gastric and duodenal ulcer:
Character Gastric ulcer Duodenal ulcer
Pain Can be greater with meal- weight loss Decrease with meal –weight gain
H. pylori In 70 % In almost 100% cases
Causes ↓ mucosal protection against gastric ↓ mucosal protection, ↑ gastric
acid, NSAID also impaired it acid secretion
Risk for carcinoma Increased Generally benign
Other Often occur in in older patient Hypertrophy of Bruner’s gland
Q. A 25 years old male gave few months history of dyspnea. On gastroscopy, gastric ulcer was seen. The gastric
biopsy revealed heavy colonization by small curved spiral organisms on the surface of mucosa.
a) Name the causative organism
b) What is the role of this microorganism in producing this gastric pathology? (Pathogenesis)
Causative Organism:
H. pylori
Pathogenesis:
 Induces intense inflammatory and immune response. Increase production of pro-inflammatory
cytokines such as IL-1, IL-6, TNF and IL-8. IL-8 recruits and activates neutrophils
 Vacuolating toxins called VacA causes epithelial injury regulated by cytotoxic associated gene
(CagA). This cluster of 29 genes encodes proinflammatory proteins
 Secretes urease that breakdown the urea to form toxic compounds such as Ammonium chloride
and monochloramine
 Bacterial proteases and phospholipase break down the glycoprotein lipid complexes
 Enhances the gastric secretions and reduces the bicarbonate so ↓pH → metaplasia
 Its proteins are immunogenic so evoke immune response and activates T and B cells
Gastric Carcinoma:
Q. A 50 years old male gives history of epigastric discomfort and weight loss for the last two months. He has no
symptoms before this; endoscopic biopsy was planned and sent for histopathology.
b) Give three macroscopic growth patterns of this neoplasm, which may be evident at both the early
and advanced age.
c) Give risk factors for gastric carcinoma.
Diagnosis:
Gastric carcinoma
Macroscopic Growth Pattern:
 Exophytic
 Flat or depressed
 Excavated
Risk factor for gastric carcinoma:
1- Intestinal type adenocarcinoma:
 Chronic gastritis with intestinal metaplasia
 Infection with helicobacter pylori
 Nitrites derived from nitrates present in food may undergo nitrosation to form Nitrosamine and
Nitrosamides
 Diets containing foods that may generate nitrites (smoked foods and vegetables)
 Decreased intake of fresh vegetables and fruits (antioxidants)
 Partial Gastrectomy
 Pernicious anemia
2- Diffused carcinoma:
 Risk factors undefined, except for a rare inherited mutations of E-cadherin
 Infection with H. pylori and chronic gastritis often absent
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Classification of gastric carcinoma:
Intraepithelial Neoplasia: adenoma Non epithelial Tumors
Adenocarcinoma Leiomyoma
Papillary adenocarcinoma Schwannoma
Tubular adenocarcinoma Granular cell tumor
Mucinous adenocarcinoma Leiomyosarcoma
Signet-ring cell carcinoma Gastrointestinal stromal tumor(GIST), (gradation from
benign to malignant )
Undifferentiated carcinoma Kaposi sarcoma
Adenosquamous carcinoma Others
Small cell carcinoma
Carcinoid tumor Note: Heaped Up Margin Pathognomonic Of Malignant
Ulcer
Pathogenesis of gastric carcinoma:
Mutation
 Germ line mutation in CDH-1 encodes E-cadherin, a protein that contributes to epithelial
intracellular adhesions are associated with familial gastric cancer, usually of diffuse type. Thus the
loss of E-cadherin function seem to be a key step in the development of diffuse Gastric cancer
 Germ line mutation in Adenomatous polyposis coli (APC) gene has increased risk of intestinal type
gastric cancer. sporadic intestinal gastric cancer is associated with several genetic abnormality
including mutation of B catenin, APC protein, Microsatellite instability .Tp53 mutation are present in
a majority of sporadic cancer
 H pylori associated with chronic gastritis, promote the development and progression of cancer
 Epstein bar virus (EBV): Approximately 10 % of gastric adenocarcinoma is associated with Epstein bar
virus (EBV)
Spread of Gastric Carcinoma
 Direct spread
Penetrate the wall to involve the serosa and then may spread to liver, spleen, esophagus and
duodenum.
 Transcelomic spread
Krukenburg’s tumor (Tumor of ovary developed from metastasis coming from gastric carcinoma
 Lymphatic spread
Extension of tumor to involve thoracic duct, gastric nodes around stomach, hepatic nodes and
supraclavicular nodes (Virchow’s nodes)
 Hematogenous spread
To liver, lung etc.
 Sister Mary joseph nodule
Subcutaneous per umbilical metastasis
 Gastric Endoscopy
 It is very helpful in diagnosis and malignancy can be confirmed
 Computed Tomography
 It is also very helpful in the diagnosis
 Exfoliative Cytology
 Exfoliative cytology can give malignant cells
 Biopsy
 Biopsy of suspected lesions, done during endoscopy, can confirm the diagnosis
 Barium meal studies
 Filling defects are seen in the antrum or body of the stomach
 Blood Examination
 Hb ↓, ESR ↑, leukocytes count ↑
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 Stool Examination
 Stool may be positive for occult blood
Q. a. How will you differentiate “diffuse” type of gastric carcinoma from the“Intestinal” type on histology
b. Defines early gastric carcinomaand advanced gastric carcinoma.
Histological Difference between Diffuse and Intestinal Variant of Gastric Carcinoma:
Diffuse variant:
 It arises de novo from native gastric mucous cells, is not associated with chronic gastritis, tends to
poorly differentiated and less common type
Intestinal variant:
 It arises from the gastric mucous cells that have undergone intestinal metaplasia in the setting of
chronic gastritis. Better differentiated andmore common type
Early gastric carcinoma:
Defined as lesion confined to the mucosa and submucosa regardless of presence and in the absence of
perigastric lymph nodes metastasis
Advanced gastric carcinoma:
Defined as a neoplasm that has extended below the submucosa into the muscular wall and
metastasizedmore widely
Intestinal Pathologies:
Hirschprung disease (Congenital Megacolon)
Definition:
Distension of colon to greater than 6 or 7 cm in diameter (megacolon)
Causes:
 Congenital:
 Mutation in RET genes and RET ligands. During development, the migration of neural crest
derived cell along the alimentary tract arrests at some points before reaching the anus. Hence,
an aganglionic segmentsis formed that lacks both the Mesissner submucosa and Auerbach
myentric plexuses. This causes functional obstruction and progressive distention of the colon
proximal to the affected segment.
 Acquired:
 Chagas disease, in which trypanosomes directly invade the bowel wall to destroy the complexes
 Organic obstruction of the bowel neoplasm or inflammatory stricture
 Toxic megacolon complicating Ulcerative colitis or Crohn’s disease
 Functional psychosomatic disorder
Idiopathic Inflammatory Bowel Disease:
This group of inflammatory bowel diseases has two important distant diseases i.e. Ulcerative Colitis and Crohn’s
Disease.
Ulcerative colitis:
Q. A 30 years old female has recurrent episodes of bloody diarrhea with long symptom free intervals.
Sigmoidoscopy shows proctocolitis with continuous involvement of rectum mucosa and extending proximally to
the splenic flexure.
a) What is your diagnosis?
b) List the gross and microscopic findings you expect to find in a colonic resection from this patient.
c) Enumerate the complication of the above disease
d) Laboratory diagnosis
Diagnosis:
Ulcerative colitis
Morphology of ulcerative colitis
Gross:
 Involves rectum, sigmoid or may involve the entire colon
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Tract
 Presentation with an even higher proximal extension (pan colitis) occurs much less frequently.
Colonic involvement is continuous from the distal colon so that skip lesions are not encountered
 Inflammatory destruction of the mucosa, with hyperemia, edema and granularity
 Extensive and broad-based ulceration of the mucosa in the distal colon or throughout its length
 Isolated islands of regenerating mucosa bulge upward to create pseudo polyps
 Colon progressively swells and becomes gangrenous (toxic mega colon)
 Chronic mucosal damage
Microscopic:
 A diffuse, predominantly mononuclear inflammatory infiltrate in the lamina propria is almost
universally present.
 Neutrophilic infiltrate of epithelial layers may produce collections of these cells in crypt Lumina (crypt
abscess).
 Granulation tissue fills in the ulcer crater, followed by regeneration.
 Sub mucosal fibrosis and mucosal architecture is destroyed, and atrophy remains as residual of
healed disease
Complication of ulcerative colitis:
 Massive hemorrhage
 Severe diarrhea and electrolyte imbalance
 Toxic mega colon with risk of ruptureand perforation with peritonitis
 Inflammatory stricture of colon and rectum
 Increased risk of carcinoma of colon
 Endoscopy and Biopsy “Gold standard”
Crohn’s Disease:
Q. A colectomy specimen from a 35 years old female with history of intermittent attacks of mild diarrhea with
fever and abdominal pain, shows “skip lesion” in the form of sharply demarcated areas of ulceration and fissuring,
also involving the distal ileum. There is “String sign” appearance on barium studies.
b) Give the morphology of the above diagnosed disease.
c) Enumerate the complications of the above condition
d) Laboratory diagnosis.
Diagnosis:
Crohn’s disease
Morphology of Crohn’s disease:
Gross:
 Sharply demarcated and typically transmural involvement of the bowel by an inflammatory process
with mucosal damage
 Fissuring with formation of fistula
 Serosa become granular and dull gray and often mesenteric fat wraps around the bowel surface
(creeping fat)
 Intestinal wall is rubbery and thick because of edema, inflammation and fibrosis
 Skip lesions
 String sign seen on radiology
Microscopy:
 Inflammation with neutrophilic infiltration into epithelial layer and accumulation with in crypt to form
crypt abscess
 Ulceration, which is usual outcome of active disease
 Chronic mucosal damage in the form of architectural distortion, atrophy and metaplasia
 Non-caseating granulomas present in 40-60%
Complications:
 Fistula formation to other loop of bowel, urinary bladder, vagina or perianal skin etc.
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 Peritonitis or abdominal abscess
 Intestinal stricture or obstruction
 Malabsorption
 Sigmoidoscopy, Colonoscopy
 Barium enema, barium follow- through
 Biopsy and histological examination
Differences between Crohn’s Diseaseand Ulcerative Colitis
Macroscopic
Features Crohn’s disease Ulcerative colitis
Bowel region Ileum and colon Colon only
Distribution of lesion Skip lesion Diffuse
Strictures Early Late/rare
Wall appearance Thickened Thin
Dilation No Yes
Microscopic
Pseudo polyps None to slight Marked
Ulcer Deep linear Superficial
Lymphoid reaction Marked Mild
Fibrosis Marked Mild
Serositis Marked Mild to none
Granulomas Yes (40-60%) No
Fistulas/sinuses Yes No
Clinical
Fat/vitamin, Malabsorption Yes No
Malignant potential Yes Yes
Response to surgery Poor Good
Appendicitis:
Q. A 30 years old female presented with severe pain in right iliac fossa. There is also history of fever and vomiting.
a) What is most appropriate diagnosis?
b) Write down the morphological findings.
c) Enumerate four diseases as differential diagnosis?
Diagnosis:
Appendicitis
Morphology of Acute appendicitis:
 Neutrophilic infiltration of the Muscularis propria
 Serosal vessels are congested
 Ulceration
 Necrosis (acute suppurated appendicitis)
 Hemorrhagic green ulceration of the mucosa
 Green black gangrenous necrosis (acute gangrenous appendicitis)
 Gastroenteritis with mesenteric adenitis
 Ruptured follicular cyst
 Ruptured ectopic pregnancy
 Meckel’s diverticulum
 Mesenteric lymphadenitis with a viral systemic infection
 PID with Tubo-ovarian involvement
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Proliferative Lesions of Intestines:
Classification of Proliferative Lesions of Intestines:
Colorectal Polyps:
Non-neoplastic polyps:
 Hyperplastic polyps
 Hamartomatous (metaplastic) polyps
 Juvenile polyps
 Peurtz- Jeghers polyps
 Inflammatory polyps
 Lymphoid polyps
Neoplastic epithelial lesion:
 Benign: (adenomas)
 Malignant lesions: Adenocarcinoma, squamous cell carcinoma of the anus)
Intestinal polyps:
 Intestinal polyp is mass that protrude into intestinal lumen.
Q.A 65 years old man presents with anemia and stool for occult blood is positive. A 3.5 cm sessile cauliflower like
mass is noted in the rectum on Sigmoidoscopy. The remaining mucosa appears normal.
a) List the THREE types of adenomas you will consider in the differential diagnosis.
b) What factors determine the risk of malignancy in similar case?
Tubular adenomas
Tubulovillous adenomas
Sessile serrated adenomas
Factors thatDetermine the Risk of Malignancy:
 Polyp size (maximum diameter is the chief determinant of the risk of malignancy)
 Histological architecture (does not provide substantive independent information)
 Severity of epithelial dysplasia
 Cancer is rare in tubular adenoma smaller than 1cm in diameter
 Likelihood of cancer is high in sessile villous adenomas larger than 4cm in diameter
 Sever dysplasia, when present it is often found in villous area
Adenoma:
Definition:
It is a benign proliferative lesion of the colon and the rectal region of the GI tract.
Q. A 55 years old male patient is found to have a 3cm polyp in the right colon while he is being evaluated for
anemia: Give major histologic features of the three types of colorectal adenoma.
Histological Feature of Colorectal Adenoma
Tubular adenoma:
 Stalk is covered by normal colonic mucosa but the head is composed of neoplastic epithelium
 Forming branching glands lined by tall, hyper chromatic cells
 These cells may or may not show mucin secretion
 Small foci of villous architecture
 Dysplasia or cytoplasmic Atypia
Villous Adenomas:
 Finger like villi forms extensions of mucosa covered by dysplastic, piled up columnar epithelium
 All degree of dysplasia encountered
 Invasive carcinoma
Tubulovillous Adenomas:
 Composed of broad mix of tubular and villous areas
 They have intermediate degree of dysplasia
 Risk of harboring intramucosal or invasive carcinoma
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Colorectal Carcinoma:
Etiology:
 Geographic Variation:the incidence of colorectal carcinoma is more common in the North America,
Northern Europe. It is commonly found in people of high socioeconomic status
 Dietary Factors: low fiber diet, high animal saturated fat consumption, low intake of Vegetables and
fresh fruits
 Non Dietary Factors:Age>50 years, cigarette smoking, prolong therapy with NSAID
 Genetics: familial adenomatous polyposis (FAP), Gardner’s syndrome, IBD, Hereditary non polyposis
colorectal cancer (HNPCC), Turcot syndrome
Pathogenesis:
Pathogenesis of the colorectal Carcinoma underwent the following sequences:
Morphological Sequence:
Normal Mucosa → Mucosa at Risk → Adenoma → Hyperplasia → Dysplasia → Carcinoma in Situ →
Invasive Carcinoma
Molecular Sequence:
 APC Mutation/β-Catenin Mechanism
 Loss of tumor suppressor gene (APC) → Leads to Activation of MYC and Cyclin D1 gene → resulting in
the cell proliferation
 Point mutation in K-RAS gene usually follows the loss of APC gene
 Deletion of DCC gene (located on the long arm of chromosome 18)
 Loss of TP53 tumor suppressor gene
Microsatellite Instability Mechanism:
 Loss of DNA repair
 Mutated TGF- β receptor gene
 Deletion of BAX gene → since it is a Pro-apoptotic gene, its deletion would result in no apoptotic process
Clinical feature:
Left sided colon cancer
 Produce occult bleeding
 Left lower quadrant discomfort
 Changes in bowel habit or cramping
Right sided colon cancer
 Bowel diameter is greater than left colon
 Fatigue and weakness due to iron deficiency anemia
AJCC TNM Classification of Colorectal Carcinoma
Tumor (T)
Tis In situ dysplasia or intramucosal carcinoma
T1 Tumor invades sub mucosa
T2 Tumor invades into, but not through Muscularis propria
T3 Tumor invades through, Muscularis propria
T4 Tumor invades adjacent organs or visceral peritoneum
Regional lymph nodes
NX Lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in one to three regional lymph nodes
N2 Metastasis in four or more regional lymph nodes
Distant metastasis
MX Distant metastasis cannot be assessed
Mo No distant metastasis
M1 Distant metastasis or seeding of abdominal region
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Investigation:
 Colonoscopy with biopsy “Gold standard’’
 DNA testing if familial polyposis history
 Check for fecal occult blood.
 Apple core lesion on barium enema
 5-Serum carcinoembryonic antigen (CEA) is to detect recurrence
Malabsorption syndrome
Definition: Syndromes resulting from impaired absorption of one or more dietary nutrients from the small
bowel.
 Many diseases or their consequences can cause malabsorption
 The mechanism may be direct impairment of absorption or abnormalities of digestion that finally
leads to impaired absorption
 Malabsorption may occur for specific nutrients such as carbohydrates, fats, or micronutrients or may
affect many nutrients at the same time
Etiologies
 Maldigestion: refers to a defect either in the intraluminal hydrolysis of triglycerides, or in micelle
formation, which results from the following conditions
 Pancreatic insufficiency due to chronic pancreatitis, pancreatic carcinoma
 Deficiency of conjugated bile salts due to cholestatic or obstructive liver diseases
 Bile salt deconjugation due to bacterial overgrowth in blind loop (after Billroth-II gastrectomy) or
jejuna diverticulitis
 Inadequate mixing of gastric contents with bile salts and pancreatic enzymes as a result of
previous gastric surgery
 Intrinsic bowl diseases (damage to the absorptive surface of the intestine)
 Celiac disease causing flattening of the intestinal villa and inflammatory cell infiltration
 Whipple’s diseases: is a systemic disease that may cause intestinal mucosal damage and
lymphatic obstruction
 Collagenous sprue: deposition of collagen substance in the lamina propria of the intestine
 Non-granulomatous Ulcerative Ileojejunitis a rare condition of unknown etiology characterized
by fever, weight loss and features of absorption
 Tropical sprue: Endemic malabsorption disorder occurring in the tropics. It is believed to have an
infectious cause
Clinical features:
Steatorrhea:
 Passage of abnormal stools, which are greasy soft, bulky, and foul smelling and may float in the toilet
because of their increased gas content: a film of greasy or oil droplets may be seen on the surface of
the water. This is often associated with abdominal distension, bloating, or discomfort and flatulence
resulting from increased intestinal bulk and gas production
Weight loss:This may be severe and involve marked muscle wasting
Secondary nutritional deficiencies:
 Deficiency of iron, folic acid or B12 leading to anemia
 Calcium deficiency (common) partly due tolack of vitamin D causing Rickets, Osteomalacia,
Parasthesia, Tetany and Carpopedal spasms
 Thiamine (vitamin B1) and B12deficiency may cause neuropathy
 Malabsorption of vitamin K (mainly fat-soluble) can lead to hypoprothrombinemia with bruising and a
bleeding tendency
 Severe riboflavin (vitamin B2) deficiency may cause a sore tongue and angular stomatitis
 Vitamin A, C, and niacin deficiencies seldom cause clinical problems
 Protein malabsorption may lead to hypoproteinemic edema, usually of the lower limbs
 Dehydration, potassium loss, and muscle weakness can follow profuse diarrhea
 Secondary endocrine deficiencies may result from malnutrition
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Special Pathology
Oral Cavity and
Celiac Disease:
Q.A 7-month baby presented with weight loss and diarrhea .on examination the child was irritable and abdomen
was distended. The child was recently started on wheat diet (2014 KMU)
a) What is your diagnosis
b) Write the pathogenesis of the disease.
c) Write down the key morphological feature of the above diagnosis?
d) What lab test will confirm the diagnosis?
Diagnosis:
Celiac disease
Pathogenesis:
 It is characterized by T-cell and IgA mediated response against gluten in genetically susceptible
individual
 It is associated with HLA-DQ2 and HLA-DQ8
Morphological Feature:
 Intraepithelial lymphocytosis
 Crypt hyperplasia
 Villous atrophy
Investigation:
 Endoscopic biopsy is the ‘’gold standard’’ test. It gives characteristics morphologic features
 Anti-tissue transglutaminase (TTG) Antibodies
 Antiendomysial IgA antibodies: most sensitive test
 Antigliadin IgA Antibodies: moderate screening test
Whipple’s disease:
 Is a systemic disease that may cause intestinal mucosal damage and lymphatic obstruction
 The small intestine mucosa is laden with distended macrophages (PAS positive) in the lamina propria
containing rod shaped bacilli seen by electron microscope
Carcinoid tumor:
 Carcinoid tumor originate from enterochromaffin cells of the intestine and are 10 % of small bowel
tumors
 They secrete serotonin or its precursor
 The most common site are terminal ileum, appendix and the rectum
 Clinically most carcinoid tumor are asymptomatic until metastases are present
 Tumor of appendix may present as acute appendicitis
 Biochemical abnormalities: The tumor secretes serotonin, Bradykinin, histamine and prostaglandin
that produce clinical features.
Investigation
 Elevated levels of serotonin metabolite 5-hydroxyindolacetic acid in 24 hours urinary collection > 10
mg
 Elevated serum serotonin
 U/S abdomen to confirm liver metastases
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Chapter Seven LIVER, GALLBLADDER AND BILIARY SYSTEM
Disorders of Liver:
General Description Related to Liver:
 Ballooning Degeneration: Hydropic swelling of a hepatocyte (i.e. mild, probably reversible cell injury)
If the cell dies, it is Ballooning Necrosis
 Confluent-Lytic Necrosis:It is defined as the death of a cluster/group of a hepatocytes
 Councilman Bodies:It is an eosinophilic structure which is composed of Single-cell necrosis
(apoptosis) of a hepatocyte, typically in hepatitis as a result of attack by a T-killer cell
 Interface Hepatitis:It is chronic inflammation which results in the necrosis of the hepatocyte,near
parenchymal connective tissue interface,it is also called piecemeal necrosis or nibbling necrosis
 Ground Glass Hepatocytes: Distinctive hepatocytes seen in chronic (not acute) hepatitis B infection.
The "ground glass" cytoplasm is an unusual accumulation of a cytokeratin
 Focal Necrosis: Death of individual cells, evidenced either by Councilman Bodies or by lytic necrosis
(i.e. collapse seen on reticulin stain)
 Bridging Necrosis:It is defined as confluent-lytic areas in which all hepatocytes have died
Hepatitis:
Alcoholic Hepatitis:
 This is a stage of liver cell necrosis that follows bouts of heavy alcohol consumption superimposed on
hepatic steatosis
 The condition can be reversible but usually leads to cirrhosis if alcohol consumption stopped
Morphology:
 Liver cell necrosis
 In perivenular regions of the lobules, foci of hepatocytes with clusters of neutrophils undergoing
coagulative necrosis are seen
 Swelling of liver cells
 It results from the accumulation of fat and water and some proteins
 Mallory bodies
 They appear as aggregation of deeply eosinophilic material around the nucleus of fat swollen or
dead hepatocytes
 These bodies are also called alcoholic hyaline
 The eosinophilic material is the intermediate filaments of pre-keratin and some other proteins.
 Inflammatory infiltrate
 Mostly neutrophils with scattered mononuclear leukocytes are found within and about
degenerating liver cells
 Fibrosis
 In majority of cases, alcohol hepatitis is accompanied by pericellular and perivenular fibrosis
Q. a. What are three main types of liver disease associated with chronic consumption of alcohol?
b. Give the salient histological features of each
 Hepatic steatosis
 Alcoholic hepatitis
 Cirrhosis
Hepatic steatosis (Fatty Liver):
 Microvascular lipid droplets in the hepatocytes
 With chronic alcohol intake clear Macrovascular globules accumulate in cells
 Perivenular fibrosis
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Liver, Gallbladder &
Biliary System
Alcoholic hepatitis:
 Hepatocytes swelling and necrosis
 Mallory bodies
 Neutrophilic reaction
 fibrosis
Cirrhosis:
 Bridging fibrous septa in the form of delicate band linking portal tract with one another. Fibrosis is
the key feature of progressive damage to liver
 Parenchymal nodules containing hepatocytes encircled by fibrosis. (Nodularity)
 Disruption of architecture of entire liver
Viral Hepatitis:
Differentiate Between Hepatitis A, B And C Viruses:
Virus Hepatitis A Hepatitis B Hepatitis C
Type of virus ssRNA Partially dsDNA ssRNA
Viral family Hepatovirus; related to Hepadnavirus Flaviridae
picornavirus
Route of transmission Fecal-oral route(contaminated Parentral, sexual Parentral, sexual
food or water) contact, perinatal contact,
intranasal
cocaine use is a
risk factor
Incubation period 2-6 weeks 4-26 weeks 2-26 weeks
Frequency of chronic Never 10 % 80%
liver disease
Laboratory diagnosis Detection of serum IgM Detection of HBsAg or PCR
Antibodies antibody to HBcAg ELISA-antibody
detection
Serological markers of Hepatitis B
 During the presymptomatic stage of acute hepatitis B, first HBsAg and HBV.DNA become detectable
.As the symptoms appear, first IgM anti-HBC, then anti-HBc and then anti-HBc antibodies become
detectable.
 HBsAg (Hepatitis B Surface Antigen)
 Appears during incubation period, asearly as a week after infection
 Falls after the onset of illness and is undetectable 3 months after exposure
 Significance: persistence beyond 6 months indicates chronic disease
 Evoke anti-HBs antibodies
 HBeAg
 Appears during incubation period, soon after HBsAg appearance
 Falls and disappears early in the acute illness, usually 2-3 weeks before the clearance of HBsAg.
 Significance: show HBV active viral replication with shedding of complete virion (HBV-DNA) into
the blood and thus is of high infectivity
 Anti-HBc Antibodies:
 Appears towards the end of incubation period .first IgM, followed 6-18 months later by IgG
 Persists during the acute illness and for several months to years thereafter
 Significance: not protective but are detectable in chronic disease
 Anti-HBc Antibodies:
 Appear early in the acute illness as HBcAg begins to disappear
 Persists for 2 years or more after the resolution of hepatitis
 Significance: indicates the onset of resolution of acute hepatitis
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Biliary System
 Anti-HBs Antibodies:
 Appears during convalescence, several weeks to months after the disappearance of HBsAg. The
interval between disappearance of HBsAg and the appearance of anti-HBs is called
“WINDOWPERIOD”, during which anti-HBc is the only serum marker for HBV infection. Persists
for life
 Significance: Provides immunity
Jaundice:
Definition:
It is the yellow discoloration of the skin and sclera to the accumulation of bilirubin that exceeds the
2mg/dl in the blood
Causes of jaundice
Predominantly unconjugated hyperbilirubinemia
Excess production of bilirubin
 Hemolytic anemia
 Resorption of blood from internal hemorrhage
 Ineffective erythropoiesis
Reduced hepatic uptake
 drug interference with membrane carrier system
 some cases of Gilbert syndrome
Impaired bilirubin conjugation
 Physiologic jaundice of new born
 Breast milk jaundice
Predominantly conjugated hyperbilirubinemia
Decreased hepatocellular excretion
 Deficiency of canalicular membrane transporter ( Rotor Syndrome), Impaired bile flow
 Hepatocellular damage or toxicity (viral or drug induced hepatitis etc.)
Impaired Intra or Extra hepatic bile flow
 Inflammatory destruction of intrahepatic bile duct (e.g. Primary Biliary Cirrhosis, Primary
Sclerosing Cholangitis, Graft Versus Host Reaction); Gallstones, Carcinoma Of The Head of the
Pancreas
Investigations:
 Total bilirubin in serum
 Direct bilirubinand Indirect Bilirubin
 Urine bilirubin
 Urine urobilinogen
Q. A 1-month old infant presenting with jaundiceis diagnosed with extra hepatic biliary atresia (obstruction).
a) What are the major histological features on the liver biopsy?
b) What two enzymes are likely to be raised in this condition?
Histological Features on Liver Biopsy:
 Marked bile ductular proliferation
 Portal tract edema
 Fibrosis
 Parenchymal cholestasis
 Paucity of bile ducts
Enzyme Elevation in Jaundice:
 Aminotransferases
 Alkaline phosphatase
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Differences between Conjugated and Unconjugated Bilirubin:

Conjugated bilirubin Unconjugated bilirubin
Water soluble Lipid soluble
Loosely bound to the albumin therefore excreted Tightly bound to the albumin , therefore cannot
in urine be excreted in urine even when the blood levels
are high
Non toxic Highly toxic particularly unconjugated bilirubin
may enter the tissue , particularly brain and
produce toxic injury called Kernicterus
Liver Cirrhosis:
Definition
 Cirrhosis is a diffuse, Fibrosing and nodular condition of the liver associated with portal
hypertension and hepatic failure
 This disorder is the end stage of various chronic disease of liver that cause of liver that causes
diffuses parenchymal damage
Classification of liver cirrhosis:
Morphologic Classification:
 Micronodular cirrhosis (nodules less than 3mm)
 Macronodular cirrhosis (nodules more than 3mm)
 Mixed cirrhosis
Etiologic Classification:
 Cirrhosis associated with alcohol abuse-60-70%
 Biliary cirrhosis (primary and secondary)-5-10%
 Cirrhosis associated with Wilson’s disease-rare
 Cirrhosis associated with α1 antitrypsin deficiency-rare
 Cryptogenic cirrhosis
 Glycogen storage disease type IV
 Cardiac cirrhosis
Pathogenesis of liver cirrhosis:
The pathogenesis of the liver cirrhosis consists of three key events
 Hepatocyte death
 Extracellular matrix deposition: in cirrhosis the normal Type IV collagen is replaced by the type I and
Type III collagen, with addition of the other extracellular matrix components, the collagen deposition
in cirrhosis is not done fibroblast but instead by stellate or into cells.Hepatocyte damage/stimulated
Kupffer cells  ROS, TNF, IL-1  activate stellate cells  TGF-Beta  fibrosis
 Vascular reorganization of the normal fenestrations present in the hepatic sinusoids,are absent in the
cirrhosis as a result the normally low pressure channels are converted into high pressure, fast flowing
channels,with can’t exchange solutes
Morphology of Liver Cirrhosis:
Gross
 Liver is enlarged in early stages but later, it becomes smaller due to loss of cells and contraction of
fibrous tissue
 Diffuse fibrosis disrupts the normal architecture of liver. Fibrosis may consist of delicate interlacing
bands .in general scarring is irreversible
 Nodularity is the most characteristics feature of cirrhosis. Fibrosis may involve a single lobe to create
a small nodule or many lobes to form a macro nodule
Microscopically
 Regenerative nodules with hyperplastic liver cells are characteristics
 Liver cells are often enlarged with atypical nuclei
 A greatly distorted vasculature due to fibrosis is also an important features
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Q. A biopsy from a 60 years old patient of chronic liver disease (hepatitis C positive) shows a nodular architecture.
a) What histological features are necessary for diagnosis of cirrhosis?
b) What type of collagen is deposited in cirrhosis of liver and what cell type produce it?
Histological Features of Liver Cirrhosis:
 Bridging fibrous septa in the form of delicate band linking portal tract with one another. Fibrosis is
the key feature of progressive damage to liver
 Parenchymal nodules containing hepatocytes encircled by fibrosis. (Nodularity)
 Disruption of architecture of entire liver
Pathogenesis:
Collagen type I and III are deposited in the space of Disse, creating fibrotic septal defect
Portal hypertension
Definition
Portal hypertension is a term used to describe elevated pressures in the portal venous system (a major
vein that leads to the liver). Portal hypertension may be caused by intrinsic liver disease, obstruction, or
structural changes that result in increased portal venous flow or increased hepatic resistance. Normally,
vascular channels are smooth, but liver cirrhosis can cause them to become irregular and tortuous with
accompanying increased resistance to flow. This resistance causes increased pressure, resulting in varices
or dilations of the veins and tributaries. Pressure within the portal system is dependent upon both input
from blood flow in the portal vein, and hepatic resistance to outflow. Normally, portal vein pressure
ranges between 1–4 mm Hg higher than the hepatic vein free pressure, and not more than 6 mm Hg
higher than right atrial pressure. Pressures that exceed these limits define portal hypertension.
Causes of portal hypertension:
Pre-sinusoidal
Prehepatic
 Portal vein thrombosis
 Superior mesenteric vein thrombosis
 Sinusoidal portal hypertension (splenic vein thrombosis)
Intrahepatic
 Idiopathic portal hypertension
 Primary biliary cirrhosis
 Primary sclerosing cholangitis
Sinusoidal
 Cirrhosis
 Vitamin A toxicity
 Infiltrative disorders (e.g.Lymphoproliferative and Myeloproliferative diseases)
Post-sinusoidal
 Veno-occlusive disease
 Budd Chiari syndrome(Hepatic Vein Thrombosis)
Pathophysiology:
The mechanism of portal hypertension has been the subject of extensive research. The pathophysiology is
thought to involve vasodilators produced by the body.Namely, cytokines such as tumor necrosis factor-
alpha (TNF-alpha) and others may play a role in stimulating endothelial vasodilators such as nitric oxide
(NO) and prostacyclin as well as non-endothelial vasodilators like glucagon. These molecules may affect
pressure and flow in the splanchnic vasculature, leading to hypertension
Clinical features:
 Hepatic encephalopathy  Ascites
 Esophageal varices→ hematemesis,  Periumbilical caput medusa
Peptic ulcers  Hemorrhoids
 Skin Spider Angiomas  Testicular atrophy
 Splenomegaly
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Complication:
 Gastroesophageal varices  Ascites
 Renal failure  Hepatic encephalopathy
 Liver cell carcinoma
Clinical Consequences of Liver Disease:
Characteristic Signs of Severe Hepatic Dysfunction
Jaundice and cholestasis
 Hypoalbuminemia
 Hyperammonemia, Hypoglycemia
 Palmar erythema
 Spider angiomas
 Hypogonadism
 Gynecomastia
 Weight loss, Muscle wasting
Portal Hypertension Associated with Cirrhosis
 Ascites with or without spontaneous bacterial peritonitis
 Splenomegaly
 Esophageal varices
 Hemorrhoids
 Caput medusae—abdominal skin
Complications of Hepatic Failure
 Coagulopathy
 Hepatic encephalopathy
 Hepatorenal syndrome
 Portopulmonary hypertension
 Hepatopulmonary syndrome
Liver Function Tests:
Hepatocyte integrity: cytosolic hepatocellular enzymes
 Serum aspartate aminotransferase (AST)
 Serum alanine aminotransferase (ALT)
 Serum lactate dehydrogenase (LDH)
Biliary excretory function: substance normally secreted in bile
 Serum bilirubin: total, direct, indirect
 Urine bilirubin
 Serum bile acids
Plasma membrane enzymes
 Serum alkaline phosphatase
 Serum γ-glutamyl transpeptidase
Hepatocyte function: protein secreted in the blood
 Serum albumin
 Prothrombin time (Factor V, VII, X, Prothrombin and Fibrinogen)
Hepatocyte metabolism:
 Serum ammonia
 Aminopyrine breath test
 Galactose elimination
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Biliary System
Inherited Metabolic Diseases of Liver

Wilson’s disease:
Wilson disease is an autosomal recessive genetic disorder that prevents the body from getting rid of extra
copper. A small amount of copper obtained from food is needed to stay healthy, but too much copper is
poisonous. In Wilson disease, copper builds up in the liver, brain, eyes, and other organs. Over time, high
copper levels can cause life-threatening organ damage.
Causes
Wilson disease is caused by a buildup of copper in the body. Normally, copper from the diet is filtered out
by the liver and released into bile, which flows out of the body through the gastrointestinal tract. People
who have Wilson disease cannot release copper from the liver at a normal rate, due to a mutation of the
ATP7B gene. When the copper storage capacity of the liver is exceeded, copper is released into the
bloodstream and travels to other organs—including the brain, kidneys and eyes.
Clinical features
Wilson disease first attacks the liver, the central nervous system, or both.
A buildup of copper in the liver may cause ongoing liver disease. Rarely, acute liver failure occurs; most
patients develop signs and symptoms that accompany chronic liver disease, including
 Swelling of the liver or spleen
 jaundice, or yellowing of the skin and whites of the eyes
 Fluid buildup in the legs or abdomen
 a tendency to bruise easily
 fatigue
 Neuropsychiatric symptoms include behavior changes, frank psychosis, or Parkinson disease like
syndrome
 Demonstration of kayser Fleischer rings or of markedly elevated hepatic copper levels in a person
with low ceruloplasmin strongly favors the diagnosis
 Urine: 24h copper excretion is high, e g >100μg/24h (normal <40μg).
 LFT: Non-specific (but ALT >1500 is not part of the picture).
 Serum copper: Typically <11μmol/L
 Serum ceruloplasmin: <200mg/L (<140mg/L is pathognomonic).
 Falsely low ceruloplasmin: Protein-deficiency states (e.g.Nephrotic syndrome, Malabsorption);
any chronic liver disease can cause decrease synthesis.
 Falsely high ceruloplasmin: Ceruloplasmin is an ‘acute phase reactant’, so sometimes high in
inflammation/infection and pregnancy.
 Molecular genetic testing can confirm the diagnosis
 Slit lamp exam:KF rings: in cornea
 Liver biopsy: Hepatic copper (Cu >250μg/g dry weight); hepatitis; cirrhosis
 MRI: Degeneration in basal ganglia, fronto-temporal, cerebellar and brainstem
α 1 Antitrypsin (α 1AT) Deficiency
α1 antitrypsin deficiency is an inherited conformational disease that can be fatal. It commonly affects lung
(emphysema) and liver (cirrhosis and hepatocellular cancer, HCC) and can present in homozygous or
heterozygous forms. α1 antitrypsin is a glycoprotein and one of a family of serine protease inhibitors
made in the liver that control inflammatory cascades. Deficiency is called a Serpinopathy. It makes up 90%
of serum 1-globulin on electrophoresis. α1 antitrypsin deficiency is the chief genetic cause of liver disease
in children. In adults, its lack is more likely to cause emphysema. Lung α1 antitrypsin protects against
tissue damage from neutrophil elastase-a process that is also induced by cigarette smoking.
Associations: Hepatocellular carcinoma (HCC), asthma, pancreatitis, gallstones, Wegener’s
granulomatosis
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Genetics The gene for this autosomal recessive disorder is found on chromosome 14; carrier frequency of
1:10. Genetic variants are typed by electrophoretic mobility as medium (M), slow(S), or very slow (Z). and
Z types are due to single amino acid substitutions at positions 264 and 342 respectively.
Symptoms: The symptomatic patients usually have dyspnea from emphysema; cirrhosis, cholestatic
jaundice. Cholestasis often remits in adolescence
Investigations:
 Serum α 1 antitrypsin: Low
 Liver biopsy: Periodic acid Schiff (PAS) +ve; diastase-resistant globules
 Phenotyping by isoelectric focusing requires expertise to distinguish SZ and ZZ phenotypes.
 Prenatal diagnosis is possible by DNA analysis of chorionic villus samples obtained at 11–13weeksof
gestation. DNA tests are likely to find greater use in the future
Hemochromatosis
Hemochromatosis is a condition in which the amount of total body iron is increased that damages the
organ including liver .it may be primary or secondary
Primary hemochromatosis (Hereditary hemochromatosis, HH)
This is an inherited disorder of iron metabolism in which intestinal iron absorption leads to iron deposition
in joints, liver, heart, pancreas, pituitary, adrenals and skin. Middle-aged men are more frequently and
severely affected than women, in whom the disease tends to present 10yrs later (menstrual blood loss is
protective).The total iron body pool ranges from 2 to 6 gm in normal adults
Genetics
The most common form is an autosomal recessive disease of adult onset caused by mutation in the HEF
gene. The gene responsible for most HH is called HFE, found on the short arm of chromosome 6. The 2
major mutations are termed C282Yand H63D. C282Y accounts for 60–90% of HH, and H63Daccounts for
3–7%, with compound heterozygotes accounting for 1–4%. Penetrance is unknown but is <100%
Clinical features
nd rd
The patient Early on: Tiredness, arthralgia (2 +3 MCP joints+ knee pseudo gout), erections↓
Later: Slate-Grey Skin Pigmentation, Signs of Chronic Liver Disease, Hepatomegaly, Cirrhosis, Dilated
Cardiomyopathy and Osteoporosis
Endocrinopathies: DM (‘bronze diabetes’ from iron deposition in pancreas); hypogonadism from pituitary
dysfunction (not from testicular iron deposition, but may be via cirrhosis, especially if drinks >60g/d of
alcohol)
Investigation
 Serum ferritin increased
 Serum iron binding capacity reduced
 Serum iron concentration increased
 Transferrin saturation>45%.1
 Images: Chondrocalcinosis
 Liver MRI: Fe over load (sensitivity 84–91%)
 Liver biopsy: Perl’s stain quantifies iron loading and assesses disease severity.
 ECG/ECHO if cardiomyopathy suspected
Complications: Hepatocellular carcinoma, Liver Cirrhosis, Diabetes Mellitus, Pancreatitis
Secondary hemochromatosis may occur if many transfusions (40L in total)have been given. To reduce
need for transfusions, find out if the hematological condition responds to erythropoietin or marrow
transplantation before irreversible effects of iron overload become too great. There is increased risk of
secondary hemochromatosis in case of beta thalassemia major due to repeated blood transfusion.
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Hepatic Tumors
Classification of liver tumors
Primary liver tumors
Benign
 Cysts  Focal nodular hyperplasia
 Hemangioma: most common benign  Fibroma
tumors of liver  Benign GIST(leiomyoma)
 Adenoma
Malignant (Prognosis—regardless of type—is poor)
 Hepatocellular carcinoma (HCC)  Fibrosarcoma and hepatic
 Cholangiocarcinoma gastrointestinal stromal tumors (GIST,
 Angiosarcoma formerly leiomyosarcoma)
 Hepatoblastoma
Secondary liver tumors
 Stomach  Breast
 Lung  Uterus
 Colon
Hepatocellular Carcinoma (HCC):
Predisposing factor:
Hepatitis B and C
The two most important etiological factors contributing to hepatocellular carcinoma are hepatitis B and
hepatitis C. In parts of China and Taiwan, 80% of hepatocellular carcinoma is due to hepatitis B. In the
United States and Europe, hepatitis C and hepatitis B contribute equally to disease cases. In Japan, where
the prevalence of hepatitis B and hepatitis C is similar, the incidence of hepatocellular carcinoma is higher
in patients with hepatitis C compared to hepatitis B (10.4% vs.3.9percentage). A Hepatitis B is also
common in these areas. The relative contribution of aflatoxins and the hepatitis B virus to the
pathogenesis of hepatocellular carcinoma in these parts of the world are poorly understood.
Cirrhosis
Cirrhosis, irrespective of its etiology, is a risk factor for the development of hepatocellular carcinoma. The
risk is 3–4 times higher in patients with cirrhosis compared to those with chronic hepatitis in a given
population. An increase in hepatocellular proliferation may lead to the activation of oncogenes and
mutation of tumor suppressor genes. These changes, in turn, may initiate hepatocarcinogeneses. In low-
incidence areas, more than 90% of patients with hepatocellular carcinoma have underlying cirrhosis.
However, the presence of cirrhosis is less (approximately 80%) in high-incidence areas, which is probably
related to vertical transmission of hepatitis B virus in these areas
Other Factors
Other etiological factors affecting disease incidence include aflatoxins, vinyl chloride, heavy alcohol
abuse, hemochromatosis glycogen storage disease α 1 antitrypsin deficiency, obesity, type 2 DM, and
anabolic steroid use . Exposure to dietary carcinogenic Aflatoxins, produced by Aspergillus flavus, is
common in certain regions of Southeast Asia and sub-Saharan Africa. Aflatoxin is found in “moldy grains
and peanuts. Aflatoxin can bind covalently with cellular DNA, resulting in mutation in genes such as TP53.
In patients with hepatitis C viral infection, alcohol has been found to be another contributing factor.
Whether this is related to a more aggressive disease due to a combination of hepatitis C virus and alcohol,
or whether alcohol is an independent factor remains unknown. The incidence of hepatocellular carcinoma
in patients with hemochromatosis can be as high as 45%, and often the tumor is multifocal.
Pathogenesis:
The pathogenesis of hepatocellular carcinoma in the presence of hepatitis B virus may be due to
increased cell turnover from chronic liver disease, or a combination of processes specific to the hepatitis B
virus. These may include integration of the hepatitis B DNA genome into the host genome, thereby
disrupting the regulatory elements of cell cycling, or via transactivation of host oncogenes by either HBx
protein or a truncated protein derived from pre-S2/S region of hepatitis B genome. The pathogenesis of
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hepatocellular carcinoma in hepatitis C is less understood. It is possible that some of these patients had
previous exposure to hepatitis B virus.
Key to Pathogenesis:
 Pre-disposing factors
 Genetic mutations like β-catenin or TP53
 Acquired defect in DNA repair mechanism
 Chronic inflammation
Morphology
Gross
 A unifocal, usually massive tumor;
 A multifocal tumor made of nodules of variable size;
 A diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver,
blending imperceptibly into the cirrhotic background
 Discrete tumor masses usually are yellow white, punctuated sometimes by bile staining and
areas of hemorrhage or necrosis. HCC has a strong propensity for vascular invasion. Extensive
intrahepatic metastases are characteristic, and occasionally snakelike masses of tumor invade the
portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even into the
right side of the heart.
Microscopically
 HCCs ranges from well differentiated lesions that reproduce hepatocytes arranged in cords,
trabeculae or glandular patterns, to poorly differentiated lesions, often composed of large,
multinucleate anaplastic giant cells
 In the better-differentiated variants, globules of bile may be found within the cytoplasm of cells
and in pseudocanaliculi between cells.
Clinical features
 Weight loss (without trying)  An enlarged spleen, felt as a mass under
 Loss of appetite the ribs on the left side
 Feeling very full after a small meal  Pain in the abdomen or near the right
 Nausea or vomiting shoulder blade
 An enlarged liver, felt as a mass under the  Swelling or fluid build-up in the abdomen
ribs on the right side  Itching
 Yellowing of the skin and eyes (jaundice)
Alpha-Fetoprotein (AFP)
Alpha-fetoprotein levels may be assessed by a blood test. Alpha-fetoprotein (AFP) is a tumor marker that
is elevated in 60–70% of patients with hepatocellular carcinoma. Normally, levels of AFP are below
10ng/ml, but marginal elevations (10–100) are common in patients with chronic hepatitis. However, all
patients with elevated AFP should be screened (abdominal ultrasound, CT scan or MRI) for hepatocellular
carcinoma, especially if there has been an increase from baseline levels.
Radiographic Diagnosis
The diagnostic accuracy of ultrasound, CT, magnetic resonance imaging (MRI) and angiography is
dependent on a number of variables: expertise of the operator (especially with ultrasound), sophistication
of equipment and technique, presence of cirrhosis and, most importantly, experience of the interpreter.
For small tumors (<2 cm), the diagnostic accuracy ranges from 60–80%. The diagnostic accuracy increases
significantly with an increase in tumor size, ultimately reaching 100% with very large tumors with all
modalities
Liver Biopsy and Histological Grading
Liver biopsy is indicated when diagnosis is in doubt. If AFP is significantly elevated and a tumor is seen in
the liver, it is reasonable to assume a diagnosis of hepatocellular carcinoma and a liver biopsy is not
warranted
Liver function tests (LFTs): Because liver cancer often develops in livers already damaged by hepatitis
and/or cirrhosis, doctors need to know the condition of your liver before starting your treatment
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Blood clotting tests: Prothrombin time help to assess this risk

Tests for viral hepatitis: to check for hepatitis B and C
Blood chemistry
Complete blood count
Staging of HCC:
The American Joint Committee on Cancer (AJCC) TNM system
Stage Detail
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 A single tumor (any size) that hasn't grown into blood vessels
T2 Either a single tumor (any size) that has grown into blood vessels, OR more than one
tumor but no tumor is larger than 5 cm (about 2 inches) across
T3a More than one tumor, with at least one tumor larger than 5 cm across
T3b At least one tumor (any size) that has grown into a major branch of a large vein of the
liver (the portal or hepatic vein)
T4 The tumor (any size) has grown into a nearby organ (other than the gallbladder) or the
tumor is growing into the thin layer of tissue covering the liver (called the visceral
peritoneum)
Nx Regional lymph node cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M0 Distant metastasis is absent
M1 Distant metastasis is present
Disorders of Gallbladder:
Gallstones:
Q. A 40 years old obese female complaints of excruciating colicky (spasmodic) pain after meal in right
hypochondrium and dyspepsia. Her gall bladder reveals gallstones by ultrasonography.
a) What are the different types of gallstones?
b) Give the risk factors involved in the etiology of gallstone.
c) Enumerate the investigation to confirm the gallstone.
d) Enumerate the complication of gallstone.
Types of Gallstones:
 Cholesterol stone: (80%): containing crystalline cholesterol monohydrate
 Pigment stone: composed of predominantly bilirubin calcium salts
 Mixed Stones
Risk factors for Gallstones:
Cholesterol stone:
 Demography: Northern Europeans,  Rapid weight reduction
North and South Americans, Native  Gallbladder stasis
American  Inborn disorders of bile acid
 Advancing age metabolism
 Female sex hormones: female gender,  Hyperlipidemia syndromes
oral contraceptive, pregnancy
 Obesity
Pigment stones:
 Demography: Asian more than western, rural more than urban
 Chronic hemolytic syndromes
 Biliary infection
 GIT disorders: Ileal disease (Crohn’s disease), Ileal resection or bypass
 Cystic fibrosis with pancreatic insufficiency
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Biliary System
Investigation:
 Ultrasound: Mostly it is used for confirmation of gallstones
 Endoscopic retrograde cholangiography (ERCP)
 By this method, we can determine the cause of common bile duct obstruction
 X ray abdomen
 Detect only radiopaque stones such as pigment stones etc. but not radiolucent and they are not
visible on x ray.
Complications of Gallstone:
 Acute cholecystitis  Cholangitis (inflammation of biliary
 Pancreatitis tree)
 Blockage of bile duct  Perforation
 Gall bladder carcinoma  Fistula formation
 Empyema  Intestinal obstruction (gallstone ileus or
Bourveret’s syndrome)
Cholecystitis:
Q. A 50-year-oldlady presents with H/O dull right upper quadrant pain and flatulence for the past one year. Plain x
ray revealed no stone in the gall bladder. Ultrasound was advised. Following which cholecystectomy was
performed. The lumen of gall bladder was found to be full of stones.
a) Enumerate the types of cholecystitis.
b) What are the expected microscopic features of removed gall bladder?
c) What complications can develop in this gall bladder (if surgery was not performed)?
Types of Cholecystitis:
 Calculus Cholecystitis
 Acalculus Cholecystitis
Microscopic Features:
 Usual pattern of acute inflammation (i.e. edema, leukocyte infiltration vascular congestion present)
 Mucosal ulceration are numerous and infrequent (chronic cholecystitis)
 Submucosa and subserosa are often thickened due to fibrosis
Complication of Cholecystitis:
 Obstructive jaundice  Gall bladder rupture with diffuse
 Bacterial super infection with peritonitis
cholangitis or sepsis  Biliary enteric fistula
 Gall bladder perforation and local  Aggravation of other disease if present
abscess formation
Cholestatic Liver Diseases
Biliary Cirrhosis:
Biliary cirrhosis results from prolonged biliary obstruction anywhere between the small interlobular bile
ducts and papillae of Vater.
Types:
 Primary biliary cirrhosis
 Primary sclerosing cholangitis
Primary biliary cirrhosis (PBC)
Essence: Interlobular bile ducts are damaged by chronic autoimmune granulomatous inflammation
causing cholestasis, which may lead to fibrosis, cirrhosis, and portal hypertension.
Cause: Unknown environmental triggers (pollutants, xenobiotic, non-pathogenic
bacteria+geneticpredisposition (e.g. IL12Alocus) leading to loss of immune tolerance to self-
mitochondrial proteins. Antimitochondrial antibodies (AMA)are the hallmark of PBC.
Risk IncreasesIf: +ve family history (seen in 1–6%); many UTIS; smoking; past pregnancy; other auto
immune diseases; Typical age at presentation: 50yrs.
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Biliary System
Clinical features
Symptoms
The patient often asymptomatic and diagnosed after finding ↑alkaline phosphatase (ALP) on routine LFT.
Lethargy, sleepiness, and pruritus may precede jaundice by years and is produced by the development of
bile acids.
Signs:
Jaundice; skin pigmentation; xanthelasma (p704); xanthomata; Hepatosplenomegaly
Investigation:
 ↑Alkaline phosphatase, ↑GT and mildly ↑AST and ALT
 late disease: ↑bilirubin, ↓albumin, ↑Prothrombin time
 Antimitochondrial antibodies present in 98 % cases
 Immunoglobulin are ↑(especially IgM)
 Serum cholesterol ↑
 Ultrasound: Excludes extrahepatic cholestasis
 Biopsy:Usually not recommended (unless drug-induced cholestasis or hepatic sarcoidosis need
exclusion); Look for Granulomas around Bile Ducts ±Cirrhosis. Liver Granuloma: Sarcoidosis, PBC, TB,
Parasites/Schistosomiasis, Brucellosis and Drug Reactions
Complications: cirrhosis, osteoporosis is common. Malabsorption of fat-soluble vitamins (A, D, E, K) due
to cholestasis and ↓bilirubin in the gut lumen results in osteomalacia and coagulopathy; HCC, so check
AFP twice yearly
Primary Sclerosing Cholangitis (PSC)
PSC is characterized by inflammation, Obliterative fibrosis, and segmental dilatation of the obstructed
intrahepatic and extrahepatic bile ducts
Symptoms/signs Pruritus ±fatigue; if advanced: ascending cholangitis, cirrhosis and end-stage hepatic
failure
Associations: of sex • HLA-A1; B8; DR3 •Autoimmune hepatitis (AIH)>80% patients also have
inflammatory bowel disease (IBD), usually ulcerative colitis (UC) of the whole colon. IBD often presents
before PSC. Despite typically inactive colitis, risk of colorectal malignancy is paradoxically much increased.
Cancers Bile duct, gallbladder, liver and colon cancers are more common, so do yearly colonoscopy
+ultrasound; consider cholecystectomy for gallbladder polyps.
Investigation:
 ↑Alkaline phosphatase ,then ↑bilirubin; Hypogammaglobulinemia; AMA –ve, but Antinuclear
antibody(ANA), SMA, and ANCA may be +ve
 Endoscopic retrograde cholangiography (ERCP) distinguishes large duct from small duct disease.
 Liver biopsy shows a fibrous, Obliterative cholangitis.
Differences between primary biliary sclerosis and primary sclerosing cholangitis
Parameter Primary Biliary Cirrhosis Primary Sclerosing Cholangitis
Age Median age 50 years (30-70) Median age 30 years
Gender 90% male 70 % male
Clinical course Progressive Unpredictable but progressive
Associated Sjogren syndrome in 70 %, Inflammatory bowel disease (70%)
condition scleroderma, thyroid disease Pancreatitis(25 %) etc.
Serology AMA(anti mitochondrial antibody) + 65 % ANCA +, 6% ANA +,
in 95 % cases, ANA +, ANCA + 0-5 % AMA +
Radiology Normal Strictures and beading of large bile
duct; pruning of smaller ducts
Duct lesion Florid duct lesions and loss of small Inflammatory destruction of extra-
Ducts only Hepatic and large intrahepatic duct
etc.
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Biliary System
Disorders of Pancreas
Acute pancreatitis:
Etiological factor:
 Metabolic
Alcoholism (commonest cause), hyperlipoproteinemia, Hypercalcemia, drugs e.g.Thiazide diuretics
 Mechanical
Trauma, gallstones, iatrogenic injury, perioperative injury, endoscopic procedure with Dye injection
 Vascular
Shock, atheroembolism, Polyarteritis nodosa
 Infectious
Mumps, Coxsackie virus, Mycoplasma pneumoniae
 Genetic mutation
Cationic trypsinogen (PRSSI) and trypsin inhibitor (SPINKI) gene
Salient feature of acute pancreatitis:
 There is sudden onset of acute abdominal pain with rigid abdomen and the pain is constant, intense
and is often referred to upper back. These manifestations are due to systemic release of digestive
enzymes and activation of inflammatory response.
 Patient show increase vascular permeability, leukocytosis, disseminated intravascular Coagulation,
acute respiratory distress syndrome and fat necrosis
 Peripheral vascular collapse can rapidly occur as a result of electrolyte disturbance and loss of fluid
volume, compound by endotoxemia and a massive release of cytokines and vasoactive agent
 The presence of Grey Turner's and Cullen's sign (indicating extravasations of hemorrhagic exudates
to the flanks or umbilical region, respectively)
Morphology of acute pancreatitis:
 Microvascular leakage causing edema
 Necrosis of fat by proteolytic enzyme
 Acute inflammatory reaction
 Proteolytic destruction of pancreatic parenchyma
 Destruction of blood vessel leading to interstitial hemorrhage
 In more severe form, acute necrotizing pancreatitis, necrosis of pancreatic tissue affect acinar and
ductal tissue as well as the islet cell of Langerhans
 In the most severe form , hemorrhagic pancreatitis,extensive parenchymal necrosis is accompanied
by diffuse hemorrhage within the substance of the gland
Pathogenesis of acute pancreatitis:
 Acute pancreatitis result when activation occur in the pancreatic duct system
 Exact pathogenesis is unknown but may include edema or obstruction of ampulla of Vater result in
reflux of bile and acid into pancreatic duct or direct injury to acinar Cells
 Activation of trypsin is a critical triggering event in acute pancreatitis
 Alcohol consumption may cause pancreatitis by several mechanism Alcohol→ release of intracellular
proenzyme and lysosomal hydrolases→activation of Enzymes→ Acinar cell injury→Activated
enzyme→Acute pancreatitis
Laboratory Finding In Acute Pancreatitis:
 Markedly elevated serum amylase during the 1 24 hours
st
 Rising serum lipase within 72 to 96 hours

 WBC: usually between 12,000 to 20,000/mm3
 Hematocrit may be as high as 50-55 % due to third-space losses
 Hyperglycemia
 Serum calcium is decreased
 Bilirubin may be increased
 X-rays of the abdomen (Supine and upright plain x-rays); Chest x-ray
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Biliary System
 Ultrasound of the abdomen (if available CT scan may also be considered as choice of investigation)
Complication of Pancreatitis:
 Pancreatic abscess
 Pancreatic Pseudocyst(75%)
 Pancreatic ascites
 Hypovolemic shock(3 fluid space)
rd
 Renal failure
Ranson’sCriteria:
Ranson's 11 prognostic signs help estimate the prognosis of acute pancreatitis
Five signs can be documented at admission:
 Age more than 55 year
 Serum glucose over 200 mg/dl (> 11.1 mmol/L)
 Serum LDH over 350 IU/L
 AST over 250 units/L and
 WBC count over 16,000/µL
 The development of the following within 48 h after admission indicates worsening
Prognosis:
 Hematocrits drop by more than 10%
 BUN rise greater than 5 mg/dl (> 1.8 mmol Urea/L)
 Serum Ca less than 8 mg/dl (< 2 mmol/L)
 Arterial Po2 less than 60 mm Hg
 Base deficit over 4 mEq/l
 Estimated fluid sequestration more than 6 L
Pancreatic carcinoma:
Q. A 65 years old man presents with pain abdomen, weight loss and obstructive jaundice .The nature of the
abdominal pain is boring and it radiates to back .physical examination reveals extreme weight loss, scratch marking
on the body, a palpable mass in the epigastrium and another mass in the right hypochondrium.
b) What are the associated risk factors?
c) Enumerate the histological classification of this condition?
d) Give brief morphological features of its commonest variety
Diagnosis is pancreatic carcinoma:
Associated risk factor:
 Black race
 Smoking
 Chronic pancreatitis
Histological classification:
 Ductal adenocarcinoma (most common)
 Acinar cell carcinoma
 Adenosquamous carcinoma
 Undifferentiated carcinoma with osteoclast like giant cells
Morphological features (pancreatic carcinoma):
Gross:
Hard, stellate, gray –white, poorly defined masses
Microscopic:
 Differentiation is moderate to poor
 Abortive tubular structures or clusters
 Showing an aggressive, deeply infiltrative growth pattern
Note: 60% pancreatic Ca in head, 15% in body and 5% in the tail. Pancreatic Carcinoma is highly invasive
and Desmoplasmic response
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Biliary System
Pathogenesis of Pancreatic Carcinoma:

 K-RAS is the most frequently altered oncogene in pancreatic cancer. It is activated by Point mutation
in 80 to 90% cases. These mutations impair the intrinsic GTPase activity
 The p16 (CDKN2A) gene is the most frequently inactivated tumor suppressor gene in Pancreatic
cancer, being turned off in 95 % cases. The p16 protein has a critical role in Cell cycle control
 The SMAD4 tumor suppressor gene is inactivated in 55% of pancreatic cancers. It codes for a protein
that play an important role in signal transduction downstream of the transforming growth factor B
receptors (TGF B)
 Tp53 tumor suppressor gene is inactivated in 50 to 70 % of pancreatic cancers
 The strongest environmental influence is smoking
Figure: Pancreatic Carcinoma
141
Chapter Eight MALE GENITAL SYSTEM
Testicular Tumors
Classification of Testicular Germ Cell Tumors:
The Testicular Tumors are classified on the Two Distinct Basis
 Germ cell tumors
Seminomatous tumors:
1. Seminoma
2. Spermatocytic seminoma
Non-Seminomatous tumors:
1. Embryonal carcinoma
2. Yolk sac (endodermal sinus) tumor
3. Choriocarcinoma
4. Teratoma
5. Malignant lymphoma
 Sex cord stromal tumors:
1. Leydig cell tumor
2. Sertoli cell tumor
OR
Tumors with One Histological Pattern:
 Seminoma
 Embryonal carcinoma
 Yolk sac carcinoma
 Choriocarcinoma
 Teratoma: (mature, immature, with malignant transformation of somatic elements).
Tumor with More Than One Histologic Pattern:
 Together grouped as non-Seminomatous tumors
Pathogenesis of Testicular Tumor
 Most germ cell tumors arise from intratubular germ cell neoplasia (ITGCN)
 Counterpart of CIS and precursor of invasive carcinoma
 50% will develop into invasive cancer within 5 years and 70% in 7 years
 Microscopic diagnosis of ITGCN on testicular biopsy is an indication for prophylactic Orchiectemy
 There are atypical primordial germ cells with large nuclei and clear cytoplasm. Cells are twice the size
of normal germ cells
Several Predisposing Factors Are Important:
 Cryptorchidism (Intra-abdominal cryptorchid testis)
 Testicular dysgenesis syndrome (cryptorchidism, hypospadias, and poor sperm quality)
 Genetic factors: Blacks have more chances of developing cancer than whites. Siblings of affected
individuals have 10 times higher risk (Germ cell maldevelopment)
Serum Markers of Testicular Tumors:
 Human Chorionic Gonadotropin (HCG)
 Alpha Fetoprotein (AFP)
 Lactate dehydrogenase (LDH)
Detail:
 Seminoma: 10% have elevated HCG
 Choriocarcinoma: 100% have elevated HCG
 Yolk sac tumor: 100% have elevated AFP
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Male Genital System
 Embryonal carcinoma: 90% elevated both HCG and AFP

 Teratoma: 50% have both elevated
 Mixed tumor: 90% have both elevated
Seminoma:
It is the most common male germ cell tumor
Morphology of seminoma:
Gross
 Present as uniform solid enlargement of testis, the surface is smooth
On cut section:
 Tumor has homogenous, gray white, lobulated appearance called “potato tumor”
 Tumor grow rapidly and entire testis are replaced
 Generally, tunica albuginea is not penetrated but occasional extension to Epididymis, spermatic cord
or scrotal sac may occur
 Large tumor may contain foci of coagulation necrosis , usually without hemorrhage
Microscopic:
 Composed of sheets or cords of uniform “seminoma cells” which are large, uniform cells with distinct
cell borders, clear, glycogen rich cytoplasmand central round nuclei with conspicuous nucleoli
 The sheets or cords of cells are divided into poorly demarcated lobules by delicate fibrous septa,
which show lymphocytic infiltration and occasional granulomas
 A few may contain syncytial giant cells that secrete HCG. The tumor cells stain positively for placental
alkaline phosphatase. HCG increased in 10% of cases
Prognosis:
It is Radiosensitive, therefore shows very good prognosis
Spermatocytic seminoma:
Q.In a 70-year-old man presenting with testicular mass would you favor:
a) A diagnosis of classicalseminoma or Spermatocytic seminoma?
b) What morphological features would you confirm your provisional diagnosis?
c) Enumerate the causes of testicular atrophy
Diagnosis:
Spermatocytic seminoma
Morphology of Seminoma:
Gross:
Soft, pale gray and cut surface reveals mucoid cysts.
Microscopy: contains population of three cells
Medium sized cells: the most numerous, with round nuclei and eosinophilic cytoplasm
Smaller cells: with narrow rim of eosinophilic cytoplasm
Scattered giant cells either uninucleated or multinucleated
Causes of Testicular Atrophy:
 Cryptorchidism
 Chronic Ischemia
 Klienfelter Syndrome
 Obstruction to Outflow of Semen
 Administration of Estrogen in Prostatic Carcinoma
 Hypopituitarism
 Aging
 Trauma
 Malnutrition and Cachexia
 Inflammatory Disease Such As Mumps Orchitis and Tuberculos Orchitis
 Radiation
 Alcoholic Cirrhosis
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Teratoma:
Morphology of Teratoma:
Gross:
 Presents as irregular and nodular enlargement of testis
 On cut section:
 Shows cystic areas
 Appearance is variated with foci of cartilage, bone or soft myxomatous tissue
 Dermoid cysts are rare in the testis
Microscopic:
 Composed of well differentiated elements such as neural tissue, muscle, cartilage, squamous
epithelium, etc. in fibrous or myxoid stroma
 These elements are arranged in no definite pattern
 The foci of squamous cell carcinoma, mucin-secreting adenocarcinoma may be seen
 Malignant Teratoma may contain yolk sac or trophoblastic tissues that secrete AFP.
Choriocarcinoma:
 It is a highly malignant type
 Composed of both cytotrophoblastic and syncytiotrophoblastic cells
 Accounting for less than 1% of all germ cell tumors
 Identical tumors may arise in the placental tissue or ovary
Morphology:
Gross:
 Usually small lesions
 No testicular enlargement
 Detected as a small nodule
 Hemorrhage and necrosis are extremely common
Microscopic:
 Syncytiotrophoblastic cell. It is large and has many irregular hyperchromatic nuclei and eosinophilic
vacuolated cytoplasm. HCG can be demonstrated in the cytoplasm of cells
 Cytotrophoblastic cells are more regular and polygonal with distinct cell borders and clear cytoplasm.
Have a single uniform nucleus
Yolk Sac Tumor:
 Yolk sac tumor is the most common primary testicular neoplasm in children younger than 3 years of
age; in this age group, it has a very good prognosis
Morphology:
Gross:
 The tumors are often large and may be well demarcated
Microscopic:
 It has Low cuboidal to columnar epithelial cells forming microcyst, less like (Reticular pattern), sheets,
glands and papillae
 A distant feature is the presence of structures resembling primitive glomeruli, the so-calledSchiller-
Duvall Bodies.
Seminoma Yolk Sac Tumor Choriocarcinoma
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Male Genital System
Disorders of Prostate
Benign Prostatic Hyperplasia (BPH):
Q.A 54 years old male develops increased frequency of micturition, urgency, overflow incontinence and nocturia.
Digital rectal examination reveals nodular prostatic enlargement. Serum PSA is <4ng/dL. Sextant prostate biopsies
are negative for malignancy:
b) If a prostatectemywas done in this patient, what gross and microscopic features would you expect to
find?
Diagnosis:
Nodular hyperplasia of the prostate (BPH)
Morphology:
Gross:
 BPH occurs in Transitional zone
 Prostate shows nodules, which weigh 300gm in severe cases
 In lateral lobe enlargement, urethra is compressed to slit like orifice
 While in middle lobe enlargement, a hemispherical mass projects under the floor of bladder
producing at times a ball valve effect
 On cross section,
 Nodules arise around the urethra from inner prostatic mass surrounded by a false capsule
 Yellow pink and soft when hyperplasia is mainly glandular, while pale gray and fibrous when
hyperplasia is mainly fibro muscular
Microscopic:
 Results from glandular proliferation and composed of glands of variable size, lined by hypertrophic
inner tall columnar epithelium and outer flattened or cuboidal cells which is thrown into numerous
papillary bud and infoldings and contain numerous hyaline concretion called ‘’Corpora Amylacea’’
 The glands are separated by stroma infiltrated with lymphocytes
 Sometime the hyperplasia is predominantly fibro muscular and contains solid masses of spindle cells
 Foci of ischemic necrosis surrounded by squamous metaplasia involving the glands may be seen
Benign Prostatic Hyperplasia
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Male Genital System
Prostate carcinoma:
Risk factor:
 Exact cause is unknown but the following factor may contribute.
 Hormonal (androgen)
 Age risk ↑ with ↑ age
 Race mostly in black
 Hereditary/genetics
 Environmental
 Acquired somatic mutation
Morphology of prostate carcinoma:
Gross:
 Hard, irregular, gray yellowish white lesion on cut section
Microscopically/Histologically:
 Moderately differentiated adenocarcinoma in more than 90 % cases
 Glands are smaller, crowded and lined by single uniform layer of cuboidal or low columnar cells lying
in back to back arrangement and characteristically lack branching and papillary infoldings
 The cytoplasm of tumor cells ranges from pale clear to a distinctive amphophillic (dark purple)
appearance. Nuclei are large and contain one or more nucleoli
Prostate specific antigen (PSA)
 Most sensitive and reliable test for Ca prostate detection. An antigen derive from Prostate cancer
cells may also be found in blood .its value is more than 4ng/mL in prostate cancer.PSA has got
prognostic value as well
Serum acid phosphatase
 It becomes elevated when tumor infiltrate outside the capsule of the gland. It is not Organ specific.
Digital palpation: hard irregular nodular appearance on DRE
Transrectal Sonography
Fine Needle Aspiration (FNA)
TNM Staging of Prostatic Carcinoma
Primary tumor (T)
Tumor (T)
T1 No clinically detectable tumor
T1a Histologic tumor found in 5% or less of tissue examined
T1b Histologic tumor found in more than 5% of tissue examined
T2 Tumor confined to the prostate
T2a Tumor in one lobe only
T2b Tumor in both lobes
T3 Tumor extends through the capsule
T3a Extra capsular extension only
T3b Tumor extends into seminal vesicles
T4 Tumor invades adjacent structures other than seminal vesicles
Regional lymph nodes
N0 No regional lymph node involvement
N1 Regional lymph node metastases present
Distant metastasis
MX Distant metastasis cannot be assessed
Mo No distant metastasis
M1 Distant metastasis present
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Male Genital System
Gleason Grading System of Prostate Cancer

Based on glandular differentiation there are 1-5 grades. Most tumors contain more thanone
pattern/grade.
 Grade 1 tumor, well-differentiated tumor, uniform neoplastic glands, and round in appearance and
packed into well-circumscribed nodules
 Grade 5 tumor, no glandular differentiation, and tumor cells infiltrate the stroma in the in the form of
cords, sheets and nests
 The grades fall in between
 Pathologists assign a grade to the primary pattern and a second grade to the secondary Pattern. The
two grades are added together to get a Gleason score
 The best-differentiated tumors have a Gleason score of 2(1+1), while very poorly differentiated
cancers have score of 10 (5+5)
 Combined with the tumor staging, the Gleason grading system has prognostic valuelower score
correlates with better prognosis
Figure: Carcinoma of prostate showing Perineural invasion by Adenocarcinoma

Gynecomastia:
 Benign growth of the glandular tissue of the male breast
 Due to an imbalance in the estrogen to androgen activity
 May be unilateral or bilateral
 Common in infancy, adolescence and adult life
 Pseudogynecomastia may be seen in obese individuals
 Causes include; drugs, chronic disease , metabolic, pubertal
 Hormonal, tumors, idiopathic, hypogonadism
Sexually Transmitted Diseases
Syphilis:
Definition:
 Syphilis is a systemic infection caused by the spirochete Treponema pallidum,which is transmitted
mainly by direct sexual intercourse (venereal syphilis) and less commonly via placenta (congenital
syphilis) or by accidental inoculation from the infectious materials.
 T. Pallidum spirochetes cannot be cultured but are detected by silver stains, dark field examination
and immunofluorescence technique
Pathogenesis:
 The organism is delicate and susceptible to drying and does not survives long outside the body.
 The organism invades mucosa directly possibly aided by surface abrasions following intercourse with
an infected person, a primary lesion, an ulcer known as the Chancre, develops at the site of infection
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Male Genital System
usually the external genitalia but also on lips and anorectal region. Within hours, the T. pallidum
passes to regional lymph nodes and gains access to systemic circulations. Thereafter, the disease is
unpredictable. Its incubation period is about 3 weeks
 Whatever the stage of the disease and location of the lesions the histologic hallmarks of syphilis are;
 Obliterative endarteritis
 Plasma cell rich mononuclear cell infiltrates
 The endarteritis is secondary to the binding of spirochetes to endothelial cells mediated by
Fibronectin molecules bound to the surface of the spirochetes. The mononuclear infiltrates have
immunologic response. Host humoral and cellular immune responses may prevent the formation of
chancre on subsequent infections with T. pallidum but are insufficient to clear the spirochetes
Morphology:
Syphilisis classified into three stages
Primary syphilis (chancre):
 Chancre appears as a hard, erythematous, firm;painless ulcerswith well-defined indurated margins and a
clean moist base (to be distinguished from soft chancres), slightly elevated papule on nodule with
regional lymph nodes enlargement. Common sites are Prepuce / scrotum in men-70%,Vulva or cervix in
females -50%
 The chancre may last for 3-12 weeks. Patients with primary syphilis who stayed for more than two
week cannot be reinfected by a challenge
Secondary syphilis:
If untreated, a few months later – secondary lesion
 Systemic spread →skin, mucous membranes, lymph nodes
 Rash – variable shape, color, distribution (involves palms, soles)
 Ulceration – snail track lesions
 Lymphadenopathy
 Fever, malaise, sore throat, alopecia
 Condylomata lata:Which is popular lesions in moist areas such as axillae, perineum, vulva and
scrotum, which are stuffed with abundant spirochetes
Tertiary syphilis:
The three basic forms of tertiary syphilis are:
1. Syphilitic Gummas:They are grey white rubbery masses of variable sizes. They occur in many organs
but mostly seen in skin, subcutaneous tissue, bone, Joints and testis. In the liver, scarring as a result of
Gummas may cause a distinctive hepatic lesion known as Hepar Lobatum
 Collapse of the bridge of the nose and palate can occur with perforation
 Osteitis and Periosteitis may lead to thickening and deformity of long bones such as the sabre tibia
 Histologically, Gummas look like a central Coagulative necrosis characterized by peripheral
granulomatous responses. TheTreponemasare scanty in these Gummas and difficult to demonstrate
2. Cardiovascular syphilis: This is the most common manifestation of tertiary syphilis. The lesions include
Aortitis, aortic value regurgitation, aortic aneurysm, and coronary artery Ostia stenosis. The proximal
aorta affected shows a tree -barking appearance as a result of medial scarring and secondary
atherosclerosis. Endarteritis and Periaortitis of the Vasa Vasorum in the wall of the aorta, is responsible
for aortic lesions and in time, this may dilate and form aneurysm and eventually rupture classically in the
arch.
3. Neurosyphllis:Occurs in about 10% of untreated patients. The neurosyphllis comprises of
 Meningiovascular syphilis– particularly in base of brain
 General PARESIS of insane it affects the cerebral artery with grey matter with subsequent atrophy.
 Tabes dorsalis– Result of damage by the spirochetes to the sensory nerves in the dorsal roots
resulting in locomotion ataxia, Charcots joint, lighting pain and absence of deep tendon reflexes
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Male Genital System
Gonorrhea
Gonorrhea is a common sexually transmitted disease (STD). A Neisseria gonorrhea is sometimes called
“the clap” causes it. Gonorrhea can infect the vagina, cervix, rectum, penis, urethra etc. Gonorrhea can be
easily cured. Because gonorrhea usually has no signs or symptoms, many people do not realize they are
infected.
Transmission:
Gonorrheais spread through unprotected sex with an infected partner – even if that person has no
symptoms. Ejaculation does not have to happen to get Gonorrhea. It can also be passed from mother to
baby during birth.
Clinical features:
Men:
 Pain or burning while urinating
 Itching inside the penis
 Painful, swollen testicle
 Purulent urethral discharge
Women:
 Unusual vaginal discharge
 Pain or burning while urinating
 Bleeding between periods or after sex
 Pain during sex
Investigation:
 Swab sample:A swab sample fromthe part of the body likely to be infected (cervix, urethra, penis,
rectum, or throat) can be sent to a lab for testing
 Urine test: Gonorrhea in the cervix or urethra can be diagnosed with a urine sample sent to a lab
 Gram stain: This is done right in a clinic or doctor's office. A sample from the urethra or a cervix is
placed on a slide and stained with dye. It allows the doctor to see the bacteria under a microscope.
This test works better for men than for women
Herpes Genitalis:
Etiologic Agent
Herpes simplex type 2
Description
Herpes Genitalisis manifested by locally painful vesicular lesions on penis in males and on vulva and cervix
in female accompanied by lymph node enlargement .systemic features such as fever, muscle ache and
headache may be present.
Chancroid
Definition:
Chancroid is a sexually transmitted disease caused by a bacterial infection that is characterized by painful,
shallow, necrotic ulcers or sores on the genitals (soft chancres)
Description:
Chancroid is an infection of the genitals that is caused by the bacterium Haemophilusducreyi. Chancroid
is a sexually transmitted disease, which means that it is spread from person to person usually by sexual
contact. However, there have been a few cases in which healthcare providers have become infected
through contact with infected patients.
Common locations for Chancroid sores (ulcers) in men are the shaft or head of the penis, foreskin, the
groove behind the head of the penis, the opening of the penis, and the scrotum. In women, common
locations are the labia majora (outer lips), labia minora (inner lips), perianal area (area around the anal
opening), and inner thighs. It is rare for the ulcer(s) to be on the vaginal walls or cervix. In about 50% of
the patients with Chancroid, the infection spreads to either or both of the lymph nodes in the groin.
Investigation:
Culture either from an ulcer or lymph node aspirate
Ducrey’s skin test against killed H.ducreyi antigen remains positive for life
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Male Genital System
Lymphogranuloma Venereum (LGV)

Etiologic Agent:
LGV is a sexually transmitted disease (STD) or infection involving the lymph nodes in the genital area. It is
caused by a specific strain of Chlamydia trachomatis serotypes L1, L2 or L3
Description of Illness:
The first symptom may be a small, painless pimple or lesion occurring on the penis or vagina. It is often
unnoticed. The infection then spreads to the lymph nodes in the groin area and from there to the
surrounding tissue.
Complications:May include inflamed and swollen lymph glands, which may drain, and bleed. Involvement
of perirectal or perianal lymphatic tissues resulting in fistulas and strictures
Laboratory Criteria for Diagnosis:
1. Isolation of C. trachomatis, serotype L1, L2, or L3 from clinical specimen, or
2. Demonstration by immunofluorescence of inclusion bodies in leukocytes of an inguinal lymph node
(Bubo) aspirate, or Frei Test is positive for LGV.
3. Positive microimmunofluorescent serologic test for a Lymphogranuloma Venereum strain of C.
trachomatis
Granuloma Inguinale
Etiologic Agent:
Calymmatobacterium granulomatis; an intracellular Gram-negative bacterium
Description of Illness:
The disease presents clinically as painless, progressive, ulcerative lesions without regional
lymphadenopathy. The lesions are highly vascular (i.e., a beefy red appearance) and bleed easily on
contact. A secondary bacterial infection might develop in the lesions, or the lesions might be co-infected
with another sexually transmitted pathogen.
Laboratory Criteria for Diagnosis:
The causative organism cannot be cultured on standard microbiologic media. Diagnosis requires
visualization of dark-staining intracytoplasmic Donovan bodies on Wright or Giemsa-stained smears or
biopsies of granulation tissue
150
Chapter Nine FEMALE GENITAL SYSTEM AND BREAST
Ovarian Tumors
Classification of Ovarian Tumors:
Surface epithelial stromal cell tumors: 65-70%, age: 20+ years
 Serous tumor
 Mucinous tumor
 Endometroid tumor
 Clear cell tumor
 Epithelial stromal (Adenosarcoma, malignant mixed mullerian tumor)
Germ cell derived tumors: 15-20%, age: 0-25+ years
 Teratoma (immature, mature, solid, cystic adenoid, monodermal)
 Dysgerminoma
 Endodermal sinus tumor (yolk sac tumor)
 Mixed Germ Cell tumor and Choriocarcinoma
Sex cord stromal tumors: 5-10%: all ages
 Fibroma
 Granulosa theca cell tumor
 Sertoli- Leydig cell tumor
 Sex cord tumor with annular tubules
 Gynandroblastoma
 Steroid (lipid) cell tumors
Metastatic cancer
 Colonic, Appendiceal (Krukenburg’s tumor, metastatic tumor of GIT)
 Gastric
 Breast
Pathogenesis of ovarian tumor:
Majority of ovarian cancers seemed to be caused by mutations in the BRCA genes, BRCA1 or BRCA2
Risk factors:
 Nulliparity
 Family history
 Prolonged used of OCP reduces risk
 Early menarche
 Pelvic irradiation
Serous Cystadenoma or Adenocarcinoma:
Q. A 45 years old woman feels pressure sensation, but no pain in pelvic region for the past 6 months. On
examination, there is right adnexal mass. Ultrasounds scan shows 10 cm fluid filled cysts or cystic masses in the
right ovary. A fine needle aspirate is performed and cytological examination of clear fluid aspirate from the mass
reveals clusters of malignant cells surrounding Psammoma bodies.
a) What is the likely diagnosis?
b) What are the gross and microscopic appearances of this tumor?
c) Write the lab diagnosis
Diagnosis:
Ovarian Papillary Serous Cyst Adenocarcinoma
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Female Genital System and
Breast
Morphology of ovarian serous cyst adenoma:
Gross:
 Shape is spherical to ovoid cyst
 Surface shows nodular irregularities
 On cut section:
 Small cysts are unilocular, while large cysts are multilocular filled with clear serous fluid
 Papillary projections are present in the cavities
Microscopic:
 Psammoma bodiesare present in the tips of papillae
 Anaplasia of the lining cells
 A single cell layer of Tall columnar epithelial cells that line the cyst
 Papillary formations are complex and multilayered
 Invasion of stroma
Investigation:
 Ultrasound abdomen pelvis
 CA-125 levels
Teratoma:
It is a benign and malignant type of tumor that arises from the three Germinal layers i.e. Ectoderm,
mesoderm and endoderm
Benign Cystic Teratoma of the Ovary:
 Benign cystic Teratoma are marked by ectodermal differentiation and lined by normal appearing skin
with its associated adnexal appendages
 Occurs b/w 20-30years of age
Morphology of Cystic Teratoma of Ovary:
Gross:
 Shape is spherical to ovoid cyst with size less than 10cm in diameter
 Surface is covered by glistening serosa
 Occurs usually unilaterally, mostly on right side
 On cut section:
 Unilocular cyst lined by normal appearing skin with it adnexal appendages especiallyHair and
sebaceous glands
 Filled with thick sebaceous secretion containing matted hair
 Teeth protruding from nodular projection (Dermoid cyst)
Microscopic:
 Lined by well differentiated skin with its adnexal appendages especially hair
 Foci of bone, cartilage, bronchial or gut epithelium are present in the nodular projection.
Gestational Trophoblastic Diseases:
It Includes the Following Diseases:
 Hydatidiform Mole
 Invasive Mole
 Choriocarcinoma
Hydatidiform Mole:
Types of Hydatidiform Mole:
Complete (classic) Mole:
 All the villi are edematous and there is diffuse trophoblastic proliferation
 Epithelial cells are diploid (46XX/46XY)
 It results from either fertilization of empty egg by a single sperm and the duplicates or from the
fertilization of empty egg by two sperms
 Embryo dies early and thus complete mole has no fetal parts
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Partial Mole:
 Some villi are edematous and there is focal trophoblastic proliferation
 Epithelial cells are triploid (69XXX, XYY,XXY),even occasionally tetraploid (99XXXY)
 It results from the fertilization of an egg with two sperms
 Embryo is viable for weeks and thus partial mole has fetal parts
Morphology:
 Usually discovered in 4th-5th month of pregnancy and uterus is large for dates
 Uterine cavity is filled with a mass of delicate, thin walled translucent, grape like bunch of cysts
Microscopic:
Complete mole:
 Hydropic swelling of all the chorionic villi
 Diffuse trophoblastic proliferation
 Absence of vessels and edematous stroma
Partial mole:
 Hydropic swelling of some of the villi
 Focal trophoblastic proliferation
Features Complete mole Partial mole
Karyotypes 46 XX,XY Triploid(69,XXY)
Villous edema All villi Some villi
Trophoblastic proliferation Diffuse Focal
Atypia Often present Absent
Serum HCG Elevated Less elevated
HCG in tissue +++ +
Behavior 2% Choriocarcinoma Rare Choriocarcinoma
Disorders of Vulva:
Non-Neoplastic Epithelial Disorders:
Lichen Sclerosus
 Thinning of the epidermis, hydropic degeneration of the basal cells and dermal fibrosis.
 Leukoplakia with parchment like vulvar skin and narrow nuclear cell infiltrates
 Lichen Sclerosus occurs in all age groups but most commonly seen in postmenopausal women
 The pathogenesis is uncertain, but the presence of activated T cells in the subepithelial
inflammatory infiltrate and the increased frequency of autoimmune disorders in affected
women suggests an autoimmune etiology
 Benign associated with slightly increased risk of squamous cell carcinoma
Lichen Simplex Chronicus(squamous cell hyperplasia)
 Lichen simplex chronicus is marked by epithelial thickening (particularly of the stratum granulosum)
and hyperkeratosis
 Hyperplasia of vulvar squamous epithelium, leukoplakia with thickening
 Associated with chronic irritation or pruritis and scratching
 In benign no increased risk of squamous cell carcinoma
Tumors
Condyloma
 Warty neoplasm of vulvar skin, often large, solitary or multifocal
 Most commonly due to Human papilloma virus (HPV) serotypes 6 and 11
 On histologic examination, the characteristic cellular feature is koilocytosis/koilocytic change, a
cytologic changes characterized by perinuclear cytoplasmic vacuolization and wrinkled nuclear
contours that is a hallmark of HPV infection
 Rarely progress to carcinoma
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Squamous Cell Carcinoma of the Vulva
 HPV-related vulvar squamous cell carcinomas usually are poorly differentiated lesions and
sometimes are multifocal. They often evolve from vulvar intraepithelial neoplasia (VIN).
 Non–HPV-related vulvar squamous cell carcinomas occur in older women, usually are well
differentiated and unifocal, and often are associated with lichen sclerosus or other
inflammatory conditions.
Paget Disease of the Vulva
 Vulvar Paget disease is characterized by a red, scaly plaque caused by proliferation of
malignant epithelial cells within the epidermis; usually, there is no underlying carcinoma,
unlike Paget disease of nipple.
 Positive staining for PAS distinguishes Paget disease cells from melanoma.
Note: Paget cells: periodic acidic Schiff (PAS) positive (+), keratin positive (+), and S 100 negative (-)
Melanoma: periodic acidic Schiff (PAS negative (-), keratin negative (-), and S 100 positive (+)
Vaginitis
The inflammation of the vagina is called vaginitis
Causes
 Trichomonas vaginalis most common in adult produces a watery, copious gray-green discharge
 Neisseria gonorrhea common in new born and older child
 Chlamydia trachomatis, Herpes virus type II, Candida albicans. Mycoplasma hominis, Human
papilloma virus etc.
Clinical feature
Vaginal discharge (leukorrhea)
Disorders of Cervix:
Cervicitis:
The inflammation of the cervix is called cervicitis
 Cervicitis can be subclassified as infectious or noninfectious
 Much more important are Chlamydia trachomatis, Ureaplasma urealyticum, T. vaginalis, Candida spp,
Neisseria gonorrhea, HSV-2 (the agent of herpes genitalis), and certain types of HPV, all of which are
often sexually transmitted. C. trachomatis is by far the most common of these pathogens, accounting
for as many as 40% of cases of cervicitis
Morphology:
Acute
 The relatively uncommon acute form is limited to women in the postpartum period and usually is
caused by staphylococci or streptococci.
Chronic
 Chronic cervicitis consists of inflammation and epithelial regeneration, some degree of which is
common in all women of reproductive age. The cervical epithelium may show hyperplasia and
reactive changes in both squamous and columnar mucosae. Eventually, the columnar epithelium
undergoes squamous metaplasia
Cervical Carcinoma:
Classification of Cervical Neoplasia:
Epithelial tumors:
 Benign: squamous cell papilloma
 Malignant: squamous cell carcinoma
 Adenocarcinoma
 Adenosquamous CA
Non-epithelial tumor:
 Leiomyoma
 Leiomyosarcoma
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Miscellaneous tumors:
 Mullerian mixed tumors
Secondary tumors:
 Squamous metaplasia
 Glandular hyperplasia
 Endometriosis
Risk Factors for Cervical Carcinoma:
 Early age at first intercourse
 Multiple sexual partners
 A male partner with multiple previous sexual partners
 Lower socioeconomic group
 Rarity among virgin
 Smoking
 Immunocompromised woman
 Persistent infection with a high oncogenic risk HPV e.g. HPV 16 or HPV 18
 High parity
 Oral contraceptives
 Certain HLA subtypes
Pathogenesis of Cervical Carcinoma:
HPV types 16 and 18 usually integrate into the host genome and express large amounts of E6 and E7
proteins that block or inactivate tumor suppressor genes p53 and RB gene, respectively. The result in
transformed cell phenotype, capable of autonomous growth and susceptible to the acquisition of further
mutation
Q. A cervical biopsy from a 35 years old sexually active female is submitted to you for reporting; previous PAP
smear exam has shown low grade intraepithelial neoplasia on two occasions and high grade intraepithelial lesion
subsequently.
a) Outline the grading system you would use histologically classify the cervical epithelial lesion in this
patient.
b) What are two commonest HPV genotype associated with high-grade cervical intraepithelial lesion?
Cervical Intraepithelial Neoplasia (CIN): Carcinoma In-Situ:
Morphology:
Histological Grading of the Cervical Epithelial Lesion:
CIN I: Mild Dysplasia.
 Lower one third epithelium is involved
 Pleomorphism
 Hyperchromatic
 Mitosis above the basal layers
 Architectural anarchy of cells
 Kiolocytes are seen
CIN II:
 Involve middle 2/3 of cervix
rd
 Moderate dysplasia
CIN III:
 Involve whole of the cervix
 Sever dysplasia and carcinoma in situ
Component of HPV Genotype:
These are the two important genotypes of HPV responsible for cervical carcinoma i.e. HPV 16 and 18
genotype.
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Clinical staging for cervical carcinoma:
Stage 0 Carcinoma in situ
Stage I Carcinoma confined to cervix
Ia Preclinical carcinoma, diagnosed only by microscopy
Ia1 Stromal invasion no deeper than 3mm not deeper than 5mm and no wider than
Ia2 7mm (micro invasive)
Ib Maximum depth of invasion of stoma deeper than 3 mm and 7mm horizontal
Invasion Greater than stage 1a2
Stage II Carcinoma extends beyond the cervix but not to the pelvic wall, vagina involve
rd
only upper 2/3
Stag III Carcinoma has extend the pelvic wall, involves the lower third of vagina
Stage IV Carcinoma has extended beyond the true pelvis or involves bladder or rectum
Endometrial Disorders
Adenomyosis:
Definition:
The growth of the basal layer of endometrium down into the myometrium is called Adenomyosiss. When
associated with fibroid it is called adenomyoma.
Endometriosis:
Q. A 45 years old female patient develops peanut-sized nodules in an old midline laparotomy scar, which becomes
painful during menstrual period. The excised nodule consists of normal looking endometrial tissue with glands and
stroma.
a) Define endometriosis
b) Give three theories of pathogenesis of such lesion s.
c) List important sites of endometriosis
Definition:
 The presence of endometrial glands and stroma in a location outside the uterus
 Histologically both glands and stroma are present
Theoriesof Pathogenesis:
 Regurgitation theory, fallopian tube (retrograde menstruation)
 Metaplastic differentiation of coelomic cavity
 Vascular or lymphatic dissemination theory
Sites of Endometriosis
 Ovaries
 Pouch of Douglas
 Uterine tubes
 Rectovaginal septum
 Pelvic peritoneum
 Large and small bowel and appendix
Note: Chocolate cyst endometriosis appears as cyst that contains an area of new and oldhemorrhage
Endometrial hyperplasia:
Definition: Pathological hyperplasia in which there is proliferation of both epithelial and Stromal elements
of the endometrium
Etiology andPathogenesis: is caused by relative or absolute hyperestronism such as seen in
 Polycystic ovaries
 Chronic failure of ovulation
 Estrogen secreting ovarian tumors
 Adrenocortical hyperfunction
 Prolonged use of exogenous estrogen
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Types of Endometrial Hyperplasia:
 Simple hyperplasia without Atypia
 Complex hyperplasia
 Atypical hyperplasia
Morphology of Endometrial Hyperplasia:
Gross:
 Uterus is enlarged
 Endometrium is thickened
 Myometrium is also thickened
Microscopic: there are three subtypes
 Simple hyperplasia without Atypia: (mild or cystic hyperplasia)
 Complex hyperplasia: (moderate or edematous hyperplasia)
 Atypical hyperplasia: (complex hyperplasia with Atypia)
Endometrial Carcinoma:
 Endometrial carcinoma is the most frequent cancer occurring in the female genital tract. It generally
appears between the ages of 55 and 65 years and is uncommon before age 40.
 Endometrial carcinomas comprise two distinct kinds of cancer:
 Endometrioid carcinoma of the endometrium
 Serous carcinoma of the endometrium
 These two types are histologically and pathogenetically distinct.
Etiology:
Endometrioid cancers arise in association with estrogen excess and endometrial hyperplasia in
perimenopausal women, whereas serous cancers arise in the setting of endometrial atrophy in older
postmenopausal women
Risk factors:
 Obesity
 Diabetes
 Hypertension
 Infertility
 Exposure to unopposed estrogen. Many of these risk factors result in increased estrogenic
stimulation of the endometrium and are associated with endometrial hyperplasia
Morphology:
Endometrioid carcinomas
 Resemble normal endometrium and may be exophytic or infiltrative
 Includes a range of histologic type, including those showing mucinous, tubal and squamous
differentiation
 Tumors originate in the mucosa and may infiltrate the myometrium and vesicular spaces
 Endometrioid carcinoma are graded I to III based on the degree of differentiation
Serous carcinomas
 Small tufts and papillae, greater cytologic atypia
 They behave aggressively and thus are by definition high grade
Microscopically:
 More than 80 % are Adenocarcinoma ,and 10 -15% are Adenosquamous
Pathogenesis:
 Endometroid carcinoma: Mutations in mismatch repair genes and the tumor suppressor gene
PTEN are early events in the stepwise development of endometroid carcinoma. Women with
germline mutations in PTEN (Cowden syndrome) are at high risk for this cancer. TP53mutations occur
but are relatively uncommon
 Serous type: Nearly all cases have mutations in the TP53 tumor suppressor gene, whereas
mutations in DNA mismatch repair genes and PTEN gene are rarely involved
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Clinical features:
 Leukorrhea and irregular bleeding
Endometrial Carcinoma
Leiomyoma:
 Leiomyomas are the most common benign tumor in females, affecting 30% to 50% of women of
reproductive age.
 Leiomyoma also called Fibroid Uterus
Etiology:
 Estrogen, pregnancy, lactation and possibly oral contraceptives stimulate the growth of
Leiomyomas; conversely, these tumors shrink postmenopausally
Morphology:
 Leiomyomas are typically sharply circumscribed, firm gray-white masses with a characteristic
whorled cut surface
 They may occur singly, but more often multiple tumors are scattered within the uterus, ranging from
small nodules to large tumors
Intramural Leiomyoma:
 Those embedded in the myometrium
SubmucosalLeiomyoma:
 Those lie directly beneath the endometrium
Subserosal Leiomyoma:
 Those lie directly beneath the serosa.
Parasitic Leiomyoma:
 Tumor may extend out on attenuated stalks and even become attached to surrounding organ, from
which they may develop blood supply
Microscopically
 Spindle shaped cells with elongated nuclei or bundles of smooth muscle cells mimicking the
appearance of normal myometrium.
 Foci of fibrosis, calcification, and degenerative softening may be present.
Complication:
 Leiomyoma very rarely undergo malignant transformation
 Menorrhagia (excessive uterine bleeding)
 Infertility
 Fetal malpresentation
 Obstructed labor
 Abortion
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Figure: Leiomyoma Uteri

Diseases of Female Breast:
Classification of Breast Tumor:
Benign Tumors:
 Fibroadenoma
 Phyllodes tumor
 Intraductal papilloma
Malignant Tumors:
Non-invasive:
 DCIS (Ductal Carcinoma In Situ). Paget disease of nipple is extension of DCIS.
 LCIS (Lobular Carcinoma In Situ)
Invasive:
 Invasive ductal carcinoma
 Invasive lobular carcinoma
 Medullary carcinoma
 Colloid carcinoma
 Tubular carcinoma
 Other types: e.g. ductal ( Scirrhous carcinoma)
Fibroadenoma:
Q. .An 18 years old female presents with solitary, discrete, movable mass in right breast which enlarges late in the
menstrual cycle. FNAC is performed which shows a benign breast lesion.
b) Give morphological details of the lesion.
Diagnosis:
Fibroadenoma
Morphology of Fibroadenoma
Gross:
 Presents as spherical, solitary nodules that is sharply circumscribed and moveable
 Size varies from 1-10 cm in diameter called giant Fibroadenoma
 Occurs mostly in upper quadrant of breast
 On cut section, it is firm and grayish white
Microscopic:
 Composed of loose fibroblastic stroma containing glandular and cystic spaces lined by single or
multiple layers of the cells
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 Glandular spaces may be open, round to oval and regular (pericanalicular Fibroadenoma) or
compressed, irregular clefts due to extensive stromal proliferation, (intracanalicular Fibroadenoma).
Intracanalicular Pericanalicular
Phyllodes Tumors
Phyllodes tumors (from Greek: phullon leaf), also cystosarcoma phyllodes, cystosarcoma
phylloides and Phyllodes tumor, are typically large, fast-growing masses that are formed from the
periductal stromal cells of the breast. They account for less than 1% of all breast neoplasms
Classification:
 Phyllodes tumors are a fibroepithelial tumor composed of an epithelial and a cellular stromal
component
 They may be considered benign, Borderline or malignant depending on histologic features including
stromal cellularity, infiltration at the tumor's edge, and mitotic activity
 All forms of phyllodes tumors are regarded as having malignant potential. They are also known as
Serocystic Disease of Brodie
Presentation
Patients typically present with a firm, palpable mass. These tumors are very fast growing, and can
increase in size in just a few weeks. Occurrence is most common between the ages of 40 and 50, prior
to menopause. This is about 15 years older than the typical age of patients with fibroadenoma, a
condition with which phyllodes tumors may be confused
Intraductal Papilloma:
Intraductal Papilloma of the breast are benign lesions with an incidence of approximately 2-3% in humans
Types:
There are two types of Intraductal Papilloma:
 The central type develops near the nipple. They are usually solitary and often arise in the period
nearing menopause
 The peripheral type is often multiple Papillomas arising at the peripheral breasts, and is usually found
in younger women. The peripheral types are associated with a higher risk of malignancy. They are the
most common cause of bloody nippledischarge in women of age 20-40 and generally do not show up
on mammography due to their small size, so the next step in treatment would be a galactogram to
guide the subsequent biopsy. The masses are often too small to be palpated or felt. A galactogram is
therefore necessary to rule out the lesion. Excision is sometimes performed.
Breast Carcinoma:
Risk factor for breast carcinoma:
Major risk factor for breast carcinoma:
 Geographic factor
 Age: increases after age 30yr
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 Genetic and family history: first degree relative with breast cancer
 Menstrual history: age at menarche< 12yr and delayed menopause
 Pregnancy: more chances in nulliparous
 Benign breast disease: proliferative lesion
Minor risk factors:
 Prolonged exposure to exogenous estrogens
 Oral contraceptive
 Obesity
 High fat diet
 Alcohol consumption
 Cigarette smoking
 Ionizing radiation
Pathogenesis of Breast Cancer:
Genetic change
 Overexpression of the HER2/NEU proto-oncogene, which undergoes amplification in up to 30 % of
invasive breast cancer, its overexpression is associated with poor Prognosis
 Amplification of RAS and MYC genes also has been reported in some breast cancer mutation of the
well-known tumor suppressor genes RB and TP53 also may present.
 Gene expression profiling can separate breast cancer into four molecular subtypes:
1- Luminal A (estrogen receptor, ER +ve, HER2/NEU negative)
2-luminal B (estrogen receptor, ER +ve,HER2/NEU overexpression)
3-HER/NEU positive (estrogen receptor, ER negative, HER2/NEU overexpression)
4-Basal like (estrogen receptor, ER negative and HER2/NEU negative)
 Mutation in BRCA1 and BRCA2 has also been reported in ⅓ of women withhereditary breast cancer
Hormonal influences
 Endogenous estrogen excess, or more accurately, hormonal imbalance, clearly has a significant role.
The risk factor (long duration of reproductive life, nulliparity and late age at birth of first child)
involves increased exposure to estrogen unopposed by progesterone. Estrogen stimulates the
production of growth factor such as transforming growth factors,and fibroblast growth factor etc.that
may promote tumor development through paracrine and autocrine mechanism.
Environmental variables
 Environmental influences are suggested by the variable incidence of breast cancer in genetically
homogenous group and the geographic differences in prevalence
Invasive Ductal Carcinoma:
Q.A 60-year-old female presents with a hard lump in the breast. It was excised and diagnosed an invasive ductal
carcinoma breast.
a) Describe morphology.
b) What further investigations will you suggest on the biopsy tissue before starting the treatment in this
patient?
Morphology of Invasive ductal carcinoma:
Gross:
 presents as delimited mass, rarely over 3-4cm in diameter, of stony consistency (hence the name
Scirrhous Ca)
 Extension of the tumor may cause dimpling of skin, retraction of nipple and fixation to chest wall
 On cut section:
 Tumor is infiltrative and retracted below the surrounding fibro fatty tissue. (Crab like shape)
 Color is grayish, white with yellow specks ( unripe pear appearance)
 Foci of chalky white necrosis and calcification may be seen
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Microscopic:
 Composed of dense fibrous stroma in which anaplastic duct lining cells disposed in nests, cords, tubes
or gland like pattern
 Neoplastic cells are round to polygonal with small dark nuclei, few mitotic figures
 Neoplastic cells are seen infiltrating surrounding tissue, perivascular and Perineural space as well as
blood vessels.
Following molecular classes correlate with prognosis and response to therapy. So we classified before
starting the treatment:
 Luminal A: (40-50% of NST CA). ER + and HER2/NEU negativechemotherapy
 Luminal B: (15-20%) ER and HER2/NEU positive, high proliferative rate: triple positive cancer,
response to chemotherapy
 Normal basal like: (6-10%)…ER + and HER2/NEU negative
 Basal like: (13-25%): ER, PR and HER2/NEU are negative: triple negative
 HER2/NEU positive: (7-12%): ER negative…. Rx (Trastazumab)
Invasive Lobular Carcinoma:
Morphology of Invasive Lobular Carcinoma of Breast
 Tumor comprises fewer than 20% of all breast cancer
 These include a tendency to become adherent to the pectoral muscles or Deep fascia of the chest
wall with consequent fixation of the lesion
 Adherence to the overlying skin with retraction or dimpling of the skin of the nipple. Important sign
observed by woman herself during self-examination
 Surround cancerous or normal appearing acini andducts creating so called Bull Eye Pattern
 Lobar carcinomas are more frequently multicentric and bilateral (10-20%)
 Involvement of the lymphatic pathway may cause local lymphedema
 Most presents as palpable masses or mammographic densities
 The skin become thickened around exaggerated hair follicles, a change known as peaudorange
(orange peel)
 All these carcinomas express hormone receptors but HER2/NEU overexpression is rare
Investigation:
 Mammography
 ultrasonography
 MRI
Prognostic and predictive factors
 Tumor size: if tumor size is 1cm then excellent prognosis. If the tumor size is more than 2 cm it shows
poor prognosis
 Lymph nodes involvement: most important prognostic factor
 If no node is involved: survival rate 70-80%
 One to three positive: survival rate 35-40%
 If more than 10 positive: 10-15% survival rate
 Distant metastasis: no distant metastasis so more curable
 HER2/NEU: is predictor of response to agents that target this transmembrane protein (e.g.
trastazumab, Lapatinib). Over expression→ poor survival.
 Estrogen/progesterone receptors(ER/PR): it is negative so poor response to the therapy so poor
prognosis.
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Medullary carcinoma
 Medullary carcinoma is a rare subtype of carcinoma, accounting for less than 1% of breast cancers.
 These cancers consist of sheets of large anaplastic cells with well circumscribed, “pushing” borders
 Medullary carcinomas occur with increased frequency in women with BRCA1mutations, although
most women with medullary carcinoma are not carriers
 These carcinomas uniformly lack the estrogen and progesterone receptors and do not
overexpress HER2/NEU (a combination that often is referred to as triple-negative)
Staging of Breast Carcinoma:
Stage Description
Stage Tis: In situ cancer (in situ lobular, pure Intraductal and Paget’s
disease of the Nipple without palpable tumor
Stage I Tumor 2 cm or less in greatest diameter and without
evidence of regional or distant spread
Stage II Tumor more than 2 cm but not more than 5 cm in greatest
dimension with regional lymph node involvement but
without distant spread
Stage III (A) Tumor of upto and more than 5 cm in diameter with or
without homolateral regional (local) spread that may or
may not be fixed, but Without distant spread
Stage III (B Tumor of upto and more than 5 cm in diameter with
homolateral metastatic supraclavicular and infraclavicular
nodes
Stage IV Tumor of any size with or without regional spread but
with evidence of distant metastasis
Paget’s disease of Nipple:
Morphology of Paget’s disease:
Gross:
 The nipple and areola is eczematous, fissured, ulcerated and oozing
 There is surrounding inflammatory hyperplasia and edema
 An underlying lump is rarely present
 Occurs in older age group, superimposed bacterial infection is common
Microscopic:
 Characteristic feature is invasion of epidermis by neoplastic cell called Paget cells.These are large,
hyperchromatic cell surrounded by a clear halo that represents intracellular accumulation of
muccopolysaccharides
 Basal epithelial cells are compressed and underlying dermis shows plasma cell infiltration
 Features of Intraductal CA are also present because Paget’s disease begins as Intraductal CA, which
later involves main excretory ducts and extends to infiltrate the skin of nipple
Q. a. pathologist is grading a breast tumor according to the Scarf-Bloom-Richardson system. What three
morphological features will he assess?
b. what is the significance of ER/PR and Her 2-neu status in a breast carcinoma?
1. Tubules formation
2. Nuclear grade
3. Mitotic rate: i. well differentiated ii. Moderately differentiated iii. Poorly differentiated
b. Overexpression of this membrane bound protein is almost always caused by amplification of the gene.
Overexpression can be determined by immunohistochemistry (which detects the protein in tissue section)
or by fluorescence in situ hybridization (which detects the number of gene copies). Over expression is
associated with poor prognosis. However, the importance of evaluating HER2-NEU is to predict response
to a monoclonal antibody (Herceptin) to the gene product. This is one of the first examples whereby an
antitumor antibody therapy has been developedbased on specific gene abnormality present in the tumor.
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Fibrocystic Diseases of Breast:

Classification of Fibrocystic Diseases of Breast:
Non-Proliferative:
 Cysts and Fibrosis
Proliferative Disorders:
 Epithelial Hyperplasia
 Sclerosing Adenosis
Q. A top tennis player was diagnosed with fibrocystic disease of the breast with atypical ductal hyperplasia.
Routine mammography showed an area of increased density
a) How does this diagnosis affect the patient’s risk of developing breast cancer?
b) What other factors will modify (increase or decrease) this risk?
c) Define atypical hyperplasia?
Risk Factors for Fibrocystic Diseases of Breast:
 The relative risk of developing of carcinoma in fibrocystic disease is 1 (3%) but due to Atypia risk
increased by 4 to 5 (13% to 17%).
 Increased risk:
 Early menarche
 Radiation exposure
 Nulliparous woman
 Tobacco
 Environmental toxin
 Risk decreased by:
 Bilateral prophylactic mastectomy
 Estrogen antagonist (Tamoxifen)
Atypical hyperplasia:
The hyperplastic cells become monochromic with complex architectural pattern. They have changes
approaching those of ductal carcinoma in situ. Such hyperplasia is called atypical
Mastitis
Inflammation of the breast is called mastitis
Puerperal mastitis
 Early stages (1 and 2 month) of lactation – 5%
st nd
 Stasis of milk in distended ducts + staphylococciabscess formation ( incision and drainage)

Granulomatous Lobular Mastitis
 Etiology unknown, suggests carcinoma
Mammary duct ectasia
 Periductalinflammation, duct sclerosis
 Intermittent nipple discharge
Tuberculosis
 Less developed regions - serious condition
 Lactating breast, inoculation via the lactiferous ducts
 Slowly growing, solitary, painless mass
Nipple Discharge
 Majority of causes are benign
 Most common cause is lactational
 Overstimulation also common
 Prolactin secreting tumors
 Hypothyroidism
 Drugs
 Bloody discharge in Intraductal and other carcinomas
 Unilateral, spontaneous, bloody discharge is suspicious
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Fat Necrosis Breast:
Definition:
Painless palpable mass, skin thickening or retraction, a mammographic density. The majority of women
have history of breast trauma or prior surgery. Major clinical significance of this condition is possible
confusion with breast cancer. Liquefactive fat necrosis is present.
Germ Cell Lesion:
Tumors Peak incidence Usual Morphological features Behavior
location
Dysgerminoma Second to third 80 to 90 % Counterpart of testicular All malignant but
decades, occur Unilateral Seminoma only one third
with gonadal Solid large to Small gray masses aggressive and
dysgenesis Sheets or cords of large cleared spread: All
cell separated by scant fibrous Radiosensitive with
strands. Stroma may contain 8% cure
lymphocyte and occasional
granuloma
Choriocarcinoma First three Unilateral Identical to placental tumor. Metastasis early and
decades of life Often small, hemorrhagic focus widely
with two type of epithelium; Primary focus my
cytotrophoblast and disintegrate leaving
Syncytiotrophoblast only mets
Resistant to
chemotherapy
Sex cord tumors:
Tumors Peak Usual Morphology Behavior
Incidence Location
Granulose Most Unilateral May be tiny or large.Gray to May elaborate large
theca cell postmenopausal yellow.Composed of mixture of amounts of estrogen
age granulose cells in cords, sheets or and so may promote
strands and spindled or plump lipid laden endometrial or breast
theca cells. Granulosa element may carcinoma
recapitulate ovarian follicle as Call Exner
bodies
Thecoma Any age Unilateral Solid gray fibrous cells to yellow plump Most hormonally
Fibroma thecal cells inactive. Rarely
Malignant
Sertoli- All age Unilateral Usually small, gray to yellow brown and Many masculinizing
Leyding cell solid or defeminizing.
Recaps development of testis with Rarely malignant
tubules or cord and plump pink Sertoli
cell
Other ovarian tumor: Teratoma
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Chapter Ten ENDOCRINE SYSTEM
Thyroid Disorders
Common disorders of Thyroid gland:
1. Sick euthyroid syndrome (SES)
2. Simple nontoxic goiter (SNG)
3. Hypothyroidism
4. Hyperthyroidism
 Graves
 Toxic multinodular goiter(TMNG)
 Toxic solitary nodular (TSN)
 Thyroiditis
 Thyroid carcinoma
Thyroid enlargement:
Goiter:
 A goiter is a simple enlargement of the thyroid gland
 It is more common in females with the highest incidence in the second to sixth decades of life
 Diffusely enlarged goiters are caused by either iodine deficiency or excess, congenital defects in
thyroid hormone synthesis and drugs (e.g., lithium carbonate) dietary causes such as cabbage,
soybean, cassava etc.
 Most are asymptomatic. It is unusual to have pain and rare to have hoarseness and tracheal
obstruction
 Thyroid function tests should be performed on all patients with goiter because it can be associated
with hypothyroidism, euthyroidism, or hyperthyroidism
 Microscopically thyroid-filled follicles lined by simple cuboidal epithelium or low columnar cells
Multinodular Goiter:
Etiology: most often caused by iodine deficiency
Signs and symptoms:
Symptoms:
Thyromegaly, occasionally with rapid enlargement and tenderness secondary to hemorrhage into a cyst
Rarely, tracheal compression may occur, causing coughing or choking
Some patients may complain of a feeling of lump in the throat
Diagnosis:
Thyroid function tests: Performed to rule out hypo or hyperthyroidism
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Endocrine System
Multinodular Goiter
Solitary Nodules:
 They are usually benign.
 One should, suspect malignancy in a patient with a history of radiation exposure, rapid enlargement,
hoarseness or obstruction, and a solid nodule that is cold on scan.
Diagnosis:
History and Radioiodine thyroid scanshould be done on every patient with a solitary nodule. Hot nodules
that take up the radioisotope are generally benign but fine-needle aspiration of a solitary nodule is
prudent.
Hyperthyroidism:
Definition: Hyperthyroidism is a Hypermetabolic state, resulting from excessive thyroid hormone
production.
Thyrotoxicosis is defined as the state of thyroid hormone excess due to any cause, endogenous or
exogenous.
Primary hyperthyroidism
 Excessive hormone secretion due to primary abnormality in the thyroid gland is called primary
hyperthyroidism
Common causes:
 Graves ‘disease
 Toxic multinodular goiter
 Toxic adenomas 80-95 % cases
Secondary hyperthyroidism:
 Excessive secretion of thyroid hormone due to primary abnormality outside the thyroid gland is called
secondary hyperthyroidism
Common causes
 Pituitary adenoma
 Ectopic thyroid secretion by ovarian tumor
Clinical features:
Metabolic changes: Elevated basal metabolic rate, weight loss with increased appetite, heat intolerance
and sweating.
Cardiovascular effects:
 Weakness, dyspnea on exertion
 Palpitation , sinus tachycardia , atrial fibrillation in the elderly
 Systolic hypertension , high output failure with wide pulse pressure
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Endocrine System
Gastro Intestinal symptoms: Loose stool or diarrhea (may be the first sign of thyroid storm)
Skin and hair changes: Skin is warm and moist because of peripheral vasodilation;fine silky hair is
characteristic finding
CNS and neuromuscular effects:
 Nervousness, hyperactivity, irritability, dysphoria(impatience), emotional liability, poor concentration
 Fine Tremors
 Muscle weakness, fatigue and proximal myopathy
 Increased reflexes
Genitourinary manifestations: Polyuria, dysmenorrhea, oligomenorrhea or amenorrhea
Ophthalmopathy:
Wide stare and lid lag (i.e. slow closing of the upper lid when the eye moves down ward, revealing sclera
between the lid and cornea) may occur in any form of hyperthyroidism
Exophthalmos:True thyroid exophthalmos is seen only in Graves’ diseases, occurring in approximately
50% of cases. The eyes are pushed forward because of mucinous and cellular infiltration of extra-ocular
muscles. There is inflammation of the conjunctiva and surrounding tissue. The patient may complain
tearing, eye irritation, pain and double vision. In sever case vision may be threatened
Other findings:
 Goiter
 Gynecomastia
Hypothyroidism:
Definition:
Primary hypothyroidism: refers to a thyroid hormone deficiency because of thyroid gland disease.
Secondary hypothyroidism: refers to a decrease thyroid hormone because of pituitary TSH deficiency.
Tertiary hypothyroidism: results from thyrotropin-releasing hormone (TRH) deficiency).
Cretinism hypothyroidism in babies and young child
Myxedema hypothyroidisminadults and older children
Etiology:
Without thyroid enlargement
 Hypothyroidism frequently develops following treatment of Graves’ disease with 131I therapy or
thyroidectomy.
 Idiopathic hypothyroidism: is idiopathic atrophy of the thyroid gland. It is one of the commonest
causes of hypothyroidism.
 Developmental defects and TSH or TRH deficiency are less common causes.
With thyroid enlargement
 Chronic thyroiditis /Hashimoto’s thyroiditis is one of the most common causes of spontaneous
hypothyroidism.
 Drugs, iodine deficiency, and inherited defects in thyroid hormone synthesis are rare causes.
Signs and symptoms:
 Fatigue, weakness, lethargy, slow movement, cold intolerance
 Slight to moderate weight gain, but appetite tends to be diminished
 Carpal tunnel syndrome, edema of the face and extremities,
 Hearing loss, hoarseness of the voice, large protruding tongue
 Dry yellow skin, hair loss, sparse eyebrows with loss of the lateral half
 Pericardial effusion and ascites occasionally occur
 Atherosclerosis, diastolic hypertension
 Constipation, umbilical hernias are common
 Menorrhagia,
 Memory impairment
 Psychosis may develop with long-standing hypothyroidism and may be precipitated by thyroid
hormone replacement
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Endocrine System
Q. A 30 years old female presents with soft, warm and flushed skin. Heat intolerance and excessive sweating. She
gives history of weight loss despite increase appetite and frequent attacks of diarrhea, palpitation and experiences
nervousness, tremor and irritability. On examination, she has a wide, staring gaze and lid lag is present. She is
provisionally diagnosed to have thyrotoxicosis.
a) What is triad of manifestations in grave disease?
b) What are the morphological features of a thyrotoxicosis thyroid?
Triad of Clinical Manifestation in Graves’ Disease:
Thyrotoxicosis
Ophthalmopathy
Dermopathy (pretibial edema)
Morphological feature of hyperthyroidism
Gross:
 Diffused hypertrophy and symmetrical enlargement
 On cut section:
 Soft meaty appearance resembling normal muscles
Microscopic:
 Epithelium tall and more corroded, small papillae projecting into the follicular lumen, pale colloid,
lymphoid infiltrate with germinal Centre.
Q. A 35 years old female presents with generalized apathy, mental sluggishness, restlessness, cold intolerance and
obesity. She is suspected to have myxedema.
a) What lab tests will you order to confirm the diagnosis?
b) What lab findings are going to be present if she is diagnosed to have Hashimoto’s Thyroiditis?
c) Why some patients with Grave’s disease spontaneously developed episodes of Hypothyroidism?
Laboratory Tests:
 TSH level: ↑ in primary hypothyroidism
 T4 Level: ↓
 T3 level: ↓
Anti-microsomal and Anti-thyroglobulin antibodies
 TSH-binding inhibitor immunoglobulin (TBII): These anti-TSH receptor antibodies prevent TSH from
binding normally to its receptors on thyroid epithelial cell. Some forms of TBBIIs mimic the action of
TSH and resulting in the stimulation of thyroid epithelial cell activity. Whereas other forms may
actually inhibit the thyroid cell function. It is not usual to find the coexistence of stimulating and
inhibiting immunoglobulin in the serum of the same patient, this finding explain why some patient
with grave disease spontaneously develop episodes of hypothyroidism.
Thyroiditis
Definition:
Inflammation of the thyroid, thyroiditis, is more often due to non-infectious causes and is classified on the
basis of onset and duration of disease into acute, subacute and chronic as under:
Classification:
I. Acute thyroiditis:
a. Bacterial infection e.g. Staphylococcus, Streptococcus
b. Fungal infection e.g. Aspergillus, Histoplasma, Pneumocystis
c. Radiation injury
II. Subacute thyroiditis (postpartum):
a. Subacute granulomatous thyroiditis (de Quervain’s thyroiditis, giant cell thyroiditis, viral
thyroiditis)
b. Subacute lymphocytic (postpartum, silent) thyroiditis
c. Tuberculous thyroiditis
III. Chronic thyroiditis:
a. Autoimmune thyroiditis (Hashimoto’s thyroiditis or chronic lymphocytic thyroiditis)
b. Riedel’s thyroiditis (or invasive fibrous thyroiditis)
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Hashimoto Thyroiditis:
Q. A 45 years old woman presents with painless enlargement of thyroid. On examination, her physical and mental
responses appear sluggish. Histological examination of thyroidectomy specimen shows lymphocytic infiltrate with
germinal Centre formation along with thyroid follicles, few showing “Hurtle cell” change.
a) Give diagnosis and immunological mechanism of cell injury.
b) Name two endocrine diseases associated with this condition.
Diagnosis:
Hashimoto thyroiditis
Pathogenesis:
 The possible reaction of CD4+ T cells to thyroid antigens, thus producing cytokines –Interferon γ (IFN-
γ). Which promote inflammation and activate macrophages, as in Delayed type hypersensitivity
reactions
 CD8+ cytotoxic T cell mediated cell death:
 Binding of antithyroid antibodies followed by antibody dependent cell mediated cytotoxicity
mediated by natural killer cells
a) Subacute Granulomatous Thyroiditis
b) Subacute Lymphocytic Thyroiditis
Morphology of Hashimoto’s Thyroiditis:
Gross:
 Diffuse and symmetrically enlarged.
 On cut section, there is pale and gray tan appearance.
Microscopically:
 There is an infiltration of the parenchyma by mononuclear inflammatory infiltrates containing
lymphocytes, plasma cells with the formation of well-developed germinal centers.
 The presence of abundant eosinophilic granular cytoplasmic cells, termed Hurthle’s or Oxyphil cells.
On ultra-structural examination, the Hurthle’s cells are characterized by numerous prominent
mitochondria.
Q. Give laboratory findings of serum T3, T4 and TSH level in typical cases of Grave’s disease, Hashimoto’s
thyroiditis; diffuse non-toxic goiter and multinodular goiter.
Laboratory Findings of Different Thyroid Disorders:
Graves’s disease:
 TSH ↓, T3 ↑, T4 ↑
Hashimoto’s thyroiditis:
Initial phase (Hashi-toxicosis)
 TSH ↓, T3 ↑, T4 ↑
Delayed phase
 TSH ↑, T3 ↓, T4 ↓
Diffuse and multinodular Goiter:
 TSH↓ or normal compensatory increased T3 ↑or normal, T4 ↓ or normal.
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Hashimoto’s Thyroiditis
Grave’s disease:
 Most common cause of endogenous hyperthyroidism
 Relatively common cause of females affecting 4-5 times more commonly than males
 Associated with HLA-DR3
Pathogenesis of grave’s disease
Graves’s disease is autoimmune disorder in which a variety of antibodies may be present in the serum,
including antibodies to the TSH receptor, thyroid peroxisomes and thyroglobulin:
1. Thyroid stimulating immunoglobulin (TSI)
2. Thyroid growth stimulating immunoglobulin (TGIs)
3. TSH binding inhibitor immunoglobulin (TBBII)
Clinical features
 Diffuse enlargement of thyroid appear as a mass in the neck
 Thyroid or Graves’ ophthalmic disease characterized by wide, staring gaze, wide-open eyes, decrease
blinking and reduced eye movement. Exophthalmos(forward displacement of an eyeball) also present
 Dermopathy characterized by localized area of thickening and hyperpigmentation of the skin over the
anterior aspect of feet and legs
TSH ↓, T3↑, T4 ↑
Tumors of Thyroid:
Classification of thyroid carcinoma
Tumors of thyroid:
Benign:
1. Follicular thyroid adenoma
2. Toxic adenomas
Carcinomas:
1. Papillary carcinoma: 75-85% (good prognosis)
2. Follicular carcinoma: 5-15%
3. Medullary carcinoma: 5%
4. Anaplastic carcinomas: <5%
Predisposing factors
Ionizing radiation
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Endocrine System
Papillary Carcinoma:
Morphology of papillary carcinoma
Gross
 Ranges from microscopic lesions to large masses more than 10 cm in diameter
 Usually infiltrative but may be circumscribed
Microscopic features
 Nuclei of papillary carcinoma cells contain very finely dispersed chromatin
 This chromatin imparts an optically clear appearance, giving rise to designation “ground glass” or
“orphan Annie eye” nuclei
 Invaginations of cytoplasm (pseudo-inclusions)
 Psammoma bodies calcified structure present in most papillary carcinoma
Medullary Carcinoma:
It arises from the parafollicular C cells
Morphology of medullary carcinoma:
Gross:
1. Medullary carcinomas may arise as a solitary nodules or may present as multiple
2. Multicentricity is particularly common in familial cases
3. Larger lesion often contains areas of necrosis and hemorrhage and may extend to capsule.
Light Microscopy:
1. They are composed of polygonal to spindle shaped cells, which may form nests, trabeculae, andeven
follicles.
2. Acellular amyloid deposits derived from altered calcitonin molecules are present in adjacent stroma
and is distinctive feature of these tumors
Electron microscopy:
1. Reveals variable numbers of intra-cytoplasmic membrane bound electron dense granules
2. One of the peculiar features is the presence of multicentric C-cells hyperplasia in the surrounding
thyroid parenchyma, a feature usually absent in sporadic lesion.
3. The cold nodules has high risk of being cancerous or malignant than that of hot nodules so more
dangerous
Laboratory diagnosis for thyroid carcinoma
 Ultrasound: nodules
 Scintigraphy/radioiodine uptake: cold nodules without or littleuptake
 CT/MRI of neck
 FNA with cytology or biopsy
 Serum Calcitonin level ,
 Staging Is Based On : CXR, CT, Bone Scintigraphy
Parathyroid Disorders
Parathyroid hormone and hyperparathyroidism:
Parathyroid hormone (PTH) is normally secreted in response to low ionized Ca2 +levels, by
4parathyroid glands situated posterior to the thyroid. The glands are controlled by negative
2+
feedback via Ca2 +levels. PTH acts by: •↑Osteoclast activity releasing Ca andpO4 from bones
2+
•↑Ca and ↓PO4 –reabsorption in the kidney •Act via 1,25dihydroxy-vitamin D3production is
2+
↑Overall effect is ↑Ca and ↓PO4
Primary hyperparathyroidism
Causes: 80% solitary adenoma, 20% hyperplasia of all glands, <0.5% parathyroid cancer
2+
Presentation: Often ‘asymptomatic’ (not in retrospect, with ↑Ca on routine tests)
Signs:
 ↑Ca :Weak, tired, depressed, thirsty (polydipsia), dehydrated-but-polyuria; also renal
2+
stones, abdominal pain, pancreatitis and ulcers

 Bone resorption effects of PTH can cause pain, fractures, and osteopenia/osteoporosis.
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 BP↑:So check Ca +in everyone with hypertension. Association: MEN-1

2
2+
Tests: Serum Ca ↑and PTH ↑
2+
Secondary hyperparathyroidism Ca ↑, PTH↑ (appropriately)
Causes:↓Vit D intake, chronic renal failure
2+
Tertiary hyperparathyroidism Ca ↑,↑PTH (inappropriately).Occurs after prolonged secondary
hyperparathyroidism, causing glands to act autonomously having undergone hyperplastic or
2+
adenomatous change. This causes Ca ↑from ↑secretion of PTH, unlimited by feedback control.
Seen in chronic renal failure
Some squamous cell lung cancers, breast and renal cell carcinomas produce malignant
2+
hyperparathyroidism Parathyroid-related protein (PTHrP). This mimics PTH resulting in Ca ↑,
(PTH is ↓, as PTHrP is not detected in the assay)
Hypoparathyroidism:
Primary hypoparathyroidism PTH secretion is ↓due to gland failure
2+
Tests: Ca ↓, Po4↑
Signs: Those of hypocalcaemia, Tetany, Trousseau’s sign and Chvostek’s sign
Causes: Autoimmune; congenital (Di George syndrome)
Secondary hypoparathyroidism Radiation, surgery (thyroidectomy, parathyroidectomy)
commonest cause, hypomagnesaemia (magnesium is required for PTH secretion)
Pseudohypoparathyroidism Failure of target cell response to PTH
Signs:Short metacarpals (especially4th and 5th), round face, short stature, calcified basal ganglia,
IQ↓
2+
Tests: Ca ↓, ↑PTH
Pseudohypoparathyroidism The morphological features of pseudo hypoparathyroidism, but with
normal biochemistry. The cause for both is genetic
Multiple Endocrine Neoplasia (MEN) Syndromes:
 The MEN syndromes are a group of inherited dominant diseases resulting in proliferative lesion
(hyperplasia, adenomas, and carcinoma) of multiple endocrine organs.
MEN 1(Wermer’s syndrome) =3p’s
 Parathyroid tumors
 Pituitary tumors (Prolactin or GH)
 Pancreatic endocrine tumors-Zollinger Ellison syndrome, Insulinoma etc.
MEN 2A (Sipple’s syndrome) =2p’s
 Medullary thyroid carcinoma(secrete calcitonin)
 Pheochromocytoma
 Parathyroid tumor
MEN 2B=1p
 Medullary thyroid carcinoma(secrete calcitonin)
 Pheochromocytoma (Paraganglionoma)
Diabetes mellitus:
Q .A 50-year-old women consulted her family Dr because of tiredness general body aches and weight gain. On
questioning, she admitted to feeling thirsty and had notice that she had been passing more urine than normal.
a) What is diagnosis
b) What lab investigation are recommended
c) What are major characteristics of type 1 and 2 diabetes mellitus?
d) Classify the diabetes (KMU 2014)
e) Enumerate the acute complications of diabetes (KMU 2014).
Diagnosis:
Diabetes mellitus (DM)
Recommended investigations:
 Fasting blood sugar (FBS)
 Random blood sugar (RBS)
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 Oral glucose tolerance test (OGTT)

 HbA1c (glycosylated Hb)
 Less commonly
 Serum insulin level
 Serum C-peptide level
 Islet cells antibodies (ICAs)
Major characteristics of type 1 and type 2 DM:
Parameters Type 1 DM Type 2 DM
CLINICAL
Onset <20 years Onset >30 years
Normal weight Obesity
Markedly decreased blood insulin Increased blood insulin (early);normal to
moderate decrease insulin (late)
Antibodies to islet cells No antibodies to islet cells
Ketoacidosis Ketoacidosis rare; non ketotic hyperosmolar
coma
GENETICS
30% to 70 % concordance in twins 50 % to 90 % concordance in twins
Linkage to MHC class 2 HLA genes No HLA linkage
Linkage to candidate “diabetogenic” genes
PATHOGENESIS
Autoimmune destruction of B-cells Insulin resistance in skeletal muscles,
mediated by T cells and humoral mediators adipose tissue, and liver
Absolute insulin deficiency Relative insulin deficiency and B- cell
dysfunction
ISLET CELLS
Insulitis early No Insulitis
Marked atrophy and fibrosis Focal atrophy and amyloid deposition
B-cell depletion Mild B-cell depletion
Classification of diabetes mellitus:
1 Type I Diabetes
Beta Cell Destruction
2 Type II Diabetes
Insulin Resistance and Beta Cell Dysfunction
3 Genetic Defects of Beta Cell Function
4 Genetic Defect in Insulin Action
Insulin Receptor Mutation
5 Exocrine Pancreatic Defects
Chronic Pancreatitis, Neoplasia, Cystic Fibrosis
6 Endocrinopathies
Growth Hormone, Cushing’s Syndrome, Hyperthyroidism, Pheochromocytoma
7 Infection
Cytomegalovirus, Coxsackievirus, Congenital Rubella
8 Drugs
Beta Adrenergic Agonist, Glucocorticoids
9 Genetic Syndromes Associated with Diabetes
Down’s Syndrome, Klinefelter’s Syndrome, Turner Syndrome
10 Gestational Diabetes
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Acute complications of diabetes:

 Diabetic ketoacidosis
 Hyperosmolar non Ketotic coma
 Hypoglycemia
Q. A 18 years old known diabetic girl, suddenly felt ill, developed vomiting and became drowsy. She was taken to
the emergency, where on examination she had B.P of 95/60mm of Hg with pulse rate 112/min and cold
extremities. She had deep, sighing respiration (kussmuaul’s respiration) and her breath smelt of acetone.
b) Give any four clinical and four metabolic features of this condition.
Diagnosis:
Diabetic Ketoacidosis Coma
Sever insulin deficiency→ increase lipolysis→ increase free fatty acid level→ increase FFA oxidation in
liver → ketone bodies formation → ketonemia and ketonuria → acidosis→ diabetic coma
 Acetone breath
 Osmotic diuresis
 Dehydration
 Ketonemia, ketonuria
 Metabolic acidosis
Chronic Complications of Diabetes mellitus:
It may be micro vascular, macro vascular or avascular
Microvascular:
Retinopathy:
 Non-proliferative: ‘dot and blot’ and retinal hemorrhages, cotton wool/protein exudates
 Proliferative: neovascularization, vitreous hemorrhage, retinal detachment, blindness
 Both treated with photocoagulation
Nephropathy:
 Microalbuminuria -> proteinuria +/- Nephrotic syndrome -> eventual renal failure
 Diffuse glomerular basement membrane thickening
 Treatment: strict BP control, ACE-I, low protein diet
Neuropathy:
 Symmetric peripheral neuropathy: symmetric distal sensory loss, parasthesia, +/- motor loss
 Autonomic neuropathy: gastroparesis, neurogenic bladder, impotence, orthostatic hypotension
 Mononeuropathy: sudden onset of peripheral or Cranial nerve (CN) deficit (foot drop, CN iii>vi>iv)
Macrovascular:
 Stroke, myocardial infarction or peripheral arterial disease
 Accelerated atherosclerosis in coronary, cerebral and peripheral arterial beds (i.e.: diabetics are at a
higher risk for MI, CVA, and foot ulcers)
 Avascular (infections)
 Diabetic foot*, candidiasis, mucormycosis, necrotizing otitis Externa
Dermatologic:
 Necrobiosis lipodica diabetic rum, lipodystrophy, acanthosis nigricans
Insulin resistance
The resistance to the effects of insulin on glucose uptake, metabolism and storage is called insulin resistance. It is
characteristic feature of type 2 diabetes. The evidence that insulin resistance has a major role in the pathogenesis
of type 2 D.M can be gauged from the findings that:
1. Insulin is often detected 10 to 20 years before the onset of diabetes in predisposed Individuals
(offspring of type II diabetic)
2. In prospective studies the insulin resistance is the best predictor for subsequent progression to
diabetes
 Genetic defect of insulin receptor and insulin signaling pathway
 Obesity and insulin resistance
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Pituitary Gland
Classificationpituitary adenoma
 Densely and sparsely granular
 Functional and non-functional
 Macronodular and Micronodular
Note: Most common pituitary adenoma is prolactinoma.
Anterior pituitary diseases may result from:
 Insufficient production of pituitary hormones: hypopituitarism
 Excess production of pituitary hormones:
 Acromegaly,
 Cushing’s diseases
 Hyperprolactinoma
 Local effect of pituitary tumors
Posterior Pituitary diseases
 Syndrome of inappropriate ADH
Hyperprolactinoma /Galactorrhea:
Definition: Hyperprolactinoma is a clinical condition resulting from excess secretion of prolactin in men,
or in women who are not breastfeeding.
Etiology:
 Prolactin secreting pituitary adenomas (Prolactinoma) is more common in women than in men,
usually appearing during reproductive years. Majority are microadenomas; ACTH, prolactin secreting
adenoma (< 10 mm in size). Men tend to have larger tumors, Growth hormone secreting adenoma
(macroadenomas), which usually are suspected because of neurologic impairment and hypogonadism
 Damage to the hypothalamus or the pituitary stalk: by tumors, granulomas and other process may
prevent the normal regulatory effect of hypothalamic dopamine on lactotrope activity, resulting in
hypersecretion of prolactin
 Drugs: drugs that inhibit dopamine activity, and thus interfere with its regulatory activity on prolactin
secretion. Some of the drugs are phenothiazine, antidepressants, antihypertensive (methyldopa,
reserpine), opioids, cimetidine, metoclopramide, contraceptives etc.
 Other rare causes :
 Primary hypothyroidism
 Chronic liver disease
 Renal failure
 Ectopic prolactin production from tumors (paraneoplastic syndromes)
Clinical features:
In women:
 Galactorrhea: is the direct result of prolactin excess
 Amenorrhea or menstrual irregularities due to inhibition of hypothalamic GnRH production by
prolactin as well as the direct effect of prolactin on the ovaries
 Signs of estrogens deficiency may be seen such as hot flushes and dyspareunia
In men:
 Loss of libido and potency, hypogonadism
 Headaches, visual difficulties result from the compression effect of tumors, which are often larger in
men
Diagnosis:
 Prolactin levels: are elevated. A serum prolactin level greater than 300ng/ml strongly suggests the
presence of prolactinoma. Functional causes such as drugs seldom elevate the prolactin level above
100-200ng/ml
 Skull x-ray (lateral): CT/MRI: are used to visualize the adenoma
 Visual field examination
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Endocrine System
Syndrome of inappropriate ADH secretion:

Causes include:
 Ectopic ADH from small cell carcinoma of lung
 CNS disorders/head trauma
 Pulmonary disease (Paraneoplastic syndrome)
 Drugs(e.g. cyclophosphamide)
Syndrome of inappropriate ADH secretion:
 Excessive water retention
 Hyponatremia with continue urinary Na excretion
 Urine osmolarity >serum osmolarity
Adrenal Gland Disorders:
Adrenal cortex 3 region as following
 Zona glomerulosa secretes aldosterone and is controlled by renin angiotensin system
 Zona fasciculata secretes cortisol and is controlled by pituitary gland through ACTH
 Zona reticularis secretes androgen and is controlled by pituitary gland through ACTH
Adrenal medulla
 Derived from neural crest cells and secretes epinephrine and norepinephrine
Adrenal Insufficiency:
Causes of adrenal insufficiency:
Acute
Waterhouse Friederichsen syndrome
Sudden withdrawal of long term corticosteroid therapy
Stress in patients with underlying adrenal insufficiency
Chronic
Autoimmune Adrenalitis. Tuberculosis, Acquired immunodeficiency syndrome, Sarcoidosis
Systemic amyloidosis, Fungal infections, Hemochromatosis, Metastatic disease
Pheochromocytoma:
Rule of 10’s:
 10% malignant
 10% bilateral
 10% extra-adrenal
 10% calcify
 10% kids
Morphology of pheochromocytoma
Gross:
 Range in size from small, circumscribed lesion confined to adrenal gland to large, masses weighing
several kilogram
 On Cut section: yellow-tan, well defined lesion, lesion tend to be hemorrhagic, necrotic and cystic
Microscopically:
 Composed of polygonal to spindle shaped chromaffin cells and their supporting
cells,Compartmentalized into small nests, or Zellballen, by high vascular network
Hyperadrenalism:
Cushing syndrome:
Cushing’s syndromeis caused by excessive concentration of cortisol or other glucocorticoid hormones in
the circulation
Etiology:
 Bilateral adrenal hyperplasia (Cushing’s diseases) is the commonest cause of Cushing’s syndrome in
setting of endogenous corticosteroid. It is caused by increased pituitary secretion of ACTH. Pituitary
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Endocrine System
tumors large enough to be seen by skull x-ray, are present in more than 10 % of these patients, and
smaller basophilic adenomas are found in more than 50 % of patients
 Adrenal adenomas and adrenal carcinoma may produce excess cortisol
 Ectopic ACTH production by tumors, such as oat cell carcinoma of the lung, carcinoma of the
pancreas , bronchial carcinoid tumors , and other, cause adrenal hyperplasia and Cushing’s syndrome
 Iatrogenic (Exogenous) Cushing’s syndrome: It is the overall most common cause of Cushing
syndrome. It is an expected complication in patients receiving long-term glucocorticoid treatment for
asthma, arthritis, and other conditions
Clinical features
 Central obesity is caused by the effect of excess cortisol on fat distribution. Fat accumulation in the
face, neck and trunk, while the limbs remain thin. The “moon face” , “buffalo hump”( cervical fat pad
) and supraclavicular fat pads contribute to the Cushingoid appearance
 Hypertension : result from the vascular effects of cortisol and sodium retention
 Decreased glucose tolerance: is common, 20 % of patients have overt diabetes. This is a result of
hepatic gluconeogenesis, and decreased peripheral glucose utilization
 Symptoms of androgen excess (e.g. oligomenorrhea, hirsutism, and acne) may occur in women with
Cushing’s diseases, because of stimulation by ACTH of adrenal androgen production.
 Purple striae: are linear marks on the abdomen, where the thin, wasted skin is stretched by
underlying fat. Atrophic skin with senile purpura may be seen
 Muscle wasting and weakness: reflects the catabolic effect of cortisol on muscle protein.
 Osteoporosis: is caused by increased bone catabolism
 Susceptibility to bruising: is probably caused by enhanced capillary fragility
 Psychiatric disturbance, especially depression, is frequently seen
 Poor wound healing: due to impaired immune function
 Growth retardation in children may be severe
Diagnosis:
 Overnight Dexamethasone suppression test: is recommended as an initial screening test Administer
dexamethasone 1 mg PO at 11 PM at midnight and measure serum cortisol at 8:00 AM the following
day
The serum cortisol level should be <5 µg/dl in most individuals, indicating normal suppression of ACTH
and cortisol by dexamethasone. Because this test is sensitive, the diagnosis of Cushing’s syndromeneed
not be considered further in these cases. Patients with Cushing’s syndrome will have cortisol level > 5
µg/dl, usually greater than 10 µg/dl .This result indicates further study is needed.
 The standard dexamethasone suppression test: is the most relied up on test for Cushing’s syndrome
Response
Diagnosis Suppression with low dose Suppression with high dose
Normal Yes Yes
Cushing’s disease No Yes
Adrenal tumor or ectopic ACTH No No
production
 ACTH measurement: may help to differentiate the cause of Cushing’s syndrome
 High normal or slightly elevated ACTH andCushing’s diseases
 Markedly elevated ACTH andEctopic ACTH production
 Extremely low ACTH levelandautomatically functioning adrenal tumor is the source of excess
cortisol. Pituitary secretion of ACTH is suppressed due to the excess cortisol
 Serum cortisol level: in normal individuals. It is highest in early morning and decreases throughout
the day, reaching a low point at about midnight. Although the morning level may be increased in
patients with Cushing’s syndrome, a loss of the normal diurnal variation and an increase in the
evening level are findings that are more consistent
 The 24 hours urinary free cortisol excretion rate: is increased in most patients with Cushing’s
syndrome
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Endocrine System
Hyperaldosteronism:
Aldosteronism: is a syndrome associated with hypersecretion of the mineralocorticoid, aldosterone.
Etiology:
 Primary Aldosteronism: the cause of excess aldosterone production resides with in the adrenal
gland.
 Aldosterone producing adrenal adenoma (Conn’s syndrome): in most cases , unilateral small
adenoma which can occur on either side
 Adrenal carcinoma: rare cause of Aldosteronism
 Bilateral cortical nodular hyperplasia /idiopathic Hyperaldosterinism
Secondary Aldosteronism: the stimulus for excess aldosterone production is outside the adrenal gland. It
refers to appropriately increased production of aldosterone in response toactivation of the renin-
angiotensin system
 Accelerated phase of hypertension
 Pregnancy
 Other edema states: nephritic syndrome, etc.
Pathophysiology: The excess aldosterone increases the reabsorption of sodium and excretionof
potassium and hydrogen ions, in the distal renal tubules, which results progressive depletion of potassium
and leads to hypokalemia.
 Hypokalemia in hypertensive patients is often the clue that triggers the search for Primary
Aldosteronism
 Metabolic alkalosis
 Serum aldosterone level: elevated aldosterone and metabolites in 24hour urine
 Plasma renin activity: is the most important useful indicator of whether elevated aldosterone is
primary or secondary. Increased plasma renin activity favor the diagnosis of secondary
Aldosteronism. While raised aldosterone level with reduced plasma renin activity suggests primary
Aldosteronism
 CT scan and MRI: may detect aldosterone-secreting adenomas
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Essential Special Pathology Musculoskeletal System
Chapter Eleven MUSCULOSKELETAL SYSTEM
Osteogenesis imperfecta (OI):

1. Osteogenesis imperfecta, also known as, “brittle bone” disease is actually a group of genetic
disorders caused by defective synthesis of type I collagen. The fundamental abnormality in all form of
OI is too little bone , resulting in extreme skeletal fragility
2. The classical finding of blue sclera in type I OI is attributed to decrease scleral collagen content
3. Hearing loss→conduction defect in the middle and inner ear bones
4. Small misshapen are a result of dentine deficiency
Osteoporosis:
Definition:
 Reduction in bone density or presence of a fragility fracture
 Bone density = amount of bone mineral per unit area
 Decreased bone density (mineral and matrix) leads to increased fractures, resulting in increased
morbidity and mortality
 The bone loss, averaging 0.5 % per year and is most prominent in areas containing abundant
trabecular bone namely the spine and femoral neck
Causes of Osteoporosis:
Primary:
 Postmenopausal
 Senile
Secondary:
 Endocrine Disorders:
 Hyperparathyroidism
 Hypo or hyperthyroidism
 Hypogonadism
 Pituitary tumors
 Diabetes, type 1
 Addison disease
 Neoplasia:
 Multiple myeloma
 Gastrointestinal Disorders:
 Malnutrition andMalabsorption
 Hepatic insufficiency
 Vitamin C, D deficiencies
 Drugs:
 Anticoagulants
 Chemotherapy
 Corticosteroids
 Anticonvulsants(carbamazepine)
 Alcohol
 Miscellaneous:
 Osteogenesis imperfect (OI)
 Immobilization
 Homocyctinuria
 Anemia
Morphology:
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Musculoskeletal System
The hallmark of osteoporosis is a loss of bone. The cortices are thin, with dilated Haversian canals, and the
trabeculae are reduced in thickness and lose their interconnections
Pathogenesis:
Bone remodeling: Bones are dynamic organs that undergo constant remodeling to adapt to physical
stress placed upon them. They also act as a calcium reserve to aid in the maintenance of serum calcium
levels
Osteoclasts:Cause Resorption of bone and release calcium into blood
Osteoblasts:Formation and mineralization of new boneBalanced osteoblastic and osteoclastic activity
results in maintenance of a stable bone mass/density
Most adults reach a peak bone density between 20-30 years of age. After this point, increased
osteoclastic activity and reduced osteoblastic activity result in imbalanced bone remodeling and increased
overall bone Resorption relative to formation (normal = 1 -2% per year)
Age related changes:
 The age related loss of bone mass may be caused by decreased replicative activity of osteoprogenitor
cells
 Decreased synthetic activity of osteoblasts cells
 Decreased biologic activity of matrix bound growth factors
 Reduced physical activity
Hormonal influences: Play a significant role in the development of osteoporosis, especially in
postmenopausal women. Estrogen ↑ bone mass
Decrease serum estrogen→↑ production of cytokines (IL-1, IL-6, TNF levels→↑ expression of RANK,
RANKL →↑ osteoclast activity and suppression of osteoprotegrin cells (OPG production)
Genetic factors: The maximum bone density depends on genetic factors responsible for normal bone
development. Vitamin D receptors polymorphism appears to influence the peak bone very early in life
Physical activity: Reduced physical activity is associated with accelerated bone loss, whiles the weight
bearing increase the mass or increased physical activity such as jogging
Calcium nutritional state: calcium and vitamin D intake in diets prevents osteoporosis
Secondary causes: smoking, corticosteroids and alcoholism decrease bone mass
Prevention and Treatment:
 Calcium and Vitamin D intake in diets
 Bisphosphonates
 The estrogen replacement therapy in postmenopausal women
Osteomyelitis:
 The inflammation of the bone marrow cavity is called osteomyelitis
 It may be acute , subacute or chronic osteomyelitis
Types
 Pyogenic osteomyelitis
 Tuberculous osteomyelitis
Causative agent
 Stap aureus in 80-90%, mycobacterium tuberculosis, Klebsiella, pseudomonas
 E.coli and group B streptococci are important cause of acute osteomyelitis in neonate
 Salmonella is common cause of acute osteomyelitis in sickle cell disease
Modes of Spread of Infection into Bone
 Hematogenous spread e.g. in systemic pyogenic diseases
 Local invasion from adjacent structures undergoing inflammatory process e.g. in chronic maxillary
sinusitis
 Direct inoculation e.g. orthopedic surgery or traumatic accidents
Sequences of event in pyogenic osteomyelitis
 Localization of bacteria
 Bacteria induces acute inflammatory reaction and cell death (influx of neutrophils that destroy bone)
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 Sequestrum formation in osteomyelitis, the lifted periosteum impairs the blood supply to the
effected region, and both the suppurative and ischemic injury may cause segmental bone necrosis;
the dead piece of bone is called Sequestrum
 Continue exudate raises the tissue pressure
 Infection travels via Haversian system to periosteum
 Subperiosteal abscess formation
 Lifting of periosteum, further impair blood flow
 Devitalization of bone resulting in dead bone tissue formation
 Rupture of periosteum and formation of a draining sinus
 Involucrum After the first week chronic inflammatory cells become numerous and their release of
cytokines stimulates osteoclastic bone Resorption, ingrowth of fibrous tissue and deposition of
reactive bone in the periphery. When the newly deposited bone forms a sleeve of living tissue around
the segment of devitalized infected bone, known as Involucrum
Features of Tuberculous osteomyelitis:
 Bone infection complicates an estimated 1 to 3 % of cases of pulmonary tuberculosis
 The organism usually reaches the bone via blood stream or by direct inoculation. Long bones and
vertebrae are favored site
 Lesions are often solitary but can be multicentric in immunocompromised patients
 Because the tubercle bacillus is microaerophilic, the synovium is common site due to high oxygen
pressure
 The infection then spread to the adjacent epiphysis, where it causes typical Granulomatous
inflammation with caseous necrosis and extensive bone destruction
 Tuberculosis of vertebral bodies(Pot’s Disease) causes vertebral deformity and collapse with
Secondary neurologic deficit
Tuberculous osteomyelitis
 Extension of infection to the adjacent soft tissue is fairly common in tuberculosis of spine and often
manifests as a so called cold abscess in the psoas muscle
 WBCs count ↑
 ESR ↑
 C-reactive protein(CRP)↑
 X rays important for diagnosis
 CT scan
Complication
 Draining sinus tracts
 Suppurative arthritis
 Pathologic fractures
 Secondary ankylosis (fibrosis and fusion of joint)
 Endocarditis and bacteremia
 Squamous cell carcinomaand chronic non healing ulcer(Marjolin’s ulcer)
 Chronic osteomyelitis
Osteoarthritis:
Q .A 45 year’s old child presents with morning stiffness that started from small joints of hand, and now involves
wrist, elbow and knees bilaterally. On examination, the joints are found swollen. The x-ray studies show peri-
articular osteopenia.
a) What is most likely diagnosis?
Diagnosis:
Osteoarthritisthe degenerative disease of joint in which degeneration of articular cartilage occurs
Predisposing condition for osteoarthritis:
Primary osteoarthritis: without apparent initiating cause
Secondary osteoarthritis:Predisposing conditions:
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 Previous traumatic injury

 Developmental deformity
 Underlying systemic diseases:
 Diabetes
 Ochronosis
 Hemochromatosis
 Obesity /overweight
 Old age
Pathogenesis of osteoarthritis:
 Mechanical insults i.e. trauma
 Biochemical abnormalities of cartilage .The chondrocytes release IL1, TNF. This causes the release of
catabolic metalloproteinase collagenase
 Destruction of the articular cartilage matrix
 Release of prostaglandins PGs and collagen fragments into the synovial fluid
 Exposed subchondral bone become new bone articular surface that resembles ivory
 Genetic factors, including polymorphisms and mutations in genes encoding components of the matrix
and signaling molecules, contribute to osteoarthritis susceptibility
 The risk of osteoarthritis also increase with increasing bone density, as well as sustained high
estrogen levels
Morphology of osteoarthritis:
 Earliest structural changes in osteoarthritis include enlargement, proliferation and disorganization of
chondrocytes in the superficial part of the articular cartilage
 Fibrillation and cracking of the matrix: when superficial layer is degraded
 Bone eburnation: friction exposed bone giving appearance of polished ivory
 Joint mice: fracture can dislodge the pieces of cartilage into the joint by forming Loose bodies
 Mushroomed osteophytes : bony outgrowths
 Pannus: A synovial fibrous cover that covers the peripheral portion of the articular surface
Clinical features
 Crepitus:A crackling caused by friction between exposed surfaces of bone
 Joint stiffness and pain: Joint stiffness and pain particularly in the morning. Repeated use of joint
leads to aggravate the pain
 Heberden’s nodes:Small osteophytes on the distal interphalengeal joints
 Bouchard’s nodes: Osteophytes on proximal interphalengeal joints
 Joint deformity: Joint deformity develop over a long period of time
 X ray show narrowing of joint spaces
 Show osteophytes in joint spaces
Rheumatoid arthritis:
Definition:
It is a chronic multisystemic inflammatory disease of unknown cause, characterized by persistent
inflammatory synovitis, usually involving peripheral joints in a symmetrical distribution. The potential of
the synovial inflammation to cause cartilage damage and bone erosion and subsequent changes in joint
integrity is the hallmark of the disease
Etiology:
The cause of RA remains unknown. It is suggested that RA may be a manifestation of a response to an
infectious agent in a genetically susceptible host
 Genetic factors:
Genetic susceptibility to altered immune response may play a role. The presence of HLA-DR4 allogene
is associated with high incidence of RA
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 Infectious agent:
May play a role in triggering an autoimmune reaction. Infectious agents such as rubella, Mycoplasma,
CMV and EBV virus may play a role in the pathogenesis
Pathogenesis
 RA is an autoimmune disease caused mainly by cytokines mediated inflammation, with CD4 + T cells
being the principal source of the cytokines
 Antibodies against cyclic citrullinated peptides (CCPs), which may contribute to the joint lesions.in RA,
antibodies to citrullinated fibrinogen, type II collagen, α-enolase, and vimentin are the most
important and form immune complexes that deposit in the joint
 Genetic factor: RA is associated with class II MHC genes like HLA-DR4 orHLA-DR1
 Environmental factors: Environmental insults such as smoking and infections may induce the
Citrullination of some self-proteins, creating new epitopes that trigger autoimmune reactions
 Increased osteoclast activity in the joint contributes to the bone destruction in rheumatoid arthritis;
this may be caused by the production of the TNF family cytokines RANK ligands by activated T cells
Clinical features:
Onset
 Insidious onset: In about 2/3 of patients, the RA begins insidiously with prodromal nonspecific
symptoms such as fatigue, weight loss, anorexia, generalized body weakness and vague
musculoskeletal symptoms, for weeks or months before the occurrence of specific joint symptoms.
 Acute onset: in about 10 % of patients RA has an acute onset, with rapid development of
polyarthritis, associated with constitutional symptoms, including fever, lymphadenopathy and
splenomegaly
Articular (joint) manifestations:Result from persistent inflammatory synovitis.
 Pain, swelling and tenderness of involved joints, aggravated by movement
 Generalized joint stiffness is often seen after a period of inactivity. Morning stiffness that lasts
greater than 1 hour, which is a feature of inflammatory arthritis, is a common complaint
 Bilateral, symmetrical small joint involvement is typical for RA
Commonly affected joints are:
 Wrist joints: Metacarpophalangal joints and proximal interphalangal PIP) joints are often involved but
distal interphalangal joints are often spared. The elbow joint, and keen joints are affected by RA.
 Wrist joint: Synovitis of wrist joint is very common in RA , and may lead to limitation of movement,
deformity and median nerve entrapment ( Carpal tunnel syndrome)
 Elbow joint: involvement may lead to flexion contracture
 Knee joint: commonly involved with synovial hypertrophy, chronic effusion and frequent ligamentous
laxity. Pain and swelling behind the knee may be caused by extension of inflamed synovium in to
popliteal space (Baker’s cyst)
 Arthritis of the forefoot, ankles and subtalar joints can produce severe pain with ambulation as well
as a number of deformities.
 Axial involvement is limited to cervical spines; Atlantoaxial ligament involvement, in the cervical
spine can lead to instability between C1 and C2 vertebrae and potential neurologic complaints
Extraarticular features: RA is a systemic disease with a variety of extraarticular manifestation
 Rheumatoid nodules:
Are the most common features of extraarticular diseases and are found in 20-25 % of patients. These
firm subcutaneous masses typically are found in areas on periarticular structures and on areas
exposed to repetitive trauma (e.g. extensor surface of the forearm, the olecranon at the elbow,
proximal ulna, Achilles tendon and the occiput)
 Rheumatoid vasculitis:
This can affect nearly any organ system and is seen in patients with severe RA, and high titer of
circulating Rheumatoid factor.
Peripheral nerves: Distal sensory neuropathy or Mononeuritis multiplex
Skin: Cutaneous ulceration, dermal necrosis
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Digital gangrene
Visceral infarction: Myocardial infarction, vasculitis involving the lungs, bowel, liver, spleen, pancreas
kidneys etc.
 Eye involvement:
Keratoconjuctivitis sicca seen in 10-15% of rheumatoid arthritis patients who have a secondary form
of Sjogren syndrome.Scleritis or episcleritisoccur less common
 Lungs:
Pleuritis and pleural effusion may be seenin some patients. The pleural fluid typically has low glucose
concentration. Rheumatoid nodulesmay appear on the lung, single or multiple
 GIT:
Intestinal fibrosis is another clinical feature that occurs in the Rheumatoid Arthritis
 Heart:
Asymptomatic Pericarditisis found in 50% of patients on autopsy. It is often associated with pleural
effusion
Myocarditis and Valvular dysfunction are rare findings
 Neurologic manifestations: The CNS is not directly affected
Peripheral nerves are affectedthrough Entrapment (carpal tunnel syndrome) or Vasculitis related
mononuritis multiplex
Atlantoaxial subluxation: may lead to compression of spinal cord
 Hematologic features
Anemia of chronic diseases
Thrombocytosis
Felty’s syndrome: Chronic RA with splenomegaly and neutropenia, with an occasional
thrombocytopeniaand anemia.
Revised American revised Criteria for classification of RA
1. Morning stiffness: lasting > 1 hour
2. Arthritis of three or more joint areas:
3. Arthritis of hand joints: wrist, MCP and PIP
4. Symmetrical arthritis
5. Rheumatoid nodules: subcutaneous nodules over bony prominences
6. Serum rheumatoid factor
7. Radiologic changes: periarticular bony erosion and other findings
 RA factor:About 80 % of patients have serum immunoglobulin M (IgM) autoantibodies that bind to
the Fc portion of their own IgG. These autoantibodies are called rheumatoid factor. RA factor is
positive in 80% cases
 Antinuclear antibody tests (ANA):ANA is positive in 30 % cases
 Anti-CCPs: They are more sensitive than RA factor
 Blood:Anemia, ESR↑, C-reactive protein (CRP) ↑, WBC↑
 X ray: Show loss of joint space, mouse bite bony secretion, cystic formation
 Biopsy
Differences between osteoarthritis and rheumatoid arthritis
Features Osteoarthritis Rheumatoid arthritis
Basic process Degenerative process Immunologic, inflammatory
Site of initial lesion Articular cartilage Synovium
Age 5o + Any age but peak at age of 20-4o years
Sex Males or females Female> male
Joint involved Especially knees, hip, spine etc. Hand, later large joint
Fingers Heberden’s node Ulnar deviation, spindle swelling
Nodules No Rheumatoid nodules
Systemic features None Uveitis , pericarditis
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Paget’s disease of bone:

Q. A woman aged 45 years presented with pain in right proximal femur. Provisional diagnosis made was Paget’s
disease.
a) Write down the morphological finding findings.
b) Briefly, give the pathogenesis of Paget’s is of bone.
c) Give laboratory investigations.
d) What are the common complications?
Morphology of Paget’s disease (Osteitis Deformans):
Lytic phase
 Osteoclast are numerous, abnormally large, and have increased number of nuclei.Howship lacunae
present
Mixed phase
 Osteoclast persists but osteoblast reacts by actively lying down new bone, which balances the
osteolysis and maintain the total bone volume. The marrow is replaced by loose connective tissue
containing progenitor cells as well as numerous blood vessels
Burn out phase
 Osteoblastic activity is greatly in excess of osteoclastic resorption, leading to marked thickening of
bony trabeculae and cortex. Chalk stalk deformity (bone is very fragile) present in this final phase
Microscopically
 Mosaic pattern(Jigsaw puzzle)
 Annealing of lamellar bone
Pathogenesis of Paget’s disease:
 Environmental and genetic risk factor
 Mutation in SQSTMI gene is present in 40 to 50 % in familial Paget’s disease
 The SQSTMI enhance NF-KB activated by RANK signaling
 Paramoxyvirus →↑ IL 1, 6 secretion from infected cells and macrophages colony stimulating
factor(M-CSF) are produced in large amount in Paget’s disease and potently activate osteoclasts
 X-ray
 Increased serum alkaline phosphatase
 ↑ urinary excretion of hydroxyproline
Complications:
 Neuromuscular abnormalities
 Cardiovascular problems
 Sarcoma
Gout:
Q .A 30 years old develops excruciating pain in the first metatarsophalangeal joint following a weekend of binge
drinking. The pain was associated with localized hyperemia, warmth and tenderness.
a) What is the likely diagnosis
b) What laboratory tests will you order to confirm the diagnosis?
c) Describe the morphology of tophi.
d) Give the pathogenesis of gouty arthritis.
Diagnosis:
Gout
Laboratory Tests:
X-Ray, Serum and Urine: Uric Acid Levels, Joint Aspiration Is Confirmatory.
Morphology of Tophi
 Tophi are the pathognomonic hallmarks of the gout
 Formed by large aggregations of urate crystals surrounded by intense inflammatory reactions of
lymphocytes, macrophages and foreign body giant cells, attempting to engulf the mass of crystals
 Tophi can appear in articular cartilage of joints and peri articular ligaments
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 Superficial tophi can lead to large ulcerations of the overlying skin

Pathogenesis of Gouty Arthritis:
Primary causes:
 Overproduction of uric acid by de novo synthesis and salvage pathway
 Reduced excretion of uric acid
Secondary causes:
 Increased nucleated cell turnover e.g. Leukemia
 Decreased renal excretion e.g. lead poisoning and alcoholism
Bone Tumors:
Histological Classification of Bone Tumors:
Histologic type Benign Malignant
Hematopoietic 40% Myeloma
Malignant lymphoma
Chondrogenic 22% Osteochondroma Chondrosarcoma
Chondroma Differentiated chondrosarcoma
Chondroblastoma Mesenchymal Chondrosarcoma
Osteogenic 19% Osteoid osteoma Osteosarcoma
Osteoblastoma
Fibrogenic Fibroma Fibrosarcoma
Non-ossifying fibroma
Fibrous Histocytoma
Unknown origin 10% Giant cell tumor
Unicameral cyst
Aneurismal bone cyst
Neuroectodermal Ewing sarcoma
Notochordal Benign Notochordal cell tumor Chondroma
Classification on the Basis of Differentiation:
Tumors Type Common locations Age (year) Morphology
Bone Forming
Benign
Osteoma Facial bone, skull 40-50 Exophytic growths
Osteoid osteoma Metaphysis of femur, 10-20 Cortical tumor, interlacing trabeculae of bone
tibia
Osteoblastoma Vertebral column 10-20 Similar to osteoid osteoma
Malignant
Osteosarcoma Metaphysis of Distal 10-20>40 Outward growth
Femur, Proximal Show malignant cells bone forming
Tibia and Humerus ‘’Osteoid’’
CartilageForming
Benign
Osteochondroma Metaphysis of long 10-30 Bone particles encircled by cartilaginous cap,
tubular bones may be single or multiple
Malignant
Chondrosarcoma Shoulder, pelvis, 40-60 Arise in medullary cavity
femur and ribs
Miscellaneous
Giant cell tumor Epiphysis of long 20-40 Lytic lesion that erode cortex
(benign) bones
Ewing tumor Diaphysis and 10-20 sheets of round cell contain glycogen
(malignant) metaphysis
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Differences betweenOsteoid Osteoma andOsteoblastoma:

Osteoid osteoma Osteoblastoma
1-Favored site are proximal femur, tibia and Humerus Most common site is vertebrae
2-They are less than 2 cm in greatest dimension More than 2 cm in greatest dimension
3-Severe pain in night relieved by aspirin Severe pain in night not relieved by aspirin
Osteosarcoma:
Q A 14 years old boy presents with a one month H/O pain in the knee joint. There is H/O weight loss and pallor but
no fever. X-rays of knee joint reveals densely sclerotic lesion in the distal femur extending from the growth plate
into the diaphysis. The periosteum is lifted, forming an angle with the cortex. The surrounding soft tissue
resembles a “sun burst” on the radiograph
b) Enumerate the common sites involved by this tumor.
c) Give different subtypes of this tumor.
Diagnosis:
Osteosarcoma
Common Sites Involve:
 Metaphyseal region of the long bones
 60% occurring around the knee
 15% around the hip
 10% at the shoulder
 8% in the jaw
Subtypes of osteosarcoma
 Primary osteosarcoma
 Solitary osteosarcoma
 Intramedullary osteosarcoma
 Poorly differentiated osteosarcoma
 On the basis of site of involvement: (medullary vs cortical)
 On the basis of degree of differentiation: (solitary vs multicentric)
Morphology of osteosarcoma:
Gross:
 Gritty, gray-white tumors, often exhibiting hemorrhage and cystic degeneration
 Frequently destroy the surrounding cortices and produce soft tissue mass
 Production of mineralized or unmeneralized bone (osteoid) by malignant cell
 When malignant cartilage is abundant, tumor is called chondroblatic osteosarcoma
Microscopy:
 Hyper chromatic nuclei
 Bizarre tumor giant cells
 High mitosis
Giant cell tumor:
 Common in 20-40 years of age It is benign and locally aggressive
 GCTs are dominated by multinucleated osteoclast type giant cell hence the synonym Osteoclastoma
 Current opinion suggests that the giant cell component is likely a reactive macrophage Population
and the mononuclear cells neoplastic
Morphology of giant cell tumor:
 Tumors are large or red brown with frequent cystic degeneration
 They are composed of uniform oval mononuclear cells with frequent mitosis
 They are composed of uniform oval mononuclear cells with frequent Mitosis with scattered
osteoclast type joint cells containing 100 or more nuclei
 Necrosis, hemorrhage and reactive bone formation are also commonly present
188
Clinical course:
 Majority of GCTs arise in the epiphysis of the long bones around the knee
 Frequently cause arthritis like symptoms
 Occasionally GCTs presents as pathologic fractures
 Radiographically, GCTs are large, purely lytic and eccentric; the overlying cortex is frequently
destroyed producing a bulging soft tissue mass with a thin shell of reactive bone (Soup-bubble
appearance)
 Although GCTs are histologically benign, roughly half recur after simple curettage and as many as 2 %
metastasize to the lungs
Ewing sarcomaand Primitive Neuroectodermal Tumor (PNET):
 The Ewing’s sarcoma is the second most common primary malignant bone tumor seen in children
after osteosarcoma. 80% are younger than 20 years
 The sites involve are femur and pelvis flat bones
 There is characteristics periosteal elevation with deposition of bone in an onionskin pattern
Morphology:
Gross:
Ewing sarcoma arises in the medullary cavity and invades the cortex and periosteum to produce a soft
white tumor mass, frequently with hemorrhage and necrosis.
Microscopic:
 Composed of sheet of uniform small, round blue cells that are slightly larger than lymphocytes,
typically few mitotic figures and little intervening stroma
 The cells have scant glycogen rich cytoplasm. The presence of Homer-wright rosettes (tumor cells
circled about a central fibrillary space ) indicates neural differentiation
Pathogenesis
 The most common chromosomal abnormality is translocation that causes fusion of the EWS gene on
22q12 with a member of the ETS family of transcription factors
 The most common fusion partners are the FL1 gene on chromosome 11q24 and the ERG gene on
chromosome 21q22.The resulting chimeric protein functions as a transcription factor, but precisely it
remain uncertain
Myasthenia Gravis:
It’s an autoimmune disease characterized by autoantibodies against the acetylcholine receptors at the
neuromuscular junction. It is type 2 hypersensitivity reaction
Pathophysiology:
15% cases are associated with tumor of the thymus (Thymoma)Antibodies bind the motor end
platecomplement activation endocytosis of the Ach receptors because IG-g crosslinks the remaining part
of the receptor. Decrease in the number of Ach receptors per muscle fiber widening of synaptic spaces
Clinical features
Symptoms may wax and wane
 Ptosis most common initial finding
 Diplopia
 patients feel tired at the end of the day
 Muscle weakness improves with rest and worsens with exercise
 Dysphagia for solids and liquids occurs because of the fact that skeletal muscles are present in the
upper one third of esophagus
 There is weakness in the muscles of neck, proximal limbs and diaphragm
 Reflexes are normal and sensation and coordination is also normal
Investigations
 Tensilon test: Give edrophonium,short acting acetyl cholinesterase inhibitor,it improves muscle
strength in myasthenia gravis patient
 Serum antibody assays for anti-acetyl choline receptor antibody may be done
189
 Serum
Chapter CENTRAL
assay for anti-P/Q-type
Twelve NERVOUS
voltage-gated calcium SYSTEM
channels (anti-VGCC)
Meningitis:
Q.A 20 year old,military cadet ,who has been living in a dormitory ,presents to you with,headache, high grade
fever,on examination his neck movements are painful and has photophobia,the spinal tap is performed and it
shows that the glucose has decreased and the protein have increased, with neutrophils.
b) Write pathogenesis of its bacterial form.
c) Write its morphology.
d) What is the routine lab investigations normally performed?
Diagnosis:
Meningitis...Inflammation of the leptomeninges (pia and arachnoid matter) covering the brain.
Pathogenesis:
Neisseria meningitis
 Adherence to the normal mucosa of the nasopharynx which leads to bacteremia eventually
 Translocation through the blood brain barrier
 Bacteria in subarachnoid space attract neutrophils
E. coli meningitis … newborns are effected, they acquire E. coli infection from birth canal of mother
E. coliare neutralized by IG-M antibodies, which do not cross placenta so newborns are affected
Routes of infection:
 Otitis media
 Skull fracture and exogenous organism entering from the fractured bones
 Through meningeal vessels
 Through choroid plexus
 Osteomyelitis
Morphology:
Gross:
 Purulent exudate is seen over the surface of brain mostly over the cerebral hemispheres with
engorged blood vessels
Microscopic:
 Inflammatory exudate consisting of neutrophils is present
 Inflammatory exudate is mostly around leptomeninges
 Sometimes the exudate of fibrin and leukocytes may opacify the arachnoid space producing
hydrocephalous
CSF features Bacterial Viral Fungus
Total cell count Increased Usually normal or slightly Usually
increased normal or
slightly
increased
Differential count Neutrophils in most cases Mostly lymphocytes Lymphocy
except TB tes
CSF glucose Decreased Normal Decrease
d
CSF protein (think of Increased Increased Increased
inflammation leaky vessels
Gram staining Mostly positive Negative +ve
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Central Nervous System
Another way to do it
CSF analysis: BACTERIAL MENINGITIS if 1) WBC >1000 /µL 2) neutrophil >50 /µL 3) protein >100 mg/dl4)
glucose <30mg/dl
VIRAL OR HERPES IF 1) WBC <1000 /µL 2) neutrophil <50/µL mg/dl 3) protein <100 mg/dl 4) glucose >30
mg/dl
Check RBCs in blood if more than 10 its herpes or if less than 10 it’s viral
Brain Tumors:
Classification:
1) Parenchymal:
 Supporting Cell Tumors (Gliomas):
 Astrocytoma
 Ependymoma
 Oligodendroglioma
 Choroid Plexus Papilloma
 Tumors of Neuron:
 Neuroblastoma
 Ganglioneuroblastoma
 Ganglioneuroma
 Embryonal Tumors:
 Medulloblastoma (Small Blue Cells)
2) Non-Parenchymal:
 Meningeal Tumors:
 Meningioma
 Meningeal Sarcoma
3) Nerve Sheath Tumors:
 Schwannoma
 Neurofibroma
4) Vascular Tumors:
 Hemangioblastoma
5) Miscellaneous Tumors:
 Malignant Melanoma
 Pineal Gland Tumor
 Pituitary Tumor
6) Metastatic Tumors:
Astrocytoma:
General
 Originate from astrocytes
 Account for 80% of Primary CNS tumors
 Are either Fibrillary or Pilocytic
1. Fibrillary Astrocytoma
 Based on Nuclear Atypia, Necrosis, Mitoses, and Vascular Proliferation (VP)
Grade
 Grade 1 = Pilocytic Astrocytoma: ↑ Cellularity Only
 Grade 2 = Diffuse Astrocytoma: ↑ Cellularity + Atypia
 Grade 3 = Anaplastic Astrocytoma: ↑ Cellularity + Atypia + Mitosis
 Grade 4 = Glioblastoma: ↑Cellularity + Atypia + Mitoses + VP
 Glioblastoma Multiforme (GBM)
 Most common CNS tumor and is ring enhancing
 Has rows of anaplastic cells lined up around a region of central necrosis, called
pseudopalasadingnecrosis
191
 Vascular proliferation looks like a glomerulus, so is termed glomeruloid

 Occur in white matter and frequently cross the corpus callosum “Butterfly Lesion”
 Death within 1 year, difficult to resect, unresponsive to chemotherapy
2. Pilocytic Astrocytoma
BenignAstrocytic tumor of children and young adults
 Characteristic cystic lesion connected to a mural nodule seen on MRI
 Contain Rosenthal fibers
 Occurs in posterior fossa
 Surgical resection yields good prognosis
Oligodendroglioma
 Derived from oligodendrocytes of middle aged patients
 Lesion of white matter that does not cross corpus callosum
 Characteristic fried‐egg appearance of a central nucleus with Perinuclear clearing
 Blood vessels form a chicken wire appearance→ “chicken wire + fried eggs”
 Slow‐growing tumor with decent prognosis (5‐10 years), though they tend to recur
Ependymoma
 Derived from ependymal cells lining the ventricles
 Location by age
 Children = Posterior Fossa = 4 Ventricle
th
 Adults = Anterior Fossa = Lateral ventricle (spinal canal)

 Gross = tumors from the wall of the ventricles growing inside CSF
 Microscopically = ependymal rosettes (cells organizing themselves around a central lumen) and
Perivascular pseudorosettes (cells organizing themselves around a central blood vessel)
 Since they are in free floating CSF, they may cause hydrocephalus and may embolize down the spinal
column
Meningioma
 Derived from meningothelial cells of the arachnoid
 Tumors occur in adulthood, men more often than women
 This lesion is literally attached to the Dura and does not invade
 Pathognomonic cellular whorls + Psammomabodies tip you off
 Because it does not invade, resection is curative
Medulloblastoma
 Derived from primordial neuroglial precursors, so is a poorly differentiated tumor
 Commonlyfound in children, usually in the cerebellum
 Histology shows small, blue, round cells that may break off into CSF
 May disseminate through the CSF to the cauda equina called drop metastases
 Amendable to radiation
Schwannoma
 Originates in the Schwann Cells of cranial or spinal nerves

th
The most frequent location is the 8 cranial nerve, called acoustic neuromas
 Presents with hearing disturbances and tinnitus
 Commonly show areas of hypercellularity (Antoni A regions) mixed with areas of hypocellularity
(Antoni B regions)
 Pathognomonic for Schwannoma are Verocay Bodies and expression of S‐100
 There is good prognosis with surgical resection
Craniopharyngioma
 Arises from the remnant of Rathke’s Pouch near the pituitary gland
 Usually affects children and young adults
192
 It is benign but tends torecurs and degenerate after resection

 It is a cystic lesion that may impinge on the optic chiasm →bitemporal hemianopia
CNS Lymphoma
 High grade B‐cell non‐Hodgkin lymphoma, commonly infected with Epstein Barr Virus
 Occurs in immunocompromised such as AIDS
Differences between primary and metastatic tumor
Comparison By Derivation
Primary Secondary
Poorly Circumscribed Well Circumscribed
Usually singular Often Multiple
Location varies on type Located at Junction of Grey and White Matter (where
vessels narrow)
Just Less than 50% of all CNS Tumors Just greater than 50% of all CNS Tumors
Glioblastoma>Meningioma>Schwannoma Breast > Lung > Skin
Comparison By Age Group

Childhood Adult
Posterior Fossa Anterior Fossa
Pilocytic Astrocytoma Glioblastoma Multiforme
Medulloblastoma, Craniopharyngioma, Oligodendrocytoma, Meningioma, Schwannoma,
Ependymoma Ependymoma
Meningioma:
Definition: predominantly benign tumors of adults, usually attached to the Dura and arising from the
meningothelial cells of arachnoid and from stromal arachnoid cells of the choroid plexus of ventricles.
Morphology:
Gross:
 Located most commonly in the front half of the cranial cavity….hemispheric convexity, falx, and lesser
wing of sphenoid and olfactory groove
 Appear as irregular bosslated masses that are firmly attached to Dura and indent surface of brain.
Occasionally growth occurs in plate like fashion producing meningioma
 Hyperostosis and occasional superficial invasion of overlying bone is also seen
 On cut section, tumor is firm, solid with whorl like pattern
Microscopic:
 There are three histologic types:
 Syncytial with prominent cellular whorls and nodules
 Fibroblastic composed of elongated cells and abundant collagen
 Transitional with intermediate characteristic andPsammoma bodies (which are spherical, laminated,
calcified structures)
 Xanthomatous and myxomatous degeneration and ectopic bone formation can be seen
 Malignant meningiomas occasionally occur. These resemble fibrosarcomas and may invade the brain
metastasis
Poorly Differentiated Tumors:
 Medulloblastoma
 Neuroblastoma
 Primitive Neuroectodermal Tumors (PNET)
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Multiple Sclerosis
Q. A 35 years old white female to neurology clinic for her long-term neurological complaints. She had noticed some
significant changes in neurological function. Her visual acuity also seemed to be changed periodically during
several years. She could not hold objects in her hands, had significant tremors and severe exhaustion. Spinal tap
was also done which revealed the presence of oligoclonal bans in CSF. Visual evoked response testing was
abnormal with slow conduction in optive nerve
a) What is your Diagnosis?
b) Give the pathogenesis of the above diagnosis
c) Discuss its morphology
d) Give the clinical features of the above diagnosis and give its laboratorydiagnosis
Diagnosis:
Multiple sclerosis: Chronic demyelinating disease of the central nervous system
Pathogenesis: an autoimmune disease, which may be triggered by genetics or environment
 Genetic predisposition ------ 25% concordance in monozygotic twins ,and increased risk in 2nd and
3rd degree relatives
 Viruses e.g. EBV, HHV-6 etc.
CD-TH1 and TH17 cells react against self-myelin antigens
CD4-TH1 secretes. TH17 cells release cytokines
↓ ↓
(Interferon gamma)
↓
Activates macrophages to produce TNF-alpha Recruits neutrophils and monocyte
↓ ↓
The leukocytes and the TNF alpha damage the oligodendrocytes and the myelin sheath that causes the
demyelination.
Morphology:
 Demyelinating plaques are hallmark of the disease, rarely exceeding 2cm
 The lesions exhibit a preference for the optic nerves, chiasm, and paraventricular white matter and
spinal cord, but any part of the CNS may be affected
 It mainly effects the white matter but also breach the gray matter
 The plaques become more isolated and distinct, as the lesion gets older.
Clinical features:
MS affects different parts of the brain at separate times
It follows a relapsing and remitting course
MS typically begins with effecting the optic nerves (causing retrobulbar optic neuritis, patient cannot see
but the fundus is normal) spinal cord or brainstem.
Other clinical signs/symptoms of disease are
 Sensory dysfunction e.g. parasthesia
 Autonomic dysfunction
 Upper motor neuron symptoms e.g. spasticity
 Transverse myelitis: acute degenerating disease within the spinal cord
 Demyelination of the medial longitudinal fasciculus
 Scanning speech
 Intention tremor and Nytagmus
LaboratoryInvestigations:
Spinal tap: Increased CSF CD4+ count, increased CSF protein, normal glucose, antibodies against myelin
basic protein
MRI It is highly sensitive
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Traumatic Brain Disorders

Concussion:
Definition:
It is clinical syndrome of altered consciousness secondary to head injury typically brought about by a
change in momentum of head when moving head is suddenly arrested by Impact on rigid surface. The
characteristic neurological picture includes instantaneous onset of transient neurologic dysfunction, loss
of consciousness, temporary respiratory arrest and loss of reflexes. Pathogenesis involves dysregulation of
reticular activating system.
Contusion:
Definition:
It is lesion associated with direct parenchymal injury of the brain either through transmission of kinetic
energy to the brain or bruising analogue to what is seen in soft tissue. Contusion develops due to coup
and counter coup injury.
Intracranial Hemorrhage
Intracerebral (Intraparenchymal) Hemorrhage
Definition
Bleeding into the cerebral tissue from cerebral vasculature within the tissue. This is bleeding inside the
brain
Pathogenesis
Hypertension is the most common cause of primary brain hemorrhage
Causes hyaline changes in arterioles, sometimes with frank necrotization of the arterioles
Vessel wall changes make the wall weaker and prone to rupture
 Charcot‐Bouchard Microaneurysm, minute hemorrhages caused by HTN, appear in regions supplied
by small penetrating arteries, especially in the basal ganglia
 Systemic Coagulation disorders (cancer, vasculitis, A/V malformations etc.) all encourage
nontraumatic hemorrhage
 Trauma can, but is unlikely to cause, intraparenchymal hemorrhage
Morphology:
 Most commonly originates in the putamen, but can occur anywhere
 Ganglionic Hemorrhage = basal ganglia + thalamus
 Lobar Hemorrhage = Cerebral Lobes
 Chronically, infarcts from hemorrhage look just like infarcts from obstruction
 Acutely, there is a central clot with compressed parenchyma on gross as well as anoxic changes with
edema
Clinical Features:
 When large, it is devastating; when small, it can be slowly progressive
 This is an arterial bleed, so pressure increases
 Presents with headache, nausea, projectile vomiting, and focal lesions
Subarachnoid Hemorrhage + Ruptured Saccular Aneurysm
Definition
Bleeding into and around the brain parenchyma (between pia and arachnoid layers) from cerebral
vasculature
Pathogenesis
 The most common cause of subarachnoid hemorrhage is rupture of a Berry Saccular aneurysm
 Associated with Autosomal Dominant Polycystic Kidney Disease, Vascular Collagen disorders like
Marfan’s or Ehlers‐Danlos, and coarctation of aorta
 Smoking and Hypertension are predisposing factors
 While the aneurysm is not present at birth, the genetic defect in the arteriolar wall is; all berry
aneurysms come from some congenital defect
195
Morphology
 Small outpocketing Circle of Willis, usually in the anterior circulation
 Brownish discoloration of surrounding tissue = previous hemorrhage
 Adventitia is continuous, media and intima are thickened in the aneurysm but absent at the neck of
the aneurysm
Clinical Features:
 Rupture is most common in the 4 and 5 decades of life.33% Recover, 33% Recur, 33% Die
th th
 Completely spontaneous or associated with strain (having an orgasm or bearing down to force stool)
 “Worst Headache of my Life”
Cerebrovascular Disease
Salient feature:
Stroke is clinical term for a disease with acute onset of a neurologic deficit as a result of vascular lesion,
either due to hemorrhage or loss of blood supply
 Cerebral infarction follows loss of blood supply and can be widespread, focal or affected region with
the last robust vascular supply (watershed infarct)
 Focal cerebral infarcts are most commonly embolic
 Primary intraparenchymal hemorrhages are typically due to either hypertension in white and gray
matter or cerebral amyloid angiopathy
 spontaneous subarachnoid hemorrhages is usually caused by a structural vascular abnormality such
as aneurysm or arteriovenous malformation
Alzheimer’s disease:
Definition:
A progressive degenerative disease of the cerebral cortex caused by accumulation of abnormal proteins,
demonstrable as plaques and tangles
Pathogenesis:
Amyloid Precursor Protein (APP) and Aβ
 APP is normally present in astrocytes and glial cells and has 3 sites of secretase activity (α, β, and γ)
 Cleavage by α‐secretase = normal soluble protein, Aβ = 26 amino acids
 Cleavage by γ‐secretase = separation of cytoplasmic (Carboxy‐terminus) unit and Aβ unit; has no
relevance to Alzheimer’s (it’s the same site in the good and the bad protein)
 Cleavage by β‐secretase = insoluble protein, Aβ42 = 42 amino acids
 Larger, insoluble protein forms extracellular aggregates called plaques, or fibrils
 Stains positivefor Congo red
 Are considered to be directly neurotoxic
Presenilin‐1
 Has y‐secretase activity leading to aberrant activation of Presenilin‐1 may also contribute to
formation of Aβ42 and the generation of plaques
Genetics of Alzheimer’s disease
Chromosome Gene Mutations, Alleles Consequences
21 Amyloid • Single missense mutations Double • Early‐onset FAD Increased
precursor missense mutation Trisomy 21 Aβproduction
protein (APP) (gene dosage effect)
14 Presenilin‐1 • Missense mutations Splice site • Early‐onset FAD Increased
(PS1) Mutations Aβ production
1 Presenilin‐2 • Missense mutations • Early‐onset FAD Increased
(PS2) Aβproduction
19 Apolipoprotein • Allele ε4= risk • Increased risk of
E (ApoE) • Allele ε3 = normal development of
• Allele ε2 = protective AD Decreased age at onset
of AD
196
Clinical Features:
Insidious onset, time course is approximately 10 years from onset to death
Cerebral Atrophy is seen, severity ↑ with passage of time
Memory (first short term then long‐term), logic and mathematics, motor skills (incontinence, walking, fine
motor) will all be lost
Death usually results from a secondary source (pneumonia)
Treated now with Acetyl‐Choline Agonists though this only prolongs the inevitable, giving the patient
more healthy time
Morphology:
Gross:
 Cortical Atrophy especially in the frontal, temporal, and parietal lobes
 Widening of sulci (more space between gyri)
 Compensatory ventricular enlargement (hydrocephalus ex vacuo)
Microscopically:
 These are not specific for Alzheimer’s, though is almost always present
Neuritic Plaques:
 Most often in the hippocampus and amygdala
 Dilated, tortuous, silver staining neuritic processes (dystrophic neurites) surrounding a central
Amyloid core (Aβ42)
 Stains positive for Congo Red, as all Amyloid does
Neurofibrillary Tangles:
 Found in the cytoplasm of cortical pyramidal neurons
 Caused by a hyperphosphorylated state of a microtubule‐associated protein called tau
 Tau aggregates while microtubules fall apart; tau aggregates are insoluble, producing “ghost tangles”
that persist after neuron dies, in the classic flame shape seen on Silver Stain and H&E
GranulovacuolarDegeneration:
 There are vacuoles within the neurons in a granular pattern
Hirono Lesionsa classical finding in Alzheimer’s disease
Diagnosis:
Diagnosis is made on morphological characteristics only after death; clinical symptoms are highly
suggestive of the disease and therefore treatment algorithms.
Take away is that there are 4 classic lesions: Plaques, Tangles, Granulovacuolar Degeneration and
Hirono bodies, all found at autopsy following someone with cerebral atrophy and dementia. Bythe time
hydrocephalus ex vacuolar is noticeable, the patient is deep into their dementia, too deep to be helped
Prions Disease
Definition:
Transmissible spongiform encephalopathy that share a common etiology to abnormal forms of the prion
protein (PrP) normally present in neurons
Pathogenesis:
 PrP is the normal, stable form of the protein
 A sporadic (slow rate), inherited (high rate), or infectious (highest rate) conformational change in the
PrP α‐ helix to the β‐Sheet “activates” protein
 “Activated” PrP, termed PrPsc, resists digestion and cooking, and, more importantly, facilitates
cooperative conversion of normal PrP to PrPsc
 SC is named for Scrapie, the disease in sheep where prions were found
 There is a genetic link, on chromosome 20, PRNP gene, which ↑ risk of PrPsc formation, particularly
in familial prion diseases; Met → Val@ codon 129
 Accumulation of PrPsc causes pathology; however this is uncertain
197
Morphology:
 Macro = few findings, except atrophy in long‐standing cases
 Micro = spongiform transformation (pathognomonic) of grey matter in the cerebral cortex,
sometimes found in deep grey structures (caudate/putamen)
 No inflammatory infiltrate
 Unevenly distributed, varied in size, large, vacuoles in neutrophil
 Neuronal loss, reactive gliosis, cyst‐like vacuoles in advanced cases
 Immune related = PrPsc Proteins
Types and Clinical Features:
Creutzfeldt‐Jakob Disease (CJD;
 Mostly sporadic formation in mid-7th decade of life, though familial forms exist (iatrogenic
transmission from corneal implants reported)
 Rapidly progressive dementia with death within 7 months
 Subtle changes in memory and behavior precede the dementia (all cortical lesions) often with
involuntary jerks (basal ganglia)
 Pathogenesis described above is classic for CJD
Variant Creutzfeldt‐Jakob Disease (vCJD; Mad Cow Disease)
 Met/Met Homozygous patients; no mutation in PRNP gene
 Younger patients affected with a slower progression and clinical course
 Symptoms are the same, autopsy findings are the same
 Pandemic limited to UK, thought to be ingestion of infected meat
Gerstmann‐Straussler‐Scheinker (GSS)
 Slower progressive (like vCJD) but with a PNRP mutation (like CJD)
 Spongiform + PrPsc plaques and neurofibrillary tangles
 Death occurs in years, not months
Fatal Familial Insomnia (FFI)
 Prion disease with varying clinical course and symptoms
 Initial stages = insomnia, followed by ataxia, stupor, coma, and death
 Inherited, though mutation is not listed in Robbins
 No spongiform, No cortical Lesions, instead, neuronal loss in thalamus
Hydrocephalus
 Hydrocephalus is an increase in CSF volume, usually resulting from other impaired absorptionorrarely
from excessive secretion
 This obstruction of the cerebrospinal fluid circulation results in dilatation of the ventricular system of
the brain
Types:
Communicating hydrocephalus:
 If obstruction is outside the ventricular system (usually in basal cistern), it is called communicating
hydrocephalus). Ventricular CSF can communicate with the subarachnoid space. Ventriculoperitoneal
shunting of CSF may result in prompt relief of symptoms
Causes:
 Bacterial meningitis(esp. tuberculosis)
 Sarcoidosis
 Subarachnoid hemorrhage
 Head injury
 Idiopathic (normal pressure)
Non-communicating hydrocephalus:
 Hydrocephalus resulting from obstruction within the ventricles is called non communicating
hydrocephalus
198
Causes:
 Tumors
 Arnold chiari syndrome
 Aqueduct stenosis
 Cerebellar abscess
 Cerebellar or brain stem hematoma
Cerebral Herniation
Definition:
Mean ICP of CSF > 200mmH2O with patient recumbent, occurring when expansion of the brain
parenchyma exceeds compression of veins and CSF.
Types of Herniation:
Subfalcine Herniation = Cingulate Gyrus
 Unilateral expansion of the cerebral hemisphere displaces the cingulate gyrus under the falxcerebri,
compressing pericollosal arteries (arteries of corpus callosum) and anterior cerebral circulation
Transtentorial Herniation = Uncal
Medial Aspect of Temporal lobe goes through the tentorium cerebelli
 Compression of the 3rd CN = Ipsilateral pupil dilation and eye paralysis
 Compression of the posterior cerebral artery = infarct of visual cortex
 Compression of the contralateral peduncle = Ipsilateral hemiparesis (relative to the herniation);
called Kernohan’s Notch
 Hemorrhage in midbrain and pons may result (Duret’s Hemorrhage)
Tonsilar Herniation = Cerebellum
 Fatal herniation of cerebellum through the foramenmagnum
 Compresses brainstem, leading to death
199
Chapter Thirteen CHEMICAL PATHOLOGY
Proteinuria:
Definition:
 Presence of detectable amount of protein in urine is known as proteinuria
 Normal urine protein: (less than 150mg/24hr)
Types
 Transient proteinuria
 Orthostatic proteinuria
 Functional proteinuria
 Organic proteinuria
Mechanism
 Over flow:
Due to presence in plasma of high concentration of low molecular weight protein, which is filtered in
a quantity exceeding tubular reabsorbtive capacity e.g. Bence jones protein
 Glomerular:
Due to increased glomerular permeability
 Tubular:
Due to impaired or saturated reabsorption of protein filtered by normal glomeruli e.g. β2
microglobulin
 Secreted:
Due to secretion by kidneys or epithelium ofurinary tract e.g. Tamm-Horsfall protein
Grading of proteinuria:
 Marked Proteinuria: (more than 5gm/day)
 Severe GN (Nephrotic syndrome)
 SLE
 CCF
 Renal vein thrombosis
 Amyloidosis etc.
 Moderate Proteinuria: (0.5gm/day to 4 gm/day)
 Multiple myeloma
 Pregnancy toxemia
 Diabetic nephropathy
 Hypertensive nephropathy etc.
 Minimal proteinuria: (less than 0.5gm/day)
 Mild GN
 Polycystic kidneys
 Renal tubular disorders
 Lower urinary tract disorders diverticula etc.
 Bence jones proteinuria:
 Light chain immunoglobulin
 Low molecular weight
 Appears in multiple myeloma
 Diagnosed by Electrophoresis
200
Chemical Pathology
Investigation:
 Methods for Detection of Proteins
 Urine Dipstick method
 Heat coagulation method
 Sulphosalicylic acid method
 Other tests like
 Renal biopsy/ 24 hour urine protein estimation
 Total serum protein/serum albumin/serum globulin/renal function
 Diabetic nephropathy—FBG/RBS/RF
 Hypertensive nephropathy-Lipid profile/RF etc.
 Microalbuminuria RIA
 Electrophoresis of urine
 Bence jones proteins
Thyroid Function Tests:
Serum T3and T4level:
 Measures the total bound (99 %) and free (1 %) hormone level in the circulation. This gives some clue
about serum level of thyroid hormone, but has limitation since serum level of the hormone is
influenced by conditions affecting the level of carrier proteins
 T3 and T4 levels are elevated in hyperthyroidism and decreased in hypothyroidism
Serum TSH level:
 It is the most important test to asses thyroid hormone function
 In hypothyroidism, TSH level is elevated, because of feedback effects of low thyroid hormone level. It
is a very sensitive test and, because it usually becomes elevated even before thyroid hormone, (T3
and T4) level decline below normal
 In hyperthyroidism, TSH level is decreased, because the elevated thyroid hormone concentration,
leads to suppression of TSH release, through a negative feedback mechanism. It is a very sensitive
test, because TSH may be suppressed even when thyroid hormone level are not elevated above
normal range
131
Radioactive Iodine Uptake I :
 Evaluates synthetic activity of the thyroid gland. Iodide is used to synthesize thyroid hormone.
 Increased uptake indicates increased synthesis of T4 e.g. Graves' disease, toxic nodular goiter
 Decreased uptake of I¹³¹ indicate Inactivity of the gland e.g. patient taking thyroid hormone,
Inflammation of the gland (acute/subacute/chronic thyroiditis)
 Also Evaluates functional status of thyroid nodules
 Decreased uptake in a nodule ‘’Cold nodule’’ — cyst, adenoma, cancer
 Increased uptake in a nodule ‘’Hot nodule’’ — toxic nodular goiter
Thyroid stimulating antibodies:
 Circulating antibody against T3and T4is an evidence for autoimmune disease of thyroid glands
Thyroglobulin:
 Marker for thyroid cancer
Renal function test:
Serum Blood Urea Nitrogen (BUN):
Normal serum BUN is 7-18 mg/dl.
End-produce of amino acid and pyrimidine metabolism
Serum levels depend on the following:
 Glomerular filtration race (CFR)
 Protein concentration in the diet
 Proximal tubule reabsorption
 Functional status of the urea cycle
201
Chemical Pathology
 Increased serum BUN

 Decrease cardiac output, increase protein intake, increased tissue catabolism
 Acute glomerulonephritis, post renal disease
 Decreased serum BUN
 Increased plasma volume, decreased urea synthesis, decreased protein intake
 Serum creatinine
 Normal serum creatinine level is 0.6-1.2 mg/dl
 Metabolic end-product of creatinine in muscle
 Creatinine binds phosphate in muscle for ATP synthesis
 Creatinine is filtered by the kidney and not reabsorbed nor secreted
 Excellent metabolite for renal clearance testing
 Serum level increased with age and decreased in muscle wasting
 Increase in serum bun and creatinine is called azotemia
 Causes of increased and decreased serum creatinine is similar to serum bun
 Serum BUN: creatinine ratio
 Using normal values, the normal ratio is 15
 Creatinine is filtered and is neither reabsorbed nor secreted
 Urea is filtered and partly reabsorbed in the proximal tubule
 BUN:Cr ratio depends on changes at several times:
 Before the kidneys (pre-renal)
 Within the kidney parenchyma (renal)
 After the kidneys (post-renal)
Pre-Renal Azotemia:
 Azotemia refer to increase serum BUN and Creatinine
 Causes are decrease cardiac output and dec GFR
 Normal value is >15
Renal Azotemia (Uremia):
 Caused by acute tubular necrosis and chronic renal failure
 Normal value is less than or equal to 15
Post-Renal Azotemia:
 Caused by prostatic hyperplasia and blockage of ureter by stone
 Normal value less than15
 Creatinine Clearance (CCr):
Useful in detecting renal dysfunction
 Increased CCr
Early Pregnancy
 Decrease CCr
Elderly people, acute and chronic renal failure
202
Chapter Fourteen MULTIPLE CHOICE QUESTIONS
BLOOD VESSEL
1. Most common cause of death in dissecting aneurysm:
a. Rupture of dissection into d. Aortic stenosis
peritoneal, pericardial or pleural e. Obstruction of great arteries of
cavity neck
b. Congestive cardiac failure
c. MI
A.
2. The most common cause of abdominal aortic aneurysm is
a. Syphilis d. Occlusion of the vasavasorium
b. Congenital weakness of aortic wall e. Bacterial arteritis
c. Atherosclerosis
C.
3. A patient has had since birth a single, large red blue or Port wine discoloration of skin on the face. The
lesion is probably:
a. Cavernous Lymphangioma d. Hereditary hemorrhagic
b. Hemangioma telangiectasia
c. Kaposi sarcoma e. Aneurysm
B.
4. All of the following are risk factors for atherosclerosis except
a. Age d. HDL
b. Hypertension e. LDL
c. Diabetes
D.
5. All of the following are modifiable risk factors for atherosclerosis except
a. Age d. Hyperlipidemia
b. Hypertension e. Cigarette smoking
c. Diabetes
A.
6. Smoking, hypertension and hypercholesterolemia are found to play a significant role in causation of
atherosclerosis. Which of the following event is the most important direct biologic consequence of these
factors?
a. Alteration of hepatic lipoprotein c. Conversion of smooth muscle cells
receptor to foam cell
b. Alteration of endogenous factors d. Endothelial cell injury and its
regulating vasomotor tone sequelae
e. Inhibition of LDL oxidation
D.
7. A 56 year old man has persistent raised blood pressure of 175/110 mm Hg for the last few months. If he is
not treated, this man is at risk for which of the following condition:
a. Tricuspid insufficiency d. Hyperplastic arteriosclerosis
b. Polyarteritis nodosa e. Giant cell myocarditis
c. Pulmonary passive congestion
D.
203
8. An aneurysm of the abdominal is:

a. Usually the end result of syphilitic c. A frequent complication of
aortitis Polyarteritis nodosa
b. Usually the end result of d. Called a berry aneurysm
atherosclerosis e. Is usually the end result of the
hypertension
B.
9. Capillary Hemangioma are characterized by:
a. Frequent malignant transformation c. Exposure to polyvinyl chloride
to sarcomas d. Frequent regression
b. Infection by retrovirus e. Frequently seen in adult
D.
10. A 60 year old male had a 3 month Hx of severe throbbing pain and tenderness over the temple. He now
present with blindness, the most likely Dx is:
a. Raynaud’s disease c. Thromboangitis obliterans (
b. Syphilitic arteritis Buerger disease)
d. Giant cell arteritis
D.
11. The most diagnostic histopathological finding associated with HTN is :
a. Interstitial fibrosis of myocardium d. Aortic medial calcification
b. Arteriosclerosis e. Aortic aneurysm
c. Atherosclerosis
B.
12. All of the following are true of Thromboangitis obliterans (Buergers Disease) except:
a. Is associated with severe pain c. Characteristically and
b. May lead to gangrene of predominantly occur in females
extremities d. Is aggravated by smoking
e. Postmenopausal women
C
13. A 48 year old man suffers from the sudden onset of severe tearing pain in his mid-upper back, his BP is
210/120, radial pulse are markedly unequal in intensity, the most likely Dx is:
a. Thromboangitis obliterans c. Dissecting aneurysm
b. Coarctation of aorta d.
C.
14. Factors operative in the morphogenesis of atherosclerotic plaque include all of the following except:
a. Endothelium injury with platelet c. Vascularization of Atheromatous
aggregation plaque
b. Incorporation of mural thrombi d. Perivascular inflammation
into arterial intima e. Fatty accumulation in intimal cell
D.
15. Giant cell arteritis is associated with all of the following except:
a. Old age d. Failure to respond to steroid
b. Temporal artery therapy
c. Pain e. Visual symptoms
D.
16. Aneurysms associated with generalized atherosclerosis(ATH) are found most often in the:
a. Circle of Willis d. Ascending aorta
b. Abdominal aorta e. Arch of aorta
c. Renal arteries
B.
204
17. All of the following statements apply to varicose veins except:

a. Are caused by increased venous d. Most common in women then in
pressure man
b. Common source of large e. Occur in association with cirrhosis
pulmonary thromboembolism of liver
c. Frequently become thrombosed
B.
18. The primary anatomic site of pressure regulation in vascular system is :
a. Aorta d. Capillaries
b. Arteries e. Heart
c. Arterioles
C.
19. Pain is usually or often a symptom of each of the following except:
a. Thromboangitis obliterans d. Temporal arteritis
b. Kaposi sarcoma e. Dissecting aneurysm
c. Glomangioma
B.
20. A young pregnant female develop ulcerated peduncular lesion of the upper gingival and has attained a
bigger size in one month the most likely lesion is:
a. Peripheral ossifying fibroma d. Squamous cell CA
b. Pyogenic granuloma e. Squamous papilloma
c. Irritation fibroma
B.
21. Which of the following lesion is in no way neoplastic:
a. Anaplasia d. Desmoplasia
b. Metaplasia e. Severe dysplasia
c. Mild dysplasia
D
22. Which one of the following is not involved in etiology of systemic hypertension :
a. Arteriosclerosis d. Pheochromocytoma
b. Chronic glomerulonephritis e. Raised sodium intake
c. Conn’s syndrome
A.
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HEART
1. Characteristic features of rheumatic fever include each of the following except:
a. Fibrinous pericarditis d. High Antistreptolysin O titer
b. Emboli from valvular verrucae e. Myocarditis
c. Arthritis
B.
2. Acute rheumatic endocarditis follows infection with:
a. α –hemolytic streptococci d. coagulase positive staphylococcus
(strepto viridans) aureus
b. enterococci e. group A hemolytic streptococci
c. streptococcus pneumonia
E.
3. which is pathognomonic of active Rheumatic fever:
a. Russell body d. Fibrinous pericarditis
b. Granuloma e. Aschoff body
c. Bact. Vegetation
E.
4. These condition may occur as complication of infective endocarditis:
a. Libman-sack endocarditis c. Erosion of the chordate tendinae
b. Diffuse proliferative d. Intra cerebral infarction
glomerulonephritis e. Carcinoid heart disease
C.
5. Syphilitic heart disease most commonly involves:
a. Myocardium d. Aortic valve
b. Mitral valve e. Tricuspid valve
c. Pulmonary valve
D.
6. Alcoholism cause what kind of cardiomyopathy:
a. Dilated d. Restrictive
b. Hypertensive e. Atrophic
c. Hypertrophic
A.
7. Cor pulmonale is defined as
a. Right side heart failure due to c. Left side heart failure due to
systemic hypertension emphysema
b. Right side heart failure due to d. Both right and left ventricular
pulmonary disease failure due to pulmonary disease
e. Degenerative valve disease
B.
8. A 43 year old male complains of frequent chest pain. The sensation is typically brought on by minimal
exertion and is not relived by rest and nitroglycerine. He denies having any association arm or neck pain,
cough, shortness of breath, or difficulty swallowing. On physical examination his BP is 140/90 mmHg and
pulse is 80/Mint and regular. EKG is normal. What is the probable diagnosis?
a. Stable angina d. Prinzmetal’s angina
b. MI e. Aortic dissection
c. Unstable angina
C.
9. The most common cause of aortic stenosis
a. Rheumatic fever d. Syphilis
b. Calcific aortic degeneration e. Marfan syndrome
c. Bacterial endocarditis
B.
206
10. The LDH has ______________ of isoenzymes.

a. Two forms d. Five forms
b. Three forms e. Six forms
c. Four forms
D.
11. The cholesterol which is beneficial to human body is ?
a. LDL d. Chylomicron
b. VLDL e. TGA
c. HDL
C.
12. Diagnosis of myocardial infarction in confirmed by:
nd th
a. Elevated level of CRP on the 2 d. Elevation of CK-MB on the 10
day day of chest pain
b. Increased level of CK-MM e. Increased total creatinine kinase
c. Elevated level of CK-MB and
troponin in the first 24 hour of
M/I
C.
13. Commonly pulmonary hypertrophy occur in :
a. Tetralogy of Fallot d. Persistant truncus arteriosus
b. Transposition of great vessel e. Tricuspid atresia
c. Ventricular septal defect (VSD)
C.
14. Complication of left side heart failure is :
a. Decrease risk of embolic stroke d. Atrial fibrillation
b. Disappearance of alveolar septa e. Increase renal perfusion
c. Decrease risk of thrombus
formation
D.
15. Following features are seen in right side heart failure:
a. Engorgement of portal and c. Pulmonary congestion is common
systemic system is pronounced d. Pleural effusion is uncommon
b. Bulging of the ventricular septum e. Cardiac cirrhosis is uncommon
toward right
A.
16. A very wide patent foramen oval causing an atrial septal defect is describe as:
a. Ostium primum defect d. Ostium secundum defect
b. Roger`s disease e. Aorta overrides the VSD
c. Sinus venous defect
D.
17. Left side heart failure is most often cause by:
a. Increased resistance in pulmonary d. Mitral valvular disease
circulation e. It is not a consequence of
b. Mostly in cor pulmonale ischemic heart disease
c. By engorgement of systemic and
pulmonary system
D.
207
18. Ventricular rupture in patient with myocardial infarction occurs:

a. Commonly with the previous c. Most common in normotensive
history of M/I male patient
b. In necrotic and inflamed d. Common site is ventricular
myocardium septum
e. Common in young patient
B.
19. In cyanotic congenital heart disease there is:
a. Early right to left shunt d. Poor oxygenated blood entering
b. Increased pulmonary vascular the pulmonary circulation
resistance e. Polycythemia
c. Early left to right shunt
A.
20. Which of the following bacteria is most likely to cause bacterial endocarditis on a previously normal
valve:
a. Clostridia d. Streptococcus viridans
b. Staphylococcus e. Pseudomonas
c. Streptococcus Pyogenes
B.
21. A folic acid deficient diet probably puts a person at risk for coronary disease caused by raising plasma:
a. Homogentisic acid d. Lipoprotein A
b. Oxidized LDL e. Homocysteine
c. Total HDL
E.
22. Unstable angina is mostly due to:
a. Thrombus forming and lysing d. Several hemorrhages within the
b. Extreme hypercholesterolemia plaque
and rapid atherosclerosis e. Various rhythm disturbance
c. Multiple emboli to the coronaries developing and disappearing
D.
th
23. A patient who died of myocardial infarction on 4 day with raised CK-MB and 75% stenosis of the left
anterior descending artery. Which of the following microscopic finding is most likely to be present in left
ventricular myocardium at the time of death:
a. Extensive transmural collagen d. Edema and loss of cross
deposition striations
b. Lymphocytic interstitial e. Perivascular and interstitial
infiltration amyloid deposition.
c. Necrosis with dead neutrophils
and macrophages
C.
24. The commonest congenital heart disease in infancy is :
a. Ventricular septal defect (VSD) d. Coarctation of aorta
b. Atrial septal defect (ASD) e. Transposition of great arteries
c. Patent DuctusArteriosus (PDA)
A.
25. All of the following are cyanotic congenital heart disease except:
a. Transposition of great arteries d. Truncus Arteriosus
b. Tricuspid atresia e. Coarctation of aorta
c. Tetralogy of Fallot
E.
208
26. The commonest congenital heart disease in adult life:

a. Transposition of great arteries c. Truncus Arteriosus
b. Total anomalous pulmonary d. Atrial septal defect (ASD)
venous drainage (TAPVD) e. Ventricular septal defect (VSD)
D.
27. A 60-year-old man complaining of severe crushing pain is diagnosed to have myocardial infarction on
ECG changes and elevated serum troponin. If he dies the next day which of the following would almost
certainly be found on histologic examination of affected myocardium.
a. Coagulative necrosis with d. Slight swelling of tissue and changes of color
Neutrophilic infiltration e. Young fibroblast and new vessel
b. Fibrotic tissue replacing infracted tissue
c. No histologic changes
A.
28. A 50-year-old man complains of chest pain after exercise, whichis relieved by rest or sublingual
nitroglycerine. Which of the following cardiac lesion is most likely present?
a. Calcific aortic stenosis d. Rheumatic mitral stenosis
b. Coronary atherosclerosis e. Viral myocarditis
c. Restrictive cardiomyopathy
B.
29. A 55-year-old woman gives history of angina pectoris after exercise for the last 2 year. Coronary
angiography shows a fixed 75% narrowing of LAD. Which of the following type of cells is the initial target
in the pathogenesis of this arterial lesion?
a. Endothelial cells d. Platelets
b. Monocytes e. Smooth muscles
c. Neutrophils
A.
30. In atherogenesis, macrophages transform themselves into foam cell. Which of the following is most likely
to produce this effect?
a. C-reactive protein d. Platelet derived growth factor
b. Homocysteine e. VLDL
c. Oxidized LDL
C.
31. A 60-year-old man is hospitalized following a myocardial infarction 4 days back. He is kept under
observation for special danger of which of the following complication at this point of time
a. Arrhythmia d. Myocardial Rupture
b. Mural Thrombosis e. Ventricular Aneurysm
c. Myocardial (Pump) Failure
D.
32. A 50 years old man complains of chest pain after jogging for 10 minutes. The pain is relieved after rest.
Which of the following best describe this patient state?
a. Arrhythmia c. Prinzmetal’s angina
d. Stable angina pectoris
b. Myocardial infarction e. Unstable angina pectoris
D.
33. What could be the most likely prominent microscopic finding of myocardium in patient within 12-24
hours of M/I, who has tachycardia, irregular rhythm and raised serum CK-MB:
a. Capillary proliferation c. Contraction band necrosis
b. Formation of granulation d. Collagen deposition
tissue e. Macrophage infiltration
C.
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34. A middle-aged man was admitted for chest pain and found to be in shock. The pain began about an hour
before admission. Which of the following possible complications is least expected over the next week?
a. Congestive failure d. Atrial fibrillation
b. Mural thrombosis e. Fibrinous pericarditis
c. Ventricular aneurysm
C
35. In a moderate-sized myocardial infarct it would take approximately how long to replace the necrotic
muscle with fibrous tissue?
a. 2 days d. 2 years
b. 2 weeks e. 3 weeks
c. 2 months
C.
36. The single most frequent complication of myocardial infarction is:
a) Mural thrombosis d) Aneurysm of left ventricle
b) Embolism e) Arrhythmia
c) Rupture of myocardium
E.
37. Eight days after a documented myocardial infarct, a patient experiences recurrence of chest pain and
equivocal changes on electrocardiogram suggesting that a second infarct has occurred. Levels for which
serum enzyme would be most useful in resolving the problem?
a) Lactic dehydrogenase d) Alanine aminotransferase
b) Creatine kinase e) Alkaline phosphatase
c) Aspartate aminotransferase
B.
38. Left ventricular hypertrophy occurs characteristically in each of the following except:
a) Mitral stenosis d) Aortic valve stenosis
b) Mitral insufficiency e) Aortic valve insufficiency
c) Systemic hypertension
A.
39. When a person dies suddenly from a “heart attack”, the most likely event that lead to the sudden death
is:
a) Rupture of the heart d) Coronary artery embolism
b) Congestive heart failure e) Cardiac arrhythmia
c) Angina pectoris
E.
40. The major cause of death in myocardial infarction is:
a) Rupture of mitral papillary muscle d) Arrhythmia
b) Congestive failure e) Septal rupture
c) Ventricular aneurysm
D.
41. Which of the following is a cause of high output heart failure?
a) Pulmonary emphysema d) Hypothyroidism
b) Mitral stenosis e) Arterio-venous fistula
c) Ventricular aneurysm
E.
210
42. Serious coronary occlusion in a young man is more likely to be fatal than in an older man with a history
of coronary heart disease because:
a) The older man is less active and will not d) The older man will have a well-developed
overtax his heart collateral circulation in the coronary system
b) The young man has a better functioning e) The younger man will have less mature
coagulation mechanism collagen in his heart wall
c) The older man will probably have poorly
functioning heart valves and will be unable
to develop high intraventricular pressures
C.
43. The most common location of myocardial rupture due to infarction is:
a) Posterior wall of left ventricle d) Anterior wall of right ventricle
b) Intraventricular septum e) Left atrial appendage
c) Anterior wall of left ventricle
f)
C.
44. A HEALED myocardial infarction is characterized by:
a) An infiltrate of eosinophil’s d) Aschoff bodies
b) Scar tissue e) Secondary amyloidosis
c) Giant cells
B.
45. Uremic individuals characteristically develop which type of pericarditis?
a) Fibrinous d) Serous
b) Hemorrhagic e) None of the above
c) Purulent
A.
46. Cor Pulmonale may be caused by all of the following except:

a) Interstitial fibrosis of the lung c) Pulmonary emphysema
b) Multiple emboli of the pulmonary d) Aortic valvular disease
vasculature e) Ischemic heart disease
D.
47. .Each of the following is a manifestation of pure right heart failure except:
a) Ankle edema d) pulmonary edema
b) Hepatomegaly e) Prerenal azotemia
c) Ascites
D.
48. The most common cause of death in patients with untreated hypertension is:
a) Malignant nephrosclerosis d) Congestive heart failure
b) Intracerebral hemorrhage e) Arrhythmia
c) Ruptured berry aneurysm
D.
49. Among the following, the congenital cardiac anomaly most commonly associated with cyanosis is:
a) Ventricular septal defect d) Coarctation of the aorta
b) Atrial septal defect e) Patent DuctusArteriosus
c) Tetralogy of Fallot
C.
50. The most common cause of pulmonary stenosis is:
a) A congenital lesion d) Carcinoid syndrome
b) Rheumatic endocarditis e) Syphilis
c) Bacterial endocarditis
A.
211
51. Which of the following developmental abnormalities is most common?

a) Atrial septal defect d) Coarctation of the aorta
b) Ventricular septal defect e) Patent DuctusArteriosus
c) Tetralogy of Fallot
B.
52. Acute rheumatic endocarditis follows infections with:
a) Alpha-hemolytic streptococci c) Coagulase +ve Staphylococcus aureus
(Streptococcus viridans) d) Streptococcus pneumoniae
b) Group A beta-hemolytic streptococci e) Enterococci
B.
53. Deformities secondary to rheumatic endocarditis most often affect the:
a) Mitral valve d) Tricuspid valve
b) Aortic valve e) Pulmonary valve
c) Left atrial endocardium
A.
54. Congestive cardiac failure in the first attack of acute rheumatic fever usually results from:
a) Endocarditis d) Anemia
b) Myocarditis e) Mitral stenosis
c) Pericarditis
B.
55. Which congenital cardiovascular anomaly is the most common in the neonatal period?
a) Patent DuctusArteriosus d) Mitral atresia
b) Pulmonic atresia e) Coarctation aorta
c) Transposition
A.
56. Each of the following is a major manifestation (Jones criteria) of acute rheumatic fever except:
a) Carditis d) Migratory polyarthritis
b) Erythema Marginatum e) Chorea
c) Glomerulonephritis
C.
57. The most frequent clinically significant residual lesion of acute rheumatic fever is:
a) Aortic stenosis d) Myocardial hypertrophy
b) Mitral stenosis e) Pericardial adhesions
c) Myocardial fibrosis
B.
58. An 80-year-old man with typical angina has a systolic murmur at the base of the heart transmitted
toward the left axilla. The left ventricle is moderately enlarged. The most likely diagnosis is:
a) Acute myocardial infarction d) Calcified mitral valve annulus
b) Floppy valve syndrome e) Mitral stenosis.
c) Calcific aortic stenosis
C.
59. Which is pathognomonic of active rheumatic fever?
a) Russell body d) Fibrinous pericarditis
b) Granuloma e) Aschoff bod
c) Bacterial vegetation
E.
60. What is the most common cause of pure mitral regurgitation?
a) Cleft anterior mitral leaflet d) Infarcted mitral papillary muscles
b) Floppy mitral valve e) Infective endocarditis
c) Idiopathic chordal rupture
B.
212
61. The two valves most frequently involved in rheumatic heart disease are the:
a) Aortic and tricuspid d) Tricuspid and pulmonic
b) Mitral and pulmonic e) Aortic and pulmonic.
c) Mitral and aortic
C.
62. The most common cause of subacute infective endocarditis is:
a) Candida albicans d) Streptococcus pneumoniae
b) Immune reaction to bacterial toxins e) Streptococcus viridians.
c) Staphylococcus aureus
E.
63. Syphilitic heart disease most commonly involves:
a) Myocardium d) Tricuspid valve
b) Mitral valve e) Aortic valve.
c) Pulmonic valve
E.
64. Libman-Sacks endocarditis is associated with:
a) Carcinoid tumors d) Acute rheumatic fever
b) Fiedler’s myocarditis e) Syphilitic aortitis.
c) Systemic lupus erythematosus
C.
65. A restrictive (constrictive) type of cardiomyopathy characteristically occurs in association with:
a) Alcoholism d) Beriberi (thiamine deficiency)
b) Amyloidosis e) Chronic infection.
c) Asymmetric septal hypertrophy
B.
66. The most common primary tumor of the heart is:
a) Rhabdomyoma d) Mesothelioma
b) Myxoma e) Fibroma
c) Angiomas
B.
213
HEMATOPOIETIC AND LYMPHOID SYSTEM
1. A 15 years old cancer patient is receiving anti-cancer drug therapy for the past 18 months. Now he
developed progressive weakness, pallor and dyspnea along with history of repeated infections and
petechial hemorrhage. CBC shows pancytopenia. BM shows hypocellularity. The most likely diagnosis is.
a. Microcytic Hypochromic anemia d. G6PD Deficiency anemia
b. Macrocytic anemia e. Hereditary Spherocytosis
c. Aplastic anemia
C.
2. The decay accelerating factor which is deficient in paroxysmal nocturnal hemoglobinuria is
a. CD55 d. CD20
b. CD18 e. CD19
c. CD22
A.
3. Increase osmotic fragility is suggestive of:
a. Pyruvate Kinase deficiency d. Hereditary Spherocytosis
b. G6PD deficiency e. Megaloblastic anemia
c. Hereditary elliptocytosis
D.
4. CD33 will be positive in which of the following malignancy
a. CLL d. Small Cell Lymphoma
b. AML e. Burkitt Lymphoma
c. ALL
B.
5. Philadelphia Chromosome positive in CML Reciprocal translocation between which of the following
chromosome
a. T (9;22) d. T (11;14)
b. T (2;8) e. T (8;14)
c. T (14;18)
A.
6. Smudge cell on the peripheral smear increase count of mature lymphocyte associated with autoimmune
anemia and thrombocytopenia to be
a. ALL d. AML
b. CLL e. Burkitt Lymphoma
c. CML
B.
7. Two days after receiving the antimalarial drug primaquine, a 27-year-old man develops sudden
intravascular hemolysis resulting in a decreased hematocrit hemoglobinemia and hemoglobinuria.
Examination of the peripheral blood reveals erythrocytes, with a defect forming bite cells, when crystal
violet stain is applied many Heinz bodies area also seen. Which of the following is the most likely
diagnosis?
a. Hereditary spherocytosis d. Autoimmune hemolytic anemia
b. Glucose 6 phosphate e. Micro angiopathic hemolytic
dehydrogenase deficiency anemia
c. Paroxysmal hemoglobinuria
B.
8. The auto antibodies in warm antibody hemolytic anemia are:
a. IgG d. IgA
b. IgM e. IgE
c. IgD
A.
214
9. Replacement of glutamic acid with Valine at position-6 of β –globin chain result in:
a. G6PD deficiency d. sickle cell disease
b. β – thalassemia e. paroxysmal nocturnal
c. α – thalassemia hemoglobinuria
D.
10. A 41 year women present with increasing fatigue lethargy and muscle weakness. Her CBC reveals
decreased number of erythrocytes, leukocytes, and platelets along with an increased in the MCV of the
erythrocytes. Her blood smear shows hypersegmented neutrophils. Which of the following substance is
most likely to be deficient in this individual?
a. Amino levulinic acid d. Retinoic acid
b. Ascorbic acid e. Vinyl mandelic acid
c. Folic acid
C.
11. A 72 year old man present with increasing fatigue. Physical examination reveals multiple enlarged non
tender lymph nodes with enlarged liver and spleen. Lab examination of his peripheral blood reveals a
Normocytic normochromic anemia and a slightly decreased platelet count and a leukocyte count of
72000/microliter. Examination of the peripheral smear reveal a marked increase in the number of mature
looking lymphocytes and many smudge cells. What is the most likely diagnosis:
a. Acute lymphoblastic leukemia d. Immunoblastic lymphoma
b. Atypical lymphocytosis e. Prolymphocytic leukemia
c. Chronic lymphocytic leukemia
C.
12. Pernicious anemia is produce due to:
a. Defective absorption of folic acid c. Vit B12 deficiency due to
b. Defective absorption of vit.B 12 deficiency of intrinsic factor
resulting from deficient R binder d. Ileal resection
e. Deficiency of transcobalamin
C.
13. Caused by deletion of all four alpha globin genes
a. Beta thalassemia major d. Alpha thalassemia trait
b. Hb Bart’s hydrops fetails e. Hereditary spherocytosis
c. Diamond-Blackfan anemia
B.
14. The most important diagnostic feature for beta thalassemia trait
a. Anemia d. Reduced MCV
b. Raised HbF e. Raised HbA2
c. Reduced MCH
B.
15. Which of the following is not suggestive of hemolytic anemia?
a. Raised reticulocyte count d. Unconjugated bilirubinemia
b. Increased erythropoiesis in bone e. Absent red cell precursors in bone
marrow marrow
c. Increased urinary urobilinogen
E.
16. Iron is almost entirely absorbed in the
a. Jejunum d. Colon
b. Ileum e. Stomach
c. Duodenum
C.
215
17. Acute promyelocytic leukemia (AML M3) has the following features Except :
a. t(15;17) d. Multiple Auer rods
b. Hypergranular promyelocytes e. SBB/POX positivity
c. Gum hyperplasia
C.
18. In patient with acute lymphoblastic leukemia had prognostic sign include each of the following except:
a. CNS involvement d. WBC >50000/mm3
b. t(9;22) e. Age 2-10 year
c. male sex
C.
19. Acute myeloid leukemia is associated with all of the following except :
a. Failure of normal hemopoiesis due c. Auer rods in blast cells
to overcrowding of marrow with d. Predominant cell in peripheral
blast cells blood is myelocyte
b. Clinical finding similar to ALL e. Gum hypertrophy in AML M5
D.
20. The CBC of a 7 year old boy with fever, generalized lymphadenopathy shows Hb 8 gm/dl, TLC 25000/mm3,
platelet count 30000/mm3 and 80% blast. He receives chemotherapy and has a complete remission.
Which of the following combination of markers is most likely to be present in this patient?
a. Early pre B (CD19+,TdT+); d. T cell (CD3+, CD2+); normal
hyperdiploidy karyotype
b. Early pre B (CD19+,TdT+) ; t(9:22) e. T cell ( CD3+, CD2+); hyperdiploidy
c. Pre B (CD5+, TdT+); t(9:22)
A.
21. A 65 year old female complains of increasing back pain. Xray of the spine shows collapse of T11. A bone
marrow aspiration shows many large cells with deeply basophilic cytoplasm eccentric nuclei and
perinuclear hole. Which of the following is the most likely laboratory finding in this patient?
a. t(9;22) d. platelet count 750000/mm3
b. elevated LAP score e. WBC 350000/mm3
c. bence jones protein and M band
C.
22. A 60year old man complains of burning sensation in hand and feet, 2 month ago he had episode of
swelling with tenderness in the right leg, following by dyspnea and right side chest pain. On examination
he has hepatosplenomegaly. CBC shows Hb 14.5 g/dl, hematocrit 48%, WBC 14000/mm3, platelet count
650000/mm3 and abnormally large platelet in smear. What is the most likely diagnosis?
a. CML d. Essential thromocythemia
b. AML e. Myelofibrosis with myeloid
c. Polycythemia vera metaplasia
D.
23. A 50 year old man has had headache, dizziness and fatigue for past 3 months. He has ruddy complexion
and experiences pruritus after a warm bath. CBC shows Hb 22gm/dl, PCV 67% platelet count
450000/mm3, TLC 8000/mm3. EPO is very low. What is the most likely diagnosis?
a. MDS d. Essential thrombocythemia
b. CML e. Polycythemia vera
c. Erythroleukemia
E.
216
24. A 70 year old man with severe bone pain and repeated infection is diagnosed to have multiple myeloma
which of the following statements is true of this disorder?
a. The M band is most often IgM d. The M spike is most often
b. Renal insufficiency is the most polyclonal in nature
common cause of death e. The average age at presentation is
c. This disorder is a T-cell neoplasm 45 years
B.
25. A 13 year old boy with epistaxis, fever and lymphadenopathy is diagnosed to have acute lymphoblastic
leukemia. Which of the following statement best characterizes this disorder?
a. This leukemia is the most d. The peroxidase stain is usually
responsive to therapy positive in lymphoblast’s
b. It most often occur in adults but e. Meningeal involvement is not
can occur in children common in this disorder
c. The presence of CD 10 marker is
indicative of poor prognosis
D.
26. The characteristic cell of Hodgkin lymphoma is :
a. Sezary cell d. Hairy cell
b. Clover leaf cell e. Mott cell
c. Reed Sternberg cell
C.
27. Which of the following is not a feature of lymphoblast:
a. Inconspicuous nucleoli, scant c. Auer rods
cytoplasm d. TdT positivity
b. PAS positivity e. CD 19, CD 10 positivity
C.
28. TIBC is increased in;
a. Anemia of chronic disorder d. Sideroblastic anemia
b. Iron deficiency anemia e. Thalassemia
c. Megaloblastic anemia
B.
29. In anemia of chronic disorder:
a. Bone marrow iron is absent d. Iron is not incorporated in
b. Hyper segmentation is seen erythroblast
c. Iron level id low e. Serum ferritin is low
D.
30. Microcytic hypochromic anemia is seen in :
a. Iron deficiency d. Polycythemia Vera
b. Megaloblastic anemia e. Rh incompatibility
c. Multiple myeloma
A.
31. In chronic renal failure anemia is due to:
a. Decrease erythropoietin d. Iron absorption
b. Low iron intake e. Iron utilization
c. Increase R.B breakdown
A.
32. Differential diagnosis of CML with leukamoid reaction are based on:
a. Basophilia d. All of the above
b. LAP score e. Non of the above
c. Philadelphia chromosome
D.
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Special
Special
Pathology
Pathology
33. Regarding diagnosis of infection mononucleosis, choose on best from the below mentioned statement:
a. Lymphocytosis (>50% lymph’s) c. A positive serologic test for EBV
b. The presence of at least 10% heterophile antibodies(e.g
atypical lymphocytes on peripheral Monospot test)
smear d. Fever, sore throat and skin rashes.
e. None of the above
C.
34. In acute myeloblastic leukemia all are true except:
a. AML is less common in children c. Some patient show major
then ALL coagulation problem that leads to
b. Cytogenetic studies suggest the bleeding complication
presence of clonal proliferation of d. Leukemia blast shows cytoplasmic
leukemic cell needle like structure
e. Cytoplasmic vacuoles are common
E.
35. Choose the statement which does not favor DIC :
a. Thrombocytopenia d. Decreased level of FDPs and D-
b. Prolong PT and APTT Dimers
c. Increased level of FDPs and D- e. Fragmented RBCs
Dimers
D.
36. Bone marrow smear of 4 year old boy show numerous small blast cell. Special staining reveals that the
blast contain large, coarse, PAS positive block in the cytoplasm. The blast cells are identified as:
a. Megakaryoeblasts d. Erythroblasts
b. Myeloblasts e. Monoblasts
c. Lymphoblast’s
C.
37. All of the following are histological subtype of Hodgkin’s disease except:
a. Lymphocytic predominant d. Lymphocyte depleted
b. Mixed cellularity e. Diffuse large cell lymphoma
c. Nodular sclerosing
E.
38. Microscopic feature of neutrophilia due to infection show the following changes except:
a. Increased TLC d. Dhole bodies
b. Toxic granulation of neutrophils e. Microorganisms in neutrophils
c. Vacuolation of neutrophils
E.
39. The commonest cause of eosinophilia in KPK :
a. Connective tissue disease d. Neoplasia
b. Helminthic infestation e. Allergies
c. Idiopathic HES
B.
40. Regarding acute lymphoblastic leukemia (FAB type ALL-L1) all are present except:
a. Uniform population d. Scanty cytoplasm
b. Small size e. Cytoplasmic Vacuolation
c. Indistinct nucleoli
E.
41. The most important cause of leukoerythroblastic blood picture is:
a. Secondary carcinoma of bone d. Multiple myeloma
b. Thalassemia major e. Lymphoma
c. Acute hemolytic anemia
A.
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42. Exchange transfusion is indicated in newborn if serum bilirubin level is more than:
a. 20 mg/dl d. 17 mg/dl
b. 19 mg/dl e. 16 mg/dl
c. 18 mg/dl
A.
43. Myeloproliferative disorders include all of the following except:
a. Essential thrombocythemia d. Chronic myeloid leukemia
b. Myelofibrosis e. Paroxysmal nocturnal
c. Polycythemia Rubra Vera hemoglobinuria
E.
44. All of the following are correct except regarding classification of CML:
a. Ph +ve CML d. Chronic myelomonocytic leukemia
b. Philadelphia –ve, BCR-ABL +ve CML e. Juvenial myelomonocytic leukemia
c. Multiple myeloma
C.
45. The Epstein- Barr virus (EBV) has a proven positive association with the following condition:
a. Carcinoma of cervix d. Burkitt’s lymphoma
b. Infection mononucleosis e. Undifferentiated nasopharyngeal
c. Human T-cell lymphoma carcinoma
B.
46. The most common cause of neutrophilic leukamoid reaction is:
a. Severe acute infection by gram c. Hemolysis
positive cocci d. Bone marrow infiltration
b. Hemorrhage e. UTI by E.coli
A.
47. The following morphological features may be found in myelodysplastic syndrome except:
a. Pseudo-pelger Huet d. Macrocytosis
b. Ringed sideroblast e. Reticulocytes
c. Oval macrocytosis and hyper
segmented neutrophils
E.
48. Regarding diagnosis of leukoerythroblastic blood picture, choose the best:
a. Presence of Myeloblasts in c. The presence of immature myeloid
peripheral blood and erythroid cells in peripheral
b. Presence of nucleated RBCs in the blood
peripheral blood d. A total leukocyte count of
>50,000/cmm
C.
49. Common laboratory finding of chronic lymphocytic leukemia are:
a. Lymphocytes more then d. Thrombocytopenia may develop
50,000/cmm due to bone marrow failure
b. Smudge cells are commonly seen e. All of the above
c. Normal mature appearance of
lymphocytes
E.
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50. A patient with idiopathic thrombocytopenic purpura has:

a. Reduce platelets in peripheral c. Reduce platelets in peripheral
blood blood and normal or increased
b. Normal CBC except low platelets megakaryocytes in bone marrow
count d. Petechial, purpura, sometimes
mucosal bleeding
e. Normal PT and APTT
C.
51. All of the following are common finding in acute lymphoblastic leukemia EXCEPT:
a. Epistaxis d. Gum hypertrophy
b. Fever e. More than 30% blast cells
c. Marked elevation in WBCs
D.
52. Regarding diagnosis of neutropenia, choose one best statement from below:
a. Total leukocyte count of < c. Severe pharyngitis and tonsillitis
4000/cmm d. Cellulitis
b. An absolute neutrophils count of < e. Bacteremia and septicemia
1500/cmm
B.
53. Diagnosis of multiple myeloma is based on
a. Bence jones proteins d. Accumulation of plasma cell in the
b. M-Band bone marrow
c. Lytic lesion e. All of the these
E.
54. The Philadelphia chromosome observed in which on the following leukemia:
a. CML d. None of the above
b. AML e. All of the above
c. CLL
A.
55. The following statement about plasma cell disorders are correct except:
a. Plasma cell usually comprises 30% d. There is marked Rouleaux
or more of the marrow cells formation in peripheral blood film
b. A paraprotien is always present in and high ESR
serum e. Lytic lesion are always absent
c. The serum alkaline phosphatase is
usually raised
E.
56. Leukocytic alkaline phosphatase score is raised in:
a. CML d. Liver cirrhosis
b. Neutrophilic leukamoid reaction e. Polycythemia
c. Aplastic anemia
B.
57. All of the following features of multiple myeloma are correct except:
a. Pathological fracture d. Increased hemoglobin level
b. Increased abnormal plasma cells in e. Presence of Bence Jones
bone marrow Proteinuria
c. Increased peak serum of
monoclonal protein in
electrophoresis
D.
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58. The cell characteristic of all types of Hodgkin lymphoma is the :

a. Lacunar cell d. Sezary cell
b. L and H cell e. Clover leaf cell
c. Reed Sternberg cell
C.
59. Burkitt’s lymphoma is histologically characterized by:
a. Proliferation centers d. Reed Sternberg cell
b. Centrocytes and centroblast e. Clover leaf cell
c. Uniform nuclei, high mitotic rate,
starry sky pattern
C.
60. Adult T cell leukemia/ lymphoma is characterized by all of the following except:
a. Skin lesion d. Lymphocytosis
b. Hypercalcemia e. Hairy cell
c. Generalized lymphadenopathy
E.
61. The diffuse large cell lymphoma are :
a. Seldom curable d. Best treated palliatively
b. Rapidly fatal if untreated e. Often present with generalized
c. Have indolent course asymptomatic lymphadenopathy
B.
62. All of the following are T cell disorders except:
a. Mycosis fungiodes d. Anaplastic large cell lymphoma
b. Sezary’s syndrome e. Large granular lymphocytic
c. Burkitt’s lymphoma leukemia
C.
63. In G6PD deficiency hemolysis of RBC occur due to:
a. Inability to inactive oxidant d. Presence of abnormal Hb
b. Ability to activate oxidants e. Iron overload
c. Inability to activate oxidants
A.
64. Homozygous sickle cell disease usually becomes apparent at the age of about;
a. 3 months d. 12 months
b. 6 months e. 2 year
c. 9 months
B.
65. The most common cause of megaloblastic anemia is the deficiency of :
a. Vit B1 d. Iron
b. Vit B2 e. Mg
c. Vit B12
C.
66. Aplastic anemia is a disorder of hematopoiesis in which there is pancytopenia in peripheral blood and
decrease cellularity of bone marrow with:
a. No abnormal infiltrate in bone d. Presence of leukemic cells in bone
marrow marrow
b. Abnormal infiltrate in bone e. Presence of cancerous cells in
marrow bone marrow
c. Increase in reticulin in bone
marrow
A.
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67. The warm antibody that play important role in immune hemolytic anemia are mostly:
a. Ig A d. Ig M
b. Ig G e. Ig E
c. Ig D
B.
68. Regarding staging of tumors what is important:
a. Nuclear cytoplasmic ratio d. Pleomorphism
b. Local invasion e. Tumor giant cells
c. No. of mitotic figures
B.
69. In later stage of iron deficiency anemia, on peripheral blood examination the RBC are found to be
a. Normocytic, hypochromic d. Normocytic, normochromic
b. Macrocytic, normochromic e. Macrocytic, hypochromic
c. Microcytic, hypochromic
C.
70. Cold antibody has enhanced activity at temp:
a. <30 degree centigrade d. >40 degree centigrade
b. >30 degree centigrade e. At 37 degree centigrade
c. >37 degree centigrade
A.
71. The most commonly employed test in Dx of immune hemolytic anemia is :
a. Direct coombs test d. Culture
b. Indirect coombs test e. Both a and b
c. PCR
E.
th
72. Substitution of valine for glutamic acid at 6 position produces:
a. HbA d. HbE
b. HbA2 e. HbF
c. HbS
C.
73. The most commonly employed test for hereditary spherocytosis is:
a. Osmotic fragility test d. Reticulocyte count
b. Coombs test e. BM examination
c. Hb estimation
A.
74. In hereditary spherocytosis hemolysis of RBC occur due to:
a. G6PD deficiency d. Defect in Hb synthesis
b. ATP deficiency e. Presence of abnormal Hb
c. Defect in red cell membrane
cytoskeleton
C.
75. Hemosiderin which is a stored form of iron is mostly found in:
a. BM d. Kidneys
b. Liver e. a,b,c is correct
c. Spleen
E.
76. The most common cause of anemia in women of child bearing age is:
a. Iron deficiency d. Zinc deficiency
b. Cobalt deficiency e. Folate deficiency
c. Vit B12 deficiency
A.
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Pathology
Pathology
77. Which of the following lesion is in no way neoplastic

a. Anaplasia d. Desmoplasia
b. Metaplasia e. Severe dysplasia
c. Mild dysplasia
D.
78. Smoking cause all of the following tumors except
a. Carcinoma larynx d. Acute leukemia
b. Bronchogenic carcinoma e. Carcinoma esophagus
c. Bladder carcinoma
D.
79. What is the most common glycolytic enzyme deficiency associated with pentose phosphate pathway?
a. Pyruvate kinase deficiency d. Glutathione reductase deficiency
b. Glucose-6-phosphate e. Methemoglobin reductase
dehydrogenase deficiency deficiency
c. Hexokinase deficiency
B.
80. Which of the following is NOT a cause of vitamin B12 deficiency?
a. Atrophic gastritis d. Chronic glossitis
b. Blind loop syndrome e. Fish tape worm
c. Total gastrectomy
D.
81. Which of the following is not a feature of acute monocytic leukemia (AML M5)
a. Gum hyperplasia d. T (15;17)
b. Non specific esterase positivity e. Raised serum lysozyme
c. Splenomegaly and
lymphadenopathy
D.
82. The protein part bound to lipid is called ;
a. Apoprotein d. Phosphoprotein
b. Glycoprotein e. None of the above
c. Hem protein
A.
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LUNG
1. The type of emphysema involving the proximal part of acini formed by respiratory bronchioles is:
a. Centriacinar emphysema d. Compensatory emphysema
b. Panacinar emphysema e. Bullous emphysema
c. Distal acinar emphysema
A.
2. Which of the following is defined as persistent productive cough for at least 3 consecutive months in at
least two consecutive year:
a. Emphysema d. Asthma
b. Chronic bronchitis e. Bronchiolitis
c. Bronchiectasis
B.
3. The most common cause of lobar pneumonia is:
a. Klebsiella d. Pseudomonas
b. Fungi e. Pneumococci
c. Staphylococci
E.
4. A 9 year old boy was identified in childhood as having elevated sweat chloride. Though he appeared to be
normal term baby, his neonatal course was complicated by development of meconius ileus. Throughout
childhood he has experienced multiple increasingly severe bouts of pneumonia with productive cough,
often with pseudomonas aeruginosa. Based on these finding he is at risk for developing of which of the
following condition:
a. Adenocarcinoma d. Emphysema
b. Bronchiectasis e. Chronic bronchitis
c. Pleural fibrosis plague
B.
5. Malignant mesothelioma is most commonly associated with which of the following :
a. Silicosis d. Immunodeficiency
b. Asbestosis e. Anthracosis
c. Allergy
B.
6. The most common cause of Panacinar emphysema is:
a. Smoking d. immunodeficiency
b. α 1 antitrypsin deficiency e. Type 1 hypersensitivity
c. infection
B.
7. Which of the following is a characteristic histological finding in chronic bronchitis?
a. Thinning and destruction of d. Ulceration of epithelium of bronchi
alveolar walls e. Accumulation of eosinophil’s in
b. Decreased in alveolar capillaries bronchial wall
c. Increased in number of goblet cells
C.
8. A paraneoplastic syndrome associated with ACTH or ADH production is most likely to be associated with
which type of lung carcinoma:
a. Squamous cell CA d. Large cell carcinoma
b. Adenocarcinoma e. Carcinoid tumor
c. Small cell carcinoma
C.
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9. Which of the following lung tumor arise centrally, is more common in men, is associated with cigarette
smoking and has keratin pearls on histopathology;
a. Squamous cell CA d. Large cell carcinoma
c. Small cell carcinoma
A.
10. Which fungus is commonly known to occur in a patient who has previously been treated for tuberculosis
and has developed a cavitary lesion in lung parenchyma;
a. Histoplasmosis d. Aspergillus
b. Blastomycosis e. Candida
c. Mucor
D.
11. 70 year old women develop an acute febrile illness and coughing. Chest radiograph shows infiltrates that
nearly fill the left lower lobe. Her family elects not to treat her illness, and she dies 4 days later. At
autopsy, there is extensive consolidation of the lower lobe with numerous neutrophils within alveoli.
Which of the following infection agent is most likely to cause her pulmonary disease?
a. Pneumocystis carinii (jiroveci) d. Mycobacterium tuberculosis
b. Listeria monocytogenes e. Streptococcus pneumonia
c. Cryptococcus neoformans
E.
12. A 50 year old woman is non-smoker, but she has had increasing shortness of breath, weight loss, and
night sweats for four months. On physical examination her temperature is 37.6 C. there are fine rales
auscultated in all lung fields. A chest radiograph reveals hilar lymphadenopathy and a reticulonodular
pattern of small densities in all lung fields. She demonstrates anergy by skin testing to mumps and
candida antigens. A transbronchial biopsy is preformed that microscopically shows numerous small
pulmonary interstitial non-caseating granulomas. Which of the following is the most likely Dx?
a. Histoplasmosis d. Usual interstitial pneumonitis
b. Adenocarcinoma e. Tuberculosis
c. Sarcoidosis
C.
13. A 60 year old man has a 90 pack year history of smoking. For the past 5 years, he has had cough
productive of copious amount of mucoid sputum for months at a time. He has had episodes of pneumonia
with streptococcus pneumonia and E.coli cultured. His last episode of pneumonia is complicated by
septicemia and brain abscess and he dies. At autopsy, his bronchi microscopically demonstrate mucus
gland hypertrophy. Which of the following condition is most likely to explain his clinical course?
a. Squamous cell carcinoma d. Bronchial asthma
b. Congestive heart failure e. Centrilobular emphysema
c. Chronic bronchitis
C.
14. A 58 year old man has been a smoker for 40 years. He has had an 8 kg weight loss over the past 6 months
accompanied by a chronic cough and malaise. He reports no fever, nausea, or vomiting. He had a recent
episode of hemoptysis. A chest radiograph reveals a 5 cm diameter mass in the medial left upper lobe.
Bronchoscopy reveals a mass lesion involving the left superior segmental bronchus. Which of the
following is the most likely Dx?
a. Squamous cell carcinoma d. Large cell carcinoma
b. Small cell carcinoma e. Carcinoid tumor
c. Adenocarcinoma
A.
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15. A resident in the surgery department is conducting a survey to identified risk factors for lung cancer in the
local population. In which subset of patients is he likely to encounter the highest frequency of tobacco
smokers?
a. Squamous cell carcinoma d. Large cell carcinoma
b. Small cell carcinoma e. Bronchoalveolar carcinoma
c. Adenocarcinoma
A.
16. A 2 year old child, resident of Islamabad has seasonal bouts of breathing difficulty with prolonged cough
productive of copious mucinous secretions, each spring season. Peripheral smear shows eosinophilia
during an episode and sputum examination reveals charcoat-laden crystals. What is the most potent
mediator of bronchospasm in this patient:
a. TNF- α d. Histamine
b. Leukotriene’s e. Prostaglandins
c. Interleukins
D.
17. In pathogenesis of bronchiectasis the susceptibility to infection is due to:
a. Progressive fibrosis of lung c. Chronic inflammation of airways
parenchyma leading to epithelial sloughing
b. Accumulation of thick and viscid d. Immunodeficiency status
secretions obstruction the airways e. Repeated hospital admission and
exposure to nosocomial infection
B.
18. While examining a bronchoscopic biopsy a pathologist notice a tumor composed of cell smaller then
lymphocytes with deeply staining nuclei and scanty cytoplasm. What is the likeliest Dx?
a. Adenocarcinoma d. Bronchoalveolar carcinoma
b. Large cell carcinoma e. Small cell carcinoma
c. Squamous cell carcinoma
E.
19. Pathology resident is reviewing slides of cases of lung cancer reported during the last two year. He finds
20 cases of squamous cell carcinoma, 12 cases of adenocarcinoma, 4 cases of small cell carcinoma, and 2
each of bronchoalveolar carcinoma and large cell carcinoma. If he orders p53 staining on all these cases
which tumor type is likely to be most frequently positive?
a. Adenocarcinoma d. Bronchoalveolar carcinoma
b. Large cell carcinoma e. Small cell carcinoma
C.
20. Following renal transplantation a patient develops high grade fever with chills and cough productive of
mucopurulent sputum. Chest radiograph shows foci of consolidation. Which bacterial infection would you
most suspect in this patient?
a. Staphylococcus aureus d. Streptococcus pneumonia
b. Klebsiella pneumonia e. Legionella pneumophilia
c. Pseudomonas
E.
21. 45 years old patient comes with the history of cigarette smoking associated with chronic dyspnea, which
started insidiously and progressed steadily. The chest is barrel shaped with obviously prolonged
expiration. Histologically there is thinning and destruction of alveolar walls. Which of the following is the
most likely diagnosis:
a. Chronic bronchitis d. Asthma
b. Bronchiectasis e. Bronchiolitis
c. Emphysema
C.
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22. Four stages of the inflammatory response occur in:

a. Bronchopneumonia d. Lobar pneumonia
b. Pulmonary tuberculosis e. Hypersensitivity pneumonitis
c. Asthma
D.
23. All the following statements regarding bronchopneumonia are correct except:
a. Patchy areas of red or gray d. Fibrinosuppurative consolidation
consolidation affecting one or of a large portion of a lobe
more lobes e. More often involving the lower
b. Frequently found bilaterally zone
c. The suppurative exudates fills
bronchi, bronchioles and adjacent
alveolar space
D.
24. A 17 year old patient comes with the history of upper respiratory tract infection, pleural effusion and
positive cold agglutination test. Clinical diagnosis was atypical pneumonia. What is the most likely such
type of the disease:
a. Mycoplasma pneumonia d. Psittacosis
b. Legionnaire’s disease e. Fever
c. Tularemia
A.
25. Typical features of a squamous cell carcinoma of the lung include except:
a. Hypercalcemia d. Mucin production
b. Central location e. Keratin pearls
c. Fungating mass
D.
26. An elderly patient with history of cystic fibrosis develops typical pneumonia, Pleuritic chest pain and
endocarditis. The gram staining of sputum revealed gram +ve bacteria. What is the most likely pathogen:
a. Streptococcus pneumonia d. Streptococcus pyogenes
b. H.influenza e. Klebsiella pneumonia
c. Staphylococcus aureus
A.
27. A 57 years old female present with a 3 week’s history of cough and Pleuritic chest pain. A chest
radiography reveals an ill-defined area of left lower lobe opacification. After a month of antibiotic
therapy, she is no better, and the radiographic lesion remains. A left lower lobe lung needle biopsy is
performed and shows lepidic pattern of growth of neoplastic cells. Which of the following best matches
the above description?
a. Adenocarcinoma d. Small cell carcinoma
b. Bronchial carcinoma e. Squamous cell carcinoma
c. Bronchoalveolar carcinoma
C.
28. A 40 years old nonsmoking male has had increasing cough with hemoptysis for 2 weeks. Bronchoscopy
reveals an obstructing mass filling the bronchus to the right lobe. Which of the following neoplasm is most
likely to be producing these finding?
a. Hamartoma d. Kaposi sarcoma
c. Large cell carcinoma
E.
227
29. A 70 year old female is referred to an ophthalmologist for right eye problem. The finding includes
enopthalmos, meiosis, anhidrosis and ptosis. She also has pain in the right upper chest region. A chest
radiograph reveals right upper lobe opacification along with bony destruction of the right first rib. Which
of the following conditions is she most likely to have?
a. Bronchopneumonia d. Sarcoidosis
b. Bronchiectasis e. Tuberculosis
c. Bronchogenic carcinoma
C.
30. Smoking cause all of the following tumors except:
a. Carcinoma larynx d. Acute leukemia
b. Bronchogenic carcinoma e. Carcinoma esophagus
c. Bladder carcinoma
D.
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KIDNEYS AND ITS COLLECTING SYSTEM
1. Azotemia associated with clinical signs and symptoms is termed as:

a. Acute nephritic syndrome d. Nephrotic syndrome
b. Uremia e. Nephrolithiasis
c. Chronic renal failure
B.
2. Genetic mutations responsible for adult polycystic kidney disease
a. MSH and MLH 1 d. Rb
b. WT 1 and WT 2 e. t(9;22) (q34;q11)
c. PKD 1 and PKD 2
C.
3. A patient presents with hemoptysis and focal pulmonary consolidation. He later develops hematuria,
hypertension and oliguria. Renal biopsy shows linear immunofluorescence. What is the diagnosis:
a. Polyarthritis nodosa c. Wegener’s granulomatosis
b. Acute post streptococcal d. Tuberculosis
glomerulonephritis e. Goodpasture’s syndrome
E.
4. A 2 year old child present with massive generalized edema. Urinalysis shows proteinuria>3.5g/day and
lipiduria. The child responds well to corticosteroid treatment. What is the most probable diagnosis:
a. Focal segmental GS d. Minimal change disease
b. Membranous nephropathy e. IgA nephropathy
c. Alport syndrome
D.
5. A woman with a long history of migraine headache present to O.P.D with anemia, epigastric pain and
hypertension. She also complains of hematuria. Renal biopsy shows papillary necrosis and cortical
tubulointerstitial nephritis. The most probable cause is:
a. Analgesic nephropathy d. Acute tubular necrosis
b. Urate nephropathy e. Nephrolithiasis
c. Chronic pyelonephritis
A.
6. 2 weeks after recovery from a severe bout of pharyngitis, an 11 year old girl is seen with periorbital
edema, hematuria, malaise, nausea and headache. Which of the following finding is expected?
a. Hypotension d. Polyuria
b. Increased Antistreptolysin O titer e. Positive urine culture for β
(ASO) hemolytic streptococci
c. Masked hypoalbuminemia
B.
7. A 7 year old child presents with hypoalbuminemia, edema, hyperlipidemia, and proteinuria, the edema is
in the periorbital region initially and eventually spreads to the rest of the body. The patient is given
steroid therapy and the disease goes away. What is a key morphological feature of the patient’s disease?
a. Fusion of the foot processes d. Hemosiderin laden macrophages in
b. Destruction of the basement the kidney
membrane e. None of the above
c. Destruction of the glomerulus
A.
229
8. A child after a strep infection presents 10 days later with hypertension, hematuria, edema, and sometime
oliguria. There appears to be elevated titers of anti-streptolysin O antibodies. What is a key morphological
feature of his disease?
a. Spike and dome appearance d. Rupture in glomerular basement
b. Humps membrane
c. Deposition of Ig G and C3 e. B and C
E.
9. A patient presents with hematuria, proteinuria on urine analysis, edema and recurrent episodes of gross
hematuria. C3 levels are low and examination of the basement membrane reveals thickening of the
glomerular loop or tram-tracking. He is diagnosed with the type 1 of MPGN. Electron dense deposition is
most commonly seen in:
a. The subendothelial area d. The loop of henle
b. Glomerular basement membrane e. None of the above
c. Mesangium
A.
10. A cause of nephritic syndrome in children and adolescents, as well as an important cause of kidney failure
in adult. On biopsy only some of the glomeruli are involved, only part of entire glomerulus is involved and
there is scarring of the glomerulus.
a. Cryoglobulinaemia c. Mesangiocapillary
b. Focal segmental glomerulonephritis
glomerulosclerosis d. Wegener’s granulomatosis
e. Goodpasture’s syndrome
B.
11. Renal failure is typically detected by an elevated serum:
a. ALT d. AST
b. Albumin e. ALP
c. Creatinine
C.
12. Which of the following is not post renal cause of acute renal failure?
a. Benign prostatic hyperplasia d. Congestive heart failure
b. Urethra obstruction e. Urolithiasis
c. Prostatic cancer
D.
13. An autoimmune disease predominantly affecting the nasal passages, lungs, and kidneys characterized by
granuloma formation in addition to arteritis. Untreated the disease is usually fatal, but it can be controlled
(sometime for year) with steroids, cyclophosphamide, and azathioprine.
a. Henoch-schonlein purpura d. Wegener’s granulomatosis
b. Post-streptococcal GN e. SLE
c. Goodpasture’s syndrome
D.
14. What is the most common bacterial cause of glomerulonephritis?
a. Streptococci d. Treponema pallidum
b. Diplococcic e. Staphylococci
c. Salmonella typhi
A.
230
15. A form of acute glomerulonephritis that result in damage within the glomerulus of the kidney. There is
rapid loss of kidney function with the formation of crescents on microscopic analysis (kidney biopsy). This
disorder may result in acute glomerulonephritis or Nephrotic syndrome, but ultimately results in renal
failure and end-stage disease.
a. Crescentric glomerulonephritis d. Anti-GBM disease
b. Membranous glomerulonephritis e. Focal segmental
c. Membranoproliferative glomerulonephritis
glomerulonephritis
A.
16. A 12 year old boy is member of a family with a history of renal disease, with males more severely affected
then females. He is found to have auditory nerve deafness, corneal dystrophy, and ocular lens dislocation.
A urinalysis shows microscopic hematuria. A renal biopsy is performed. Microscopically, the glomeruli
show glomerular capillaries with irregular basement membrane thickening and attention with splitting of
the lamina densa. The mesangial matrix is increased and epithelial cells may appear foamy. Which of the
following is the most likely diagnosis?
a. Goodpasture’s syndrome d. Dominant polycystic kidney
b. Ig A nephropathy disease
c. Alport syndrome e. Diabetes mellitus type 1
C.
17. A 2 year old child is brought to OPD with complains of huge, palpable mass in right flank. The mother also
complains of blood in the child’s urine, and delayed milestone achievement. The most probable diagnosis
is:
a. Hydronephrosis d. Nephrotic syndrome
b. Wilm’s tumor e. Acute tubular necrosis
c. Renal cell carcinoma
B.
18. 30 year old man present with fever, chill, flank pain radiating to groin. X-ray KUB is performed which
shows huge “staghorn” calculi bilaterally. What is the causative organism:
a. Proteus mirabilis d. Chlamydia
b. Streptococcus e. Enterococcus
c. E.coli
A.
19. Two weeks after taking a course of sulfonamide drugs, patient presents to you with complains of fever,
rash, blood in urine. Serum creatinine and blood urea nitrogen (BUN) are elevated. Urine R/E shows
pyuria mostly eosinophil’s. The most likely diagnosis is:
a. Acute pyelonephritis d. Acute tubular necrosis
b. Renal cell carcinoma e. Cystitis
c. Drug induced tubule interstitial
nephritis
C.
20. Which of the following is the cause of post renal azotemia?
a. BPH d. RPGN
b. Renal artery stenosis e. Hemolytic anemia
c. Shock
A.
21. A 30 year old woman on second post-partum day with a history of post-partum hemorrhage present to
OPD with oliguria, edema and raised serum creatinine and BUN. Urine R/E shows granular muddy, brown
casts. The most probable diagnosis is:
a. Acute tubular necrosis d. Transitional cell carcinoma
b. Drug induced interstitial nephritis e. Hydronephrosis
c. Pyelonephritis
A.
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22. The most common autosomal dominant mutation in polycystic kidney disease involves which of the
following gene:
a. PKD1 d. Von Hippel Lindu gene
b. PKHD1 e. MET proto oncogene
c. WT1
A.
23. A 13 year old boy present with edema, hyperlipidemia, massive proteinuria>3.5g/day. Urine R/E shows
fatty casts. The patient is diagnosed as membranous nephropathy. What is the characteristic
histopathological finding?
a. Formation of crescents d. Kimmelstiel Wilson lesion
b. Effacement of foot processes e. Spike and dome appearance with
c. Focal segmental glomerulosclerosis sub epithelial deposits
E.
24. A 30 years old married female present with fever, chills and costovertebral angle tenderness and dysuria.
Urine R/E shows pus cells in white cell casts. What is the most probable diagnosis?
a. Nephrotic syndrome d. Acute tubular necrosis
b. Nephritic syndrome e. Renal cell carcinoma
c. Acute pyelonephritis
C.
25. A 50 year old male, chronic smoker with history of working with aniline dyes present with painless
hematuria and palpable flank mass and low grade fever. The most probable diagnosis is:
a. Nephrotic syndrome d. Pyelonephritis
b. Nephritic syndrome e. Renal cell carcinoma
c. Wilm’s tumor
E.
26. A 40 year old male presents with fever, chills, right flank pain radiating to the groin. Urine R/E shows
hematuria and calcium oxalate crystals. What is the most probable predisposing factor?
a. UTI due to proteus d. Xanthinuria
b. Gout e. Hypercalcemia
c. Cystinuria
E.
27. Urinalysis result includes proteinuria, many red cells and red blood cells casts, and 1-2 white blood cells
per high power field. Which of the following disease best fits with these finding?
a. Acute cystitis d. Acute post streptococcal
b. Acute pyelonephritis glomerulonephritis
c. Chronic pyelonephritis e. Minimal change disease
D.
28. The commonest variety of renal cell carcinoma is:
a. Papillary carcinoma d. Wilm’s tumor
b. Clear cell carcinoma e. Polycystic kidney
c. Chromophobe renal carcinoma
B.
29. A patient present with proteinuria, edema, and symptoms of renal insufficiency. There appears to be
nodular hyaline masses in the glomerulus of the kidney. Tests indicate that the kidney has enlarged. The
disease with the most similar presentation would be?
a. Diabetic nephropathy d. Membranoproliferative
b. IgA nephropathy glomerulonephritis
c. Osteomyelitis e. Hydronephrosis
A.
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30. “Flea bitten” appearance of the kidney on gross examination is a feature of;
a. Ischemic acute tubular necrosis c. Benign nephrosclerosis
b. Nephrotoxic acute tubular d. Malignant nephrosclerosis
necrosis e. Acute pyelonephritis
D.
31. On immunofluorescence Berger’s disease is characterized by:
a. Granular deposits of C1q, C3, C4, c. Mesangial deposition of IgA, C3
and IgG and properdin
b. Linear deposits of C3, C4, and IgG d. Granular deposits of IgG and C3
C.
32. “Double contour” or “tram track appearance” is characteristic feature of;
a. IgA nephropathy d. Focal segmental
b. Minimal change disease glomerulosclerosis
c. Membranoproliferative e. HIV-associated nephropathy
glomerulonephritis
C.
33. “Thyroidization “ is a characteristic feature of:
a. Acute pyelonephritis d. Tubulointerstitial nephritis
b. Acute tubular necrosis e. Nephrotoxic acute tubular necrosis
c. Chronic pyelonephritis
C.
34. The following statements regarding Wilm’s tumor are true except:
a. Most common primary renal d. The tumor is derived from
tumor in children mesonephric mesoderm
b. The tumor occurs between 2-5 e. The tumor contains abortive
years of age glomeruli and tubules, primitive
c. The genetic type of the tumor is blastema cells and
known as the most common one rhabdomyoblasts
C.
35. The following statement regarding acute tubular necrosis (ATN) are true except:
a. ATN is the most common cause of d. In the nephrotoxic type of ATN,
ARF there is detachment of tubular
b. Ischemia damages tubular cells in cells into the lumen causing
ischemic ATN abortion
c. The ischemic ATN is most often e. Net effect of ATN is oliguria
caused by prerenal azotemia due
to hypovolemia
D.
36. Which of the following glomerular disorders is not apparently immunologically mediated:
a. SLE glomerulopathy d. Diabetic nephropathy
b. Post streptococcal GN e. RP glomerulonephritis
c. Allergic purpura
D.
37. A 12 year old boy with septicemia develops hematuria, HTN and oliguria. Microscopic examinations
reveals enlarge glomeruli with diffuse mesangial and endothelial hypercellularity. The best Diagnosis is:
a. Acute cortical necrosis d. Rapidly progressive GN
b. Acute proliferative GN e. Diabetic glomerulosclerosis
c. Membranoproliferative GN
C.
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38. Membranous glomerulopathy and post streptococcal GN are similar in that they both:
a. Are self-limiting and transient renal d. Have glomerular immune complex
disease deposits
b. Are commonly associated with e. Occur most frequently following an
Nephrotic syndrome infection disease.
c. Are most commonly seen in
children
D.
39. Deposition of IgG in or on the glomerular BM can be seen in all of the following except:
a. Acute post streptococcal GN d. Goodpasture’s syndrome
b. Minimal change disease e. Membranous nephropathy
c. SLE glomerulonephritis
B.
40. Following risk factors for renal cell carcinoma are true except:
a. Smoking d. Obesity, asbestos exposure,
b. Von Hippel Lindau disease exposure to lead
c. Adult polycystic kidney disease e. Chronic renal failure (CRF)
E.
41. Nephrotic syndrome is characterized by:
a. Hematuria, HTN, proteinuria d. Pyuria, oliguria, hematuria
b. Hematuria, HTN, azotemia e. Proteinuria, edema,
c. Bacteruria, azotemia, HTN hyperlipidemia
E.
42. 60 year old male patient present with hematuria, abdominal mass, weight loss and fever. All of the
following statements are true except:
a. CT scan and U/S revealed renal c. Nephrectomy revealed a bright
mass yellow mass in upper pole of
b. Gross morphology of the mass was kidney
reported as malignant tumor of d. Histologically it was reported as
kidney renal cell carcinoma
e. Histologically it was reported as
squamous cell carcinoma
E.
43. The majority of patients with acute post streptococcal glomerulonephritis(GN) :
a. Die from CHF in few weeks d. Progress through subacute phase
b. Die from renal failure in a few to chronic GN
weeks e. Recover completely
c. Pass through a latent period but
eventually develop chronic GN
E.
44. Necrotizing papillitis is associated with:
a. Acute glomerulonephritis d. Membranous nephropathy
b. Arteriolar nephrosclerosis e. Toxemia of pregnancy
c. Diabetic mellitus
C.
45. The Nephrotic syndrome is characterized by all of the following except:
a. Generalized edema d. Hypoproteinemia
b. Hematuria e. Hyperlipidemia
c. Proteinuria
B.
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46. A patient with hemoptysis and renal failure reveals Crescentric proliferative GN and linear deposits of IgG
and C3 on biopsy the Dx is :
a. Acute post infectious GN d. Membranous nephropathy
b. Goodpasture’s syndrome e. Minimal change disease
c. Acute pyelonephritis
B.
47. Red cell casts in the urine would be compatible with:
a. A transitional cell carcinoma of c. A foreign body in urinary bladder
renal pelvis d. Acute tubular necrosis
b. Anti GBM antibody induced renal e. A ureteral stone
lesion
B.
48. A renal disease characterized by presence of anti-glomerular basement membrane (GBM) antibodies is :
a. Goodpasture’s syndrome d. post streptococcal
b. Focal segmental glomerulonephritis
glomerulonephritis e. malignant nephrosclerosis
c. Minimal change disease
A.
49. which is the most characteristic feature in the urine sediment of patient with post streptococcal GN:
a. Epithelial casts d. Marked proteinuria
b. WBC casts e. Highly selective proteinuria
c. RBC and casts
C.
50. In adult polycystic disease each of the following statement is true except:
a. The disease is familial d. Hematuria, HTN and palpable
b. The renal involvement is abdominal masses are frequent
predominantly unilateral clinical finding
c. The disease is generally e. Autosomal Dominant
symptomatic until adult or middle
life
B.
51. A 50 year old male develops acute renal failure (ARF) with dark urine one week after flu like illness. Renal
biopsy is likely to reveal:
a. Renal infarction d. Acute tubular necrosis
b. Amyloidosis e. Myeloma kidney
c. Crescentric GN
C.
52. The most common appearance of glomeruli in adult with Nephrotic syndrome is :
a. Proliferative GN d. Membranous GN
b. Rapidly progressive GN e. Normal appearing glomeruli
c. Tram- track
D.
53. The organism most frequently implicated as the cause of acute pyelonephritis is:
a. Pseudomonas species d. Streptococcus fecalis
b. β -hemolytic streptococci e. Proteus species
c. E.coli
E.
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54. The Nephrotic syndrome is primarily due to :

a. Diabetic Glomerulosclerosis c. Increased permeability of
b. Toxic necrosis of renal tubular glomerular filtration barrier
epithelium d. Post streptococcal infection
e. Narrowing of afferent arteriole
C.
55. Effacement of foot process with normal glomeruli is associated with:
a. Minimal changed disease d. Membranous glomerulopathy
b. Diabetes mellitus e. Post streptococcal GN
c. Membranoproliferative GN
A.
56. Each of the following features are characteristic of the Nephrotic syndrome except:
a. Marked proteinuria d. Hypertension
b. Hypoalbuminemia e. Hypercholesterolemia
c. Edema
D.
57. The primary anatomic site of pressure regulation in the vascular system is:
a. Aorta d. Capillaries
b. Arteries e. Heart
c. Arterioles
C.
58. A histopathological glomerular lesion which when present, strongly suggest diabetes mellitus is:
a. Absence of foot processes as the c. Linear IgG and C3 on
only EM finding immunofluorescence
b. Extensive crescent formation d. Splitting of basement membrane
e. Nodular glomerulosclerosis
E.
59. Histological finding of foamy macrophages with occasional multinucleated giant cell and foamy
macrophages characterized which form of cystitis:
a. Hemorrhagic cystitis
b. Suppurative cystitis
c. Malakoplakia
d. Interstitial cystitis
e. Polypoid cystitis
C.
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FEMALE GENITAL SYSTEM
1. The Stein-Leventhal syndrome is characterized by each of the following except:

a. Many corpora luteal present in the c. Hirsutism
ovaries d. Secondary infertility
b. Obesity e. Menstrual irregularity
A.
2. Ultrasound examination of an 8 year old girl with precocious puberty reveals a 5cm firm, smooth right
ovarian mass. She most likely has a:
a. Dermoid cyst of the ovary d. Fibroma of ovary
b. Cystadenocarcinoma of the ovary e. Teratoma of the ovary
c. Granulose cell tumor
C.
3. Krukenburg’s tumor is bilateral metastatic tumor from the following primary sites except:
a. Stomach d. Appendix
b. Endometrium e. Duodenum
c. Colon
B.
4. The most common germ cell tumor of the ovary is :
a. Dysgerminoma d. Yolk sac tumor
b. Immature Teratoma e. Endodermal sinus tumor
c. Benign Teratoma
C.
5. A painless breast lump suggests each of the following except:
a. Mastitis d. Intraductal papilloma
b. Fibrocystic disease e. Paget’s disease of the breast
c. Fibroadenoma
A.
6. Which one of the following lesions usually presents as a discrete, freely movable nodule in the breast?
a. Sclerosing adenosis d. Fibroadenoma
b. Cystic disease e. Paget’s disease
c. Ductal carcinoma
D.
7. All of the following are associated with an increased risk of breast cancer except:
a. A previous mastectomy for cancer d. Increased age beyond 50 years
b. A maternal history of breast cancer e. Positive of BRCA 1 gene
c. Breast feeding
C.
8. The breast carcinoma with the worst prognosis is:
a. Infiltrating ductal carcinoma d. Papillary carcinoma
b. Medullary carcinoma e. Ductal carcinoma in situ
c. Mucinous carcinoma
A.
9. The most common clinical presentation of Intraductal papilloma is :
a. A painful lump d. Microcalcification in mammograms
b. A painless lump e. Eczematous lesion of the nipple
c. A bloody nipple discharge
C.
237
10. Each of the following is predominantly a postmenopausal condition except:

a. Sarcoma botryoides of the vagina d. Squamous cell carcinoma of the
b. Squamous epithelial hyperplasia vulva
c. Paget’s disease of the vulva e. Squamous cell carcinoma of vagina
A.
11. Adenomyosis is best regarded as a:
a. Complication of oral contraceptive d. Benign neoplasm
use e. Myometrial extension of stratum
b. Sequel of incomplete abortion basalis
c. Premalignant uterine lesion
E.
12. The ovarian tumor most likely to have a virilizing effect is :
a. Sertoli- Leydig cell tumor d. Dysgerminoma
b. Brenner tumor e. Luteoma
c. Cystadenoma
A.
13. The most frequent ovarian cyst is :
a. Follicular cyst d. Dysgerminoma
b. Serous Cystadenoma e. Cystic Teratoma
c. Mucinous Cystadenoma
A.
14. Which of the following uterine lesion carries the greatest risk for development of adenocarcinoma of the
endometrium?
a. Submucosal leiomyoma d. Cystic endometrial hyperplasia
b. Endometrial polyp e. Atypical endometrial hyperplasia
c. Adenomyosis
E.
15. Vaginal adenosis has been associated with:
a. Herpes genitalis virus infection d. Stein Leventhal syndrome with
b. In utero exposure to sterility
diethylstilbestrol e. Prolonged use of oral
c. Functional ovarian tumors with contraceptives
high estrogen levels
B.
16. Leiomyomas are least apt to:
a. Calcify d. Undergo infarction
b. Become malignant e. Form during the child bearing
c. Cause bleeding period of life
B.
17. A neoplasm of the female genital tract occurring in an 20 year old girl whose mother was treated with
diethylstilbestrol during the pregnancy is likely to be a :
a. Brenner cell tumor of ovary d. Adenocarcinoma of vagina
b. Teratoma of ovary e. Squamous cell carcinoma of vulva
c. Sarcoma botryoides of vagina
D.
18. A 30 year old female present with a painless, irregular firm to hard mass in her right breast she has history
of trauma to the breast. Excised mass consists of foci of necrotic fat cells surrounded by macrophages and
intense inflammatory reaction. What is the diagnosis?
a. Acute mastitis d. Fibroadenoma
b. Invasive carcinoma e. Lipoma
c. Fat necrosis
C.
238
19. Of the histological subtypes of breast carcinoma, which metastasize most frequently to peritoneum, retro
peritoneum and leptomeninges?
a. Invasive ductal carcinoma d. Medullary carcinoma
b. Lobular carcinoma e. Metaplastic carcinoma
c. Mucinous carcinoma
B.
20. Which lesion is more prone to develop in carcinoma breast:
a. Adenoma of nipple d. Fat necrosis
b. Mammary duct ectasia e. Granulomatous mastitis
c. Epithelial hyperplasia type
fibrocystic disease
C.
21. The most common carcinoma of breast is:
a. Mucinous carcinoma d. Metastasis from the underling lung
b. Infiltrating ductal carcinoma tissue
c. Medullary carcinoma e. None of the above
B.
22. The following is true about carcinoma of breast except:
a. Most cancers arise in the upper c. Most arise from the ductal
outer quadrant epithelium
b. Oral contraceptive increased the d. Positive family history
risk e. Viral infection
E.
23. The following risk factor is the most likely in a patient with breast carcinoma except:
a. Smoking d. Oral contraceptive
b. Obesity e. Outer quadrant of the breast
c. Family history of mother having
the same condition
E.
24. Most helpful investigation for breast lump is :
a. Mammography d. Needle aspiration biopsy
b. Computed tomography e. ductogram
c. Open biopsy
A.
25. Alveolar or tubular pattern of growth with papillary convolutions characterize which of the following
testicular neoplasm:
a. Choriocarcinoma d. Teratoma
b. Seminoma e. Yolk sac tumor
c. Embryonal carcinoma
E.
26. The most common histological variant of breast cancer:
a. Colloid carcinoma d. Medullary carcinoma
b. Paget’s disease e. Ductal invasive carcinoma
c. Lobular carcinoma
E.
239
27. In fibrocystic changes the most likely group of histological findings is:
a. Adenosis with atypical lining d. Papillary proliferation of ductal
epithelium epithelium with atypical
b. Apocrine metaplasia, cyst e. Proliferation of ducts surrounded
formation and fibrosis by dense fibrosis
c. Cystic formation inflammation and
carcinoma in situ
B.
28. If a patient is on oral contraceptives, estrogen will increased the risk of all except:
a. Breast carcinoma d. Thromboembolism
b. Vaginal carcinoma e. Endometrial carcinoma
c. Endometrial hyperplasia
B.
29. Which statement is not correct about endometrial carcinoma
a. Absolute increased in estrogen d. Is less common then cervical
b. Relative increased in estrogen cancer
c. Preceded by endometrial e. Is more common than cervical
hyperplasia cancer
E.
30. All of the following are germ cell tumors except:
a. Cystic Teratoma d. Choriocarcinoma
b. Stroma ovarii e. Clear cell carcinoma
c. Yolk sac tumor
E.
31. Correct statement about stage 2 carcinoma cervix is :
a. Carcinoma is limited to cervix d. Growth extends beyond cervix
b. Growth reaches pelvic wall e. Bladder is involved
c. Lower third of vagina is involved
D.
32. Which cancer is most common in external genitalia in females:
a. Malignant melanoma d. Paget’s disease
b. Adenocarcinoma e. Sweat gland carcinoma
C.
33. Which one of the following is germ cell tumor of ovary:
a. Endometrial tumor d. Granulose cell tumor
b. Fibroma e. Brenner tumor
c. Dysgerminoma
C.
34. Which one of the following is not a complication of pregnancy :
a. Hydatidiform mole d. Missed abortion
b. Abortion e. Endometrial carcinoma
c. Choriocarcinoma
E.
35. Which one the following lesion of the breast is precancerous:
a. Galactocele d. Breast abscess
b. Adenoma nipple e. Atypical hyperplasia
c. Fibroadenoma
E.
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36. All are germ cell tumor except:

a. Choriocarcinoma d. Struma ovarii
b. Dermoid cyst e. Brenner tumor
c. Yolk sac tumor
E.
37. About borderline serous Cystadenoma all are correct except:
a. Cyst has clear serous fluid d. Multilayering of epithelium
b. Small papillary processes are seen e. Invasion of underlying stroma seen
c. Cells are hyperchromatic
D.
38. Choriocarcinoma most commonly arises in :
a. Abortion d. Ectopic pregnancy
b. Hydatidiform mole e. Endometrial hyperplasia
c. Normal pregnancy
B.
39. Which one is not a germ cell tumor:
a. Dermoid cyst d. Embryonal carcinoma
b. Granulose cell tumor e. Yolk sac tumor
c. Dysgerminoma
B.
40. Which one of the following is the most common site for endometriosis:
a. Fallopian tube d. Appendix
b. Broad ligament e. Cervix
c. Ovary
C.
41. Which one is not a surface epithelium tumor:
a. Serous Cystadenoma d. Clear cell carcinoma
b. Endometrioid tumor e. Dysgerminoma
E.
42. Fetal parts can be seen in one of following:
a. Complete mole d. Hydatidiform mole
b. Partial mole e. Invasive mole
c. Choriocarcinoma
B.
43. Most common site of metastasis of choriocarcinoma
a. Brain d. Kidney
b. Liver e. Thyroid
c. Lungs
C.
44. About carcinoma endometrium all are correct except:
a. Causative agent is estrogen d. Preceded by endometrial
b. Occurs in older women hyperplasia
c. May be associated with ovarian e. Progesterone is causative agent
tumors
E.
241
45. A 52 year old women presenting with spotting per vaginum undergoes cervical biopsy. Histopathological
examination reveals diffuse atypia of squamous epithelium with complete lack of maturation in all layers
and no surface maturation. Basement membrane is intact. What is your diagnosis?
a. CIN I d. Normal squamous metaplasia
b. CIN II e. Invasive squamous metaplasia
c. CIN III
C.
46. Endometrial hyperplasia is linked to prolonged estrogen stimulation of the endometrium by anovulation
or increased estrogen production is the forerunner of:
a. Poorly differentiated endometrial c. Well differentiated endometrial
carcinoma carcinoma
b. Moderately differentiated d. All endometrioid endometrial
endometrial carcinoma carcinoma
e. Serous endometrial carcinoma
D.
47. A woman aged 38 had left side ovarian growth, underwent surgery. Biopsy specimen reveals on gross, a
spherical cystic growth (8cm) in diameter, with smooth and glistening serosal covering was diagnosed
SEROUS CYSTADENOMA. What is the associated microscopic morphology:
a. Cyst lined by transitional d. Cyst lined by columnar epithelium
epithelium with abundant cilia
b. Solid tumor composed of nests of e. Cyst lined by columnar epithelium
transitional cells without mucin or cilia
c. Cyst lined by stratified squamous
epithelium
D.
48. A 45 year old female diagnosed as squamous cell carcinoma of cervix with past history of multiple sexual
partners. Which one of the following virus DNA is most likely to be detected in the tumor biopsy material?
a. HPV 16 d. HSV type l
b. HPV 6 e. HSV type ll
c. EBV
A.
49. Ovarian cystectomy specimen filled with thick chocolate colored fluid. Morphological examination of cyst
wall show marked hemorrhage, with endometrial glands and stroma along with hemosiderin-laden
macrophages. What is the diagnosis?
a. Mucinous cyst adenoma d. Hemangioma
b. Serous cyst adenoma e. Endometrial carcinoma
c. Endometriotic cyst
C.
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MALE GENITAL SYSTEM
1. The most radiosensitive testicular tumor is:

a. Embryonal carcinoma d. Yolk sac tumor
b. Seminoma e. Choriocarcinoma
c. Teratoma
B.
2. The most common testicular tumor in infants is :
a. Seminoma d. Embryonal carcinoma
b. Spermatocytic seminoma e. Sex cord stromal tumor
c. Yolk sac tumor
C.
3. A more specific marker for diagnosis of carcinoma prostate is :
a. PSA d. Immunoperoxidase
b. Free PSA e. Serum amylase
c. Acid phosphates
A.
4. The commonest cause of testicular atrophy is :
a. Atherosclerotic narrowing of blood c. Mumps
supply in old age d. Hypopituitarism
b. Klinefelter syndrome e. Irradiation
A.
5. The commonest type of undescended testes depending upon level of testicular arrest is:
a. Abdominal d. Lower scrotal
b. Inguinal e. Mid abdominal
c. Upper scrotal
C.
6. The hormone involved in the development of nodular hyperplasia of prostate is:
a. Enterotoxin secreted by vibrio d. Salmonella infection
cholera e. Bacterial overgrowth in small
b. Reduced small intestinal surface intestine
c. Disaccharide deficiency
A.
7. All of the following features characterized nodular hyperplasia of prostate except:
a. Crowding of the glands d. Increased nodularity
b. Papillary projection e. Small irregular glands lying back to
c. Corpora amylacea back
E.
8. The most important factor involved in the causation of transitional cell carcinoma is:
a. Cigarette smoking d. Radiation
b. Exposure to arylamines e. Cyclophosphamide
c. Schistosoma haematobium
A.
9. Most of the prostate carcinoma arise in:
a. Central zone d. Transitional zone
b. Peripheral zone e. Region of anterior fibromuscular
c. Medial zone stroma.
B.
243
10. The most common neoplasm of the bladder accounting for 90% of the case is:
a. Squamous cell carcinoma d. Sarcoma
b. Mixed carcinoma e. Transitional cell carcinoma
c. Adenocarcinoma
E.
11. All of the following are intrinsic causes of ureteral obstruction except:
a. Calculi d. Neurogenic
b. Strictures e. Pregnancy
c. Tumors
E.
12. The most common cause of Hydronephrosis in infants and children is:
a. Double Ureter d. Ureteropelvic junction obstruction
b. Diverticula e. Megaloureter
c. Hydroureter
D.
13. Morphological features of classical seminoma include all except:
a. Large, uniform, seminoma cell d. Syncytiotrophoblastic cells
b. Tumor cells separated by fibrous e. Produce bulky masses up to 10
septa times in size of normal testis
c. Multinucleated giant cells
C.
14. A 27 year old man present with a testicular mass. The mass was diagnosed as yolk sac tumor. Which of
the following substance is most likely to be secreted by tumor cells?
a. Acid phosphatase d. PSA
b. Alpha fetoprotein e. HCG
c. Alkaline phosphatase
B.
15. Which of the following tumor marker is routinely performed in patients with prostate carcinoma?
a. CEA d. Alkaline phosphatase
b. PSA e. HCG
c. AFP
B.
16. A 55 year old man presents with painless hematuria. On cystoscopy a papillary mass is found in bladder.
Which of the following is a characteristic of this lesion?
a. Hematuria as a late complication d. Occurrence only in the bladder
b. Marked tendency to recur e. Distant metastasis at the time of
c. More likely to be benign than diagnosis
malignant
B.
17. Nodular hyperplasia prostate originates in:
a. Transitional zone d. Periurethral zone
b. Central zone e. Capsule of prostate
c. Peripheral zone
D.
18. Alpha fetoprotein level is increased in which of the following tumor:
a. Choriocarcinoma d. Granulose cell tumor
b. Yolk sac tumor e. Brenner tumor
c. Theca cell tumor
B.
244
ORAL CAVITY AND GASTROINTESTINAL TRACT
1. A 25-year-old man had been experiencing intermittent diarrhea which, over year progress to severe
diarrhea, alternating with constipation, rectal bleeding, and passage of mucus. On physical examination,
the abdomen is tender over the left iliac fossa. Stool examination fails to reveal parasites. Colonoscopy
demonstrates inflammation limited to the rectum continuous with the colon and no skip lesions. Which of
the following is the most likely diagnosis?
a. Celiac disease d. Tropical sprue
b. Crohn disease e. Ulcerative colitis
c. Hirschprung disease
E.
2. A 65 year old man develops peri-umbilical pain which then shifted to the right iliac fossa. On physical
examination, his temperature is 38 C rectally and rebound tenderness in right iliac fossa is positive. Which
of the following is the most likely diagnosis?
a. Acute appendicitis d. Pancreatitis
b. Diverticulitis e. Pyelonephritis
c. Hemorrhoids
A.
3. A 57 year old woman with anemia is found to have a decreased vitamin B12 level. Antibodies to intrinsic
factor are identified. Levels of all other vitamins are within normal limits. Which of the following is most
likely to be associated with this condition?
a. Duodenal ulcer d. Autoimmune gastritis
b. Ulcerative colitis e. Angiodysplasia
c. Dietary vit.B12 deficiency
D.
4. A 65 year old man presents to physician because of a palpable mass immediately above the left clavicle
(Virchow’s node). Biopsy of the mass demonstrates metastatic adenocarcinoma in a lymph node. Which
of the following organs should be the most strongly suspected as containing the primary tumor?
a. Bladder d. Stomach
b. Large bowel e. Pancreas
c. Liver
D.
5. What is the other name for Aphthous ulcer?
a. Leukoplakia d. Canker sore
b. Erythroplakia e. Oral candidiasis
c. Bed sore
D.
6. A 51 year old male diagnosed with decompensated chronic liver disease, suddenly starts vomiting blood
and eventually loses consciousness. His wife finds him lying on the bedroom floor. He has no prior history
of hematemesis, bleeding diathesis and had not been vomiting prior to the appearance of the blood.
Which of the following is the most likely cause of this man’s presentation?
a. Achalasia d. Plummer vinson syndrome
b. Esophageal varices e. Zenker’s diverticulum
c. Mallory Weiss tear
B.
245
7. Exploratory laparotomy of a patient with an acute abdomen demonstrates a several foot long loop of
small intestine with a dark red-to-brown, edematous appearance. The patient has history of atrial
fibrillation. The lesion ends abruptly on both the distal and proximal edges. Which of the following
diagnosis is suggested by this appearance?
a. Adenocarcinoma d. Ischemic bowel disease
b. Crohn’s disease e. Tuberculosis
c. Ulcerative colitis
B.
8. A 60 year old man presents to his physician because of progressive dysphagia, first to solids and then to
liquids. Endoscopy reveals a large Fungating mass 2cm above the Gastroesophageal junction. Biopsy of
the mass shows that the glands have extended into muscular layer and contain large hyperchromatic
nuclei. A diagnosis of esophageal adenocarcinoma is made. Which of the following conditions can result in
the development of this lesion?
a. Esophageal rings d. Scleroderma
b. Esophageal webs e. Sliding hiatal hernia
c. GERD
C.
9. A 32 year old women presents with complaints of several months of burning substernal chest pain
exacerbated by large meals, cigarettes and caffeine. Her symptoms are worse when she lies on her back,
especially while sleeping at night. Antacids often improve her symptoms. This patient is at risk for which
of the following condition?
a. Cardiac ischemia d. Leiomyoma of the esophagus
b. Columnar metaplasia of distal e. Mallory Weiss lesion in the
esophagus esophagus
c. Esophageal web
B.
10. A patient develops anemia and weight loss and slight abdominal discomfort. On questioning, the patient
is a known case of chronic gastritis. Which of the following type of malignancy is most strongly associated
with this patient’s condition?
a. Gastric lymphoma d. Squamous type of esophageal
b. Intestinal type of gastric carcinoma
adenocarcinoma e. Adenocarcinoma of esophagus
c. GIST
B.
11. A patient present to a physician complaining of recurrent episodic diarrhea, triggered by eating too much
or drinking alcohol. His wife state that “he turns as red as a beet and start wheezing” during these
episodes. Which of the following would be the most likely cause of his symptoms?
a. Carcinoid tumor d. Adenocarcinoma stomach
b. Primary TB e. Superior vena cava syndrome
c. Recurrent TB
A.
12. A 10 year old boy complains of intermittent abdominal pain. Endoscopy fails to demonstrate peptic ulcer
or chronic gastritis. The clinician suspects that the patient may have a heterotopic rest of gastric mucosa
that is producing enough acid to cause ulceration of adjacent mucosa. Which of the following is the most
likely diagnosis?
a. Ectopic pancreatic tissue d. Appendicitis
b. Meckel’s diverticulum e. Cancer of the cecum
c. False diverticulum
A.
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13. A 65 year old man present to a physician because of a palpable mass immediately above the left clavicle
(Virchow’s node). Biopsy of the mass demonstrates metastatic adenocarcinoma in a lymph node. Which
of the following organs should be most strongly suspected as containing the primary tumor?
a. Bladder d. stomach
b. Large bowel e. pancreas
c. Liver
D.
14. Major site of peptic ulcer is:
a. Ileum d. Pancreas
b. Duodenum e. Cecum
c. Esophagus
B.
15. Inflammatory bowel disease are associated with:
a. Viruses d. Psycho-somatic factors
b. Immune disorders e. Elderly age
c. Refined diet
B.
16. The granulomas of crohns’s disease are differentiated from granulomas of tuberculosis due to :
a. Presence of caseation d. Presence of lymphocytes
b. Absence of caseation e. Presence of epithelioid cell
c. Presence of giant cells
B.
17. Which of the following is a major predisposing factor for the development of pseudomembranous colitis?
a. Young age d. Refined diet
b. Malnutrition e. Obesity
c. Antibiotic use
C.
18. A 6 year old boy presents with abdominal pain and vomiting. The pain first started in the peri umbilical
region and then shifted to the right lower quadrant. His temperature is 102F and pulse is 110/mint. A
laparotomy is performed and his appendix is removed. What will be observed if the appendix is examined
by the histopathologist?
a. Lymphocytic infiltration d. Perforation of the appendix
b. Necrosis e. Adhesion
c. Neutrophilic infiltrate in muscularis
propria
C.
19. A 42 year old man presents in OPD with the complaints of passage of abnormally bulky, frothy, greasy,
yellow stools for 3 days accompanied by weight loss, anorexia, abdominal distention and flatus. On biopsy
small intestine was found to be laden with distended macrophages in the lamina propria. What is the
most likely diagnosis?
a. Whipples disease d. Giardiasis
b. Tropical sprue e. Cholera
c. Celiac disease
A.
20. Deep ulcers , marked lymphoid reaction, fibrosis, serositis, granuloma mass and fistulas are the features
of :
a. Ulcerative colitis d. Malabsorption syndrome
b. Crohn’s disease e. Colorectal carcinoma
c. Intestinal polyps
B.
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21. The most common colorectal carcinoma is :

a. Squamous carcinoma d. Adenocarcinoma
b. Basal cell carcinoma e. Mucinous carcinoma
c. Adenoma
D.
22. The most common fungal infection of oral cavity in immunocompromised individual is :
a. Thrush ( candidiasis) d. Mucormycosis
b. Blastomycosis e. Coccidioidomycosis
c. Histoplasmosis
A.
23. Secretory diarrhea is caused by:
a. Enterotoxin secreted by vibrio d. Reduced small intestinal surface
cholera e. Bacterial overgrowth in small
b. Disaccharide deficiency intestine
c. Salmonella infection
A.
24. Definitive diagnosis of celiac disease depends on:
a. History d. Detection of antibodies against
b. Intestinal biopsy tissue transglutamase
c. Clinical improvement on e. All of these
withdrawal of gluten from diet
E.
25. Hirschprung disease is characterized by:
a. Lack of Myenteric plexuses d. Lack of Auerbach and Meissners
b. Lack of Meissners plexuses plexuses
c. Death of ganglion cells e. Aganglionosis of the entire
intestinal tract
D.
26. Malabsorption syndrome is characterized by:
a. Defective absorption of fats d. Defective absorption of proteins
b. Defective absorption of e. Defective absorption of fats,
carbohydrates carbohydrates, water, minerals,
c. Defective absorption of water and proteins, vitamins, and electrolytes
minerals
E.
27. Prime culprit in inflammatory Bowel disease is:
a. CD 8+ T cells d. Excessive activation of TH2 cells
b. CD4+ T cells e. Activation of natural killer cells
c. Gamma interferon secreted by TH2
cells
B.
28. Malabsorption resulting from primary mucosal cell abnormality is due to:
a. Cystic fibrosis d. Crohn disease
b. Zollinger Ellison syndrome e. Tropical sprue
c. Abetalipoproteinemia
C.
29. Small intestinal biopsy of a child presenting with failure to thrive show sealloped or flattened mucosa,
marked villous atrophy, diffuse enteritis. The most likely histological diagnosis is:
a. Tropical sprue d. Celiac disease
b. Whipple disease e. Abetalipoproteinemia
c. Disaccharidase deficiency
D.
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30. Celiac disease results from:

a. Sensitivity to gluten d. Sensitivity to amino acids
b. Sensitivity to wheat e. Sensitivity to carbohydrates
c. Sensitivity to fats
A.
31. Meckel’s diverticulum is mostly located at:
a. Antimesenteric border of small intestine at ileocaecal valve
b. Antimesenteric border of small intestine within 85cm of ileocaecal valve
c. Mesenteric border of small intestine within one meter of ileocaecal valve
d. Along the outer border of transverse colon
e. Along the ascending colon near ileocaecal valve
B.
32. A young male complaining of abdominal pain and is passing frequent purulent bloody stools. The cause of
diarrhea is:
a. Rota virus infection d. E.coli infection
b. Shigella infection e. Giardia Lambia infection
c. Clostridium perfringes infection
B.
33. Ulcerative colitis is;
a. Chronic intestinal inflammation with formation of fissures
b. Chronic inflammation of affecting small intestine and a portion of colon
c. Ulceroinflammatory disease affecting colonic mucosa and submucosa
d. Inflammatory disease of colon with formation of non caseating granuloma
e. Ulceration of the rectal mucosa only
C.
34. A newborn male child diagnosed as case of Down’s syndrome presented with failure to pass meconium in
the immediate neonatal period followed by obstructive constipation. The most likely diagnosis:
a. Toxic megacolon d. Intestinal stenosis
b. Congenital Aganglionic Megacolon e. Imperforate anus
c. Chagas disease
B.
35. Secretory diarrhea is:
a. Isotonic with plasma d. Bloody purulent stool
b. Abates upon fasting e. More than 500ml of bloody stool
c. Less than 500ml of stool per day
A.
36. Idiopathic inflammatory bowel disease is:
a. Chronic inflammatory condition due to defective immune system
b. Chronic inflammatory condition due to persistent activation of immune system
c. Relapsing inflammatory disorder of unknown origin
d. Inflammatory disorder due to intestinal normal flora
e. Unregulated and exaggerated local immune response to commensal microbes in the gut in
genetically susceptible individuals.
E.
37. Crohn disease is characterized by:
a. Transmural inflammation with c. Mucosal ulceration, crypt abscess,
mucosal damage, fissuring, fistula pyloric metaplasia.
and non caseating granuloma d. Focal mucosal damage with non
b. Submucosal inflammation with caseating granuloma
skip lesions e. Mucosal ulceration, fissure and
fistulas
A.
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38. A 70 year old man endoscopic examination reveals a large Fungating mass above the Gastroesophageal
junction. Microscopic examination of mass shows that the anaplastic cells lining the glands extending into
muscular layer. A diagnosis of esophageal adenocarcinoma was made. Which of the following conditions
can result in the development of this lesion?
a. Reflux esophagitis d. Scleroderma
b. Esophageal webs e. Sliding hiatal hernia
c. Esophageal rings
A.
39. A 50 year old anemic female is found to have a decreased vitamins B12 level. Antibodies to intrinsic factor
are identified. Which of the following is the most likely to be associated with this condition?
a. Atrophic gastritis d. Duodenal ulcer
b. Angiodysplasia e. Ulcerative colitis
c. Dietary Vit.B12 deficiency
A.
40. A female of 50 year presents with a left supra-clavicle mass. Microscopic morphology of this mass reveal
metastatic adenocarcinoma in a lymph node.The primary tumor can arise from which of the following
organ?
a. Ovary d. Stomach
b. Large bowel e. Urinary bladder
c. Liver
D.
41. Barrets esophagus is a predisposing factor for what type of cancer:
a. Gastric carcinoma d. Squamous cell carcinoma
b. Adenocarcinoma e. Pancreatic cancer
c. Carcinoid
B.
42. Morphologic feature of classic lesion of crohns’s disease is;
a. Macrophages laden lamina c. Pseudopolyps
propria d. Flask shaped ulcer
b. Crypt abscess e. Skip lesion
E.
43. Morphological examination of colon reveals Deep ulcer, marked lymphoid reaction, fibrosis, serositis,
granulomas mass and fistulas are diagnosis of :
a. Colorectal carcinoma d. Intestinal polyposis
b. Crohns disease e. Ulcerative colitis
c. Malabsorption syndrome
B.
44. What type of colorectal carcinoma is frequently seen in colonic biopsy specimens :
a. Adenoma d. Mucinous carcinoma
b. Small cell carcinoma e. Adenocarcinoma
c. Squamous carcinoma
E.
45. What is the most important morphological criteria for the diagnosis of acute appendicitis:
a. Neutrophilic infiltration of c. Mucosal hypertrophy
muscularis propria d. Submucosal fibrosis
b. Fecolith in the lumen e. Cytological atypia
A.
46. Common form of oral candidiasis is;
a. Inflammatory d. Membranous
b. Erythematous e. Pseudomembranous
c. Hyperplastic
E.
250
47. Helicobacter pylori:

a. Is a gram positive rod d. Can be seen in tissue section with
b. Invades the gastric tissue Giemsa stain
c. Makes the gastric environment e. Is associated with autoimmune
more acidic gastritis
D.
48. Risk factor for oral cancer is:
a. Chronic use of smoking tobacco c. Jagged teeth
and alcohol d. Chronic infection
b. ill fitted dentures e. Hairy leukoplakia
A.
49. BARRET esophagus is:
a. Replacement of squamous c. Seen in young patient
epithelium by columnar d. Squamous cell CA is more
rd
epithelium in upper 1/3 of common
esophagus e. Is not a pre malignant condition
b. Columnar metaplasia of lower
rd
1/3 of esophagus
B.
50. A 44 year male presented with dysphagia and weight loss on endoscopy a Fungating ulcerative lesion is
noticed at a distance of 20cm from incisor teeth. The most likely lesion is:
a. Adenocarcinoma esophagus d. Esophageal webs
b. Carcinoma in situ e. Zenker’s diverticulum
c. Squamous cell carcinoma of
esophagus
C.
51. The intrinsic factor which plays an important role in absorption of vit B12 is secreted by :
a. Gastric parietal cells d. Upper jejunum
b. Gastric fundal cells e. Lower jejunum
c. Duodenum
A.
52. Leukoplakia is associated with:
a. Radiations d. Chronic oral ulcers
b. Spicy food e. ill fitted dentures
c. Smoking
C.
53. Peptic ulcer is produced by:
a. H.pylori invading mucosa c. Imbalance b/w gastric mucosal
b. H.pylori enhances HCO3 defense mechanism and damaging
production and impairs gastric acid forces
secretion. d. Hyperacidity is prerequisite
e. Psychological stress
C.
54. A chronic smoker and alcohol abuser old patient had a firm irregular growth on left lateral border of
tongue and hard lump in the neck on left side. The most likely diagnosis is:
a. Chronic inflammatory process with c. Squamous cell carcinoma of
lymphadenopathy tongue with distant metastasis
b. Squamous cell carcinoma of d. Squamous cell carcinoma of
tongue tongue with local metastasis
e. Adenocarcinoma of oral cavity
D.
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55. Severe autoimmune gastritis is associated with:

a. Destruction of mucus glands d. Chronic gastritis
b. Normal to high acid levels e. Antibodies to chief cells
c. Low gastric acid level to
achlorhydria
C.
56. Patient taking medication for R.A develops burning epigastric pain and vomiting after few days. Which of
the following forms of gastritis would most likely be found in this patient:
a. Acute gastritis d. Lymphocytic gastritis
b. Hypertrophic gastritis e. Chronic fundal gastritis
c. Chronic antral gastritis
A.
57. Reflux esophagitis is caused by:
a. Increased resting tone of lower c. Polypoidal growth in lower end of
esophageal sphincter esophagus
b. Defective esophageal anti-reflux d. Presence of esophageal webs
mechanism e. All of the above
E.
58. Chronic gastritis is defined as:
a. Chronic inflammation with c. Chronic inflammation of gastric
mucosal atrophy mucosa and submucosa
b. Chronic inflammation leading to d. Chronic inflammation of gastric
mucosal atrophy and intestinal mucosa of transient nature
metaplasia e. Chronic inflammation with erosive
gastritis
B.
59. Intestinal absorption of iron mostly occurs in form of :
a. Ferric iron d. Ferric hydroxide
b. Ferrous iron e. Ferritin
c. Ferrous phosphate
B.
60. About krukenberg tumor all are correct except:
a. Both ovaries are enlarged d. Always associated with ascites
b. Primary tumor is in breast e. Cells in ovaries are mucinous
c. Primary tumor is in biliary tract
C.
61. Regarding staging of tumor what is important:
a. Nuclear cytoplasmic ratio d. Local invasion
b. No. of mitotic figures e. Tumor giant cells
c. Pleomorphism
D.
62. Dentigerous cyst is:
a) Unilocular lesion around d) Multilocular teeth lesion at the
unerrupted impacted molar tooth apex of tooth with periapled
b) Unilocular lesion at the apex of any abscess
tooth e) All of the above
c) Unilocular lesion of the premolar
tooth
A.
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Essential Special
Essential Pathology
Special Pathology
LIVER, GALL BLADDER and BILIARY SYSTEM
1. A 45 year old man present with malaise, anorexia and vomiting to emergency room. The physician notices
slight jaundice. Blood examination shows marked elevation of ALT and AST with AST/ALT ratio being 2.5.
Alkaline is near normal. Serum copper and iron are normal. Histopathological reports show Mallory bodies
in hepatocytes. Liver damage from which of the following disease most likely account for these finding?
a. Biliary cirrhosis d. Hemochromatosis
b. Viral hepatitis e. Wilson’s disease
c. Alcoholic hepatitis
C.
2. During the pathogenesis of pancreatitis which enzyme after activation from its proenzyme from can
activate other enzymes and clotting, kinin and compliment systems?
a. Lipase d. Elastase
b. Phospholipase e. Alpha amylase
c. Trypsin
C.
3. Approximately 60% of pancreatic cancers arise in pancreatic:
a. Head d. Head and Tail
b. Body e. Tail and Body
c. Tail
A.
4. The commonest histological type of pancreatic cancer is:
a. Acinar cell carcinoma d. Ductal adenocarcinoma
b. Adenosquamous carcinoma e. Pancreatic adenoma
c. Undifferentiated carcinoma
D.
5. Obstructive jaundice is the feature of pancreatic carcinoma of:
a. Tail d. Tail and Body
b. Head e. Pancreatic neck
c. Body
B.
6. Malignant pancreatic neoplasm of tail are responsible for _ _ _ _ _ _ _ of pancreatic cancer.
a. 5% d. 20%
b. 10% e. 25%
c. 15%
A.
7. Two characteristic features of pancreatic cancer are:
a. Anaplasia and pleomorphism d. Highly invasive and desmoplastic
b. Increased mitotic figures and response
hyperchromatism e. Pleomorphism and invasiveness
c. Invasiveness and anaplasia
D.
8. Carrier state does not exist in:
a. HBV d. Delta virus
b. HAV e. HGV
c. HCV
B.
253
9. Spot the wrong statement about hepatitis antigens and antibodies:

a. Only anti HAV of IgM type is diagnostic of HAV infection, not IgG
b. HBsAg is a reliable marker of HBV infection
c. Anti HBV appears after 3-6 months and persists for many years
d. Anti HBc can diagnose HBV infection when HBsAg has disappeared and anti HBV has not
appeared
e. HBeAg positivity is of no significance.
E.
10. Pigment stones formation by intravascular hemolysis :
a. Occurs in bacterial infection by d. Increases solubility of free bilirubin
E.coli e. Is due to microprecipitates of
b. Occurs in migrating liver flukes inorganic or organic calcium salts
c. Cause reduced level of free
bilirubin
E.
11. Which of the following cirrhotic feature has no diagnostic value:
a. Hepatomegaly d. Palmar erythema
b. Jaundice e. Gynecomastia
c. Ascites
A.
12. The most common cause of chronic pancreatitis is :
a. Alcohol abuse d. Hereditary pancreatitis
b. Obstruction of pancreatic duct e. Cystic fibrosis
c. Tropical pancreatitis
A.
13. What is not true about Wilson’s disease:
a. There is failure in biliary copper excretion
b. Ceruloplasmin synthesis is decreased
c. Greenish brown copper deposit in corneal periphery (Kayser-Fleischer ring)
d. Hepatic disease only manifest in adult-hood
e. Recurrent acute hepatitis of unknown cause especially with hemolysis suggests Wilson’s disease
D.
14. In hepatitis B, the antigen indicating active viral replication is:
a. HBsAg d. Anti HBc
b. HBcAg e. Anti HBe
c. HBeAg
C.
15. The most severe form of acute pancreatitis is called:
a. Acute interstitial pancreatitis d. Hereditary pancreatitis
b. Hemorrhagic pancreatitis e. Tropical pancreatitis
c. Necrotizing pancreatitis
B.
16. A 45 days old infant developed symptoms and sign of acute liver failure. Child was found to be +ve for
HBsAg. The mother’s hepatitis B serological profile is likely to be :
a. HBsAg +ve only d. Mother infected with mutant HBV
b. HBsAg and HBeAg +ve e. HBc Ag Only
c. HBsAg and Anti HBeAg +ve
B.
254
17. In acute pancreatitis destruction of blood vessels leading to interstitial hemorrhage is by which of the
following enzyme:
a. Amylase d. Enterokinase
b. Phospholipase e. Elastase
c. Trypsin
E.
18. Which of the following oncogene is activated in the initial stages of progression of pancreatic
intraepithelial neoplasia to invasive carcinoma:
a. P53 d. K-RAS
b. SMAD4 e. P16
c. BRCA2
D.
19. Which serological marker of HBV (hepatitis B virus ) infection indicates recovery and immunity :
a. Viral DNA polymerase d. HBsAg
b. HBe antigen e. Anti HBc
c. Anti-HBs
C.
20. Cirrhosis accounts for portal hypertension in:
a. 90% cases d. 25% cases
b. 75% cases e. 10 % cases
c. 50% case
A.
21. The most common (85%) pancreatic neoplasm is:
a. Squamous cell CA d. Pancreatoblastoma
b. Ductal adenocarcinoma e. Solid pseudo papillary tumor
c. Mucinous Cystadenocarcinoma
B.
22. A 26 year old nurse developed fatigue, a low-grade fever, polyarthritis and urticaria. Two months earlier
she had cared for a patient with hepatitis. Which of the following findings are likely to be observed in this
nurse:
a. A negative hepatitis B surface c. A positive Rheumatoid Factor
antigen test d. A positive Monospot test
b. Elevated ALT and AST levels e. Reversal of A/G ratio
B.
23. 74% of the cysts in the pancreas are:
a. Congenital cysts d. Pseudocysts
b. Serous Cystadenoma e. Parasitic cysts
D.
24. Water is major mode of transmission of which type of viral hepatitis:
a. Hepatitis B d. Hepatitis E
b. Hepatitis C e. Hepatitis G
c. Hepatitis D
D.
25. Which of the following is risk factor for cholesterol stone:
a. Obesity d. Cystic fibrosis
b. High caloric diet e. Pregnancy
c. Chronic hemolysis
A.
255
26. Window period in hepatitis B is the interval between:

a. Disappearance of HBsAg and d. Disappearance of HBsAg and
appearance of Anti HBs appearance of Anti HBe
b. Appearance of HBcAg e. Appearance of Anti HBc IgG
c. Disappearance of HBcAg and
appearance of Anti HBc
A.
27. The classic antibody response pattern following infection with hepatitis A is:
a. Increased in IgM antibody; c. Detectable presence of IgM
decreased in IgM antibody; antibody only
increased in IgG antibody d. Decrease in IgM antibody;
b. Detectable presence of IgG increased in IgG antibody of the
antibody only IgG3 subtype
e. Decrease in anti HAV IgG
C.
28. The most commonly inactivated tumor suppressor gene (up to 95%) in pancreatic cancer is :
a. SMAD4 d. RB1
b. P53 e. MYB
c. P16
C.
29. The presence of HBs Ag, anti-HBe and often HBe Ag is characteristic of :
a. Early acute phase HBV d. Carrier state of HBV
b. Early convalescent Phase HBV e. Chronic liver disease due to HBV
c. Recovery phase of acute HBV
A.
30. A patient with cystic fibrosis is characteristically:
a. More than 45 years of age d. Subject to spontaneous fractures
b. Subject to recurring pulmonary infections e. Diabetic
c. Obese
B.
31. Which of the following best represents the histology of the pancreas in cystic fibrosis?
a. Atrophy of acini d. Enzymatic fat necrosis
b. Atrophy of islets e. Nodular hyperplasia
c. Chronic inflammatory cell infiltrate
A.
32. The Most frequent cause of death in cystic fibrosis is
a. Cirrhosis of the liver d. Meconium ileus
b. Diabetes mellitus e. Pulmonary infection
c. Malabsorption syndrome
E.
33. Acute pancreatitis is associated with:
a. Gallstones d. Neither
b. Excessive alcohol intake e. Typhoid fever
c. Both
C.
34. Each of the following is a pathologic feature of chronic pancreatitis except:
a. Atrophy of acini d. Islet cell hyperplasia
b. Diffuse fibrosis e. Squamous metaplasia of ducts
c. Focal Calcification
D.
256
35. The three most common predisposing factors to pancreatitis include:

a. Trauma, diabetes, alcoholism d. Alcoholism, trauma, gallstones
b. Gallstones, hypertension, trauma e. Infection, hypertension, diabetes
c. Diabetes, alcoholism, gallstones
D.
36. A 55-year-old man experienced severe epigastric and penetrating back pain following a cocktail party and
banquet. He was brought to the hospital in shock. Which of the following laboratory tests would be most
helpful in establishing the diagnosis early in the disease?
a. Cholecystogram d. Serum alkaline phosphatase
b. Upper gi series e. Serum amylase
c. Serum aspartate aminotransferase
E.
37. A 52-year-old female developed weight loss and an unrelenting back pain of 1 month duration. A mass
was palpable in the left upper quadrant. She developed migratory thrombophlebitis. The prognosis in this
case is best characterized as:
a. She has a normal life expectancy c. She will have a protracted course of one to
b. She is inoperable and will live on the 5 years
average 6 months or less d. She has a 5 year survival of 30%
e. She has more than 5 year survival of 30%
B.
38. Which enzyme is most implicated in the pathogenesis of hemorrhage in acute pancreatitis?
a. Alkaline phosphatase d. Phospholipase A
b. Amylase e. Trypsin
c. Elastase
C.
39. A 50 year old male develops intractable chronic peptic ulcer disease. He is found to have an elevated
serum gastrin level. The most likely diagnosis is:
a. Carcinoid syndrome d. Klatskin syndrome
b. Zollinger Ellison syndrome e. Peutz Jeghers syndrome
c. Gardner’s syndrome
B.
40. A 45-year-old white female complained of intermittent preprandial episodes of light headedness,
confusion, incoherent speech, sweating, and partial amnesia occurring three to four times a week. What
was the source of her symptoms?
a. Carcinoma of the pancreas d. Carcinoma of the adrenal
b. B-cell islet tumor of the pancreas e. Astrocytoma of the temporal lobe of the
c. Hyalinization of islet cells of the pancreas brain
B.
41. Pancreatic islet cell tumors may present with:

a. Duodenal ulcers d. Neither
b. Hypoglycemic episodes e. Hyperglycemia
c. Both
C.
42. Which of the following features is least characteristic of carcinoma of the head of the pancreas?
a. Jaundice d. Elevated serum amylase and lipase
b. Distended gallbladder e. Itching
c. Decreased urine urobilinogen
D.
257
43. The five-year survival rate for carcinoma of the pancreas is

a. 50—60% d. 5—10%
b. 30—50% e. under 5%
c. 10—30%
E.
44. A patient presents with recurrent attacks of hypoglycemia that seem to follow fasting or strenuous
exercise with relief of symptoms following glucose ingestion. The patient most likely has
a. Beta-cell adenoma of pancreatic c. Diabetes insipidus
islets d. Hemochromatosis
b. Carcinoma of the tail of the e. Alpha cell adenoma of pancreatic
pancreas islets
A.
45. Which of the following histological types of pancreatic tumor has a prognosis that is markedly at variance
from that of the others listed
a. Anaplastic large cell carcinoma d. Islet cell carcinoma
b. Adenocarcinoma e. Undifferentiated carcinoma
c. Ductal carcinoma
D.
46. Spontaneous venous thrombosis and migratory thrombophlebitis are associated with:
a. Chronic cholecystitis d. Islet cell tumor
b. Adenocarcinoma of the pancreas e. None of the above
c. Acute hemorrhagic pancreatitis
B.
47. Pancreatic pseudocysts usually occur in patients who have a history of
a. Cholelithiasis d. Diabetes mellitus
b. Pancreatitis e. Cystic fibrosis
c. Pancreatic carcinoma
B.
48. Chronic calcific pancreatitis is most often associated with:
a. Chronic alcoholism d. Diabetes mellitus
b. Acute alcoholism e. Cholelithiasis
c. Chronic gastritis
A.
49. The following is not a characteristic of cystic fibrosis:
a) Autosomal dominant heredity d) Bronchiectasis
b) Increased sweat chloride e) Pancreatic insufficiency.
c) Abnormally thick mucus
secretions throughout body
A.
50. Weight loss and abdominal discomfort is commonly found in:
a. Carcinoma of the tail of the c. Both
pancreas d. Neither
b. Chronic pancreatitis e. Inflammatory bowel disease
C.
51. The following is not a characteristic of cystic fibrosis:
a. Autosomal recessive d. Bronchiectasis
b. Decreased sweat chloride e. Pancreatic insufficiency
c. Abnormally thick mucus secretions
throughout the body
B.
258
ENDOCRINE SYSTEM
1. Causes of high prolactin level include all of the following except:

a. Prolactinoma d. Pregnancy
b. Dopamine agonists e. Haloperidol therapy
c. Craniopharygioma
B.
2. The multiple endocrine neoplasia syndrome may include all of the following neoplasms except:
a. Medullary carcinoma of thyroid d. Islet cell adenoma
b. Adrenal cortical carcinoma e. Pituitary adenoma
c. Pheochromocytoma
B.
3. Pathological fracture most typically occur with which of the following:
a. Pituitary adenoma d. Parathyroid adenoma
b. Adrenal adenoma e. Pheochromocytoma
c. Thyroid adenoma
D.
4. Diabetes insipidus is associated with a lack of :
a. Glucocorticoids d. Antidiuretic hormone
b. Insulin e. Growth hormone
c. Thyroid hormone
D.
5. All of the following may be manifestations of Sheehan’s syndrome except:
a. Hyperpigmentation of skin d. Hypothyroidism
b. Oligomenorrhoea e. Atrophy of breast and genitalia
c. Loss of axillary and pubic hair
A.
6. Changes in the thyroid gland in response to excess TSH stimulation include all of the following except:
a. Loss of colloid d. Scalloping margins of the colloid
b. Increased iodine uptake e. Papillae projecting into follicular
c. Decreased height of follicular lining lumen without fibro-vascular cores
cells
C.
7. A 36 year old woman noticed a painful enlargement of the thyroid gland approximately three weeks after
an upper respiratory infection. The history is most suggestive of which of the following finding on biopsy
of the thyroid?
a. Papillary structures with c. Multiple granulomata with giant
psammoma bodies cells
b. Polygonal to spindle shaped cells in d. Small follicles invading capsular
the form of nests, trabeculae blood vessels
e. Diffuse parenchymal fibrosis
C.
8. Which of the following thyroid carcinomas has the best prognosis?
a. Undifferentiated d. Giant cell
b. Follicular e. Papillary
c. Small cell
E.
259
9. All of the following are associated with hypersecretion of a hormone except:

a. Grave’s disease d. Cushing’s syndrome
b. Addison’s disease e. Prolactinoma
c. Conn’s syndrome
B.
10. Paroxysmal hypertension is most typically associated with:
a. Pituitary adenoma d. Parathyroid adenoma
b. Adrenal adenoma e. Pheochromocytoma
c. Thyroid adenoma
E.
11. Which of the following is the most common cause of Cushing’s syndrome?
a. Exogenous corticosteroids d. Basophilic adenoma of the
b. Adrenal cortical carcinoma pituitary
c. Oat cell carcinoma of the lung e. Adrenal adenomas
A.
12. Conn’s syndrome is associated primarily with an excess of:
a. Glucocorticoids d. Antidiuretic hormone
b. Mineralocorticoids e. Growth hormone
c. Thyroid hormone
B.
13. The most common cause of adrenocortical insufficiency is:
a. Waterhouse-Friderichsen c. Metastatic carcinoma
syndrome d. Panhypopituitarism
b. Abrupt withdrawal of e. Tuberculosis
adrenocorticosteroid therapy
B.
14. A 15 year old boy with no sexual maturation is found to have papilledema, an enlarged sella and fine
calcification above the sella on skull x-ray. The most likely diagnosis is:
a. Meningioma d. Craniopharyngioma
b. Adenoma of pituitary e. Tuberculosis meningitis
c. Cystic astrocytoma
D.
15. Patient with Hashimoto’s thyroiditis usually have:
a. Hyperthyroidism d. Circulating anti thyroglobulin
b. Abscesses in the thyroid tissue antibodies
c. Increased radioactive iodine e. Hyperplastic thyroid follicles
uptake
D.
16. Signs and symptoms of myxedema include all of the following except:
a. Slow mental processes d. Atrophy of the tongue
b. Weakness e. Coarsening of hair and facial
c. Intolerance of cold features
D.
17. Multi-nodular goiters may assume clinical importance for all of the following reasons except:
a. Cosmetic disfigurement c. Airway compression
b. Development of hyper functional d. Dysphagia
focus with thyrotoxicosis e. High frequency of malignancy
E.
260
18. Characteristic of medullary carcinoma of the thyroid include all of the following except:
a. Increased levels of calcitonin d. Multicentric C cell hyperplasia
b. Multicentric involvement e. No association with other
c. Polygonal to spindle shaped cells in neuroendocrine tumors
the form of nests, trabeculae
E.
19. Osteomalacia and kidney stones are characteristically associated with:
a. Gigantism d. Hyperparathyroidism
b. Pheochromocytoma e. Inappropriate ADH secretion
c. Acromegaly
D.
20. The most common cause of hypoparathyroidism is:
a. High phosphate diet in infancy d. Sarcoidosis
b. Aplasia of parathyroid e. Calcitonin-secreting tumor
c. Accidental surgical removal of
parathyroid at the time of
thyroidectomy
C.
21. The test of choice to monitor diabetes control over the preceding 02 months is to measure the level of:
a. Random plasma glucose d. Glycosylated serum albumin
b. Fasting plasma glucose e. Serum fructosamine
c. Glycosylated hemoglobin
C.
22. Which of the following laboratory test finding best distinguishes type 1 diabetes mellitus from other forms
of diabetes?
a. Elevated hemoglobin A1 level d. Decreased plasma insulin
b. Ketoacidosis concentration
c. Glucosuria e. Hyperglycemia
D.
23. The most significant factor that leads to the metabolic derangement seen in type 2 diabetes mellitus is:
a. Lack of 3 cells in islets of d. Overproduction of amylin protein
langerhans e. Development of autoantibodies to
b. Chronic renal failure insulin
c. Peripheral insulin resistance
C.
24. The main morphological lesions of Cushing syndrome are found in the :
a. Kidneys and pancreas d. Intestines
b. Adrenal glands e. Liver and bones
c. Pituitary and adrenal glands
C.
25. In Cushing syndrome the glucocorticoids induced effects mimic:
a. Diabetes Mellitus d. Malaria
b. Thyrotoxicosis e. Marfan syndrome
c. Rickets
A.
26. In 80 % of cases, the primary hyperaldosteronism is caused by an aldosterone secreting adenoma, called:
a. Cushing syndrome d. Addison disease
b. Conn syndrome e. Down syndrome
c. Adrenogenital syndrome
B.
261
27. Congenital adrenal hyperplasia is a group of autosomal recessive disorders, each characterized by a
hereditary defects in an enzyme involved in adrenal steroid biosynthesis, particularly:
a. Cortisol d. Estrogen
b. Aldosterone e. Glucagon
c. Thyroid hormone
A.
28. The commonest organ in both MEN -1 and MEN-2 is :
a. Thyroid gland d. Pituitary gland
b. Pancreas e. Adrenal medulla
c. Parathyroid gland
C.
29. The morphological changes seen in primary hyperparathyroidism include those in the parathyroid glands
and in other organs affected by elevated levels of:
a. Sodium d. Calcium
b. Potassium e. Lead
c. Zinc
D.
30. Persons with impaired glucose tolerance are at risk for:
a. Cardiovascular disease d. Liver disease
b. Renal disease e. Intestinal disease
c. Cerebral disease
A.
31. A common feature that all forms of diabetes mellitus share is:
a. Hypoglycemia d. Hypercalcemia
b. Hyperglycemia e. Hyper phosphatemia
c. Hypocalcaemia
B.
32. Which one of the following endocrinopathies is not associated with diabetes mellitus:
a. Conn syndrome d. Pheochromocytoma
b. Cushing syndrome e. Glucagonoma
c. Hyperthyroidism
A.
33. An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200mg/ dl or
greater 2 hours after a standard carbohydrates load of:
a. 50 mgs d. 125 mgs
b. 75 mgs e. 150 mgs
c. 100 mgs
B.
34. Biochemical finding of primary hypothyroidism are:
a. Normal TSH, decreased T3 and T4 d. Decreased TSH, decreased T3 and
b. Decreased TSH, increased T3 and T4
T4 e. Increased TSH and decreased T3
c. Decreased T3 and increased TSH and T4
E.
35. Following lipid related metabolic abnormalities are seen in Nephrotic syndrome:
a. Decreased cholesterol, c. Lipiduria
triglycerides, VLDL and LDL d. Decreased levels of apoproteins
b. Increased HDL e. Decreased levels of lipoproteins
C.
262
36. Autoimmunity in Grave’s disease lead to:

a. Nodular goiter d. Mild enlargement
b. Toxic adenoma e. No swelling at all
c. Diffused enlargement
C.
37. Target organ for prolactin is:
a. Ovary d. Thyroid
b. Breast e. Adrenal cortex
c. Testis
B.
38. Anti-Thyroid peroxidase (TPO) antibodies is diagnostic for:
a. Grave’s disease d. Hashimotos thyroiditis
b. Thyroid adenoma e. Hyperparathyroidism
c. Euthyroid
D.
st
39. What is 1 line single indicator of thyroid function:
a. Free T4 d. TSH
b. TBG e. TRH
c. T3
D.
40. Severe hypercalcemia can be due to :
a. Hyperparathyroidism d. Malignant disease
b. Sarcoidosis e. Increase calcium intake
c. Thyrotoxicosis
A.
41. 70-90 % of malignant tumors of salivary glands arise from:
a. Submandibular gland d. Parotid gland
b. Sublingual gland e. Minor salivary gland of buccal
c. Minor salivary glands to tongue mucosa
D.
42. Increased level of abnormal TBG
concentration can be found in:
a. Malnutrition d. Pregnancy
b. Acromegaly e. Hypothyroidism
c. Malabsorption
E.
43. A biopsy of mass in front of the ear of female patient reveals pleomorphic adenoma. Microscopic
examination shows which of the following:
a) Highly pleomorphic c) Dyshesive groups of cells in
hyperchromatic nuclei fibrocollagenous stroma
b) Epithelial cells intermixed with d) Compact glandular cystic spaces
myxomatous and cartilaginous e) Fibrocollagenous stroma
stroma
B.
44. The posterior pituitary is a collection of:
a. Arteries d. Fibers
b. Venules e. Lymphatics
c. Nerve endings
C.
263
45. Which methodology is more specific for hormone estimation:

a. Electrophoresis d. Chromatography
b. Spectrophotometry e. Immunoassay
c. Calorimetry
E.
46. Acromegaly is due to:
a. Pituitary atrophy d. Hyperthyroidism
b. Decreased ACTH e. Obesity
c. Increased growth hormone level
C.
47. Severe hypocalcaemia can occur in :
a. Fracture of long bones d. Hyperparathyroidism
b. Hypervitaminosis D e. Decreased calcium intake
c. Hypoparathyroidism
C.
48. Which of the following features is common to type 1 and type 2 diabetes?
a. Presence of islet cell antibodies d. Nonenzymatic glycosylation of
b. Association with certain major proteins
histocompatibility complex (MHC) e. Concordance rate of more than
class 2 alleles 90% in monozygotic twins
c. Marked resistance to the action of
insulin
D.
49. A 66 year old female has had diabetes mellitus for more than 30 year. She now has decreasing visual
acuity. There is no eye pain. Her intraocular pressure is measured as normal. Which of the following lesion
is most likely to account for her visual problems?
a. Keratomalacia d. Proliferative retinopathy
b. Optic neuritis e. Glaucoma
c. Cytomegalovirus retinitis
D.
264
MUSCULOSKELETON SYSTEM
1. The most common causative organism of pyogenic osteomyelitis is :

a. Pseudomonas d. Staphylococcus aureus
b. Streptococcus pyogenes e. Salmonella typhi
c. E.coli
D.
2. Heberdens nodes is osteoarthritis are present in :
a. Proximal interphalengeal joints d. Distal interphalengeal joints
b. Knee joints e. Shoulder joint
c. Hip joint
D.
3. The major morphological manifestation of gout are all of the following except:
a. Acute arthritis d. Nephropathy
b. Chronic tophaceous arthritis e. All of the above
c. Vasculopathy
C.
4. Most common site of tuberculosis osteomyelitis is:
a. Knee d. Lung
b. Hip e. Kidneys
c. Spine
C.
5. Which of the following is the major target for degenerative changes in osteoarthritis:
a. Blood supply of the bone d. Perichondrium
b. Bony trabeculae e. Periosteum
c. Articular cartilage
C.
6. Osteoarthritis most commonly effect which of the following site:
a. Ankle joint d. Metacarpophalengeal joint
b. Costochondral joint e. Proximal intraphalengeal joint
c. Knee joint
C.
7. Which one of the following is commonest tumor in bone:
a. Chondroblastoma d. Secondary carcinoma
b. Chondrosarcoma e. Osteosarcoma
c. Giant cell tumor
D.
8. Which of the following is not a feature of Rheumatoid arthritis :
a. Foreign body giant cell reaction to d. Panus formation
crystals e. Prominent lymphoid germinal
b. Inflamed synovium centers within hypertrophied villi
c. Necrosis of subcutaneous collagen
A.
9. Which of the following can be helpful in diagnosis of rheumatoid arthritis :
a. Rh factor d. ANA
b. Anti –CCP e. All of the above
c. X-ray
E.
265
CENTRAL NERVOUS SYSTEM

1. Unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the edge
of falx. This phenomena is called
a. Subfalcine herniation d. Hydrocephalus

b. Transtentorial herniation e. None
c. Tonsillar herniation
A.
2. Which of the following is not a common site of hypertensive Intracerebral hemorrhage?
a. Basal ganglia d. Occipital lobe

b. Cerebellum e. Pons
c. Internal capsule
D.
3. Accumulation of excessive CSF within the ventricular system is called
a. Herniation d. Stroke
b. Cerebral Edema e. None
c. Hydrocephalus
C.
4. All are CSF findings of pyogenic meningitis except
a. Increased pressure d. Elevated glucose

b. Increased Neutrophils e. None
c. Elevated proteins
D.
5. All are the CSF findings of viral meningitis except
a. Neutrophilia d. Normal glucose level

b. Moderate protein elevation e. None
c. Lymphocytosis
A.
6. Which of the following CNS tumor is characterized histologically by Rosettes and Pseudorosettes
a. Astrocytoma d. Medulloblastoma
b. Oligodendroglioma e. Meningioma
c. Ependymoma
C.
7. Medulloblastoma mostly involves which part of the brain
a. Cerebellum d. Medulla
b. Cerebrum e. None
c. Pons
A.
266
8. Small round blue cell is present in which CNS tumor?
c. Ependymoma
D.
9. Psammoma body are present in which CNS tumor?
c. Ependymoma
E.
10. Which tumor is common in children
c. Ependymoma
D.
11. Which type of brain herniation is life threatening ?
a. Subfalcine herniation d. All of the above

b. Transtentorial herniation e. None
c. Tonsilar herniation
C.
267
INDEX
A Azotemia, 108, 115, 247, 284 D
Acute gastritis, 142, 143, 319 B Debakey classification, 6
Acute Lymphoblastic Leukemia, 68 Barret esophagus, 140 Diabetes mellitus, 110, 124, 173,
Acute Myelobloastic Leukemia, 68 Benign Prostatic Hyperplasia, 178 212, 213, 214, 287, 295, 324,
Acute pancreatitis, 126, 172, 173, Biliary cirrhosis, 160, 169, 320 327
322, 323, 326 Bilirubin, 55, 56, 59, 159, 160, 162, Diabetic Nephropathy, 119
Acute pyelonephritis, 124, 293 168, 171, 269, 322 Disseminated Intravascular
Acute renal failure, 131 Bone Tumors, 228 Coagulation, 53, 79
Acute tubular necrosis, 108, 124, Brain Tumors, 233 Double Barreled Aorta, 6
132, 284, 287, 288, 290, 293 Breast Tumor, 197 Duodenal ulcer, 145, 309, 316
Adenocarcinoma, 102, 103, 104, Bronchiectasis, 89, 91, 92, 93, 276, E
106, 122, 127, 138, 141, 144, 280, 283, 327, 328 Ebstein’s Anomaly, 33
146, 151, 181, 185, 189, 194, Buergers disease, 12 Ehlers-Danlos syndrome, 5, 8
276, 278, 280, 282, 298, 301, Burkitt lymphoma, 64 Eisenmenger Syndrome, 34
310, 314, 316, 317, 318, 327 C Endometrial carcinoma, 194, 301,
Adenoid Cystic Adenoma, 138 Carcinoid tumor, 146, 155, 277, 304
Adenomas, 151, 206, 210, 212, 215, 278, 282, 310 Endometrial hyperplasia, 192, 301,
217, 218, 330 Cardiac cirrhosis, 32, 160, 253 303, 304
Adenomyosiss, 192 Cardiac temponade, 29, 30, 32 Endometriosis, 192, 303
Adult Respiratory Distress Cast, 108, 125, 126 Eosinophilia, 43, 93, 133
Syndrome, 101, 102 Celiac disease, 154, 155, 312, 314, Ependymoma, 233, 234, 235, 337,
Alpha-fetoprotein, 167 315 339
Alport’s syndrome, 110 Cerebral Herniation, 243 Erythema Marginatum, 24, 261
Alzheimer’s disease, 239, 240 Cervical Carcinoma, 189, 191 Erythroplakia, 137, 138, 309
ANCA, 9, 11, 12, 117, 171 Cervicitis, 189 Esophageal carcinoma, 140, 310
Anemia, 24, 45, 46, 47, 51, 52, 53, Chancroid, 183 Esophageal varices, 140, 142, 162,
54, 55, 57, 59, 60, 62, 73, 75, 77, Chocolate cyst, 192 309
78, 81, 137, 144, 220, 226, 261, Cholecystitis, 169 Ewing’s sarcoma, 231
264, 267 Choriocarcinoma, 175, 177, 178, F
Aneurysm, 3, 4, 5, 11, 21, 182, 238, 185, 186, 187, 204, 299, 301, Fatty streaks, 2
239, 248, 249, 251, 259, 260 303, 305, 307 Fibroadenoma, 197, 198, 296, 299,
Angina, 22, 23, 32, 252, 255, 257, Chronic bronchitis, 89, 90, 91, 276, 301
261 278, 280 Fibrocystic Diseases of Breast, 203
Anitschkow cells, 26 Chronic gastritis, 143, 145, 319, 327 Foam cells, 3
Antistreptolysin O, 24, 252, 284 Chronic Lymphocytic Leukemia, 72, Focal Segmental
Aortic Dissection, 5, 6, 7, 8 81 G
Aortic regurgitation, 39 Chronic myeloid leukemia, 43, 68, Glomerulosclerosis, 112
Aortic Stenosis, 33, 39 70, 74, 269 Gallstones, 159, 168, 324, 326
Aplastic anemia, 52, 53, 263, 271, Chronic Obstructive Pulmonary Gangrene, 4, 11, 14, 226, 249
273 Diseases (COPD), 89 Gastric carcinoma, 143, 145, 146,
Appendicitis, 149, 150, 310 Chronic Pyelonephritis, 125 147
Arrhythmia, 21, 257, 259, 260 Chronic Renal failure, 133 Gastric ulcer, 145
Arteriosclerosis, 1, 119, 120, 122, Churg-Strauss, 12 Gastroesophageal reflux disease,
249 Cold Anti-Body, 54 142
Asbestos, 96, 97 Colorectal carcinoma, 152, 314, 316 Ghon Complex, 87
Aschoff bodies, 26, 260 Conn’s syndrome, 218, 251, 330 Giant cell arteritis, 8, 9, 249, 250
Aspiration pneumonia, 83, 84 Coomb’s Test, 56 Giant cell tumor, 229
Asthma, 43, 89, 90, 91, 276, 281, Cor pulmonale, 37, 91, 92, 252 Gleason Grading System, 181
282 Corpora Amylacea, 178 Glomus tumor, 16, 18
Astrocytoma, 233, 234, 235, 326, Creatine Kinase, 21 Glucose 6-Phosphate
337, 339 Crohn’s disease, 147, 148, 149, 169, Dehydrogenase, 59
Atelectasis, 100, 102 310, 312 Goiter, 205, 206, 209, 245, 334
Atherosclerosis, 1, 3, 4, 207, 248, Cushing’s syndrome, 217, 218, 330 Gonorrhea, 183
249 Cystic diseases, 128 Goodpasture syndrome, 117
Atrial Septal Defect, 32, 34, 36 Cystic Medial Degeneration, 5 Gout, 227, 288
268
Granuloma, 12, 87, 171, 184, 252, Intraductal papilloma, 197, 296 Minimal change disease, 110, 284,
261 Invasive ductal carcinoma, 197, 199 288, 290, 291, 293
Graves’s disease, 209, 210 Invasive Lobular Carcinoma, 201 Mitral regurgitation, 38, 39
Ground Glass Hepatocytes, 156 Involucrum, 222 Mitral stenosis, 37, 38, 259, 261
Group A Streptococci, 24, 26 Iron deficiency anemia, 46, 47, 142, Mitral valve prolapse, 37, 39
Gynecomastia, 162, 181, 207, 322 267 Monocytosis, 43
H Ischemic heart disease, 22, 260 Multinodular Goiter, 205, 206
Hashimoto thyroiditis, 209 J Multiple Endocrine Neoplasia, 212
Heart failure, 11, 14, 21, 24, 26, 29, Jaundice, 52, 57, 159, 164, 165, Multiple myeloma, 74, 75, 220, 244,
30, 31, 32, 37, 38, 39, 40, 108, 167, 169, 171, 173, 320 267, 269
133, 135, 161, 218, 252, 253, K Multiple sclerosis, 237
259, 260, 278, 286 Kaposi sarcoma, 16, 146, 248, 251, Myasthenia Gravis, 231
Heart failure cells, 31 282 Myelodysplastic Syndromes, 78
Hemangioma, 16, 18, 103, 107, 166, Kawasaki disease, 11, 12 Myelofibrosis, 45, 74, 77
248, 249, 304 Kidney tumors, 126 Myeloma Cell, 77
Hematuria, 114, 124, 126, 127, 291, K-RAS, 103, 152, 174, 323 Myeloproliferative Disease, 74
293, 307 Kussmaul sign, 30 Myocardial infarction, 9, 19, 21, 23,
Hemochromatosis, 165, 216, 223, L 32, 39, 214, 253, 255, 257, 259,
320, 327 Lactate dehydrogenase, 19, 55, 162 260, 261
Hemophilia A, 78 Lead poisoning, 50 Myocarditis, 11, 29, 37, 226, 252,
Hepatitis, 9, 43, 62, 110, 113, 156, Left shift, 45 261
157, 158, 159, 161, 164, 166, Leiomyoma, 103, 146, 189, 196, Myoglobin, 19, 22, 126
167, 168, 171, 320, 322, 323, 197, 310 Myxoma, 40, 262
324 Leukemias, 67 N
Hepatocellular carcinoma, 15, 166, Leukemoid reaction, 70, 74 Nephritic syndrome, 114, 115, 288
167, 168 Leukoplakia, 137, 138, 187, 309, Nephrotic syndrome, 100, 108, 110,
Hereditary Spherocytosis, 56, 81, 317 112, 164, 214, 244, 284, 287,
263 Libman-Sacks endocarditis, 29, 262 288, 291, 293, 295, 333
Herpes Genitalis, 183 Lichen Sclerosus, 187 Neutropenia, 42, 73
Hirschprung disease, 147, 309, 314 Liver Cirrhosis, 160, 161, 165 Non-caseating granulomas, 149
Hodgkin Lymphoma, 65 Liver tumors, 166 Non-Hodgkin lymphoma, 64, 67
Homan sign, 13 Lung abscess, 85, 93 O
Hydatidiform Mole, 186 Lung tumor, 102, 278 Oligodendroglioma, 233, 234, 337,
Hydrocephalus, 242, 337 Lymphadenopathy, 12, 16, 62, 65, 339
Hydronephrosis, 130, 133, 287, 73, 182 Oral Cancer, 137, 138
288, 289, 307 Lymphangioma, 16, 103, 248 Osler-Weber-Rend disease, 16
Hyperaldosterinism, 218 Lymphocytosis, 43, 268, 273, 337 Osteoarthritis, 222, 223, 226, 336
Hyperparathyroidism, 119, 135, Lymphogranuloma Venereum, 184 Osteogenesis imperfect, 220
211, 212, 333 Lymphoma, 43, 63, 64, 65, 66, 67, Osteomyelitis, 221, 222, 336
Hyperprolactinoma, 215 81, 235, 263, 269 Osteoporosis, 171, 212, 221
Hypersegmented Neutrophil, 52 M Osteosarcoma, 228, 229, 336
Hypertension, 3, 4, 8, 37, 114, 115, M protein, 24, 26, 115 Ovarian Tumors, 185
119, 120, 122, 128, 133, 135, Malabsorption syndrome, 154, 312, P
162, 194, 217, 238, 239, 248, 314, 316, 324 P16, 104, 122, 174
295 Marfan syndrome, 5, 8, 253, 332 Paget’s disease of Nipple, 202
Hyperthyroidism, 119, 205, 206, Mastitis, 94, 203, 299 Pancreatic carcinoma, 13, 154, 173,
213, 330, 333, 335 Medullary carcinoma, 197, 210, 320
Hypoparathyroidism, 212, 332 296, 299, 300, 328 Papillary carcinoma, 210, 289, 296
Hypothyroidism, 43, 119, 203, 205, Medulloblastoma, 233, 234, 235, Para neoplastic syndrome, 107
207, 208, 259, 328, 334 337, 339 Paroxysmal Nocturnal
I Megaloblastic anemia, 51, 263, 267 Hemoglobinuria, 57
Iga nephropathy, 110, 114, 117, Membranoproliferative Patent Ductus Arteriosus, 32, 34,
284, 289, 290 Glomerulonephritis, 110, 113 36, 255, 260, 261
Infarcts, 21, 238, 239 Membranous Nephropathy, 112 Pemberton’s sign, 14
Infectious Mononucleosis, 54, 62, Meningioma, 233, 234, 235, 330, Peptic ulcer, 144, 310, 312, 326
81 337, 339 Pericardial effusion, 24, 26, 41, 135
Infective endocarditis, 8, 24, 26, 38, Meningitis, 85, 232 Pericarditis, 21, 24, 26, 29, 30, 135,
262 226, 261
269
Pheochromocytoma, 119, 212, 213, Renal function test, 245 Tetralogy of Fallot, 32, 34, 35, 253,
216, 251, 328, 330, 332, 333 Renal Stones, 130 255, 260, 261
Philadelphia chromosome, 70, 71, Restrictive lung disease, 93 Thalassemia, 45, 48, 61, 165, 264
74, 77, 268, 271 Rheumatic fever, 25, 29, 30, 38, 40, Thrombangitis Obliterans, 12
Phyllodes tumor, 197, 198 252, 253 Thrombocytopenia, 61, 62, 71, 72,
Pituitary Gland, 215 Rheumatic heart disease, 25, 26, 74, 78, 81, 226, 263
Pleural effusion, 100, 253 29, 38, 262 Thrombophlebitis, 13, 61
Pneumoconiosis, 95, 96, 97 Rheumatoid arthritis, 29, 30, 223, Thyroid carcinoma, 210, 211, 212
Pneumoconiosis, 93, 95, 96 226, 336 Thyroid carcinoma, 205
Pneumonia, 83, 84, 85 Right shift, 45 Thyroid Function Tests, 245
Pneumothorax, 85, 92, 101 S Thyroiditis, 144, 205, 208, 209, 210
Polyarteritis nodosa, 9, 11, 110, Sarcoidosis, 44, 93, 94, 123, 171, Tp53, 146, 174
117, 119, 172, 249 216, 242, 278, 283, 332, 334 Transitional cell carcinoma, 126,
Polycystic kidney disease, 131, 133, Schwannoma, 146, 233, 234, 235 185, 288, 307
284, 287, 288, 291 Seminoma, 175, 176, 178, 204, 299, Tricuspid Regurgitation, 38
Polycythemia, 60, 107, 128, 255, 305 Triple Phosphate, 130
266, 267, 269, 271 Sequestrum, 222 Troponin, 19, 253, 257
Polycythemia Vera, 74 Sickle cell anemia, 46, 57 Trousseau's syndrome, 13, 14
Polyps, 151 Sideroblastic anemia, 45, 46, 50, Truncus Arteriosus, 32, 256, 257
Portal hypertension, 161 267 Tuberculosis, 30, 84, 85, 87, 88,
Post streptococcal Skip lesions, 149 203, 216, 222, 278, 283, 284,
glomerulonephritis, 115, 284, Smoky brown urine, 115 310, 330
288, 291, 293 Solitary nodule, 206 U
Primary Sclerosing Cholangitis, 159, Spermatocytic seminoma, 175, 176, Ulcerative colitis, 148, 171
171 305 Uremia, 30, 102, 108, 247, 284
Prions Disease, 240 Splenomegaly, 55, 60, 71, 73, 74, Urinary Bladder Carcinoma, 122
Prostate carcinoma, 180, 305, 307 81, 94, 162, 275 V
Prostate specific antigen (PSA), 180 Squamous cell carcinoma, 102, 103, Vaginitis, 189
Proteinuria, 12, 108, 110, 112, 214, 104, 122, 127, 137, 138, 141, Vascular Tumor, 16
244, 284, 286, 288, 289, 291, 222, 278, 280, 282, 298, 301, Vasculitis, 8, 11, 12, 14, 37, 117,
293, 295 307, 316, 317, 318 119, 225, 226, 238
Psammoma bodies, 185, 186, 234, String sign, 148, 149 Vegetations, 28, 29
235 Sturge Webber Syndrome, 16 Venous thrombosis, 13
Pulmonary edema, 31, 132 Subarachnoid Hemorrhage, 238 Ventricular Septal Defect, 32, 36
Pulmonary Embolism, 97 Subcutaneous nodules, 24 Von-Willi brand’s disease, 78
Pulmonary embolus, 14, 32, 131 Subendothelial deposits, 113 W
Pulmonary Emphysema, 89 Sydenham’s chorea, 24 Warm Antibody, 54
Pulmonary fibrosis, 37, 97 Syndrome of inappropriate ADH Wegner granulomatosis, 12, 117
Pulmonary hypertension, 36, 37, 98 secretion, 216 Whipple’s disease, 155
Pulsus Paradoxus, 30 Syphilis, 40, 137, 181, 182, 248, Wilm’s tumor, 127, 128, 287, 288,
R 253, 261 289, 290
Ranson’s Criteria, 173 T Wilson disease, 164
Rapidly Progressive (Crescentric) Takayasu’s arteritis, 8, 9 Y
Glomerulonephritis, 117 Telangiectasia, 16, 248 Yolk sac tumor, 176, 177, 296, 299,
Raynaud’s phenomena, 14 Teratoma, 175, 176, 177, 185, 186, 303, 305, 307
Reed Sternberg Cells, 66 204, 296, 298, 299, 301, 305 Α 1 antitrypsin deficiency, 164, 166,
Reid index, 90 Testicular Tumors, 175 276
Renal cell carcinomas, 127, 212
270
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Essential of Special Patholog by Dr Zair Hassan

Book · December 2015

Zair Hassan Muneeb Jan

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Waqar Ahmad Khan

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Chapter One BLOOD VESSELS

Figure: Components of Atheromatous Plaque

 Smooth muscle cells release cytokines that produce extracellular matrix

 It often ruptures out through the adventitia causing massive hemorrhage.

Figure: DeBakey Classification of Aortic Dissection

Small vessels(WMC) Wegner’s granulomatosis(W), Microscopic polyangitis(M),

Superior and Inferior Vena Cava Syndrome:

Chapter Two HEART

Figure:Enzymes Changes following Acute Myocardial Infarction

 Acute plaque changes:

Batista Partial Left Cardiac asthma?

Causes of heart failure

Figure: Gross and Microscopic Appearance of Nutmeg Liver

Ventricular septal defect (VSD):

 Neutrophils have a multi lobe nucleus

Figure: Peripheral Smear of Iron Deficiency Anemia

Figure: peripheral Smear of Thalassemia (Arrows showing Target Cells)

Figure: Pathophysiology of Thalassemia

Figure: Sideroblastic cells

Figure: Peripheral Smear of Megaloblastic Anemia (Arrow showing Hypersegmented Neutrophil

Differentiate between warm and cold antibodies immuno hemolytic anemia

Figure: Pathogenesis of Hereditary Spherocytosis

Figure: Peripheral Smear of G6PD (Arrow showing Bite cell)

Non-Immune Transfusion Reaction:

Figure: Origin of Different Blood Lineages

Reed Sternberg Cells:

Figure: Morphology of Mixed Cellularity

Acute Lymphoblastic Leukemia (ALL)

Figure: Pathogenesis of CML

Figure: Peripheral Smear of AML Figure: Peripheral Smear of CML

Figure: Peripheral Smear of CLL

Leukocyte Alkaline Phosphatase (LAP) Test:

Figure: Peripheral Smear of Multiple Myeloma

Myelodysplastic Syndromes (MDS)

 20,000 to 50,000/mm3= posttraumatic bleeding

Chapter Four LUNG

The “typical” Community acquired pneumonia is characterized by:

 Cough is productive with purulent, blood streaked or rusty sputum

Figure: Tubercular Granuloma

 2 group: histamines, PG-D2, PAF (Platelets activating factor)

 3 group: IL-1, IL-6 and TNF

Atelectasis (Collapse Alveoli)

Direct lung injury Indirect lung injury

Histology Scant cytoplasm, small Abundant Cytoplasm,

Neuroendocrine markers Usually present Usually absent

Response to chemotherapy Often complete response Uncommonly complete

Squamous Cell Caof Lung Adenocarcinoma of Lung

Small (Oat) Cell Ca of Lung

Para Neoplastic Syndrome:

General Features of Kidney: