A tumour is a new growth of tissue (a mass) which can refer to an inflammatory swelling such as Pott’s puffy tumour or to a neoplastic growth. A neoplastic tumour is an uncontrolled proliferation of a clone of cells without useful function.
Cancer is a disease of genes. The cell is the basic unit of organisation and control. The genetic code is contained within the deoxyribonucleic acid (DNA) molecule present within the cell nucleus. Genes make proteins which govern the function and structure of a cell. There are around 100 000 genes (human genome) representing approximately 10 per cent of the DNA; each cell expresses 5—150000 genes. Since all genes are present in each cell nucleus, any gene may be expressed if the gene promoter is switched on, as occurs in neoplasia. Cancer is caused by disease of genes which control production of daughter cells from stem cells, cell proliferation, terminal differentiation and programmed cell death (apoptosis); from the Greek — shedding of autumn leaves. There are three important classes of genes involved in cancer:
• tumour suppressor genes, which control the cell cycle by slowing down the cycle or triggering apoptosis (TP53, P16, APC, RB1);
• oncogenes, which promote cell proliferation by increasing signalling activity from the cell surface to the transcription apparatus on gene promoters (KRAS, ERBB2, C-MYC);
• growth factors and their receptors which are switched on by oncogenes or switched off by tumour suppressor genes (EGF, TGFa, IGF, FGF).
A benign tumour grows by expansion without invasion of the extra-cellular matrix. A malignant tumour (cancer) grows by invasion into the extracellular matrix; most solid tumours also invade the basement membrane of endothelium and metastasise. The unit of cancer is the altered malignant cell which proliferates (clone). Different clones usually arise with different characteristics, such as the ability to metastasise via blood vessels or lymphatics. Cancer is a disease of genes which may be inherited or acquired (Table 12.1). Inherited cancers are caused by a specific DNAmutation of a tumour suppresser gene inherited in all cells. In cells of the organ affected, the (second) homologous gene is lost, initiating a sequence of genetic mutations culminating in cancer. Chemical carcinogens probably account for the majority of sporadic (acquired) cancers. Natives of Kashmir are prone to cancer of the skin of the thighs and lower abdomen. This is due to their habit of keeping warm by squatting and hugging earthenware pots containing glowing charcoal [the pot being termed a fangri , with the result that the adjacent skin is irritated by heat and fumes. ‘Chimney-sweep’s’ cancer’, ‘countryman’s lip’, and ‘tar workers’ cancer’ are other examples of carcinoma due to chemical carcinogens. DNA strand breaks are induced by ultraviolet and ionising radiation which, if not repaired, lead to cancer. Cellular instability from ageing of stem cell-lines (many common cancers) or chronic inflammation leads to increased cell proliferation and reduced apoptosis. This results in malignant transformation. Squamous cell carcinoma occasionally occurs in a chronic ulcer or in a scar . A fibrosarcoma also may arise in a scar. At least 20 per cent of cancers world-wide are caused by oncogenic viruses.
Environmental cofactors are also important. Helicobacten pylori is linked to the development of gastric cancer by an unknown mechanism. A diet high in calories and rich in saturated fats (from red meat) is implicated in many cancers including those of the colorectum and pancreas. In viral carcinogenesis there are specific cofactors for different cancers: malaria (Burkitt’s lymphoma), immunosuppression (post-transport lymphomatous proliferative disease — PTLPD), human immunodeficiency virus , smoking (cervical cancer) and aflatoxins (liver cancer).
• Hypertrophy is an increase in the size of an organ without an increase in cell numbers.
• Hyperplasia is an increase in the size of an organ due to an increase in cell numbers.
• Metaplasia. The epithelium from which the tumour grows has already changed its characteristics: bladder transitional epithelium to squamous epithelium, gallbladder columnar to squamous epithelium, bronchial columnar to squamous epithelium, gastric columnar epithelial pattern to intestinal epithelial pattern and oesophageal squamous to columnar epithelium (Barrett’s oesophagus).
• Dysplasia. This represents the earliest changes of neoplastic transformation than can be detected at the microstructural level (e.g. by light microscopy). In fact, genetic mutations are detectable at an earlier stage. Alterations in intracellular organisation, the individual size and shape of the nucleus, cellular size and shape and intercellular three-dimensional organisation indicate dysplasia. These changes may be classified as mild, moderate or severe dysplasia. Any grade of dysplasia may revert to normal due to elimination of the neoplastic clone, but is least likely with severe dysplasia.
• Carcinoma in situ. Severe dysplasia may progress to carcinoma in situ: the cellular, nuclear and three-dimensional architecture resemble cancer but without invasion into the extracellular matrix.
• Genotype. This is the molecular structure of any cell. A malignant genotype will have losses and mutations of tumour suppresser genes and the presence of oncogenes.
• Phenotype. This is the appearance of a cell at a microstructural level (microscopic phenotype) and its functional state (biological phenotype). A changed genotype will always precede a particular phenotype: for a time the cell may appear to be normal even though it has already acquired a malignant genotype.
• Differentiation. Depending on the degree to which the cells and organisation (morphology) of tumours resemble the parent tissue they are divided into well-differentiated, moderately differentiated and poorly differentiated forms.
• Anaplasia. Tumours are usually composed of cells which resemble those of the tissue from which they arise. Complete loss of differentiation (anaplasia) is associated with an aggressive cancer.
• Teratomas arise from embryonic stem cells containing representative cells from all three embryonic layers: ectoderm, endoderm, mesoderrn . Teratomatous dermoids contain hair and teeth, muscle and gland tissue. An unusual type is the sacrococcygeal teratoma, which can be considered as foetus in foeto (an ‘included’ foetus).
• Blastomas develop from ‘unipotent’ cells, and arise from any one of the three embryonic layers (e.g. neuroblastoma).
• Dermoid cysts. ‘Dermoid’ is a loose term given to cysts lined by squamous epithelium occurring in various parts of the body. Sebaceous cysts are lined by superficial squamous cells and should more accurately be called ‘epiderrnoid’.
— Teratomatous dermoids (see above) are found in the ovary, testis retroperitoneum, superior mediastinurn and the presacral area. Malignant change (carcinomatous or sarcomatous) can occur.
— Sequestration dermoids (see Cysts, below) are not new growths, but are formed by the inclusion of epithelial ‘nests’ beneath the surface at places where lines of developing skin meet and join: midline, external angular process (Fig.12.6), root of nose (Chapter 37), branchial cysts (Chapter 43).
— Implantation dermoids (see Cysts, below) may follow puncture wounds, commonly of the fingers, when living epithelial cells are implanted beneath the surface.
• Benign tumour. A benign tumour is usually encapsulated, and does not disseminate or recur after complete removal. Symptoms and effects, which can be harmful, are due to its size, position, and pressure. Certain adenomas secrete a hormone which may affect bodily functions. Benign tumours are often multiple.
• Malignant tumour. The characteristics of malignancy are:
— invasion of surrounding tissues;
— pleomorphism (variable shapes) of cells and nuclei;
— rapid growth;
— the tendency to spread to other parts of the body (metastasis) by the lymphatics, the bloodstream, along nerve sheaths and across body cavities;
— general weight loss (cachexia in advanced disease).
At an early stage, evidence of invasion is the most important sign of malignancy. Many cells of a malignant tumour have an abnormal number of chromosomes which is not a multiple of the usual haploid number (= ‘aneuploidy’).
It has been suggested that the division of tumours into these two major groups imposes a concept which is too rigid (Walter). A third group of intermediate tumors exists which includes some carcinoid tumours, adenoma of the bronchus, ‘mixed’ salivary tumours and basal-cell carcinoma. These intermediate types invade locally, but are much less inclined to lymphatic or especially vascular dissemination.
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