W2 8 Neoplasia

Question 1

What is a neoplasm?

Answer 1

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

Question 2

What does benign mean?

Answer 2

Neoplasm which is localised and cannot spread

Question 3

What does malignant mean?

Answer 3

A neoplasm that can invade and destroy adjacent structures and spread to distant sites

Question 4

What is cancer?

Answer 4

A malignant neoplasm

Question 5

What is metastasis?

Answer 5

Spread of cancer to a distant site

Question 6

What is dysplasia?

Answer 6

Pre-malignant change characterised by disordered cell growth due to the accumulation of non-lethal mutations.

Question 7

How is cancer formed?

Answer 7

Cancer is formed by the clonal expansion of a single mutated precursor cell that has a survival advantage over its neighbours

Question 8

What genetic alterations can happen in cancer?

Answer 8

Point mutations, translocations, amplifications, deletions, aneuploidy, epigenetic changes

Question 9

What are the risk factors for cancer?

Answer 9

Inherited genetic predisposition
Age
Environmental
Chronic inflammation

Question 10

Link between chronic inflammation and metaplasia?

Answer 10

Inflammation provides a permissive environment for cancer growth eg H pylori gastritis or IBD etc
Chronic inflammation at some epithelial sites may cause metaplasia (adaptive response of cells) which is a risk factor for neoplastic transformation.

Question 11

What are the 3 main pathways for neoplasia?

Answer 11

1. Genetic alterations produce benign neoplasm that never progresses to cancer (eg mole on skin)
2. Accumulation of further mutations in a benign neoplasm leads to cancer (eg colorectal cancer)
3. Genetic alterations produce a cancer in the absence of a pre-existing benign neoplasm (eg most melanomas)

Question 12

What are proto-oncogenes?

Answer 12

They promote regulated cell growth and proliferation eg growth factors

Question 13

What are oncogenes?

Answer 13

Constitutively active conferring cells self-sufficiency in growth

Question 14

What are some hallmarks for cancer?

Answer 14

Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Tumour promoting inflammation
Avoiding immune destruction

Question 15

What gene is frequently mutated in human cancer?

Answer 15

RAS is the most frequently mutated proto-oncogene

Question 16

Give some examples of oncogenes

Answer 16

TGFa, RAS, BRAF

Question 17

How can evading growth suppressors lead to cancer?

Answer 17

Mutations in tumour suppressor genes (can stop cells from dividing). Mutations in both alleles needed (unlike one allele for proto-oncogenes).

Question 18

Examples of tumour suppressor genes

Answer 18

p53, RB1

Question 19

How does a loss of p53 cause cancer?

Answer 19

When DNA becomes damaged, p53 detects this and with either repair the defect or marks the cell foR senescence or target cell for apoptosis or destruction. So if p53 is mutated, p53 dependent genes are not activated following DNA damage, allowing mutations to accumulate.
(This still is not enough to make a cell malignant)

Question 20

How does a lesion metastasise? (PG73)

Answer 20

Tumour cells break through the basement membrane. Cells migrate through the ECM. Reach a blood vessel and invade through the wall into the lumen. Then embolism to a distant site. They lodge onto an endothelium in a distant region and traverse through the endothelial barrier. Form a metastic deposit in the target organ, distant from the primary site. Complex process requiring mutations in a few different pathways for this to happen.

Question 21

What pathways can be mutated to facilitate a lesion metastasising?

Answer 21

Loosening of cell junctions
Degradation of ECM
Migration of tumour cells

Question 22

How can inflammation promote cancer growth?

Answer 22

The innate immune response to cancer promotes tumour development

Question 23

Give some mechanisms of how the innate immune responds to cancer promoting tumour development and give an example of how

Answer 23

Release of growth factors - eg EGF produced by inflammatory cells stimulated tumour growth
Removal of growth suppressors - proteases released from inflammatory cells degrade the extracellular matrix promoting cancer invasion
Resistance to cell death - integrins expressed on macrophages bind to cancer cells and prevent apoptosis
Angiogenesis - VEGF released by inflammatory cells
Evading immune destruction - TGF-b produced by macrophages suppress anti cancer CD8+ cytotoxic T-cell response

Question 24

How do tumour cells avoid immune destruction?

Answer 24

Tumour cells express a host of abnormal proteins, potentially capable of eliciting a host immunological response.

Question 25

What is the most potent immune response to tumour cells?

Answer 25

CD8+ cytotoxic T cells

Question 26

How does the immune system try and destroy tumour cells?

Answer 26

Tumour antigens are recognised and phagocytosed and processed by dendritic cells (APCs). Antigens are then expressed on MHC class I and II molecules, activating T-cells to lead to immune-mediated destruction of tumour cells. Limited by tumour cells protecting themselves from immune destruction.

Question 27

How can cancer cells avoid immune evasion?

Answer 27

Immune system fails to recognise tumour antigens Production of immunosuppressive proteins (cytokines like TGF-b, IL10, PG-E) or expression of inhibitory cell-surface proteins by tumour inhibits T-cell activation

Question 28

Compare the gross morphology: shape, size, haemorrhage, ulceration, necrosis of a benign vs malignant neoplasm

Answer 28

Benign: well circumscribed shape, generally smaller (but can be enormous), unusual to have haemorrhage ulceration or necrosis Malignant: irregular shape, generally larger, common to have haemorrhage ulceration or necrosis

Question 29

Compare the cytological features: nuclear size, nucleoli, pleomorphism, mitoses, and differentiation of benign vs malignant neoplasms (image pg76)

Answer 29

Benign: normal nuclear size, small/inconspicuous nucleoli, absent pleomorphism, mitoses are infrequent, good differentiation Malignant: enlarged nuclear size, prominent nucleoli, often marked pleomorphism, frequent (maybe atypical) mitoses, variable differentiaton

Question 30

Patterns of cancer invasion and metastasis

Answer 30

Go read Pg77/78/79 and look at the images on the page for histology Pre-invasive stromal invasion, perineural invasion, metastasis, venous invasion, satellite metastases, colorectal cancer metastases

Question 31

What are the local effects of neoplasia?

Answer 31

Compression of adjacent structures (or obstruct a lumen) Bleeding Rupture Infection Pain

Question 32

Systemic effects of neoplasia

Answer 32

Cachexia Paraneoplastic syndromes

Question 33

How does cachexia occur systemically from neoplasm?

Answer 33

Marked weight loss TNF produced suppressed appetite

Question 34

What paraneoplastic syndromes could arise from neoplasm? (Table pg80)

Answer 34

Cushing syndrome SIADH Hypercalcaemia Nephrotic syndrome (Associated tumours for each and different pathogenesis)