VIVAs in Surgical Pathology For DM 1

What is a Neoplasm? Define neoplasia?

Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue
and persist in the same excessive manner after cessation of stimuli which evoked the change. – Willis

 Genetic alterations, mutations in growth mechanisms

 Autonomous , do not respond to the usual mechanisms of growth regulation
 Clonal

What is desmoplasia?

Define hyperplasia, hypertrophy, dysplasia and metaplasia

Differentiate between Benign Vs. Malignant neoplasms

 Rate of growth
 Differentiation
 Local invasion
 Metastasis

All of the following are malignant tumours except

What is meant by the term “transformation”?

The process by which normal cells become malignant

Define sarcoma?

Define Adenoma?

Define “hamartoma”?
Disorganized mass of tissue whose cell types are indigenous to the site of the lesion

Define Choristoma:

ectopic focus of normal tissue ( heterotopia)

How are Benign tumour’s be distinguished from malignant tumours

What is meant by the term “Differentiation”?

Degree to which cells resemble mature cells of the tissue of origin

Thought to correlate with biologic behaviour, poor differentiation usually have worse prognosis

What is “Anaplasia’?
Undifferentiated, synon with malignancy
 1. Pleomorphism-(variation in cell size and shape)- particularly nuclei size , shape
2. Abnormal nuclear morphology-hyperchromasia, high N/C ratio, chromatin clumping, prominent
nucleoli- hematoxyinophilic
3. Mitoses- mitotic rate (2,3,5-10), location of mitoses
4. Loss of polarity (nuceli haphazard)

Define Tumour grade

Define Tumour stage

What are the hallmarks of malignancy?

What is Pleomorphism

What are the microscopic features of anaplasia

Define Metaplasia

Define Dysplasia

1. Abnormal growth, A part of the malignant transformation process

2. Some but not all features of malignancy may be present
3. May or may not develop into malignancy. E,g. uterine cervix, colon polyps
4. Graded as low or high

Define Carcinoma in situ

“Carcinoma” that has not infiltrated or invaded the basement membrane

Carcinoma insitu vs. dysplasia?

CIN-3

What are the main factors that determine the rate of growth of tumour
cells?
 Months or years 1 transformed cell -30 doubling
 1kg-lethal burden
 30 doublings-1g
 10 more -1kg
 Cells grow, die or mature

Define Growth fraction

Features of malignant cells

 Cellular features-
 Local invasion- capsule, basement membrane
 Metastasis-
 o unequivocal sign,
o Peritoneal seeding,
o lymphatic,
o hematogenous

Define metastasis?

What are the pathways of spread of metastasis?

What is a sentinel lymph node?

What is carcinogenesis?

List and discuss the risk factors associated with cancer

 Geographical & environmental

1. Sun exposure
2. Smoking
3. Alcohol abuse
4. Body mass
5. Body mass
6. Environmental vs racial
7. Viral exposure
 Age
 Genetic predisposition
 Nonhereditary predisposition- chronic inflammatory conditions by itself does not cause
cancer
What are the different inflammatory conditions that may lead to cancer?

 Ulcerative colitis
 Chronic Atrophic Gastritis
 Chronic Leg ulcer-marjolin

What are precursor lesions and give examples

What are Proto-oncogenes?

normal cellular genes whose products promote cell proliferation

What are the different kinds of cancer genes?

Molecular basis of cancer

 Non-lethal genetic damage

 Tumour- clonal expansion of a single precursor cell
 4 classes of normal regulatory genes
o Proto-oncogene
o Oncogeneoncoprotein
o DNA repair genes
o Apoptosis genes

Carcinogenesis- multistep process

What is an Oncogene?

mutant or overexpressed versions of proto-oncogenes that function autonomously without a

requirement for normal growth-promoting signals

oncogenes are genes that induce a transformed phenotype when expressed in cells by promoting
increased cell growth. A major discovery in cancer was the realization that oncogenes are mutated or
overexpressed versions of normal cellular genes, which are called proto-oncogenes. Most oncogenes
encode transcription factors, factors that participate in pro-growth signaling pathways, or factors that
enhance cell survival. They are considered dominant genes because a mutation involving a single allele is
sufficient to produce a pro-oncogenic effect.

Examples:

Growth factors:

 c-SIS

Receptor tyrosine Kinases:

 EGFR, VEGF, PDGF, HER2/neu (add phosphate groups to switch proteins on / OFF

Cytoplasmic tyrosine Kinases:

 Abl-CML (Phil CHr)

 Cytoplasmic Serine/ threonine kinases- RAF kinase & cyclin dependent kinase

Regulatory GTPases:

 Ras Protein- hydrolyses GTP to GDP and a phosphate once activated by a growth factor eg. EGF
or TGF beta ( ras on switch in signaling pathways that lead to cellular growth and proliferation

Transcription Factors

 nMyc gene- regulates transcription of genes that induce cellular proliferation

What is a Tumour suppressor Gene?

are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, allow the
transformed phenotype to develop. Often both normal alleles of tumor suppressor genes must be
damaged for transformation to occur. Tumor suppressor genes can be placed into two general groups,
“governors” that act as important brakes on cellular proliferation, and “guardians” that are responsible
for sensing genomic damage. Some guardian genes initiate and choreograph a complex “damage control
response” that leads to the cessation of proliferation or, if the damage is too great to be repaired, or
induce apoptosis.

List autosomal dominant and autosomal recessive conditions that predispose to cancer formation

What are driver mutations? What are “passenger” mutations?

What are the different types of ways a driver mutation may be acquired?

What are the different types of genetic mutations, or genetic alterations that can lead to
carcinogenesis?

Define carcinogenesis?

a multistep process resulting from the accumulation of multiple genetic alterations that collectively give
rise to the transformed phenotype and all of its associated hallmarks

What are the Hallmarks of Cancer and enabling factors?

1. Self sufficiency in growth signals

2. Insensitivity to growth inhibiting signals
3. Evasion of apoptosis
4. Defects in DNA repair “spell checker
5. Limitless replicative potential-telomerase
6. Angiogenesis
7. Invasive ability
8. Metastatic ability

Briefly Outline components of the growth signal pathway

Write short notes on the RAS oncoprotein and the ABL Proto-onco-protein

The ultimate consequence of signaling through oncoproteins such as RAS or ABL is inappropriate and
continuous stimulation of nuclear transcription factors that drive the expression of growth-promoting
genes.

Explain the concept of Oncogene addiction

a tumor is profoundly dependent on a single signaling molecule.

Write short notes on Nuclear transcription factors

A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, function as
transcription factors that regulate the expression of growth-promoting genes, such as cyclins. Of these,
MYC is involved most commonly in human tumors

How does dysregulation of MYC promote tumorigenesis?

by simultaneously promoting the progression of cells through the cell cycle and enhancing alterations in
metabolism that support cell growth.

MYC primarily functions by activating the transcription of other genes.

Genes activated by MYC include several growth-promoting genes, including cyclin-dependent kinases
(CDKs), whose products drive cells into the cell cycle (discussed next), and genes that control pathways
that produce the building blocks (e.g., amino acids, lipids, nucleotides) that are needed for cell growth
and division

What is the role of cyclin dependent Kinases?

progression of cells through the cell cycle is orchestrated by cyclin-dependent kinases (CDKs), which are
activated by binding to cyclins, so called because of the cyclic nature of their production and
degradation

The CDK-cyclin complexes phosphorylate crucial target proteins that drive cells forward through the cell
cycle. While cyclins arouse the CDKs, CDK inhibitors (CDKIs), of which there are many, silence the CDKs
and exert negative control over the cell cycle. Expression of these inhibitors is downregulated by
mitogenic signaling pathways, thus promoting the progression of the cell cycle

What are the two main cell cycle check points

What are the mechanisms by which onco-proteins promote uncontrolled cell proliferation?

Write short notes on Tumour suppressor Genes

Outline the role RB protein

“Governor of the cell cycle”

The function of the RB protein is to regulate the G1/S checkpoint, the portal through which cells must
pass before DNA replication commences
RB exerts anti-proliferative effects by controlling the G1-to-S transition of the cell cycle. In its active
form, RB is hypo-phosphorylated and binds to E2F transcription factors. This interaction prevents
transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in
G1.

What is Knudson’s 1974 two hit hypothesis?

Write short notes on TP53

The p53 protein is a transcription factor that thwarts neoplastic transformation by three interlocking
mechanisms: activation of temporary cell cycle arrest (termed quiescence), induction of permanent cell
cycle arrest (termed senescence), or triggering of programmed cell death (termed apoptosis)

If RB is a “sensor” of external signals, p53 can be viewed as a central monitor of internal stress, directing
the stressed cells toward one of these pathways

To summarize, p53 is activated by stresses such as DNA damage and assists in DNA repair by causing G1
arrest and inducing the expression of DNA repair genes

*TP53 encodes p53, the central monitor of stress in the cell, which can be activated by anoxia,
inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expression and activity of
genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis.

• DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of
CDKN1A (p21), which prevents RB phosphorylation, thereby causing a G1-S block in the cell cycle. This
pause allows the cells to repair DNA damage. • If DNA damage cannot be repaired, p53 induces cellular
senescence or apoptosis. • Of human tumors, 70% demonstrate biallelic mutations in TP53. Patients
with the rare Li-Fraumeni syndrome inherit one defective copy of TP53 in the germ line, such that only
one additional mutation is required to lose normal p53 function. Li-Fraumeni syndrome patients are
prone to develop a wide variety of tumors. • As with RB, p53 can be incapacitated when bound by
proteins encoded by oncogenic DNA viruses such as HPV

Describe the WNT signaling pathway

What is the role of the APC gene?

Is a tumour suppressor gene that encodes a cytoplasmic protein whose dominant function is to promote
the degradation of β-catenin, which has several functions.

TGF-β, CONTACT INHIBITION,AND APC-βCATENIN PATHWAYS

• TGF-β inhibits proliferation of many cell types by activation of growth-inhibiting genes such as CDKIs
and suppression of growth-promoting genes such as MYC and those encoding cyclins. • TGF-β function is
compromised in many tumors by mutations in its receptors (colon, stomach, endometrium) or by
mutational inactivation of SMAD genes that transduceTGF-β signaling (pancreas). • E-cadherin maintains
contact inhibition, which is lost in malignant cells. • The APC gene exerts anti-proliferative actions by
regulating the destruction of the cytoplasmic protein β-catenin.With a loss of APC, β-catenin is not
destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor. •
In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and
sporadic loss of the sole normal allele causes the development of hundreds of colonic polyps at a young
age. Inevitably, one or more of these polyps evolves into a colonic cancer. Somatic loss of both alleles of
the APC gene is seen in approximately 70% of sporadic colon cancers.

What is the Warburg effect

Even in the presence of ample oxygen, cancer cells demonstrate a distinctive form of cellular
metabolism characterized by high levels of glucose uptake and increased conversion of glucose to
lactose (fermentation) via the glycolytic pathway

Altered Cell Metabolism in cancer

Warburg metabolism is a form of pro-growth metabolism favoring glycolysis over oxidative

phosphorylation. It is induced in normal cells by exposure to growth factors and becomes fixed in cancer
cells due to the action of certain driver mutations.

• Many oncoproteins (RAS, MYC, mutated growth factor receptors) induce or contribute to Warburg
metabolism, and many tumor suppressors (PTEN, NF1, p53) oppose it. • Stress may induce cells to
consume their components in a process called autophagy. Cancer cells may accumulate mutations to
avoid autophagy, or may corrupt the process to provide nutrients for continued growth and survival.

• Some oncoproteins such as mutated IDH act by causing the formation of high levels of
“oncometabolites” that alter the epigenome,thereby leading to changes in gene expression that are
oncogenic.

Define the term Apoptosis

Regulated cell death, refers to an orderly dismantling of cells into component pieces, which are then
efficiently consumed by neighboring cells and professional phagocytes without stimulating inflammation

A pathway of cell death that is induced by a tightly regulated suicide program in which the cells are
destine dto die activate enzymes capable of degrading the cells own nuclear DNA and proteins.

What are the morphologic features of the apoptotic cell?

What are the two pathways that apoptosis can occur?

List ways apoptosis may be initiated

What is the intrinsic pathway of apoptosis?

What are the mechanisms by which cells evade apoptosis?

Evasion of cell death by cancers mainly involves acquired abnormalities that interfere with the intrinsic
(mitochondrial) pathway of apoptosis. • The most common abnormalities involve loss of p53 function,
either by way of TP53 mutations or overexpression of the p53 inhibitor MDM2. • Other cancers evade
cell death by overexpressing anti-apoptotic members of the BCL2 family,such as BCL2, BCL-XL, and
MCL1, which protect cells from the action of BAX and BAK, the pro-apoptotic members of the BCL2
family. • In a large majority of follicular B-cell lymphomas, BCL2 levels are high because of a (14;18)
translocation that fuses the BCL2 gene with regulatory elements of the immunoglobulin heavy chain
gene. • Inhibitors of MDM2 (which activate p53) and inhibitors of BCL2 family members induce the
death of cancer cells by stimulating the intrinsic pathway of apoptosis and are being developed as
therapeutic agents.

How do growing tumours develop a blood supply

Hypoxia triggers angiogenesis through the actions of HIF-1α on the transcription of the proangiogenic
factor VEGF. • Many other factors regulate angiogenesis; for example, p53
inducessynthesisoftheangiogenesisinhibitorthombospondin-1, while RAS, MYC, and MAPK signaling all
upregulate VEGF expression and stimulate angiogenesis. • VEGF inhibitors are used to treat a number of
advanced cancers and prolong the clinical course, but are not curative

What are the phases of the metastatic cascade?

What is the role of E-Cadherin?

What are the steps involved in invasion and metastases?

What is the concept of immune surveillance

Give examples of different defects in DNA repair systems

What are the three classes of Carcinogenic agents?

1. Chemical
2. Radiant energy/ Radiation
3. Microbial products

Chemical agents can be divided into direct and indirect. Indirect must first be metabolized

How does radiation cause Carcinogenesis?

What are the clinical manifestations of Cancer?
What is a paraneoplastic syndrome and give examples
Write short notes on tumour markers