MoD S10 - Neoplasm II

Question 1

What is the most lethal feature of malignant neoplasms?

Answer 1

Their ability to invade and spread to distant sites leading to greatly increased tumour burden

Untreated this results in a vast amount of ‘parasitic malignancy’

Question 2

Can benign tumours metastasise?

Answer 2

Nope

Question 3

Describe the process of metastasis in brief

Answer 3

For malignant cells to travel to a secondary site they must:

• Grow and invade at primary site
• Enter a transport system and lodge at secondary site
• Grow at secondary site to form a new tumour

At all points must evade immune destruction

Question 4

In what tumour types is metastasis studied (mainly)?

Answer 4

Carcinoma

Question 5

What cell behaviour changes are necessary for invasion of a malignant cell into a tissue?

Answer 5

Invasion of carcinomas requires:

• Altered adhesion
• Stromal proteolysis
• Motility
• Angiogenesis

These cells appear more mesenchymal than epithelial now, so this is called the epithelial to mesenchymal transition (EMT)

Question 6

What are the genetic causes of the epithelial to mesenchymal transition?

Answer 6

Altered adhesion:

• To other carcinoma cells via reduced E-cadherin expression
• To stromal proteins via altered integrin expression

Stromal proteolysis:

• Altered expression of proteases, notably matrix metalloproteinases
• MMPs digest collagen allowing metastatic cell to digest ECM and break through basement membrane
• MMP 1 = type I collagen
• MMP 2/9 = type IV

Motility:
- Changes in the actin cytoskeleton

Angiogenesis:

• Once a tumour reaches 1 - 2 mm3 it must form new blood vessels or will turn hypoxic, restricting growth
• Must upregulate pro-angiogenesis factors (E.g. angiopoietin, VEGF)
• Thin walled vessels created provide easy route for metastasis

Question 7

What is a cancer niche?

How is it helpful to malignant cells?

Answer 7

Malignant cells and surrounding non-neoplastic cells form a cancer niche, a cancer permissive microenvironment

Malignant cells take advantage of other non-neoplastic cells in the niche to provide proteases and growth factors

Question 8

What transport routes are available for metastasis?

Answer 8

Malignant cells enter:

• Blood vessels via capillaries and venules
• Lymphatic vessels
• Fluid in the body cavities (pleural, peritoneum, brain ventricles) this is also known as transcoelomic spread

Question 9

What is colonisation in reference to malignancy?

Answer 9

At secondary sites where malignant cells grow, they colonise

Question 10

What are the outcomes of malignant colonisation?

Answer 10

Growth of malignant cells at secondary site to form a metastases

Failure to grow or death

Failure to grow and survival, leading to small malignant cell deposits known as micrometasases

Question 11

What is the consequence of micrometastases formation?

Answer 11

Tumour dormancy:
- An apparently disease free person may harbour many micrometastases

Malignant neoplasm can then relapse (even after years) when they start to grow

Question 12

What does the site of secondary tumours depend on?

Answer 12

Regional drainage of blood, lymph or coelomic fluid:

• Blood borne most likely to lodge in next capillary bed
• Transcoelomic to other areas in coelom or adjacent organs
• Lymph borne drain into lymph nodes

Seed and soil phenomenon:

• Certain tumours ‘seed’ certain organs with micrometastases (organotropism)
• Must be a secondary site with favourable conditions (a suitable niche can then be set up)

Question 13

Give an example of the seed and soil phenomenon

Answer 13

Stomach cancer often metastasises to the ovaries

Colon cancer often metastasises to the liver

Question 14

By which routes do carcinoma and sarcoma typically spread?

Answer 14

Carcinoma

• First into lymphatics and lymph nodes
• Then turns blood borne and spreads to distant sites

Sarcoma:
- Spreads initially via blood

Question 15

Where are some common sites of blood borne metastases?

Include the locations/tumour types the metastasis is commonly from at each site of metastasis

Answer 15

Lungs:

• Wide range of malignancies
• Sarcomas (osteosarcoma)
• Carcinomas (breast, stomach)
• Kidney
• Testis

Bone:

• Carcinomas (bronchial, breast, thyroid)
• Can cause dense bone (osteosclerosis)

Liver

• Common site of carcinomas from large intestine (portal vein)
• Carcinomas (bronchial, breast)

Brain:

• Cause wide range of neurological symptoms and act as space occupying lesions
• Metastasis common from bronchial, breast and testicular carcinoma as well as melanoma

Question 16

What neoplasms most frequently spread to bone?

Answer 16

Breast
Bronchus
Kidney
Thyroid
Prostate

Question 17

How do malignant tumours vary in ‘aggressiveness’?

Answer 17

Some metastasise early in their course:
- Small cell bronchial carcinoma

Others almost never metastasise:
- Basal cell carcinoma

Question 18

What is likelihood of metastasis of a tumour related to?

Answer 18

Size of primary tumour

This is the basis of cancer staging

Question 19

How can the effects of neoplasm on the host be classified?

Answer 19

Direct local effects:
- Due to primary or secondary tumours

Indirect systemic effects:
- E.g. Hormonal effects

These effects are sometimes referred to as paraneoplastic syndromes

Question 20

For benign neoplasm, what effects on the host are most relevant?

Answer 20

Local effects

Hormonal effects

Question 21

Give some of the causes of local effects of neoplasms

Answer 21

Direct invasion and destruction of tissue (malignant only)

Ulceration of surface and bleeding

Compression of adjacent structures (pressure atrophy)

Blocking of tubes and orifices

Question 22

What are some of the systemic effects of neoplasm?

BIG card

Answer 22

Increasing tumour burden (Malignant specific):

• Cachexia (decreased appetite and weight loss)
• Malaise
• Immunosuppression (Can be due to direct bone marrow destruction)

Endocrine (commonly benign):

• Well differentiated so often produce hormones
• Thyroid adenoma = Thyroxine
• Bronchial small cell carcinoma = ACTH or ADH

Neuromuscular:

• Problems with balance
• Sensory/sensorimotor neuropathy
• Myopathy and myasthenia

Skin problems:

• Increased pigmentation
• Pruritis
• Herpes zoster
• Dermatomyositis

Pyrexia

Haemotological:

• Anaemia (bone marrow infiltration, leukaemia)
• Low WBC and platelets (BM infiltration + treatments)
• Thrombosis (pancreatic carcinoma)

Question 23

Give an example of a benign and malignant tumour that can cause hypercalcaemia and include mechanism(s)

Answer 23

Benign = Parathyroid adenoma:

• Increased PTH production
• Increased Ca2+ release from bone
• Increased Ca2+ re-uptake from kidneys
• Increased Ca2+ absorption in intestines

Malignant = Bronchial squamous cell carcinoma

• Primary or secondary tumour causes osteolysis
• Increased Ca2+ release from bone into blood
• OR
• Humoral hypercalcaemia as above (PTH-rP more likely mediator)

Question 24

Define Cachexia

Answer 24

Loss of weight, muscle atrophy, loss of appetite in someone not actively trying to lose weight

Question 25

What factors are involved in the development of cancer cachexia?

Answer 25

TNF
IL-1
IL-6

No precise mechanism known.

Question 26

How do neoplasms kill people?

Answer 26

Local effects:

• Raised intracranial pressure
• Perforation
• Haemorrhage

Systemic effects:
- Replacement of essential body organs (E.g. bone marrow, lung tissue, liver)