Neoplasia - 1

13.10.06

Terminology
• Cancer: all malignant disease.
• Neoplasm: any autonomous growth.
-Benign or malignant.
• Malignant: shows invasion and/or metastasis.
• Benign: local growing only.
• Tumour: a swelling.
-[But colloquially = cancer.]
• Non-neoplastic "tumours."
-Choristoma, hamartoma.
• Dysplasia: cellular and architectural changes of neoplasia.
• Anaplasia: lack of differentiation, marked pleomorphism.
• Differentiation: degree to which neoplastic tissue resembles normal equivalent.
• Carcinoma: epithelial malignancy.
• Adenocarcinoma: malignancy of glandular tissue.
• Sarcoma: mesenchymal/connective tissue malignancy.
• Lymphoma: solid malignancy of immune system.
• Leukaemia: malignant blood cells in blood.

Definition of neoplasm:
• Abnormal mass of tissue, growth of which exceeds and is uncoordinated with that of normal tissues and persists in same excessive manner after cessation of stimulus that evoked change.

Cancer - the size of the problem
• 1 in 3 people will get it.
• 1 in 4 will die from it.
• England and Wales deaths from cancer: ~150,000/year.
• Mainly in older age groups but important, rarer types in children and young people.
• "Genetic" types occur at younger ages.

Theory of neoplasia
• Stem cell defect, often with chromosomal abnormality, resulting in expression of oncogenes or deletion of anti-oncogenes.
• Clonal theory, clonigenic cells.
• Versus field change.

Histogenic classification
• Clonal theory results in:
• Histogenic classification:
-Differentiation may vary in subclones.
-Other components: stroma, blood vessels, inflammatory cells.

Expansion
• Doubling times.
• Cell loss from tumour.
• Submutation and clonal evolution.
• Tumour angiogenesis.
• Mechanisms of invasion and metastasis.
-Detachment, invasion, spread to planes and vessels, embolisation, implantation.

E.g. colorectal tumour

Normal

APC loss/mutation

Metaplasic polyp

Loss of DNA methylation

Adenoma

Ras mutation (12p)

Adenoma

Loss of DCC (18q)

Late adenoma

Loss of p53

Carcinoma



Epithelial neoplasms
• Spectrum of benign, dysplasia, carcinoma in situ, invasive carcinoma.
• Concept of intra-epithelial neoplasia.
• Cytogenic and flow of cytometric abnormalities.

Features of dysplasia
• Loss of polarity (maturation towards surface).
• Basal cells above bottom layer.
• Mitoses above basal layer.
• Heaping up of layers.
• Individual cells show features of atypia.

Carcinogenesis
• Initiation and promotion.
• Multistep transformation.
• Mutations:
-Balanced translocations.
-Deletions.
-Gene amplification.
-Amplification.
-Extra/deleted chromosomes.

Mechanisms
• Initiation.
-Permanent change to DNA, mutations.
-Requires replication to stabilise it.
• Promotion.
-Reversible change, not capble alone of producing tumour.
-Allows changes of initiation to become effective.
• Mainly apply to chemical carcinogenesis.

Principal agents
• Radiation:
-Ionising.
-Non-ionising.
• Chemicals.
• Micro-organisms:
-Viruses.
-Bacteria.

Radiation carcinogenesis
• UV:
-A: 320-400nm.
-B: 280-320nm.
-C: 200-280nm.
• Damage pyrimidine dimers.
• Ras and p53 mutations.
• Cell mediated immunity reduced.
• Ionising:
-X-rays, γ-rays.
-Particles.
• Sources:
-Radiology.
-Radiotherapy.
-Miners.
-Bomb survivors.
-Chernobyl.
-Radiation workers.

Viral carcinogenesis
• Animal viruses (historical/experimental).
• HUMAN VIRUSES.
• HPV (especially 16, 18, 33 35, 51).
• EBV (Burkitt's, NPC, AIDS-lyphoma).
• Hepatitis B (and C).
• HTLV-1 (T-ALL and NHL).

Bacterial carcinogenesis
• H. pylori.
-Gastritis.
-Gastric ulcers etc.

Chemical carcinogenesis
• Initiators.
• Direct acting (electrophilic).
-Alkylating and acylating agents.
• Indirect (cytochrome p450 dependent).
-Polycyclic hydrocarbons.
-Aromatic amines.
-Plant and bacterial/fungal.
-Man-made.