• Metaplasia – Replacement of one cell type with another, almost always assocated with tissue damage, repair and regeneration.
  • Dysplasia (‘disordered growth’) – Increased cell growth (more mitoses visible than normal), presence of atypical morphology (e.g. abnormally large nuclei) and altered differentiation (e.g. cellular immaturity). May be caused by chronic physical or chemical injury. May be reversible only in early stages, often pre-neoplastic. Often pre-neoplastic. Marked dysplasia involving entire thickness of the epithelium, confined by the basement mebrane is carcinoma in situ, a preinvasive neoplasm.
  • Neoplasia (‘new growth’) – Abnormal, uncoordinatedand excessive cell growth, persisting after initiating stimulus has been withdrawn. Associated with genetic alterations. Influence behaviour of normal cells by

the production of hormones and growth factors. Tumour (swelling) is now usually synonmous with neoplasm. Neoplasms are classified by behavioural (benign/malignant) and histogenic (cell of origin) characteristics.

  • Benign tumour – Relatively innocent characteristics, will remain localised with expansile growth only, unable to spread to other sites. Few mitoses, normal or slight increase in nucleus:cytoplasmic ratio. Cells uniform throughout the tumour. Usually havea fibrous capsule derived mostly from extracellular matrix of native tissue due to atrophy of normal parenchyam cells (does not prevent tumour growth). Mesenchymal tumours include fibroma, lipoma, chondroma, osteoma. Adenomas are epithelial tumours derived from glands (may or may not form glandular structures). Papillomas are epithelial tumours with finger-like or warty projections. Cystadenomas form large cystic masses. Papillary cystadenomas have papillary projections into cystic spaces. Polyps are macroscopic projections above the mucosa, may be benign or malignant.
  • Malignant tumour (cancer) – Can invade and destroy adjacent stranctures and spread to distant sites. Many mitoses with some abnormal forms, high nuclear:cytoplasmic ratio, cellular and nuclear pleomorphism (vary in shape and size). Sarcomas are from mesenchymal tissue, are fleshy with little connective tissue stroma. Carcinomas originate from epithelial cells (ectodermal, mesodermal or endodermal); squamous cell carcinoma (SCC) when they resemble stratified squamous epithelium; and adenocarcinoma when they grow in glandular patterns. Undifferentiated cells are of unknown tissue origin.
  • Choristoma/Heterotopia – Normal cells or tissues in abnormal location, eg ectopic pancreatic rests, adrenal rests.
  • Hamartoma – Excessive focal overgrowth of cells and tissues native to that organ with abnormal architexture. Demarcation between hamartoma and benign neoplasms is unclear.

All tumours have parenchyma (clonal neoplastic cells) and reactive stroma (connective tissue, blood vessels, variable macrophages and lymphocytes). Stroma is required for growth and evolution. Soft and fleshy tumours have little stromal support. Desmoplastic tumours have abundant collagenous stroma, may be stony hard, scirrous. Most are of monoclonal origin; mixed tumours have divergent differentiation of a single neoplastic clone (pleomorphic adenoma); but are of only a single germ layer (cf teratoma from totipotential stem cells)

Differentiating characteristics

  • Cellular differentiation – Extent that the cell resembles the normal parenchymal cell (morphologically and functionally). Anaplasia is lack of differentiation, often associated with pleomorphism, abnormal nuclear morphology (hyperchromatic with clumping, high nuclear:cytoplasmic ratio, variable irregualr shape, large nucleoli), increased mitoses, loss of polarity (disturbed orientation), tumour giant cells (single huge polymorphic nuclears or >/= 2 large hyperchromatic nuclei), ischaemic necrosis (due to scant vascular stroma).
  • Rate of growth – Mathematically a cell must undergo at least 30 doublings to weight ~1g (clinically detectable, with a further 10 doublings before weighing ~1kg (usually maximal size compatible with life). Rate of growth determined by doubling time, fraction of tumour cells in the replicative pool (growth fraction), and rate that the cells are shed or die. The total cell cycle time fore most tumours is equal to or longer than normal cells; but cfell cycle controls are derranged. As tumours grow there is rapidly increasing numbers that leave the proliferative pool due to shedding, lack of nutrients, necrosis, apoptosis, differentiation and reversion to G0( nonproliferative phase of the cell cycle); hence by the time a tumour is detected, most cells are not in the replicative pool with most growht fractures <20%. Tumours grow only when proliferation exceeds cell death. Fast-growing tumours generaly have high cell turnover with high rates of proliferation and apoptosis. Chemotherapy targets the replicative pool, hence tumours with low growht fractions are relatively refractory; shifting from cells from G0 can be aided by debulking with surgery or radiation, hence making them more susceptible.

Warburg effect – Most cancer cells shift glucose metabolism from oxydative phosphorylation in mitochondria to aerobic glycolysis. This enables detection via FDG-PET. ?Due to reduced oxygen demands, increasing the number of tumour cells that can be supported by the vasculature (tumour angiogenesis inreases vasculature, but vessels are poorly formed).

Invasion is breach of the underlying basement membrane. There is dissociation from other cells (altered intercellular adhesion molecues eg E-cadherins), degradation of the basement membrane and interstitial connective tissue (secrete or induce stromal cells eg fibroblasts and inflammatory cells to release proteolytic enzymes), attachment to novel ECM components and migration/locomotion through tissues.

Metastases are tumour implants discontinuous with the primary tumour. Almost all cancers (except rarely CNS glial tumours, skin basal cell carcinomas) eventually metastasize. ~30% of newly diagnosed solid cancers present with metastases. Routes of spread include:

  • Lymphatic spread (most common) – Via draining lymphatic vessels to local lymph nodes where they grow as secondary tumours. Tumours don’t contain functional lymphatics, but entre lymphatics at the tumour margins. Venous-lymphatic anastomoses (esp after inflammation or radiation obliterating lymphatic channels) allow bypassing of nodes (skip metastases). Enlargement of nodes may be due to spread and growth of the cancer cells or reactive hyperplasia.
  • Haematogenous/vascular spread – Via the veins draining the primary lesion (arteries have thicker walls). Gastrointestinal tumours spread via the portal vein giving to the liver. Tumours close to the vertebral column (esp tyroid, prostate) spread to the vertebrae via paravertebral plexus. Common metastases in the lung, bone marrow, brain and adrenal glands. RCC and HCC often grow into the veins, but may or may not be associated with dissemination. In the circulation tumour cells tend to aggregate, esp with platelets. The cells may have adhesion molecules to endothelium of preferential organs, or they may be certan chemokines in the target tissue. Some tissues may have nonperssive environments (‘unfavourable soil’) eg skeletal muscles. Tumour cells are relatively inefficient in colonising distant organs, with numerous cells being shed by the primary without developing gross metastases.
  • Trans-coelomic spread – Penetration of a natrual cavity (peritoneum, pleura, pericadium, subarachnoid, joint). Seeding of the surface ± penetration.

Epidemiology and Aetiology

Majority of cancers are prostate/breast, lung and colorectal. 1/4 of all deaths.

Predisposing factors:

  • Obesity overal ~50% increase
  • Alcohol abuse – Oropharungeal, larynx, oesophageal, HCC.
  • Smoking – Lung, mouth, pharynx, larynx, oesophagus, pancreas, bladder. Synergistic with alcohol in the upper aerodigestive tract.
  • Age at first intercourse and number of sexual partners – Cervical (HPV).
  • Age – Most >55yo. ?accumulation of somatic mutations. Children usually develop small round blue cell tumours (neuroblastoma, Wilms, retinoblastoma, leukemias, rhabdomyosarcomas). Carcinomas rare in children.
  • Hereditary – <10% of cancers have predisposing inherited mutations
    • Autosomal dominant syndromes (usually of tumour suppressor gene) – Including RB tumour suppressor gene (40% of retinoblastomas, osteosarcoma), adenomatous polyposis coli (APC) tumour suppresor gene (FAP) p53 (Li-Farumeni syndrome), multiple endocrine neoplasia type 1 and 2 (MEN 1/2), hereditary nonpolyposis colon cancer (HNPCC), BRCA1/2, neurocutaneous syndromes (NF, vHL etc)
    • Defective DNA-repair syndromes – Usually autosomal recessive, including xeroderma pigmentosum, ataxia-telangiectasia, bloom syndrome, fanconi anaemia
    • Familial cancers – Undefined transmission, may occur in almost all types of cancers. early age of onsent, in additional 2 or more close relatives, multiple/bilateral tumours. Siblings have 2-3x increased risk. ?Multiple low-penetrance alleles, each contributing to only a small increase in risk.
  • Sites of unresolved chronic inflammation – Esp UC, H.pylori gastritis, viral hepatitis, chronic pancreatitis
  • Precancerous conditions – Conditions with high asosciation with cancer, including chronic atrophic gastritis of pernicious anaemia, solar keratosis of the skin, chronic UC, leukoplakia or the oral cavity vulva and penis, colonic villous adenoma
  • Occupational exposures (chemicals) – Initiators induce permanent DNA damage, but promotors are required for evolution into cancers.
    • Arsenic (some alloyrs, semiconductors, meds, herbicieds, fungicides) – Lung, skin, haemangiosarcoma
    • Asbestos – Lung, mesothelioma, GIT
    • Benzene (light oil, solvents) – Leukemia, hodgkin lymphoma.
    • Berylliom (aerospace) – Lung
    • Cadmium (yellow pigments, batteries) – Prostate
    • Chromium (alloys, paints, pigments) – Lung
    • Radon (quarries, mines, uranium) – Lung
    • Vinyl chloride (refrigerant, adhesive) – Angiosarcoma, liver
  • Radiation
  • Viruses
    • Human T-Cell leukaemia virus type 1 (HTLV-1) – RNA virus endemic in parts of Japan and Caribbean basin. Transmission via intercourse, blood products, breastfeeding. Leukemia in 3-5% of infected individuals with 40-60yr latent period.
    • Human papillomavirus (HPV) – >70 distinct types. Some types (1,2,4,7) cause benign squamous papillomas (warts). High-risk types (eg 16,18) may cause cancer via integration of viral DNA into the host cells, esp SCC cervix and anogenital region. Genital warts have low malignant potential, associated with low-risk HPVs (6,11).
    • Epstein-Barr virus (EBV) – African Burkitt lymphoma (>90% in Africa have EBV, only 15-20% elsewhere), B-cell ymphomas in immunosuppresed, some Hodgkin lymphomas, nasopharyngeal carcinomas (100% associated with EBV), some gastric carcinomas, rare T-cell and natural killer cell lymphomas.
    • Hepatitis B and C viruses (HBV, HCV) – 70-85% of HCC worldwide due to HBV/HCV, endemic in Fart east and Africa.
    • Kaposi sarcoma herpesvirus
    • Merkel cell polyomavirus – Merkel cell carcinomas
  • Helicobacter pylori – Gastric adenocarcinoma and gastric lymphomas

Carcinogenesis is a multistep process, accumulating multiple nonlethal mutations. The principle genes involved include the growth-promoting proto-oncogenes (dominant), growth-inhibiting tumour suppressor genes (generally recessive), genes regulating programmed cell death (apoptosis) and genes involved in DNA repair. Tumours are monoclonal, originating from a single precursor cell, but further mutations may develop heterogeneity and subclones.

Paraneoplastic Syndromes

In 10% of those with malignancy. Many syndromes are of unclear aeitiology and include:

  • Endocrinopathies – Ectopic hormone production
    • Cushing syndrome – Lung SCC (ACTH-like), pancreatic carcinoma, neural tumours.
    • Syndrome of inappropriate antidiuretic hormone secretion (SIADH) – ADH or atrial natriuretic hormones in lung SCC, intracranial neoplasms.
    • Hypercalcemia (most common) – Lung SCC (parathyroid hormone-related protein PTHRP, TGF-α, TNF, IL-1), breast/renal carcinoma, T-cell leukemia/lymphoma. Hypercalcaemia from skeletal metastases is not a paraneoplastic syndrome.
    • Hypoglycaemia – Ovarian carcinoma, fibrosarcoma (insulin-like), mesencymal sarcomas.
    • Carcinoid syndrome – Flusing, diarrhoea, heart failure, bronchospasm from secretion of vasoactive serotonin. HCC, bronchial adenoma/carcinoid (serotonin, bradykinin), pancreastic carcinoma.
    • Polycythaemia – Gastric carcinoma, RCC (erythropoietin), cerebellar haemangioma, HCC.
  • Nerve and muscle syndromes
    • Myasthenia – Bronchogenic carcinoma (immunological).
    • Disorders of the CNS and PNS – Breast carcinoma.
  • Dermatologic
    • Acanthosis nigraicans – Gastric carcinoma (immunological), lung/uterine carcinoma.
    • Dermatomyositis – Immunological in bronchogenic, breast carcinoma.
  • Hypertrophic osteoarthropathy (HPOA) – Bronchogenic carcinoma (in 5%, unkown aetiology), rarely other cancers. Periostitis at distal long bones, MTs/MCs and proximal phalanges, arthritis, finger clubbing.
  • Vascular and Haematological
    • Venous thrombosis (migratory thrombophlebitis, Trousseau syndrome) – All disseminated cancers esp pancreatic and bronchogenic, from tumour products activating clotting.
    • Nonbacterial thrombotic endocarditis – Advanced cancers with hypercoagulability.
    • Red cell aplasia – Thymic neoplasms (unknown aetiology).
  • Nephrotic syndrome – Tumour antigens, immune complexes in various cancers.

Samples for analysis must be adequate, representative and properly preserved. The periphery may not be representative, nd centre largely necrotic. Immunohistochemistry utilises specific antigens for undifferentiated tumours, determination of site of origin of mets, detection of molecues with prognostic/therapeutic significance (eg receptors status). Flow cytometry quantitavely measures cell characteristics eg membrane antigens, DNA content.

Tumour Markers

Often have low sensitivity and specificity. Markers include:

  • Hormones
    • Human chorionic gonadotropin (HCG) – Trophoblastic tumours, choriocarcinoma.
    • Calcitonin – Medullary thyroid cancer.
    • Ectopic hormones – Paraneoplastic syndromes.
  • Oncofetal antigens
    • α-fetoprotein (AFP) – HCC, yolk sac/endodermal sinus tumour, neuroblastoma, hepatoblastoma.
    • Carcinoembryonic antigen (CEA) – Carcinomas of the colon, stomach, pancreas, lung, breast, medullary thyroid.
  • Isoenzymes
    • Prostatic acid phosphatase (PAP) – Prostate cancer.
    • Neuron-specific enolase – Lung SCC, neuroblastoma.
  • Specific proteins
    • Immunoglobulins – Multiple myeloma, gammopathies.
    • Prostate specific antigen (PSA) – Prostate cancer.
  • Mucins and Glycoproteins
    • CA 19-9 – Pancreatic cancer; also elevated in colorectal, oesophageal, biliary duct cancers, HCC.
    • CA 125 – Ovarian cancer; also elevated in endometrial, fallopian tube, lung, breast, GI cancers.
    • CA 15-3 – Breast cancer.