S8) Invasion, Metastasis and Effects of Neoplasms

Question 1

Explain why invasion and metastasis are the most lethal features of a malignant neoplasm

Answer 1

• The ability of malignant cells to invade and spread to distant sites leads to a greatly increased tumour burden
• Untreated, this results in vast numbers of “parasitic” malignant cells

Question 2

Invasion and metastasis is a multi-step journey.

In three steps, explain what is necessary for malignant cells to get from a primary site to a secondary site?

Answer 2

⇒ Grow and invade at the primary site

⇒ Enter a transport system and lodge at a secondary site

⇒ Grow at the secondary site to form a new tumour (colonisation)

At all points the cells must evade destruction by immune cells

Question 3

Invasion involves three important alterations.

What are they and what effect do they have?

Answer 3

• Invasion into surrounding tissue by carcinoma cells requires altered adhesion, stromal proteolysis and motility
• These changes create a carcinoma cell phenotype that appears more like a mesenchymal cell than an epithelial cell, hence this is called epithelial-to-mesenchymal transition (EMT)

Question 4

Describe the changes which drive altered adhesion in the process of invasion for malignant cells

Answer 4

• Altered adhesion between malignant cells involves a reduction in E-cadherin expression
• Altered adhesion between malignant cells and stromal proteins involves changes in integrin expression

Question 5

Describe the changes which drive proteolysis in the process of invasion for malignant cells

Answer 5

• The cells must degrade basement membrane and stroma to invade
• This involves altered expression of proteases, notably matrix metalloproteinases (MMPs)

Question 6

Explain the role and components of a cancer niche in the invasion of malignant cells

Answer 6

• Malignant cells take advantage of nearby non-neoplastic cells, which together form a cancer niche
• These normal cells provide some growth factors and proteases

Question 7

Describe the changes which drive altered motility in the process of invasion for malignant cells

Answer 7

• Altered motility involves changes in the actin cytoskeleton
• Signalling through integrins is important and occurs via small G proteins such as members of Rho family

Question 8

Transport to distant sites is via three routes, what are they?

Answer 8

Malignant cells can enter:

• Blood vessels via capillaries and venules
• Lymphatic vessels
• Coelomic spaces (transcoelemic spread – fluid in pleura, peritoneum, pericardium and brain ventricles)

Question 9

Explain how malignant cells must grow at a secondary site to form a clinical metastasis and the consequences of this

Answer 9

• Colonisation is when malignant cells successfully grow at a secondary site
• Failed colonisation occurs with many malignant cells which lodge at secondary sites but die/fail to grow into clinically detectable tumours (greatest barrier to successful metastasis)

Question 10

What are micrometastases?

Answer 10

Micometastases are surviving microscopic deposits which failed to grow at a secondary site

Question 11

What is the significance of micrometastes?

Answer 11

• An apparently disease-free person may harbour many micrometastases aka tumour dormancy
• When a malignant neoplasm relapses years after an apparent cure it is typically due to one or more micrometastases starting to grow

Question 12

What determines the site of a secondary tumour?

Answer 12

• Regional drainage of blood, lymph or coelomic fluid
• The “seed and soil” phenomenon

Question 13

Explain how the regional drainage of blood, lymph or coelomic fluid determines the site of the secondary tumour

Answer 13

• Lymphatic metastasis → regional lymph nodes
• Transcoelomic spread → other areas in the coelomic space / adjacent organs
• Blood-borne metastasis → next capillary bed that the cells encounter (lungs/liver)

Question 14

Explain how the “seed and soil” phenomenon determines the site of the secondary tumour

Answer 14

The “seed and soil” phenomenon states that the seemingly unpredictable distribution of blood-borne metastases is due to interactions between malignant cells and the local tumour environment, i.e. the niche at the secondary site

Question 15

How do carcinomas and sarcomas spread?

Answer 15

• Carcinomas typically spread via lymphatic metastasis first and then to blood-borne distant sites
• Sarcomas tend to spread via blood-borne metastasis

Question 16

What are the common sites of blood borne metastasis?

Answer 16

• Lung
• Liver
• Bone
• Brain

Question 17

Identify the five neoplasms that most frequently spread to bone?

Answer 17

• Breast
• Bronchus
• Kidney
• Thyroid
• Prostate

Question 18

Using two examples, explain how different malignant tumours have “personalities” in terms of metastasis

Answer 18

• Some malignant neoplasms are more aggressive and metastasise very early in their course e.g. small cell bronchial carcinoma
• Some malignant neoplasms almost never metastasise e.g. basal cell carcinoma of the skin

Question 19

What determines the likelihood of metastasis?

Answer 19

The likelihood of metastasis is related to the size of the primary neoplasm (basis of cancer staging)

Question 20

What are some of the effects of neoplasms?

Answer 20

• Direct local effects
• Indirect systemic effects (aka paraneoplastic syndromes)

Question 21

What are the causes behind the local effects of primary and secondary neoplasms?

Answer 21

• Direct invasion and destruction of normal tissue
• Ulceration at a surface leading to bleeding
• Compression of adjacent structures
• Blocking tubes and orifices

Question 22

Identify some systemic effects of neoplasms

Answer 22

• Thrombosis
• Reduced appetite and weight loss (cachexia)
• Immunosuppression (also due to direct bone marrow destruction)
• Malaise

Question 23

Differentiate between the systemic effects of benign and malignant neoplasms

Answer 23

• Benign neoplasms of endocrine glands are well differentiated so typically produce hormone e.g. a thyroid adenoma produces thyroxine
• -* Malignant neoplasms sometimes also produce hormone e.g. bronchial small cell carcinoma produces ACTH/ADH, bronchial squamous cell carcinoma produces a PTH-like hormone

Question 24

Identify some miscellaneous systemic effects of neoplasms

Answer 24

• Neuropathies affecting the brain and peripheral nerves
• Skin problems e.g. pruritis, abnormal pigmentation
• Fever
• Finger clubbing
• Myositis

Question 25

Provide definitions for the following terms: - Oncology - Clonal - Scirrhous

Answer 25

- **Oncology:** the study of tumours or neoplasms - **Clonal:** the entire population of cells within a tumour arises from a single cell, that has incurred genetic change - **Scirrhous:** stony hard tumours

Question 26

Provide definitions for the following terms: - Cystadenoma - Polyp - Meningioma

Answer 26

- **Cystadenoma**: benign epithelial neoplasm that forms large cystic masses - **Polyp**: benign/malignant neoplasm producing macroscopically visible projection above a mucosal or skin surface and projecting into a lumen - **Meningioma**: benign tumour arising from the dura (one of the meninges)

Question 27

Provide definitions for the following terms: - Rhabdomyosarcoma - Haemangioma - Angiosarcoma

Answer 27

- **Rhabdomyosarcoma:** malignant tumour of striated muscle - **Haemangioma:** benign tumour of blood vessels, often in the skin, may present as a birthmark - **Angiosarcoma:** malignant neoplasm arising from vascular endothelial cells

Question 28

Provide definitions for the following terms: - Mesothelioma - Rhabdomyoma - Hepatocellular carcinoma

Answer 28

- **Mesothelioma**: malignant neoplasm of mesothelium - **Rhabdomyoma**: benign tumour of striated muscle - **Hepatocellular** **carcinoma**: malignant tumour derived from hepatocytes

Question 29

Provide definitions for the following terms: - Naevus - Malignant melanoma - Hamartoma

Answer 29

- **Naevus:** a congenital growth/mark on the skin (mole – benign melanocytic tumour) - **Malignant melanoma:** malignant tumour of melanocytes, usually in the skin **- Hamartoma:** mass of disorganised but mature specialised cells/tissue resembling the cells of its origin

Question 30

Provide definitions for the following terms: - Seminoma - Teratoma - Choriocarcinoma

Answer 30

- **Seminoma:** malignant germ cell tumour, usually of the testis - **Teratoma:** germ cell tumor composed of multiple tissues (which can be derived from all three germ layers), malignant in the testes, benign dermoid cysts in the ovaries - **Choriocarcinoma:** malignant tumour derived from trophoblastic tissue that develops typically in the uterus following pregnancy, miscarriage or abortion

Question 31

Provide definitions for the following terms: - Astrocytoma - Papilloma

Answer 31

- **Astrocytoma**: malignant tumour of the astrocytes of the CNS - **Papilloma**: benign epithelial neoplasm producing micro-/macroscopically visible finger-like/warty projections from the epithelial surface

Question 32

Hypercalcaemia can be due to both benign and malignant neoplasms, and the mechanisms generally differ between the two types. Which benign tumours cause a high serum calcium and how?

Answer 32

**Primary parathyroid adenomas produce hyperparathyroidism:** - Raised serum ionised calcium and bone resorption - Hypophosphataemia - Increased excretion of calcium and phosphate in the urine

Question 33

What is paraneoplastic syndrome?

Answer 33

**Paraneoplastic syndrome** is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells

Question 34

Hypercalcaemia can be due to both benign and malignant neoplasms, and the mechanisms generally differ between the two types. Which malignant tumours cause high serum calcium and how?

Answer 34

- **Ectopic secretion of PTH-related protein in a paraneoplastic syndrome:** I. Mediated by humoral factors excreted by tumour cells / an immune response against the tumour II. Carcinomas of the breast, kidney, ovary, lung *e.g. squamous cell bronchogenic carcinoma* - **Destruction of bone tissue:** I. Primary tumours of bone *e.g. multiple myeloma, leukaemia* II. Diffuse skeletal metastases *e.g. breast cancer*

Question 35

What are the symptoms of hypercalcaemia?

Answer 35

- Painful **bones** (fractures) - Renal **stones** - Abdominal **groans** (constipation, peptic ulcers, pancreatitis, gallstones) - Psychiatric **moans** (depression, lethargy, seizures)

Question 36

Anaemia (low haemoglobin) can be either the presenting feature of a tumour or a major complication. What types of anaemia can occur?

Answer 36

- **Microcytic anaemia** due to chronic external haemorrhage - **Anaemia of chronic disease** secondary to cytokine production - **Myelophthisic anaemia** due to space occupying lesions that destroy bone marrow - **Immunohaemolytic anaemia** secondary to reaction to tumour/drugs - **Aplastic anaemia** secondary to irradiation or drugs - **Megaloblastic anaemia** secondary to folate acid antagonists

Question 37

Which tumours cause anaemia and how?

Answer 37

- **Chronic blood loss** – gastric carcinoma, colonic carcinoma, renal or bladder tumours, uterine cancer - **Anaemia of chronic disease** – Hodgkin’s lymphoma, carcinomas of lung and breast - **Myelophthisic anaemia** – carcinomas of breast, lung and prostate - **Immunohaemolytic anaemia** – lymphomas and leukaemias

Question 38

Cachexia (severe weight loss and debility) is a common feature of malignancy. What are the various factors which are involved in its aetiology and how do they exert their effects?

Answer 38

- Increased expenditure of resting energy due to cytokines produced by the tumour *e.g TNF, IL1, IL6, interferon gamma* - Production of lipid and protein-mobilising factors - Anaemia and decreased food intake