VIVA: Pathology - Neoplasia

Question 1

Describe the steps involved in tumour cell invasion of the extracellular matrix

Answer 1

1. Detachment* (“loosening up”) of the tumour cells from each other:
   - Breaking of intercellular bonds
   - Downregulation of E-cadherin expression
   - Mutations in genes for catenins
2. Attachment* to extracellular matrix (ECM) components:
   - Via laminin and fibronectin receptors
3. Degradation* of ECM:
   - Via proteases (serine, cysteine, and matrix metalloproteases including type IV collagenase) and plasminogen activator, creating passageways
4. Migration* of tumour cells:
   - May then lead to vascular dissemination, with arrest and extravasation of tumour emboli at distant sites
   - Adheres to endothelium, egress through basement membrane (same mechanisms as above)
   - Within circulation, aggregate in clumps (homotypic / tumour-platelet aggregations)

*3/4 needed to pass

Question 2

Describe possible mechanisms that influence the distribution of metastases

Answer 2

1. Tumour cell adhesion molecules:
   - Ligands preferentially expressed on target organ cells
2. Chemokines:
   - For target tissues
3. Chemoattractants:
   - From target organs

Question 3

What is the importance of matrix metalloproteases in the process of tumour invasion?

Answer 3

Collagenases are produced by tumour cells or surrounding stromal tissue, and cleave type IV collagen of epithelial and vascular basement membranes to generate, from ECM, factors that promote angiogenesis, tumour growth and tumour cell motility

Question 4

How do tumour cells metastasise?

Answer 4

1. Invasion of extracellular matrix:
   - Clonal expansion, growth, diversification, angiogenesis
   - Invasion of ECM
   - Metastatic subclone
   - Adhesion to and invasion of BM
   - Passage through ECM
   - Intravasation (blood/lymphatic)
2. Vascular dissemination and homing:
   - Interaction with host lymphoid cells
   - Tumour cell embolus -> platelet tumour aggregates
   - Adhesion to BM
   - Extravasation
   - Metastatic deposit
   - Angiogenesis
   - Growth

Question 5

Why do some tumours metastasise to sites other than their natural blood and lymphatic drainage areas?

Answer 5

Due to:
- Adhesion molecules whose ligands are expressed preferentially on target organs
- Chemokine receptors for target chemokines highly expressed in some organs
- Target tissue may be unpermissive environment (e.g. skeletal)

Question 6

What is a paraneoplastic syndrome?

Answer 6

A complex of symptoms that cannot be readily explained by the local or distant spread of a tumour, or by elaboration of hormones from the tissue in which the tumour arose

Question 7

What are the main types of paraneoplastic syndromes?

Answer 7

1. Endocrinopathies*:
   - ACTH (small cell lung Ca) -> Cushing’s syndrome
   - ADH (small cell lung Ca, intracranial tumour) -> SIADH
   - Parathyroid-like hormones, TNF, TGF, IL-1 (squamous cell lung Ca, breast Ca) -> hypercalcaemia
   - Serotonin/bradykinin (bronchial adenoma, pancreatic and gastric Ca) -> carcinoid syndrome
   - EPO (renal Ca) -> polycythaemia
2. Nerve and muscle syndromes:
   - ? immune mechanism (bronchogenic Ca) -> myasthaenia
   - Breast Ca -> CNS/neuro
3. Dermatological:
   - Gastric, lung and uterine Ca -> acanthosis nigricans
   - Bronchogenic and breast Ca -> dermatomyositis
4. HPOA
   - Bronchogenic Ca

*needed to pass with at least two examples and one other category

Question 8

What is the cause of cachexia in cancer?

Answer 8

Not generally understood
Anorexia
Elevated BMR
? humoral factors (TNF, cytokines)
Other tumour-produced factors

Question 9

What are the mechanisms by which paraneoplastic syndromes can occur?

Answer 9

1. Ectopic hormone production (e.g. ACTH in small cell lung Ca, PTHrP in squamous cell lung Ca)
2. Immunologic/autoimmune (e.g. Eaton-Lambert, dermatomyositis, myasthaenia-like)
3. Tumour antigens (e.g. acanthosis nigricans, HPOA, thrombosis)

Question 10

What is the definition of a neoplasm?

Answer 10

All 3 needed to pass:
- Abnormal growth of a tissue
- Growth exceeds and is uncoordinated with that of the original tissue
- Growth continues in the absence of the stimuli which evoked the change
(- Preys on host and serves no purpose)

Question 11

How may a malignant tumour affect the host?

Answer 11

3/4 to pass:
- Local and metastatic direct effects (e.g. pressure, bleeding, ulceration, rupture, infarction)
- Cachexia
- Hormonal
- Paraneoplastic