Tumour Pathology

Question 1

Describe the main differences between benign and malignant tumours

Answer 1

Both differ in various ways:
•	Growth pattern
•	Presence of capsule
•	Invasion
•	Presence of metastases
•	Differentiation
•	Appearance of tumour cells
•	Function
•	Behaviour

Question 2

Describe the properties of benign cancer cells

Answer 2

• Non-invasive growth pattern
• Usually encapsulated
• No evidence of invasion
• No metastases
• Cells similar to normal in function and appearance
• Benign tumours are “well-differentiated”
• Rarely cause death

Question 3

Describe the systemic effects of cancer

Answer 3

• Secretion of hormones
• Weight loss-cachexia – unwanted, though can also be due to obstruction etc.
• Paraneoplastic syndromes
• Effects of treatment

Question 4

Describe the local effects of cancer

Answer 4

Pressure
Obstruction
Tissue destruction during invasion
Bleeding due to damage of vessels during invasion
Pain due to pressure on nerves
Effects of treatments e.g. IV infusion reactions

Question 5

Identify the concepts of neoplasia and intraepithelial dysplasia

Answer 5

Dysplastic = abnormal growth or development of existing tissue. 
Neoplastic = relates to a new growth or tumor.

Question 6

Describe the cell cycle of normal cells

Answer 6

Mitosis:
• Mechanism of cellular replication
• Nuclear division plus cytokinesis
• Generates two identical diploid daughter cells
Cell Cycle = time interval between mitotic divisions. Called interphase where the chromosomes and cellular contents are duplicated.

Question 7

Outline the process of carcinogenesis and describe its effects on the cell cycle. 


Answer 7

• Cancer is a genetic disease
• Carcinogenesis is caused by mutation of genetic material that upsets the normal balance between proliferation and apoptosis (cell death)
• Uncontrolled proliferation of cells leads to tumours
• Only mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation via cell cycle dysregulation

Question 8

List the major aetiological agents of cancer. 


Answer 8

• Non-lethal genetic damage - Environmental agents e.g. Chemicals, Radiation, Oncogenic viruses
• Inherited
• Geographic and environmental factors
• Age

Question 9

Describe the properties of a cancer cell

Answer 9

•	Altered genetics
–	Loss of tumour suppressor genes
–	Gain of function of oncogenes
•	Altered cellular function
–	Tumour-related proteins
•	Abnormal morphology
•	Cells capable of independent growth
•	But no single feature is unique to cancer cells

Question 10

What is the clinical significance of cancer biomarkers?

Answer 10

• Screening
• Diagnosis
• Prognostic- Identifying patients specific outcome
• Predictive - who will respond to a particular therapy

Question 11

Give some examples of cancer biomarkers

Answer 11

Alpha-fetoprotein
•	Teratoma of testis
•	Hepatocellular carcinoma
Carcino-embryonic antigen (CEA)
•	Colorectal cancer
Oestrogen receptor
•	Breast cancer
Prostate specific antigen
•	Prostate cancer

Question 12

Describe some clinically useful predictive biomarkers

Answer 12

Kras (GTPase)
–	Colorectal cancer
EGFR (epidermal growth factor receptor)
–	Lung cancer
Her2 (neu in rodents, EGFR associated with aggressive breast cancers) 
–	Breast cancer
–	Gastric cancer
Braf (protooncogene that helps direct cell growth)
–	Melanoma

Question 13

How can we identify cancer cells by appearance alone?

Answer 13

• Cellular and nuclear pleomorphism
– Marked variation in size and shape
• Mitoses (dividing cells) present and often abnormal

Question 14

What usually worsens the prognosis of cancer?

Answer 14

High degree of angiogenesis, invasion and cancer spread

Question 15

Describe the different modes of cancer spread

Answer 15

• Local spread
• Lymphatic spread
• Blood spread
• Trans-coelomic spread

Question 16

Describe some common sites of metastases

Answer 16

• Liver
• Lung
• Brain
• Bone - Axial skeleton e.g. vertebrae, pelvis
• Adrenal gland

Question 17

Where do breast cancers commonly metastasise?

Answer 17

Bone

Question 18

Where do prostate cancers commonly metastasise?

Answer 18

Bone

Question 19

Where do colorectal cancers commonly metastasise?

Answer 19

Liver

Question 20

Describe two hormones that are abnormally produced in certain cancers

Answer 20

ACTH - lung cancer

ADH - lung cancer

Question 21

Define paraneoplastic syndromes

Answer 21

Syndromes or symptoms that cannot be explained by local or metastatic effects of tumours, caused by humoral factors e.g. neuropathy, myopathy. Thought they may be caused due to immune or hormonal factors

Question 22

Describe the importance of cyclins, cycling dependent kinases and cyclin dependent kinase inhibitors in cancer

Answer 22

Many genes mutated in cancer regulate the cell cycle
Two regulatory pathways frequently disrupted -
1. The cyclin D-pRb-E2F pathway
2. p53 pathway

Active CDK/cyclin complexes phosphorylate target proteins which results in activation/inactivation of that substrate, which regulate events in the next cycle phase.

pRb is hypophosphorylated, and is phosphorylated by CDK/cyclin complexes as cells progress through the cell cycle. Hypophosphorylated/active Rb inactivates E2F, while phosphorylated/inactive pRb loses affinity for E2F. Free E2F transcription factor activates vital target genes and is a potent stimulator of cell cycle entry. If this system is not regulated, uncontrolled progression through the cell cycle occurs.

Question 23

Where in the cell cycle are cancer cells usually dysregulated and why?

Answer 23

Virtually all cancers are dysregulated at G1-S because of mutation in one of four genes:
o Rb, CDK4, cyclin D and p16

Question 24

What is p53, its function and its role in cancer development?

Answer 24

• p53 is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppressor gene. Maintains genomic integrity
• p53 levels increase in damaged cells and induces cell cycle arrest at G1 to allow DNA repair
• Severe damage: p53-induced apoptosis (programmed cell death)
• Cells with mutated p53 do not G1 arrest or repair damaged DNA and these genetically damaged cells proliferate and form malignant neoplasms

Question 25

Define tumour suppressor genes

Answer 25

Normal growth-inhibiting genes that discourage cell growth or temporarily halt cell division to carry out DNA repair. Huge role in carcinogenesis • Genes negatively regulating mitosis - Rb • Genes regulating apoptosis • Genes regulating DNA repair

Question 26

Define proto-oncogenes

Answer 26

Normal genes that promote normal cell growth and mitosis

Question 27

Describe the two hit hypothesis

Answer 27

The Knudson hypothesis, also known as the two-hit hypothesis or multiple-hit hypothesis, is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA

Question 28

What % of cancers are inherited?

Answer 28

5-10%

Question 29

Whats the difference between inherited cancer and familial cancer?

Answer 29

Inherited cancer syndromes • Strong family history of uncommon site-specific cancers • Autosomal dominant inheritance of a single mutant gene – Increased risk of second cancers eg bone sarcomas ``` Familial cancers • Family clustering of cancers but individual predisposition unclear • Multifactorial inheritance • Early age of onset • Multiple/bilateral tumours ```

Question 30

Name some inherited cancer syndromes

Answer 30

``` Familial retinoblastoma Familial adenomatous polyposis Multiple endocrine neoplasia Neurofibromatosis Von Hippel-Lindau syndrome ```

Question 31

Name some familial cancers

Answer 31

* Some Breast cancers * Some Ovarian cancers * Non-FAP colon cancers

Question 32

How do oncogenes arise from protooncogenes?

Answer 32

Oncogenes are derived from proto-oncogenes, which are activated by: o Alteration of proto-oncogene structure • Point mutation • Chromosome rearrangements + translocations o Dysregulation of proto-oncogene expression • Gene amplification • Overexpression

Question 33

Name some cancers caused by the over expression of some proto-oncogenes

Answer 33

Burkitt lymphome - over expressed c-myc in IgH gene Mantle cell lymphoma - over expressed cyclin D1 in IgH gene

Question 34

Name some cancers caused by recombination of proto-oncogenes to form chimaeric proteins

Answer 34

Chronic myeloid leukaemia

Question 35

Describe how aetiological factors of cancer disrupt the cell cycle

Answer 35

Viruses - insert genomes near protozoans-oncogenes and viral promoter causes over expression or they can insert oncogenes into genome Chemical - Adduct formation at particular chromosome sites lead to activation of oncogenes and suppression of anti-oncogenes e.g. benzopyrene

Question 36

Name some DNA viruses that cause cancer

Answer 36

DNA viruses known to cause cancer in humans – HPV (cervical cancer) – Hepatitis B (liver cancer) – EBV (Burkitt lymphoma)