Staging & Grading of Cancer

Question 1

What is staging?

Answer 1

Refers to the tumour as a whole

Question 2

What is grading?

Answer 2

Refers to the overall appearance of cells relating to diiferentiation

Question 3

Systems specific to different types of cancer

Answer 3

Dukes : Colorectal cancer
FIGO: Gynaecological cancer

Question 4

TNM system

Answer 4

Used for nearly all solid tumours
T- Tumour
N- Nodes
M - Metastasis
Might have a prefix:
-cTNM - clinical stage
-pTNM ; pathological stage
-yTNM - post chemo-radiotherapy

Question 5

Grading categories

Answer 5

Largely just reflects differentiation of cancer
GX: Grade cannot be assessed (undetermined grade)
G1: Welldifferentiated(low grade)
G2: Moderately differentiated (intermediate grade)
G3: Poorly differentiated (high grade)
G4:Undifferentiated(high grade)

Question 6

Grading - Specific Grading systems - Breast Cancer (Nottingham System)

Answer 6

Breast Cancer - Nottingham System
- Tubule formation: how much of the tumour tissue has normal breast (milk) duct structures
- Nuclear grade: an evaluation of the size and shape of the nucleus in the tumour cells
- Mitotic rate: how many dividing cells are present, which is a measure of how fast the tumour cells are growing and dividing

Question 7

Grading - Specific Grading systems - Prostate Cancer (Gleason Score)

Answer 7

The primary pattern represents the most common tissue pattern seen in the tumour
The secondary pattern represents the next most common pattern.
Each pattern is given a grade from 1 to 5.
The two grades are then added to give a Gleason score.

Question 8

Differentiation - relates to tumour grading

Answer 8

Based on how well cells resemble the cells of origin
Well Differenitated: Good sign, healthy cels
Moderately differentiated: Damaged cells, still look similar to normal cells
Poorly differentiated: More severely damaged, may show some features of normal cells but look markedly different
Anaplastic: Loss of normal features, not recognisable as a particular cell type

Question 9

What is Metastasis? What are the different methods?

Answer 9

-Spread of a tumour to a distant site.
Haematogenous: via the blood system
Lymphatic: via the lymph vessels and lymph nodes
Transcelomic: via the body cavities
Direct Spread: Grows through one organ into another

Question 10

What are Metastases? What is the relevance of metastsis to cancer

Answer 10

Metastases: Tumour implant separate from the primary tumour
Metastasis marks a tumour as malignant - benign neoplasms do not metastasize.
Cancer spreads by penetrating into blood vessels/ lymphatics/body cavities - all cancers can metastasize but not all do.
Cant judge metastatic potential from microscopic examination of primary tumours but there is progress on this in molecular biology.
approx 30% of newly diagnosed patients with solid tumours present with metastases.

Question 11

Major steps in metastasis

Answer 11

Invasion
Migration
Intravasation
Escape of immune surveillance
Extravasation
Formation of Secondary tumour

Question 12

Angiogenesis

Answer 12

Tumours need a blood supply.
Epithelia have no direct blood supply
Tumours need to create their own vasculature as they grow and for metastasis
Angiogenesis/ neo-vascularisation is the formation of new blood vessels

Question 13

Factors involved in Angiogenesis

Answer 13

VEGF (vascular endothelial growth factor): key molecule involved in the production of new blood vessels
In tumours with low oxygen (hypoxia) HIF activated and stabilised and can transcriptionally activate VEGF for blood vessel formation and other genes for tumour cell mitosis/ metabolism/ survival

Question 14

tumourBM (Basement membrane?) degradation

Answer 14

Tumour cells create passage ways for migration to metastasize.
Invasion of the extracellular matrix (ECM) is not due to passive grwoth pressure - requires activation enzymatic degradation of ECM components.
Tumour cells secrete proteolytic ezymes themselves or induce host cells ( stromal fibroblasts and infiltrating macrophages) to express proteases
Activity of proteases tightly regulated by antiproteases
Balance between proteases and antiproteaes titled in favour of proteases at the invading edge of tumours.

Question 15

Three classes of proteases

Answer 15

serine, cysteine, and matrix metalloproteinases (MMPs).

Question 16

MMPS - role

Answer 16

Degradation of collagen and other ECM proteins is achieved by a family of matrix metalloproteinases (MMPs), which are dependent on zinc ions for their activity.

Question 17

MMPs - how are they synthesised and activated?

Answer 17

Synthesised as pro-peptides requiring proteolytic cleavage for activation.

Question 17

Components of MMPs and their role in MMPs function

Answer 17

• interstitial collagenases (MMP-1, 2, and 3), which cleave the collagen types I, II, and III
• gelatinases (MMP-2 and 9), which degrade amorphous collagen as well as fibronectin
• stromelysins (MMP-3, 10, and 11), which act on a variety of ECM components, including proteoglycans, laminin, fibronectin, and amorphous collagen.

Question 17

MMPs - types and their role in tumor cell invasion (examples)

Answer 17

• MMP9 and MMP2: collagenases that cleave type IV collagen of epithelial and vascular basement membranes.
• MMPs degrade type IV collagen in tumor cell invasion: produced in high level sin Several invasive carcinomas, melanomas, and sarcomas. MMP expression is higher as tumors enlarge.
• In situ lesions and adenomas of breast and colon express much less collagen IV-degrading collagenases than do invasive lesions.

Question 17

Inhibitors of MMPs

Answer 17

Mesenchymal cells secrete MMPs inhibitors ( Tissue inhibitors of metalloproteinases)

Question 17

Inhibitors of MMPs - role in treatment of cancer

Answer 17

Inhibition of collagenase activity by transfection with the gene for tissue inhibitors of metalloproteinases greatly reduces metastases in experimental animals.
Synthetic compounds with MMP inhibiting activity are being tested as therapeutic agents in certain forms of cancer

Question 17

Cancer Treatment

Answer 17

Surgery - surgical removal of the tumour is curative if its all out
Hormone therapy - breast, prostate, ovaraian
Biological therapies
Chemotherapy - cytotoxic drugs

Question 17

Prevention of Angiogenesis - Inhibitors

Answer 17

Angiogenesis: Normal procress that is highjacked by tumours.
Inhibitors are mostly monoclonal antibodies against the signalling receptors or ligand.

Question 18

Prevention of Angiogenesis - Inhibitor examples

Answer 18

Avastin and bevacizumab: bind to VEGF(vascular endothelial growth factor), so it cannot bind to the receptor
Ramucirumab binds to VEGFR
Sunitinib and vatalanib are VGFR inhibitors – even if stimulated, the receptor cannot signal