Behaviour of Tumours

Question 1

What are the two genetic mechanisms that could cause cancer?

Answer 1

Mutation in a stimulatory gene e.g. cells growing and dividing - protooncogene -> oncogene
Mutation in inhibitory genes e.g. repairing DNA mistakes - tumour suppressor gene

Question 2

Which factors are important in tumorigenic mechanisms?

Answer 2

• Parallel pathways exist
• Variable in cancer types and subtypes:
  1. Order that mutations occur
  2. Which mutations occur
• Certain mutations may decrease the number of steps required to complete tumorigenesis
• Case 1
  o p53 loss – angiogenesis and resistance to apoptosis and genetic instability (5 steps)
• Case 2
  o Two or more genetic changes required
  o For invasion/metastasis and resistance to apoptosis (8 steps)

Question 3

Which mutation causes hyperplasia?

Answer 3

Mutation APC

Question 4

Which mutation causes adenoma (polyps)?

Answer 4

Mutation K-RAS

Question 5

Which mutation causes adenoma to progress to adenocarcinoma (colon cancer)?

Answer 5

Deletion p53

Question 6

What can other mutations cause adenocarcinoma to progress to?

Answer 6

Metastatic cancer

Question 7

What are cancer stem cells and what are their properties?

Answer 7

• Small unique population of different cells with self renewal potential in order to produce the variety cells that form the tumours
• These cellular combinations are called cancer stem cells because of their stem like properties in comparison with stem cells
• Remarkable properties of these cells comprise extensive ability to differentiation and also self renewal

Question 8

What is the cancer stem cell hypothesis?

Answer 8

Mutations acquired which reactivate genes responsible for increased proliferative activity, cell-division and differentiation

Question 9

How does the clonal evolution model link to origin of tumour heterogeneity?

Answer 9

Clonal evolution model states that CSCs can be generated from differentiated mammary cells by dedifferentiation process
Tumour heterogeneity increases as a result of the formation of intra-tumoral clones by the sequential mutations

Question 10

How are tumours classified? What are the three critical determinants?

Answer 10

• Clear histopathological classification of tumours is essential for diagnosis and clinical management
• This involves using morphological and molecular features
• Three critical determinants:
  o Differentiation states
  o Embryonic and normal origin of the cell/tissue
  o How the cell behaves (benign or malignant)

Question 11

What are the three types of differentiation states?

Answer 11

Epithelial
Non-epithelial
Mixed

Question 12

What are the three embryonic orgins?

Answer 12

Ectoderm
Endoderm
Mesoderm

Question 13

What are the two biological behaviours of tumours?

Answer 13

Benign

Malignant

Question 14

What is the histogenetic origin of tumours?

Answer 14

• Tumours are derived from specialised cell types
• Depending on the (the tissue or cell type from which the tumour arose) it can generally be divided into epithelial and mesenchymal types (~1% tumours)

Question 15

What are the two major categories of carcinomas which reflect two major functions of the epithelia?

Answer 15

• Covering and Lining Epithelia
  o Forms the surface of the skin and some internal organs
  o It forms the inner lining of ducts and body cavities and the interior of the respiratory, digestive, urinary and reproductive systems – stratified squamous
• Glandular Epithelia
  o Are found in organs such as the thyroid, adrenal glands and sweat glands
  o And glands in breast and prostate
  o Specialised polarised cells which secrete into ducts or cavities – simple cuboidal and simple columnar

Question 16

Which epithelia are derived from which germ layers of the embryo?

Answer 16

Ectoderm:
Skin epidermis
Glandular tissue of breast

Mesoderm:
Ovaries

Endoderm:
Lungs
Liver
Gall bladder
Pancreas
Stomach
Intestine

Question 17

What proportion of human cancers are epithelial in origin (carcinomas)?

Answer 17

• > 80% cancer-related deaths in Western world
  1. Producing recognisable squamous cells: squamous cell carcinoma (nasal cavity, larynx, lung, cervix, skin)
  2. Glandular growth pattern: adenocarcinoma (lung, colon, breast, pancreas, stomach prostate)

Question 18

What is the nomenclature of a benign tumour?

Answer 18

• Suffix – oma to the cell of origin
• Name of cell origin + morphological character + oma
• E.g. tumours of squamous epithelium – squamous cell papilloma (soft fibroma on eyelid)

Question 19

What are examples of benign epithelial tumours?

Answer 19

• Adenoma: tumour forming glands
• Papilloma: tumour with finger-like projections
• Cystadenoma: cystic tumour in ovary
• Papillary Cystadenoma: papillary pattern in cystic tumour forming glands
• Polyp: tumours tat projects above the mucosal surface

Question 20

What is the nomenclature of malignant tumours?

Answer 20

• Name of origin of cell + morphological character + sarcoma/carcinoma
• Description/name depends on the tissue of origin:
  o Epithelial -> carcinoma
  o Mesenchymal -> sarcoma
• E.g. a malignant tumour of the prostate is prostate (tissue) adenocarcinoma (glandular epithelium) or an adenocarcinoma of the prostate
• Other malignant tumours:
  o Hematopoetic -> Leukaemia/lymphoma/myeloma
  o Neuroectodermal -> Glioma/neuroblastoma
  o Embryonic (immature tissue) -> Blastoma

Question 21

What is the difference between benign and malignant tumours?

Answer 21

• Benign tumours are NOT cancer
  o Remain localised to the tissue from which they arise
  o Curable by surgery (BUT can compress vital organs e.g. meningioma in the CNS)
  o Grow by expansion
• Malignant tumours ARE cancer
  o Grow by expansion and infiltration
  o Tumour cells become detached and extend through the adjacent tissues
  o May be carried away by the lymph to local lymph node and to more ditant organ such as liver or lungs OR spread directly through the bloodstream – metastasise
  o Surgical resection becomes difficult
• Invasive/basement membrane breached
• Non-encapsulated (often irregular shape)

Question 22

What are the characteristics of cancer cells?

Answer 22

• Cancer cells are not under normal cell growth controls – immortal:
  o Cell division is high
  o Centre of tumour does not receive sufficient food and oxygen
  o Ischemic necrosis
  o Shedding or loss of tumour cells
• Dead cells appear as apoptotic figures
• Both normal and abnormal mitotic figures seen in dividing cells – tumour growth

Question 23

What are the degrees of tumour differentiation?

Answer 23

• Well-differentiated neoplasm
  o Resembles mature cells of tissue of origin
• Poorly differentiated or undifferentiated neoplasm
  o Composed of primitive cells with little differentiation
  o Rate of growth of malignant tumour directly proportionate to the degree of differentiation
  o Aggressive growth pattern
• Correlation with biologic behaviour
  o Benign tumours are well differentiated
  o Poorly differentiated malignant tumours usually have worse prognosis

Question 24

What is involved in well-differentiated squamous cell carcinoma of the skin?

Answer 24

• Malignant squamous cells grow in all directions

- Invading cells retain ability to synthesise keratin and keratin is often trapped inside the tumour – ‘keratin pearls’

Question 25

What is the natural history of malignant tumours?

Answer 25

1. Malignant change in the target cell, referred to as transformation
2. Growth of the transformed cells
3. Local invasion
4. Distant metastases

Question 26

How is malignancy characterised by metastasis?

Answer 26

• Metastasis complex process
  1. Vascularisation of tumour occurs
  2. Cells detach from the primary tumour
  3. Basement membrane is degraded and invasion into the ECM occurs
  4. Intravastion of nearby blood vessels
  5. Tumour cells circulate in the vascular system
  6. Some cells adhere to the walls of blood vessels
  7. Extravastion and migration to local tissue occurs
  8. Where secondary tumour can form
• Haematogenous dissemination
• Lymphatic dissemination

Question 27

What is the significance of nodal metastasis?

Answer 27

• Example: breast cancer
  o A modified radical mastectomy removes the entire breast – including the breast tissue, skin, areola and nipple – and most of the underarm (axillary) lymph nodes which most common site for metastasis
• Prognostic
  o Number of involved nodes is an important component of the TNM staging system
• Therapeutic
  o Overall risk of recurrence
  o Extent of nodal involvement
  o Histological grade and other considerations
  o Adjuvant therapy

Question 28

How are tumours graded?

Answer 28

• Grading
  1. Degree of anaplasia (degree of differentiation)
  2. Rate of growth
  o Numeric grade describes tumour based on how abnormal the cells and tissue look under a microscope
  o Indicator of how quickly a tumour is likely to grow and spread
  o Well-differentiated – tumours tend to grow and spread at a slower rate than undifferentiated tumours
  o The factors used to determine tumour grade can vary between different types of cancer
  o Grade – I
   Well differentiated (< 25% anaplastic cells)
  o Grade –II
   Moderately differentiated (25-50% anaplastic cells)
  o Grade –III
   Moderately differentiated (50-75% anaplastic cells)
  o Grade- IV
   Poorly-differentiated or anaplastic (>75% anaplastic cells
  o GX means that the grade can’t be assessed.
   It is also called undetermined grade.
  o Some cancers have their own grading system
   E.g. Prostate cancer Gleason Score

Question 29

How are tumours staged?

Answer 29

1. Size of tumour
2. Extent of growth (or spread)
   o Cancer stage refers to the size and/or extent (reach) of the (primary) tumour
   o Whether or not cancer cells have spread in the body
   o Based on factors such as:
    Location of the primary tumour
    Tumour size regional lymph node involvement
    Number of tumours present
   o Two types:
3. Tumour Nodes Metastasis (TNM)
4. Number system
   o T - size of the cancer and how far it has spread into nearby tissue
   o N refers to whether the cancer has spread to the lymph nodes – it can be between 0 (no lymph nodes containing cancer cells) and 3 (several lymph nodes containing cancer cells)
   o M refers to whether the cancer has metastasised – it can either be 0 (no spread) or 1 (the cancer has spread)
   o Tx Tumour size cannot be assessed

Question 30

What are paraneoplastic syndromes?

Answer 30

• Clinical syndromes not caused by direct invasion or metastasis of tumour which accompany malignant disease
• Non-metastatic manifestation of malignant disease
• Vary in functional impact and clinical presentation
• The most common associated malignancies include small cell lung cancer, breast cancer, gynaecological tumours and haematological malignancies
• Arise from tumour secretion of:
  o Hormones
  o Peptides
  o Cytokines
  (these 3 interfere with normal metabolic pathways)
  o Immune cross-reactivity between malignant and normal tissues
• Four categories depending on the organ system involved:
  o Endocrine
  o Neurologic
  o Dermatologic and rheumatologic
  o Hematologic

Question 31

What are examples of paraneoplastic syndromes and what are they caused by?

Answer 31

Hormones -> Endocrone paraneoplastic syndromes -> Cushing Syndrome

Functional peptides -> Endocine paraneoplastic syndromes -> Hypoglycaemia

Cytokines -> Haematologic paraneoplastic syndromes -> thrombocytosis

Antigen -> B cell -> Antibody secretion (e.g. anti-AChR)/autoimmune response) -> Normal cell of CNS/neurologic paraneoplastic syndromes -> Myasthenia gravis

Question 32

Summarise characteristics of tumours.

Answer 32

1. Disobey growth signals – proliferate rapidly
2. Escape from death signals – immortality
3. Imbalance between cell proliferation and growth- excessive growth
4. Contain cancer stem cells which vary in origin and produce cells with distinctive genotypes
5. Lose differentiation ability – no function
6. Are instable – accumulate mutations
7. Overrun the neighbouring tissue- invade locally
8. Have the ability to travel from the sight of origin to another part of the body – distant metastasis