Adrenal Glands

- Adrenal cortex has 3 zones

o Zona glomerulosa
o Zona fasciculata (75% of the total cortex)
o Zona reticularis
- The adrenal cortex synthesizes 3 different types of steroids:
o Glucocorticoids (cortisol), synthesized primarily in the zona fasciculata
o Mineralocorticoids (aldosterone) generated in the zona glomerulosa
o Sex steroids (estrogens and androgens), produced in the zona reticularis
- The adrenal medulla
o Chromaffin cells : synthesize and secrete catecholamines
Adrenocortical Hyperfunction (Hyperadrenalism)
- Cushing syndrome - excess of Cortisol
o Exogenous  Administration of glucocorticoids (“iatrogenic” Cushing syndrome)
o Endogenous ACTH dependent/ Independent
- Ex. A 60-year-old woman with small cell carcinoma of the lung notes rounding of her face, upper truncal obesity, and
muscle weakness. Physical examination reveals thin, wrinkled skin, abdominal striae, and multiple purpuric skin lesions. The patient’s blood pressure is 175/95 mm
Hg. Laboratory studies will likely show elevated serum levels of which of the following hormones? Corticotropin
o This patient most likely has a paraneoplastic condition associated with a corticotropin (ACTH)-producing small cell carcinoma of the lung. The major
clinical manifestations of hypercortisolism in patients with Cushing syndrome include emotional disturbances, moon facies, osteoporosis, hypertension,
upper truncal obesity (buffalo hump), amenorrhea, muscle weakness, thin wrinkled skin, purpura, glucose intolerance, poor wound healing and skin
ulcers.
Ex. A 45-year-old man with a recent history of bizarre behavior is seen by a psychiatrist, who recommends evaluation of his endocrine status. On physical
examination, the patient appears moderately obese (BMI = 31 kg/m2), with mild hypertension, facial acne, fat accumulation in the supraclavicular fossae, and a
protuberant abdomen. Laboratory studies demonstrate a neutrophilic leukocytosis, with a decrease in the percentage of lymphocytes and an absence of eosinophils.
The hematocrit and hemoglobin are normal. There is a mild hypokalemia and mild metabolic alkalosis. The fasting serum glucose is within the reference range, but on
a 2-hour glucose tolerance test, both the 60- and 120-minute samples had glucose concentrations greater than 200 mg/dL. Laboratory studies show free urinary
cortisol of 156 mg per 24 hours (normal = 10 to 100 mg per 24 hours). Which of the following questions would be of most help in establishing a diagnosis? Are you
receiving corticosteroids for some other disease?
- Ex. A 40-year-old woman with a history of diabetes complains of recent changes in her bodily appearance. A photograph of the patient is shown in the image.
Laboratory studies reveal elevated serum corticosteroids and low serum corticotropin. Administration of dexamethasone does not lower
serum levels of corticosteroids. This patient most likely has a tumor that originates in which of the following anatomic locations?
Adrenal cortex, zona fasciculata.
- Ex. A 46-year-old woman with severe asthma presents with increasing weight and back pain for 9 months. The patient is taking
corticosteroids for her asthma. An X-ray of the vertebrae will likely reveal which of the following pathologic findings? Osteoporosis
o Long-term administration of corticosteroids causes increased bone resorption and decreased bone formation, thereby leading
to osteoporosis. As many as 20% of patients with Cushing syndrome suffer compression fractures of the vertebrae.
- Hyperaldosteronism - excessive aldosterone
- Adrenogenital or virilizing syndromes - excess of androgens
Hypercortisolism (Cushing Syndrome)
- Cushing Disease
o ACTH-secreting pituitary adenomas - 70% of endogenous cases
o Mostly young women
- Secretion of ectopic ACTH by non-pituitary tumors - 10%
o Mostly men in the 40s and 50s
o Small-cell carcinoma of the lung, carcinoids, medullary carcinoma of the thyroid, islet cell tumors
- Primary adrenal neoplasms
o Adrenal adenoma (~10%), Carcinoma (~5%)
o Most common cause for ACTH-independent Cushing syndrome
o ↑ Cortisol , ↓ACTH
Hyperplastic adrenals
- Mostly ACTH dependent
- Primary cortical hyperplasia (ACTH-independent hyperplasia)
o Macronodular: nodules > 3 mm in diameter
o Sporadic (non-syndromic) condition observed in adults
o Cortisol production regulated by non-ACTH hormones (GIP, LH, ADH)
o McCune-Albright syndrome: somatic mutations activate GNAS (encodes a stimulatory Gsα)
- Morphology
o Pituitary
 Changes are seen regardless of the cause
 Crooke hyaline change - granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary becomes homogeneous and
paler (accumulation of intermediate keratin filaments in the cytoplasm)
 Corticotrophs showing increased eosinophilic cytoplasm filled with perinuclear cytokeratin
o Adrenals
 Bilateral cortical atrophy
 Suppression of endogenous ACTH from exogenous glucocorticoids results in to a lack of stimulation of the zonae fasciculata
and reticularis by ACTH
 Zona glomerulosa is of normal thickness
 Diffuse hyperplasia
 ACTH-dependent Cushing syndrome
 Both glands are enlarged (up to 30 gm)
 Hyperplastic cortex with expanded “lipid-poor” zona reticularis, surrounded by an outer zone of vacuolated “lipid-rich” cells
o Any nodules present are usually composed of vacuolated “lipid-rich” cells, which account for the yellow color of
diffusely hyperplastic glands
 Macronodular hyperplasia
 Adrenals almost entirely replaced by prominent nodules of varying sizes (≤3 cm)
 Nodules contain an admixture of lipid-poor and lipid-rich cells
 Areas between macroscopic nodules show microscopic nodularity
Primary adrenocortical neoplasms
- Malignant or benign
- More common in women in their 30s to 50s
- Adrenocortical adenomas
 o Small tumors (usually <30gms)
o Yellow tumors surrounded by thin or well-developed capsules
o Composed of cells similar to normal zona fasciculata
- Adrenocortical carcinomas
o Larger than the adenomas (> 200 to 300 gm)
o Unencapsulated masses with anaplastic characteristics
- In functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of the contralateral adrenal
gland are atrophic, as a result of suppression of endogenous ACTH by high cortisol levels
Clinical course of Cushing syndrome
- Early stages - hypertension and weight gain
- Later - truncal obesity, moon facies, and accumulation of fat in the posterior neck and back (buffalo hump)
- Selective atrophy of fast-twitch (type 2) myofibers, resulting in decreased muscle mass and proximal limb weakness
- Glucosuria and polydipsia (secondary diabetes)
- Loss of collagen - thin, fragile, and easily bruised skin ; wound healing is poor; cutaneous striae in the abdominal
area
- Bone resorption - osteoporosis
- ↑ risk for a variety of infections
- Mood swings, depression, and frank psychosis
- Hirsutism and menstrual abnormalities
- Diastolic hypertension: due to increase in weak mineralocorticoids (corticosterone, 11-deoxycorticosterone), glucocorticoids, and insulin (↑mineralocorticoid
activity)
Lab diagnosis of Cushing syndrome
- ↑ 24-hour urine free-cortisol concentration
- Loss of normal diurnal pattern of cortisol secretion
o Pituitary Cushing syndrome
 ↑ ACTH levels cannot be suppressed by low dose of dexamethasone
(no reduction in urinary excretion of 17-hydroxycorticosteroids)
 After higher doses of injected dexamethasone, ↓ pituitary ACTH secretion,
(suppression of urinary steroid secretion)
o Ectopic ACTH secretion
 ↑ACTH, completely insensitive to low or high doses of exogenous
dexamethasone
o Adrenal tumor
 ↓ACTH because of feedback inhibition of the pituitary
 Both low and high-dose dexamethasone fail to suppress cortisol release
Primary Hyperaldosteronism
- Autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased
plasma renin activity
- Blood pressure elevation is the most common manifestation
o Bilateral idiopathic hyperaldosteronism (IHA)
o Adrenocortical neoplasm
o Glucocorticoid-remediable hyperaldosteronism
- Bilateral idiopathic hyperaldosteronism
o Bilateral nodular hyperplasia of the adrenal glands
o 60% of cases
o Older age, less severe hypertension
o Germline mutations of KCNJ5 (encodes a potassium channel)
- Adrenocortical neoplasm
o Adenoma (more common) “ Conn syndrome”
o Rarely adrenocortical carcinoma
o Adult middle life, more common in women
o Somatic mutations of KCNJ5
o Ex. A 50-year-old man complains of muscle weakness and dizziness of 3 months in duration. His blood pressure is 185/100 mm Hg. Laboratory studies
show hypernatremia and hypokalemia. Endocrine studies reveal elevated serum aldosterone and low renin and angiotensin. BUN is 24 mg/dL, and
creatinine is 1.2 mg/dL. Endocrinologic studies rule out Cushing syndrome. Which of the following is the most likely cause of hypertension in this
patient? Conn syndrome
- Primary aldosteronism:
o Hypertension, Hypernatremia, Hypokalemia, Metabolic Alkalosis, ↓Plasma Renin
Glucocorticoid-remediable hyperaldosteronism
- Rearrangement involving chromosome 8, places CYP11B2 (gene encoding aldosterone synthase) under control of ACTH responsive CYP11B1 gene promoter
- ACTH stimulates production of aldosterone synthase
- Suppressible by dexamethasone (aldosterone production is under control of ACTH)
Secondary Hyperaldosteronism
- Aldosterone release in response to activation of renin-angiotensin system
- ↑Plasma Renin
o Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
o Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)
o Pregnancy (Estrogen-induced increases in plasma renin substrate)
Aldosterone-producing adenomas
- Gross:
o Solitary, small (<2 cm in diameter), well-circumscribed lesions
o More on left side, More in women in the 30s and 40s
- Cut section: bright yellow
- Microscopic:
o Lipid-laden cortical cells resembling fasciculata cells
o Cells mostly uniform in size and shape (mild pleomorphism)
o Spironolactone bodies - eosinophilic, laminated cytoplasmic inclusions
o Do not usually suppress ACTH secretion (adjacent adrenal cortex and contralateral gland are not atrophic)
Bilateral idiopathic hyperplasia
- Diffuse and focal hyperplasia of cells resembling normal zona glomerulosa
- Wedge-shaped, extending from the periphery toward the center of gland
- The enlargement may be subtle (an adrenocortical adenoma must be carefully excluded as the cause for hyperaldosteronism)
 - Ex. A 40-year-old woman has experienced increasingly frequent episodes of weakness accompanied by numbness and tingling in her hands and feet for the past year.
On examination her blood pressure is 168/112 mm Hg. Laboratory studies show sodium, 142 mmol/L; potassium, 2.9 mmol/L; chloride, 104 mmol/L; HCO3, 28
mmol/L; and glucose, 74 mg/dL. Her plasma renin activity is low. Which of the following radiologic findings is most likely to be present in this woman? Adrenal
nodular enlargement
Clinical Course
- Primary hyperaldosteronism
o Common cause of secondary hypertension
 Prevalence of 5 to 10% among non-selected hypertensive patients
 20% in patients classified as having treatment-resistant hypertension
- Sodium reabsorption leads to ↑ reabsorption of water, expanding ECF volume and elevating cardiac output
- Cardiovascular compromise (LVH, ↓ diastolic volumes)
- ↑ prevalence of adverse events (stroke and myocardial infarction)
- Hypokalemia was considered a mandatory feature
o From renal potassium wasting
o Neuromuscular manifestations (weakness, paresthesias, visual disturbances, and occasionally frank tetany)
o Normokalemic patients are now being diagnosed
Diagnosis and treatment
- ↑ ratio of plasma aldosterone concentration to plasma renin activity (screening test)
- Aldosterone suppression test - confirmatory test
- Adenomas
o Surgical excision
- Bilateral hyperplasia (mostly children and young adults)
o Managed medically with an aldosterone antagonist (Spironolactone)
- Secondary hyperaldosteronism
o Correcting the underlying cause stimulating the Renin-Angiotensin-system
Adrenogenital Syndromes
- Adrenal cortex secretes 2 compounds (dehydroepiandrosterone and androstenedione) that can be
converted to testosterone in peripheral tissues
- ACTH regulates adrenal androgen formation
- Excess Androgen secretion
o Either as a “pure” syndrome or as a component of Cushing disease
o Adrenocortical neoplasms
 Mostly androgen-secreting adrenal carcinomas
 May be associated with hypercortisolism (“Mixed syndrome”)
- Congenital adrenal hyperplasia (CAH)
o Autosomal-recessive, inherited metabolic errors
o Deficiency or total lack of a particular enzyme involved in the biosynthesis of cortical steroids , including cortisol and aldosterone
- Consequences of C-21 hydroxylase deficiency. 21-Hydroxylase deficiency impairs the synthesis of both cortisol and aldosterone at different steps. The resultant
decrease in feedback inhibition (dashed line) causes increased secretion of ACTH, resulting ultimately in adrenal hyperplasia and increased synthesis of testosterone
Congenital Adrenal Hyperplasia
- 21-hydroxylase deficiency (mutations of CYP21A2) Most common, > 90% of cases
o Salt-wasting (“classic”) adrenogenitalism
1. Total lack of the hyroxylase, presents soon after birth (*In utero the electrolytes and fluids can be maintained by the maternal kidneys)
2. Inability to convert progesterone into deoxycorticosterone (↓ cortisol)
3. Salt wasting, hyponatremia, and hyperkalemia which induce acidosis, hypotension, cardiovascular collapse, and
possibly death
4. Excess production of androgens lead to virilization, easily recognized in the female at birth or in utero
5. Male children recognized 5 to 15 days later because of “salt losing crisis”
o Simple virilizing adrenogenitalism
o “Non-classic” adrenogenitalism
o Ex. A 5-year-boy has developed features that suggest puberty over the past 6 months. On physical examination, the boy has
secondary sex characteristics, including pubic hair and enlargement of the penis. Which of the following morphologic
features is most likely to be seen in his adrenal glands? Cortical hyperplasia
o Ex. A female infant is born at term to a 41-year-old Yupik woman after an uncomplicated pregnancy. Soon after birth, the
neonate develops hypotension. Physical examination shows ambiguous genitalia with a prominent clitoris. Laboratory studies show Na+, 131 mmol/L;
K+, 5.1 mmol/L; Cl–, 93 mmol/L; CO2, 18 mmol/L; glucose, 65 mg/dL; creatinine, 0.4 mg/dL; testosterone, 50 mg/dL (normal <30 mg/dL); and cortisol,
2 μg/dL. An abdominal ultrasound scan shows bilaterally enlarged adrenal glands. Which of the following enzyme deficiencies is most likely to be present
in this infant? 21-Hydroxylase
o Ex. Physical examination of a neonate shows peculiar genitalia (shown in the image). Cytogenetic studies reveal a 46, XX karyotype. Laboratory studies
will most likely reveal a deficiency of which of the following? 21-Hydroxylase.
 The infant described in Question 13 is shown to have an autosomal recessive genetic disorder. The infant is expected to manifest which of the
following developmental anomalies? Adrenal hyperplasia
o Ex. A 7-week-old infant develops severe dehydration and hypotension and expires. The kidneys and adrenal glands at autopsy are shown in the image.
Hypovolemic shock in this infant was most likely caused by inadequate synthesis of which of the
following hormones? Aldosterone
Congenital Adrenal Hyperplasia
- Simple virilizing adrenogenitalism without salt wasting
o Presents as genital ambiguity, No salt wasting
o 1/3rd of patients with 21-hydroxylase deficiency
o Sufficient mineralocorticoid to prevent a salt-wasting “crisis”
o ↓Glucocorticoid level fails to cause feedback inhibition of ACTH secretion
o ↑Testosterone leads to progressive virilization
- “Non-classic” late onset adrenogenitalism
o Significantly more common than the classic patterns
o Partial deficiency in 21-hydroxylase function
o Mild manifestations - hirsutism, acne, and menstrual irregularities
o Cannot be diagnosed on routine newborn screening
o Demonstration of biosynthetic defects in steroidogenesis
- Morphology
o Adrenals
 Bilateral hyperplasia (sustained elevation in ACTH)
 Gross: adrenal cortex is thickened and nodular
  C/S : cortex appears widened and brown (total depletion of all lipid)
 Micro: compact, eosinophilic, lipid depleted cells, intermixed with lipid-laden clear cells
o Anterior Pituitary
 Hyperplasia of corticotroph (ACTH-producing) cells
- Clinical Course
o Abnormalities related to androgen excess, with or without aldosterone and glucocorticoid deficiency
o In severe salt-wasting 21-hydroxylase deficiency
o ‘ Low cortisol levels + Adreno-medullary dysplasia ‘ ↓ catecholamine secretion, predisposing to hypotension and circulatory collapse
o In females, excessive androgenic activity in 21-hydroxylase deficiency
 Clitoral hypertrophy and pseudohermaphroditism in infants
 Oligomenorrhea, hirsutism, and acne in postpubertal females
o In males, androgen excess associated with
 Enlargement of external genitalia and precocious puberty in prepubertal age
 Oligospermia in older males
o CAH should be suspected in any neonate with ambiguous genitalia
o Severe enzyme deficiency in infancy can be a life-threatening condition with vomiting, dehydration, and salt wasting
o Treament with exogenous glucocorticoids
 Provides adequate levels of glucocorticoids
 Suppresses ACTH levels (↓ excessive synthesis of the steroid hormones)
o Mineralocorticoid supplementation
 Required in the salt-wasting variants
o Neonatal metabolic screens for CAH
o Molecular testing for antenatal detection of 21-hydroxylase mutations
11-Hydroxylase deficiency
- Impaired cortisol, mineralocorticoid excess (salt retainer), ↑androgens
- Increase in 17-KS, testosterone, and DHT
o All proximal to the enzyme block
- Increase in mineralocorticoids (11-deoxycorticosterone; salt retainer)
o 11-Deoxycorticosterone is proximal to the enzyme block
o Salt retention produces hypertension
- Increase in 17-OH
o 11-Deoxycortisol is proximal to the enzyme block
- Increase in 17-hydroxyprogesterone
o Proximal to the enzyme block
17-Hydroxylase deficiency
- Impaired cortisol and androgens, ↑ mineralocorticoid production
- ↓ in 17-KS, 17-OH, 17-hydroxyprogesterone, testosterone, and DHT
o All distal to the enzyme block
- Increase in mineralocorticoids (salt retainers)
o Zona glomerulosa mineralocorticoid pathway is wide open
Diagnosis of adrenogenital syndrome
- Serum 17-OH progesterone is an excellent screening test
o Increased in 21- and 11-OHase deficiency
o Decreased in 17-OHase deficiency
o Can measure prenatally with chorionic villous sampling
o Screening test in most but not all states on newborns
- Urine for 17-hydroxycorticoids and 17-ketosteroids
Adrenocortical Insufficiency
- Primary hypoadrenalism: primary adrenal disease
- Secondary hypoadrenalism: deficiency of ACTH
o Primary acute adrenocortical insufficiency (Adrenal crisis)
o Primary chronic adrenocortical insufficiency (Addison disease)
o Secondary adrenocortical insufficiency
Primary Acute Adrenocortical Insufficiency
- As a crisis in individuals with chronic adrenocortical insufficiency precipitated by stress
- In patients maintained on exogenous corticosteroids
- Rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
- Massive adrenal hemorrhage
o Newborns following prolonged and difficult delivery
o Patients maintained on anticoagulant therapy
o Postsurgical patients who develop disseminated intravascular coagulation
o Disseminated bacterial infection ‘Waterhouse- Friderichsen syndrome’
- Ex. A 29-year-old woman with systemic lupus erythematosus has been treated with corticosteroid therapy for several years because of recurrent lupus nephritis. She
undergoes an emergency appendectomy for acute appendicitis. On postoperative day 2, she becomes somnolent and develops severe nausea and vomiting. She then
becomes hypotensive. Blood cultures are negative, and laboratory studies now show Na+ of 128 mmol/L, K+ of 4.9 mmol/L, Cl– of 89 mmol/L, CO2 of 19 mmol/L,
glucose of 52 mg/dL, and creatinine of 1.3 mg/dL. Which of the following morphologic findings in the adrenal gland cortex is most likely to be present in this
patient? Atrophy
o This woman has findings of acute adrenocortical insufficiency (acute addisonian crisis). Long-term corticosteroidtherapy shuts off corticotropin
stimulation to the adrenal glands, leading to adrenal atrophy. When this history is not elicited, and the patient is not continued on the corticosteroid the
stress of surgery. When tuberculosis is more prevalent and more severe without drug therapy, dissemination to adrenals occurs more frequently
Waterhouse-Friderichsen Syndrome
- Overwhelming bacterial infection
- Neisseria meningitidis
- Pseudomonas, pneumococci, H influenzae, or staphylococci
o Rapidly progressive hypotension leading to shock
o Disseminated intravascular coagulation associated with widespread purpura, particularly of the skin
o Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
- More common in children
- Basis for the adrenal hemorrhage is uncertain
- Waterhouse-Friderichsen syndrome - at autopsy, the adrenals were grossly hemorrhagic and shrunken; microscopically, little residual cortical architecture is
discernible
 - Ex. A 19-year-old, previously healthy woman collapsed after complaining of a mild sore throat the previous day. On examination she is hypotensive and febrile with
purpuric skin lesions. Her peripheral blood smear shows schistocytes. Imaging studies show her adrenal glands are enlarged, and there are extensive bilateral cortical
hemorrhages. Infection with which of the following organisms best accounts for these findings? Neisseria meningitidis
Addison Disease
- Primary Chronic Adrenocortical Insufficiency
- Uncommon disorder
- Progressive destruction of the adrenal cortex
- No clinical manifestations until 90% of the cortex has been compromised
- More common in whites and in women
- Majority of cases are due to autoimmune adrenalitis, tuberculosis, AIDS, or metastatic cancers
- Ex. A 55-year-old man has experienced increasing lethargy for the past 7 months. Physical examination shows hyperpigmentation of the skin. Vital signs include
temperature of 36.9 deg C, pulse of 70/min, respirations of 14/min, and blood pressure of 95/65 mm Hg. Laboratory studies include a serum cortisol level of 3 μg/mL
at 8:00 am with a serum corticotropin level of 65 pg/mL. Which of the following diseases most often occurs in patients with this disorder? Hashimoto thyroiditis
o Addison disease (primary chronic adrenocortical insufficiency) most often results from an idiopathic autoimmune condition (in areas of the world where
the incidence of active tuberculosis is low). Autoimmune adrenalitis is associated with the appearance of other autoimmune diseases in about half of all
cases. Such autoimmune phenomena are frequently seen in other endocrine organs, such as the thyroid gland. Other presumed autoimmune diseases, such
as systemic lupus erythematosus, ulcerative colitis, and the vasculitides, are usually not forerunners to adrenal failure, although treatment of these
conditions with corticosteroids can lead to iatrogenic adrenal atrophy.
- Ex. A 44-year-old woman has become increasingly listless and weak and has had chronic diarrhea and a 5-kg weight loss over the past 7 months. She also notices that
her skin seems darker, although she rarely goes outside because she is too tired for outdoor activities. On physical examination, she is afebrile, and her blood pressure
is 85/50 mm Hg. A chest radiograph shows no abnormal findings. Laboratory findings include serum Na+, 120 mmol/L; K+, 5.1 mmol/L; glucose, 58 mg/dL; urea
nitrogen, 18 mg/dL; and creatinine, 0.8 mg/ dL. The serum corticotropin level is 82 pg/mL. Which of the following is most likely to account for these findings?
Autoimmune destruction of the adrenals
Autoimmune adrenalitis
- 60 to 70% of cases
- Autoantibodies to steroidogenic enzymes (21-hydroxylase, 17-hydroxylase)
- Autoimmune polyendocrine syndrome type 1 (APS1)
o APECED - Autoimmune PolyEndocrinopathy, Candidiasis, and Ectodermal Dystrophy
o Association with autoimmune disorders ((autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia)
o Mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22
o In the absence of AIRE function, central T-cell tolerance to peripheral tissue antigens is compromised, promoting autoimmunity
o Autoantibodies against IL-17 and IL-22 (principal effector cytokines secreted by TH17 T-cells)
- Autoimmune polyendocrine syndrome type 2 (APS2)
o Starts in early adulthood
o Combination of adrenal insufficiency + autoimmune thyroiditis or type 1 diabetes
o No mucocutaneous candidiasis, ectodermal dysplasia or autoimmune hypoparathyroidism
- AIRE is expressed primarily in the thymus, where it functions as a transcription factor that promotes the expression of many peripheral tissue antigens
Infections
- Tuberculous adrenalitis
o Associated with active infection in other sites (lungs, GU tract)
- Fungal infections
o Disseminated Histoplasma capsulatum and Coccidioides immitis
- AIDS sufferers
o CMV, Mycobacterium avium-intracellulare and noninfectious (Kaposi sarcoma) complications
Other causes
- Metastatic neoplasms
o Mostly carcinomas of the lung and breast
o Gastrointestinal carcinomas, malignant melanoma, hematopoietic neoplasms
- Genetic causes
o Congenital adrenal hypoplasia (adrenal hypoplasia congenita)
o Adrenoleukodystrophy
Morphology
- Primary autoimmune adrenalitis
o Irregularly shrunken glands
o Scattered residual cortical cells in a collapsed network of connective tissue
o Variable lymphoid infiltrate in the cortex
- Tuberculous and fungal disease
o Adrenal architecture is effaced by a granulomatous inflammation
- Metastatic carcinoma
o Architecture obscured by the infiltrating neoplasm
o Ex. A 73-year-old woman has experienced malaise and a 10-kg weight loss over the past 4 months. She also has developed a chronic cough during this
time. She has a 100 pack-year history of smoking cigarettes. Physical examination shows muscle wasting and 4/5 motor strength in all extremities.
Abdominal CT scan shows bilaterally enlarged adrenal glands. A chest radiograph shows a 6-cm perihilar mass on the right and prominent hilar
lymphadenopathy. Laboratory studies show Na+, 118 mmol/L; K+, 6 mmol/L; Cl–, 95 mmol/L; CO2, 21 mmol/L; and glucose, 49 mg/dL. Her 8:00 am
serum cortisol level is 9 ng/mL. What is the most likely diagnosis? Metastatic carcinoma
 The lung mass is likely a primary lung carcinoma, and the bilaterally enlarged adrenal glands can be explained by metastases to the adrenal
glands. Destruction of over 90% of the adrenal cortices is responsible for adrenal failure manifested by malaise and the low serum cortisol
concentration and the electrolyte disturbances.
Clinical Course
- Early manifestations – Non specific (progressive weakness and easy fatigability, anorexia, nausea, vomiting, weight loss, and diarrhea)
- Hyperpigmentation of the skin:
o Sun-exposed areas and at pressure points (neck, elbows, knees, knuckles)
o Elevated levels of pro-opiomelanocortin (POMC)
o Not seen in persons with adrenocortical insufficiency caused by primary pituitary or hypothalamic disease
- Hyperkalemia, hyponatremia, volume depletion, and hypotension
- Hypoglycemia (impaired gluconeogenesis)
- Stress (trauma, surgery, infection) can precipitate an acute adrenal crisis
- Acute adrenal crisis can manifest as intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse
- Death occurs rapidly unless corticosteroid therapy begins immediately
Laboratory findings in Addison disease
- Short and prolonged ACTH stimulation test
o No increase in cortisol or 17-OH
 - Metyrapone test
o ↓cortisol → ↑ACTH → ↓11-deoxycortisol
- Increased plasma ACTH
- Electrolyte findings
o ↓serum sodium, cortisol, bicarbonate; ↑serum potassium, ACTH
- Aldosterone deficiency leads to a hypertonic loss of sodium in the urine (hyponatremia), retention of potassium (hyperkalemia), and retention of hydrogen ions
(metabolic acidosis)
Deficiency of ACTH
- Metyrapone test
o Stimulation test of pituitary ACTH and adrenal gland reserve
o Metyrapone inhibits adrenal 11-hydroxylase, which causes a decrease in cortisol and a corresponding increase in plasma ACTH (pituitary) and 11-
deoxycortisol (adrenal), which is proximal to the enzyme block
o In hypopituitarism, neither ACTH or 11-deoxycortisol are increased
o In adrenal disease, ↑ ACTH but ↓11-deoxycortisol
- Schematic of the metyrapone test: a normal response (A) and the response expected in hypopituitarism (B). A, Metyrapone blocks 11-hydroxylase in the adrenal
cortex. This decreases cortisol leading to an increase in ACTH and 11-deoxycortisol. B, A decrease in cortisol does not increase pituitary ACTH indicating
hypopituitarism as the cause of hypocortisolism. Because ACTH is not increased, there is no increase in 11-deoxycortisol proximal to the enzyme block.
Secondary Adrenocortical Insufficiency
- Hypothalamic /pituitary disorder that reduces the output of ACTH
o Metastatic cancer, infection, infarction, or irradiation
- Prolonged administration of exogenous glucocorticoids
o Suppresses the output of ACTH and adrenal function
- Hyperpigmentation of primary Addison disease is lacking
o Levels of melanocyte-stimulating hormone are not elevated
- Deficient cortisol and androgen output but normal aldosterone synthesis
o Marked hyponatremia and hyperkalemia are not seen
- The cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The medulla is unaffected
- Secondary disease can be differentiated from Addison disease by demonstration of low levels of plasma ACTH in the former
Adrenocortical Neoplasms
- Adenomas and carcinomas equally common in adults
- Carcinomas predominate in children
- 2 familial cancer syndromes ↑ predisposition
o Li-Fraumeni syndrome (germline TP53 mutations)
o Beckwith-Wiedemann syndrome (disorder of epigenetic imprinting)
- Functional adenomas
o Associated with hyperaldosteronism and Cushing syndrome
- Carcinoma
o Associated with virilization
- Ex. A 60-year-old man with small cell carcinoma of the lung is rushed to the emergency room in a coma after suffering a clonic-tonic seizure. The patient’s
temperature is 37°C (98.6°F), blood pressure 100/50 mm Hg, and pulse 88 per minute. Laboratory studies show a serum sodium of 103 mmol/L, normal serum levels
of BUN and creatinine, and a dilute but otherwise normal urine. A CT scan of the head is normal. Which of the following is the most likely cause of seizures in this
patient? Syndrome of inappropriate ADH secretion
o The inappropriate production of ADH by a tumor may cause a paraneoplastic syndrome that features water retention, which is manifested as water
intoxication with hyponatremia, resulting in altered mental status, seizures, coma, and sometimes death. This syndrome is most often related to small cell
carcinoma of the lung. It is also reported with carcinomas of the prostate, gastrointestinal tract, and pancreas and with thymomas, lymphomas, and
Hodgkin disease
Adrenocortical adenoma
- Mostly clinically silent
o Well-circumscribed, nodular lesion up to 2.5 cm in diameter
o Functional adenomas are associated with atrophy of the adjacent cortex
o Cortex adjacent to non-functional adenomas is normal
- C/S: yellow to yellow-brown (presence of lipid)
- Microscopic:
o Cells similar to cells of normal adrenal cortex
o Some pleomorphism (“endocrine atypia”)
o Cytoplasm eosinophilic to vacuolated, depending on lipid content
o Mitotic activity is generally inconspicuous
- Ex. A 39-year-old man has had headache, weakness, and a 5-kg weight gain over the past 3 months. He has experienced mental depression during the same period.
On physical examination, his face is puffy. His temperature is 36.9Åã C and blood pressure is 160/75 mm Hg. He has cutaneous striae over the lower abdomen and
ecchymoses scattered over the extremities. A radiograph of the spine shows a compressed fracture of T11. Laboratory mmol/L. The plasma cortisol level is 38 μg/dL
at 8:00 am and 37 μg/dL at 6:00 pm. Administration of low and high doses of dexamethasone fails to suppress the plasma cortisol level and excretion of urinary 17-
hydroxycorticosteroids. The plasma corticotropin level is 0.8 pg/mL. Which of the following lesions is most likely to be present in this man? Adrenal cortical
adenoma
o The clinical and laboratory features of this case point to Cushing syndrome. The dexamethasone suppression test is used to localize the source of excess
cortisol. When low-dose and high-dose dexamethasone trials fail to suppress cortisol secretion, a pituitary corticotropin-secreting adenoma as the source
of excess glucocorticoids is unlikely. The choice is an ectopic source of corticotropin, such as a lung cancer, or a tumor of the adrenal cortex that is
secreting glucocorticoids. The plasma corticotropin level distinguishes between these two possibilities. Corticotropin levels are high if there is an ectopic
source, whereas glucocorticoid secretion from an adrenal neoplasm suppresses corticotropin production by the pituitary, leading to atrophy of the
contralateral adrenal cortex.
- Ex. A 28-year-old, otherwise healthy man has had headaches for the past 2 weeks. Physical examination yields no remarkable findings except for a blood pressure of
174/116 mm Hg. An abdominal CT scan shows an enlarged right adrenal gland. A right adrenalectomy is done; the figure shows the gross appearance of the
specimen. Which of the following laboratory findings in his blood was most likely reported in this patient before surgery? Low renin level
o The figure shows a circumscribed tumor that has arisen in the adrenal cortex. In young, otherwise healthy individuals who are hypertensive, a surgically
curable cause of hypertension should be sought, because the far more common essential hypertension is found in an older patient population. This patient
had an adrenal cortical adenoma that secreted aldosterone (Conn syndrome). Hyperaldosteronism reduces the synthesis of renin by the juxtaglomerular
apparatus in the kidney. Adrenal adenomas can be nonfunctional or can secrete glucocorticoids or mineralocorticoids. Had this been a glucocorticoid-
secreting adenoma, the patient could be hypertensive, but he also would have some clinical features of Cushing syndrome. There is no effect on blood
glucose or insulin levels. Patients with hyperaldosteronism have low serum potassium levels, and sodium retention occurs. Aldosterone does not exhibit
feedback suppression of the anterior pituitary, and corticotropin levels are not
affected.
Adrenocortical carcinomas
- More likely to be functional than adenomas
o Virilism or other clinical manifestations of hyperadrenalism
 - Mostly large, invasive lesions, may exceed 20 cm in diameter
- C/S: variegated, poorly demarcated lesions containing areas of necrosis, hemorrhage, and cystic change
- Strong tendency to invade the adrenal vein, vena cava, and lymphatics
- Metastases to regional and periaortic nodes are common
- Distant hematogenous spread to the lungs and other viscera
- Median patient survival is about 2 years
- Well-differentiated to bizarre, monstrous giant cells
- Some composed predominantly of spindle cells
- Metastatic bronchogenic carcinomas may be difficult to differentiate from primary cortical
carcinomas
- Metastases are more common than primary adrenocortical carcinomas
- Adrenal carcinoma (A) revealing marked anaplasia, contrasted with normal adrenal cortical cells
(B)
- Ex. A 43-year-old woman has had absent menstrual cycles along with increasing weakness and weight gain over the past 5 months. She notes low back pain for the
past week. On physical examination, vital signs include blood pressure of 155/95 mm Hg. She has a prominent fat pad in the posterior neck and back. Facial plethora,
hirsutism, and abdominal cutaneous striae are present. Laboratory findings include Na+, 139 mmol/L; K+, 4.1 mmol/L; Cl–, 96 mmol/L; CO2, 23 mmol/L; glucose,
163 mg/dL; creatinine, 1.3 mg/dL; calcium, 8.9 mg/dL; and phosphorus, 4.1 mg/dL. Her serum ACTH level is low. A radiograph of the spine shows decreased bone
density with a compression fracture at T9. Which of the following radiographic findings is most likely to be present in this patient? Adrenal 10-cm solid mass with
abdominal CT scan
o The clinical findings of Cushing syndrome with masculinization suggest an adrenal cortical carcinoma, which
is more likely to have endocrine function in women.
Other Adrenal lesions
- Adrenal myelolipomas
o Unusual benign lesions composed of mature fat and hematopoietic cells
- Adrenal incidentaloma
o Incidental discovery of adrenal masses in asymptomatic individuals or individuals in whom the presenting complaint is not directly related to the
adrenal gland
o Prevalence of “incidentalomas” discovered by imaging is 4%, with an age-dependent increase
o Majority are small non-secreting cortical adenomas of no clinical importance
Adrenal medulla
- Chromaffin cells and Sustentacular cells
- Major source of catecholamines (epinephrine, norepinephrine)
- Extra-adrenal paraganglia
o Branchiomeric
o Intravagal
o Aorticosympathetic
Pheochromocytoma
- Composed of chromaffin cells (synthesize and release catecholamines)
- Rare cause of surgically correctable hypertension
- “Rule of 10s”
o 10% of pheochromocytomas are extra-adrenal (Paragangliomas)
o 10% of sporadic adrenal pheochromocytomas are bilateral
o 10% are biologically malignant
o 10% are not associated with hypertension
- 25% of individuals harbor a germline mutation (2 classes)
o Enhance growth factor receptor pathway signaling (RET, NF1)
o Increase activity of transcription factor HIF-1α (VHL)
o Younger age, more likely to be bilateral
- Morphology
o Small, circumscribed lesions to large hemorrhagic masses
o Richly vascularized fibrous trabeculae produce a lobular pattern
o C/S: Smaller tumors are yellow-tan. Larger lesions tend to be hemorrhagic, necrotic, and cystic and efface the adrenal gland
o Incubation of fresh tissue with a potassium dichromate solution turns the tumor a dark brown color (CHROMAFFIN)
o Definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the presence of metastases
- Microscopic features
o Clusters of polygonal to spindle-shaped chromaffin cells or chief cells surrounded by supporting sustentacular cells, creating small nests or alveoli
(zellballen) supplied by a rich vascular network
o Cytoplasmic granularity best demonstrated with silver stains (due to the presence of granules containing
catecholamines)
o Round to ovoid nuclei with a stippled “salt and pepper” chromatin
o Electron microscopy: membrane-bound, electron-dense secretory granules
o Immunoreactivity
 Neuroendocrine markers (Chromogranin and Synaptophysin) in the chief cells
 S-100 in the peripheral sustentacular cells
- Clinical Course
o Hypertension in 90% of patients, most patients demonstrate chronic, sustained elevation in blood pressure
punctuated by paroxysms
o Paroxysmal episodes
 Associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension (not seen in essential hypertension)
 May be associated with pain in the abdomen or chest, nausea, and vomiting
 Precipitated by emotional stress, exercise, changes in posture, and palpation in the region of the tumor
 May acutely precipitate congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular
accidents
o Catecholamine cardiomyopathy, catecholamine-induced myocardial instability and ventricular arrhythmias
o Patients with urinary bladder paragangliomas occasionally precipitate a paroxysm during micturition
- Diagnosis and Treatment
o Demonstration of ↑urinary excretion of free catecholamines and their metabolites (vanillylmandelic acid and
metanephrines)
o Isolated benign tumors
 Treated with surgical excision, after preoperative and intraoperative medication of patients with
adrenergic-blocking agents to prevent a hypertensive crisis
o Multifocal lesions
  Require long-term medical treatment for hypertension
- Ex. A 37-year-old woman states that, although most of the time she feels fine, she has had episodes of palpitations, tachycardia, tremor, diaphoresis, and headache
over the past 3 months. When her symptoms are worse, her blood pressure is measured in the range of 155/90 mm Hg. She collapses suddenly one day and is brought
to the hospital, where her ventricular fibrillation is converted successfully to sinus rhythm. On physical examination, there are no remarkable findings. Which of the
following laboratory findings is most likely to be reported in this patient? Increased urinary free catecholamines
- Ex. The tumor in the patient described in Question 38 is removed, and a section stained with Congo red reveals birefringent amyloid stroma. Genetic studies show
that this patient has a familial cancer syndrome. In addition to hyperparathyroidism, the patient is advised that she is at risk of developing which of the following
neoplastic diseases? Pheochromocytoma
- A 34-year-old man complains of sudden attacks of dizziness, blurred vision, and excruciating headaches of 4 months in duration. During one of these attacks, his
blood pressure was 180/120 mm Hg. The patient’s father had been treated for thyroid cancer about 15 years ago. Laboratory studies show normal serum levels of
aldosterone, renin, and angiotensin. A 24-hour urinalysis reveals increased metanephrines. Episodic hypertension in this patient is most likely caused by a tumor in
which of the following endocrine organs? Adrenal
o Pheochromocytoma is a rare tumor of chromaffi n cells of the adrenal medulla that secretes catecholamines. Such tumors also originate in extra-adrenal
sites, in which case they are termed paragangliomas. The clinical features associated with pheochromocytoma are caused by the release of
catecholamines. Patients with pheochromocytoma come to medical attention because of (1) asymptomatic hypertension discovered on a routine physical
examination, (2) symptomatic hypertension that is resistant to antihypertensive therapy; (3) malignant hypertension (e.g., encephalopathy, papilledema,
proteinuria), (4) myocardial infarction or aortic dissection, or (5) convulsions.
Neuroblastoma
- Tumors of sympathetic ganglia and adrenal medulla derived from primordial neural crest cells
- Most common extracranial solid tumor of childhood
- Mostly sporadic, 1-2% are familial (germline mutations in the anaplastic lymphoma kinase)
- 5-year survival about 40%
- Locations
o Adrenal medulla(40%)
o Sympathetic chain in paravertebral region of abdomen (25%) and posterior mediastinum (15%)
o Pelvis, neck, brain
- Morphology
o In-situ lesions to large masses (>1 kg)
o C/S: soft grey tan (larger tumors have areas of necrosis, cystic change , hemorrhage or calcification)
o Adrenal neuroblastoma in a 6-month-old child, the hemorrhagic, partially encapsulated tumor has displaced the opened left kidney and is impinging
on the aorta and left renal artery
- Microscopic appearance
o Small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders growing in solid sheets
o Mitotic activity, nuclear breakdown (“karyorrhexis”), and pleomorphism
o Background of faintly eosinophilic fibrillary material (neuropil)
o Homer-Wright pseudorosettes
- Positive immunohistochemical reactions for neuron-specific enolase
- Ex. A 25-year-old woman gives birth to a term infant following an uncomplicated pregnancy. On physical examination,
the newborn is found to have an enlarged abdomen, but there are no other abnormal findings except for slightly elevated
blood pressure. An abdominal ultrasound scan shows a right retroperitoneal mass in the adrenal gland. An increase in
which of the following substances is most likely to be associated with the lesion in this neonate? Urinary
homovanillic acid (HVA) level
- Ex. A 4-year-old girl is brought to the pediatric clinic by her mother who reports that her daughter has decreased
appetite, lethargy, and an enlarging belly. Physical examination reveals a large, firm, irregular, nontender mass in the
child’s abdomen. A CT-guided biopsy reveals neoplastic “small blue cells.” The child’s malignant neoplasm is
removed and the surgical specimen is shown in the image. Which of the following laboratory tests would be useful in monitoring this patient for recurrence of
disease? Urinary vanillylmandelic acid.
 Genetic analysis of tumor cells taken from the patient described in Question 41 may reveal which of the following mutations? N-myc
amplification
-
Spontaneous or therapy induced maturation
- Ganglioneuroblastoma
o larger cells with more abundant cytoplasm, large vesicular nuclei, and a prominent nucleolus (ganglion cells) admixed with primitive neuroblasts
- Ganglioneuroma
o more mature ganglion cells with few neuroblasts
- Presence of “Schwannian stroma” (organized fascicles of neuritic processes, mature Schwann cells, and fibroblasts) is a histologic prerequisite for
ganglioneuroblastoma and ganglioneuroma (favorable outcome)
- Ganglioneuromas (spontaneous or therapy induced maturation of neuroblastomas): large cells with vesicular nuclei and abundant eosinophilic cytoplasm represent
neoplastic ganglion cells (arrow), spindle-shaped Schwann cells are present in the background stroma
Clinical Course
- Children < 2 years, - large abdominal masses, fever, and weight loss
- Older children
o Metastases produce bone pain, respiratory symptoms, or gastrointestinal complaints, proptosis and ecchymosis
o Bladder and bowel dysfunction from paraspinal neuroblastomas
- Neonates - disseminated neuroblastomas with multiple cutaneous metastases cause deep blue discoloration of skin
(“blueberry muffin baby”)
- “Blueberry muffin baby” - large adrenal neuroblastoma, creating a greatly distended abdomen with numerous bluish
subcutaneous nodules of tumor
Prognostic factors
- Age and stage
o Stages 1, 2A, or 2B: excellent prognosis, irrespective of age
o Stage 4S: Special subtype: spontaneous regression
- Children < 18months: excellent prognosis, irrespective of stage
o Morphology – better prognosis with differentiation
- Amplification of the MYCN oncogene: “high”-risk category, irrespective of age, stage, or histology
- Ploidy of the tumor cells
o Correlates with outcome in children <2 years
o Hyper-diploid : better prognosis
o Chromothripsis
Molecular variables with prognostic implications
- Chromosomal deletions
o Hemizygous deletion of 1p36: MYCN amplification
o Hemizygous loss of 11q genetic material: adverse prognosis
 - Expression of specific neurotrophin receptors
o High TrkA expression - favorable (low-stage tumors lacking MYCN amplification, younger patients)
o High TrkB expression – unfavorable (MYCN amplification and higher disease stage)
- Recurrent mutations in genes involved in neuritogenesis
o more aggressive, higher stage neuroblastomas
Screening programs
- 90%, regardless of location, produce catecholamines - diagnostic
o ↑blood levels of catecholamines
o ↑urine levels of vanillylmandelic acid and homovanillic acid
- Community-based screening programs for neuroblastomas are not currently advocated
o 2 large studies in Europe and North America failed to demonstrate improved mortality rates with population screening
o Most tumors detected had favorable biologic characteristics
Experimental treatment strategies
- Use of retinoids as an adjunct therapy for inducing the differentiation of neuroblastoma
- Tumors harboring activating ALK mutations are potentially susceptible to targeted inhibitors of ALK
Multiple Endocrine Neoplasia Syndromes (MEN)
- Tumors occur at a younger age than sporadic tumors
- Arise in multiple endocrine organs, either synchronously (at the same time) or metachronously (at different times)
- Even in one organ, the tumors are often multifocal
- The tumors are usually preceded by an asymptomatic stage of hyperplasia involving the cell of origin
- These tumors are usually more aggressive and recur in a higher proportion of cases than do similar sporadic endocrine tumors
- Ex. A 27-year-old man has headaches that have occurred frequently for the past 3 months. On physical examination, he is afebrile, and his blood pressure is 140/85
mm Hg. There are no neurologic abnormalities and no visual defects; however, he has an enlarged thyroid. Laboratory studies show that his serum calcitonin level is
elevated. A total thyroidectomy is performed, and on sectioning, the thyroid has multiple tumor nodules in both lobes. Microscopically, the thyroid nodules are
composed of nests of neoplastic cells separated by amyloidrich stroma. The endocrinologist says that the patient’s family members could be at risk for development of
similar tumors and advises that they undergo genetic screening. Which of the following morphologic findings in the adrenal glands is most likely to be present in this
patient? Bilateral 4-cm medullary masses
o These findings suggest multiple endocrine neoplasia (MEN) type 2A (Sipple syndrome) or possibly MEN type 2B (Williams syndrome). These patients
have medullary carcinomas of the thyroid, pheochromocytomas, and parathyroid adenomas. This patient’s headaches could be caused by hypertension
from a pheochromocytoma arising in the adrenal medulla. More than 70% of cases of pheochromocytomas are bilateral when familial. Medullary
carcinoma also tends to be multifocal in this syndrome. This syndrome is associated with germline mutations in the RET proto-oncogene. Family
members who inherit the same mutation are at increased risk of developing similar cancers. Genetic screening followed by increased surveillance of
affected family members is advised.
Multiple Endocrine Neoplasia, Type 1
- Wermer syndrome, 3 Ps - Parathyroid, Pancreas, and Pituitary glands
- Parathyroid:
o Primary hyperparathyroidism is the most common manifestation (80 to 95% )
o In almost all patients by age 40 to 50
o Hyperplasia and adenomas
- Pancreas:
o Leading cause of morbidity and mortality in persons with MEN-1
o Usually aggressive and often present with metastatic disease
o Mostly functional
 Pancreatic polypeptide is the most commonly secreted product , hence no hypersecretion syndrome
 Gastrinomas (Zollinger Ellison syndrome) Insulinomas (hypoglycemia)
- Pituitary
o Prolactinoma is the most common
- Ex. A 26-year-old man developed sudden severe abdominal pain. On physical examination, he had marked abdominal tenderness and guarding. Laboratory studies
showed serum glucose, 76 mg/dL; calcium, 12.2 mg/dL; phosphorus, 2.6 mg/dL; creatinine, 1.1 mg/dL; and parathyroid hormone, 62 pg/mL (normal range 9 to 60
pg/mL). During surgery, four enlarged parathyroid glands were found and excised, with reimplantation of one half of one gland. After the surgery, serum calcium
concentration returned to normal. Three years later, he had an episode of upper gastrointestinal hemorrhage. An endoscopy and biopsy specimen showed multiple
benign gastric ulcerations. Abdominal MRI indicated multiple 1- to 2-cm mass lesions in the pancreas. He underwent surgery, and multiple tumors were found.
Which of the following additional neoplasm lesions is he most likely to have? Pituitary adenoma
Multiple Endocrine Neoplasia, Type 1
- Germline mutations in the MEN1 tumor suppressor gene, which encodes a protein called menin
o MEN1 inactivating mutations
 Menin + JunD blocks transcriptional activation by JunD (loss of this tumor suppressor interaction contributes to MEN-1)
o Wild-type menin + MLL leads to the formation of a tumor promoting transcriptional complex in a subset of leukemias
- Clinical presentation: recurrent hypoglycemia due to insulinomas, intractable peptic ulcers in persons with Zollinger-Ellison syndrome, nephrolithiasis caused by
PTH-induced hypercalcemia, or symptoms of prolactin excess from a pituitary tumor
Multiple Endocrine Neoplasia, Type 2A
- Sipple syndrome “Medullary carcinoma thyroid + pheochromocytoma + parathyroid hyperplasia”
- Medullary carcinomas
o Almost 100% of patients, multifocal and associated with foci of C-cell hyperplasia in the adjacent thyroid. May elaborate calcitonin, clinically aggressive
- Pheochromocytoma
o 40 to 50% of patients, bilateral and may arise in extra-adrenal sites
- Parathyroid hyperplasia and evidence of hypercalcemia or renal stones
o 10% to 20% of patients
- Germline gain-of-function mutations in the RET proto-oncogene on chromosome 10q11.2 - constitutively activate the RET receptor
- Loss-of-function mutations in RET lead to intestinal aganglionosis and Hirschsprung disease
Multiple Endocrine Neoplasia, Type 2B
- Medullary Thyroid Carcinomas + Pheochromocytomas + Neuromas / Ganglioneuromas + Marfanoid Habitus
- No primary hyperparathyroidism
- Medullary Thyroid Carcinomas
o multifocal and more aggressive than in MEN-2A
- Germline mutation leading to a single amino acid change in RET, distinct from the mutations that are seen in MEN-2A
- Diagnosis via screening of at-risk family members in MEN-2 kindred is important because medullary thyroid carcinoma is a life-threatening disease that can be
prevented by early thyroidectomy
- Familial medullary thyroid cancer is a variant of MEN-2A, in which there is a strong predisposition to medullary thyroid cancer but not the other clinical
manifestations of MEN-2A or MEN-2B