MoD session 9: invasion and metastasis

Question 1

What is the effect of the ability of malignant cells to invade and spread to distance sites?

Answer 1

Leads to a greatly-increased tumour burden

Question 2

What is the general mechanism of invasion and metastasis?

Answer 2

To get from primary to secondary site, the cells (that have been pre-selected to be good at metastasis) must:

1. Grow and invade at the primary site
2. Enter a transport centre and lodge at a secondary site
3. Grow at the new site to form a new tumour: COLONISATION

Question 3

Why is the process of metastasis inefficient?

Answer 3

At all points cells have to evade destruction by immune cells. Majority fail at the transport system as are too big for capillaries

Question 4

Describe alterations in invading carcinoma cells

Answer 4

1. Altered ADHESION: between malignant cells and stromal proteins due to changes in integrin expression which signals through the Rho family
2. Stromal PROTEOLYSIS: cells must degrade basement membrane and stroma to invade. Due to altered expression of proteases such as MMPs (matrix malleoproteases) which come from the niche
3. MOTILITY: changes to the actin cytoskeleton

Question 5

What is EMT?

Answer 5

Cellular alteration creates a carcinoma cell phenotype thats more like a mesenchymal cell than an epithelial cell–> epithelial to mesenchymal transition (EMT)

Question 6

What is a cancer niche?

Answer 6

Non-neoplastic cells taken advantage of by malignant cells to aid their survival. Niche produces growth factors and proteases to assist the malignant cells

Question 7

How might malignant cells spread to distant sites?

Answer 7

1. Blood vessels: via thin-walled capillaries and venules. Cancers have to undergo angiogenesis for nutrient supply, and since new blood vessels are ‘leaky’ it is easier for cancer cells to enter
2. Lymphatic vessels: lymphatic growth is a good prognostic marker as indicates increased risk of metastasis to local regions
3. Transcoelomic spread: fluid in body cavities (pleura, peritoneal, pericardial and brain ventricles). Cancer cells break off into the fluid of that space and travel to lodge in a different area

Question 8

What is colonisation?

Answer 8

Growth of malignant cells at a secondary site

Failed colonisation biggest barrier to successful metastasis as many malignant cells lodge at secondary sites but die/fail to grow

Question 9

What is extravasian?

Answer 9

Leaving a vessel

Cancer cells must do this before they can colonise

Question 10

What are micrometastases?

Answer 10

Surviving microscopic deposits that fail to grow

Question 11

What is tumour dormancy?

Answer 11

The presence of many micrometastases in an apparently disease-free individual. Common in melanoma and breast cancer.
Dormant as immune attack and angiogenesis at a hostile secondary site with a niche that doesn’t support the tumour
Malignant neoplasm can relapse many years after an apparent cure due to one or more micrometastases starting to grow

Question 12

What determines the secondary sites of a tumour?

Answer 12

1. Regional drainage:
   - lymphatic very predictable due to the lymph nodes that drain the area of the primary tumour
   - blood-borne is sometimes to the next capillary bed that cells encounter
   - transcoelomic is predictable to other areas in the coelomic space/adjacent areas
2. Seed or soil phenomenon
   - may explain the seemingly unpredictable distribution of blood-borne metastases as there are certain patterns
   - interactions between malignant cells and local tumour niche at secondary site: sometimes the “soil” is inhospitable so the “seeds” can’t grow

Question 13

What is the difference between spread of carcinomas and sarcomas?

Answer 13

Carcinomas usually spread via lymph nodes first and then blood-borne to distant sites
Sarcomas usually spread via the blood stream

Question 14

What are the common sites of blood-borne metastases?

Answer 14

Lung
Bone
Liver
Brain

Question 15

Which neoplasms commonly spread to bone, and why are secondary bone cancers often picked up incidentally?

Answer 15

Breast, bronchus, kidney, thyroid and prostate

Often picked up as patient has primary tumour unbeknown to them, and secondary bone metastasis causes pathological fracture or changes in bone

E.g. prostate-osteosclerotic metastasis causes bone development so there will be an area of dense bone where the metastasis has occurred

Question 16

Differences in metastatic spread time

Answer 16

Likelihood is related to the size of the primary neoplasm, therefore this forms the basis of the staging of the cancer. Additionally, some tumour types are by nature more aggressive than others:

• bronchial small cell carcinoma metastasises very early
• basal cell carcinoma almost never metastasises

Question 17

Describe the local effects of cancer

Answer 17

1. Direct invasion and destruction of normal tissue (e.g. weakened bones causing pathological fractures after minimal force)
2. Ulceration at an epithelial surface due to necrosis, causing bleeding. Haemorrhage due to perforation may occur, or chronic bleeding may cause anaemia
3. Compression of adjacent structures
4. Blockage of tubes/orifices, e.g. obstruction of lymph nodes in the face due to a blocked SVC

Question 18

Describe the systemic effects of cancer

Answer 18

Indirect effects aka paraneoplastic syndromes

Increased tumour burden causes a parasitic effect on the host: leads to weight loss (extreme: cachexia), malaise, thrombosis, immunosuppression (may also be due to bone marrow destruction)

Secretion of factors such as cytokines have similar effects

Sometimes hormones are produced: bronchial small cell carcinoma produces ACTH or ADH, and bronchial squamous cell carcinoma produces PTHrP

Other effects:

• neuropathies of brain and peripheral nerves
• skin problems e.g. pruritus and abnormal pigmentation
• fever
• finger clubbing
• myositis

Question 19

Systemic effects of benign neoplasms

Answer 19

Usually well-differentiated so when effecting endocrine glands will produce hormones, e.g. thyroid adenomas produce thyroxine

Question 20

What are the common primary sites of a secondary brain tumour?

Answer 20

Brest, lung, kidney, stomach, colon, prostate, skin

Question 21

Describe the microscopic appearance of a lymphoid follicle

Answer 21

Dark periphery-lymphocytes

Light centre-blast cells (Activated cells); germinal centre lighter patches euchromatin

Question 22

Sites for melanoma metastasis

Answer 22

Liver, lung, bone, brain

Question 23

Where can malignant melanoma arise?

Answer 23

Skin
Mucous membranes: anus, mouth, GU and GI tracts
Eye
Meninges

Question 24

What is a sentinel lymph node and how is it biopsied?

Answer 24

The first lymph node to which cancer cells are most likely to spread from a primary tumour.
Inject dye into tumour, see dye moving into lymph node and assume thats the first node to which it metastasises. If this node is involved there is worse prognosis so will require surgery to remove lymph nodes

Question 25

What is a carcinoid tumour and where do they commonly occur?

Answer 25

A well-differentiated neuroendocrine tumour which is derived from entero-chromaffin cells

Small intestine, stomach, rectum, appendix, tracheal-bronchial tree, lung

Question 26

What is carcinoid syndrome?

Answer 26

Intermittent abdominal pain, diarrhoea, sweating an flushing due to production of neurotransmitters such as serotonin from a carcinoid tumour
Indicates that the carcinoid tumour has metastasised

Question 27

What are the top 5 most common primary metastases that result in secondary lung cancer?

Answer 27

Breast/prostate, colon, bladder, kidney, skin

Also GI tract, bladder, ovary

Question 28

What are cannonball lesions?

Answer 28

Large round pulmonary metastases

Likely to be metastatic having reached the lung via blood as it is the first capillary bed for many tissues that cells are likely to encounter

Question 29

Which benign tumours cause a high serum calcium and how?

Answer 29

Parathyroid tumours: as overproduce PTH which stimulates the release of calcium from bone

Question 30

How can malignant tumours cause high serum calcium?

Answer 30

Production of parathyroid hormone-related peptide

Question 31

Which tumours can cause anaemia and how? What types of anaemia are usually present?

Answer 31

GI tract: cause ulceration and perforation of the epithelia leading to chronic haemorrhage and so anaemia develops
Lymphoma/leukaemia/myeloma: destroy bone marrow so it is not able to produce as many new blood cells

Anaemia types: haemolytic, Falcon’s, sideroblastic

Question 32

How can cachexia be caused by malignancy?

Answer 32

Cytokines
Increased protein kinase R causing muscle atrophy
Lipolysis due to chemical triggers
Apetite loss