Neoplasia

Cancer is the second commonest cause of death (25%) in the Western world after heart disease. Knowledge of non-neoplastic proliferation is helpful in understanding neoplasia.

Physiological proliferation occurs:

1. In somatic growth during fetal development.

2. In tissues where constant proliferation is needed in RAPID CELL TURNOVER from stem cells (p.48) e.g. in:

3. Proliferation at a much slower rate occurs in tissues where cell turnover is low, e.g. LIVER, but will increase rapidly following injury.

ENLARGEMENT of an organ due to increase in the parenchymal cell mass may be due to:

(1) an increase in the size of the individual cells – hypertrophy

or (2) an increase in the number of cells – hyperplasia

or (3) commonly a combination of (1) and (2).

The stimuli responsible are:

(a) increase in functional demand

(b) increased trophic hormonal activity.

Physiological enlargement of organs is common and well illustrated by the increase in muscle bulk consequent upon training and the enlargement of uterus and breasts in pregnancy. Pathological enlargement is the result of disease processes.

Hypertrophy

Enlargement of the heart as a result of hypertension is a good example of hypertrophy: the result of the increased functional demands to maintain the high blood pressure is an increase in the size of the myocardial cells.

Non-Neoplastic Proliferation

Hyperplasia

The two main causes are:

(a) Chronic irritation (and inflammation), e.g. in the skin, increased thickness results.

(b) Imbalance of hormonal activity, e.g. the irregular enlargement of the prostate in old age is due to hyperplasia of the component tissues.

Note: If the abnormal stimulus is removed, the affected organ can return to normal.

Metaplasia

This is a change from one type of differentiated tissue to another, usually of the same broad class but often less well specialised. The change is commonly seen in lining epithelia but occurs also in connective tissues. There is frequently an associated hyperplasia.

Dysplasia

This term refers to disordered growth which is frequently the precursor of malignancy. It is described on page 145.

Neoplastic Proliferation

A tumour is a proliferation of cells which persists after the stimulus which initiated it has been withdrawn, i.e. it is autonomous. It is:

1. Progressive

2. Purposeless

e.g. Tumour of fibrous tissue

The fibres of a tumour of fibrous tissue have no regular arrangement and serve no useful purpose.

In normal fibrous tissue, the strands have a definite arrangement, supporting some structure such as an epithelial surface.

3. Regardless of surrounding tissue

4. Not related to needs of the body

5. Parasitic

The tumour draws its nourishment from the body while contributing nothing to its function. It induces the body to provide a blood supply and, in the case of epithelial tumours, a supporting stroma.

Neoplasms – Classification

Tumours may be classified in two ways: 1. clinical behaviour and 2. histological origin.

1. CLINICAL BEHAVIOUR

The tumour is classified according to its morbid anatomy and behaviour. Two main groups are recognised – benign (simple) and malignant. The contrast between these two groups is as follows:

	BENIGN	MALIGNANT
Spread (the most important feature)	Remains localised	Cells transferred via lymphatics, blood vessels, tissue planes and serous cavities to set up satellite tumours (metastases)
Rate of Growth	Usually slow	Usually rapid
Boundaries	Circumscribed, often encapsulated	Irregular, ill-defined and non-encapsulated
Relationship to surrounding tissues	Compresses normal tissue	Invades and destroys normal tissues
Effects	Produced by pressure on vessels, tubes, nerves, organs, and by excess production of substances, e.g. hormones. Removal will alleviate these	Destroys structures, causes bleeding, forms strictures

In practice, there is a spectrum of malignancy. Some tumours may grow locally and invade normal tissues but never produce metastases. Others will produce metastases only after a very considerable time while, at the other end of the spectrum, there are tumours which metastasise very early in their development.

2. HISTOLOGICAL ORIGIN

Tumours may arise from any tissue in the body and they can be conveniently accommodated in five groups.

1. Epithelia.

2. Mesenchymal tissues including fibrous tissue, bone, cartilage and vessels.

3. Neuroectoderm.

4. Haemopoietic and lymphoid cells.

5. Germ cells.

The commonest tumours arise from tissues which have a rapid turnover of cells and which are exposed to environmental mutagens, e.g. epithelium of mucous membranes, skin, breast and reproductive organs and lymphoid and haemopoietic tissues.

Benign Tumours – Histology

In general, the cells of benign tumours are well differentiated. They:

1. Mimic the structure of their parent tissue.

2. Resemble the cells of their tissue of origin.

3. As in normal tissue, show a remarkable uniformity in size, shape and nuclear configuration.

4. Show evidence of normal function.

5. Have relatively infrequent mitotic figures: these are of normal type.

Malignant Tumours – Histology

The cells of malignant tumours tend to be less well-differentiated than those of benign tumours.

They:

There is a spectrum within malignant neoplasms from slowly growing well differentiated examples to rapidly growing undifferentiated highly malignant tumours.

Benign Epithelial Tumours

Benign epithelial tumours are essentially of two types: 1. papillomas and 2. adenomas.

Papilloma

Papillomas take origin from an epithelial surface. As the epithelium proliferates it is thrown into folds which become increasingly complex.

The epithelial proliferation is accompanied by a corresponding growth of supporting connective tissue and blood vessels.

Typical examples are found in the skin, e.g. the common wart.

In these benign tumours:

(a) The normal arrangement of epithelial cells is maintained, e.g. in skin papillomas the surface cells are squamous and proliferation is confined to the deepest layers.

(b) The relationship of epithelium to connective tissue is normal.

(c) Blood vessels are well formed.

Adenoma

Adenomas are derived from the ducts and acini of glands, although the name is also used to cover simple tumours arising in solid epithelial organs.

Again the proliferation of epithelium of a gland causes the formation of tubules which ramify and become compound. The original communication with the parent gland duct or acinus tends to become lost.

In the case of a hollow viscus, such as the intestine, the adenomatous proliferation, instead of growing down into the underlying connective tissue, is usually pushed upwards into the lumen of the viscus.

The growth therefore combines the features of a papilloma and an adenoma. The term adenomatous polyp is often applied in such a case.

In the type which grows into the subjacent connective tissue, the progressive budding of the epithelium results in new acini which become nipped off from the parent acini.

In cases in which retention of secretion is marked, a cyst forms and the tumour is then called a CYSTADENOMA which may reach an enormous size, e.g. some cystadenomas of the ovary may be 30–40 cm in diameter, particularly those which secrete mucus.

As in a hollow viscus, the proliferating epithelium may be heaped to form papillomas and the tumour then becomes a PAPILLARY CYSTADENOMA. These are also common in the ovary (see p.511).

Fibroadenoma

In the breast the term is clinically useful for a small nodule consisting of a mixture of acinar elements and prominent supporting fibrous tissue. The histological appearances are variable depending on the distribution of the fibrous tissue (see also p.520). This is not now considered to be a true neoplasm.

Benign Connective Tissue Tumours

Benign connective tissue tumours are composed of mature connective tissues – fat, cartilage, bone and blood vessels. They tend to form encapsulated rounded or lobulated masses which compress the surrounding tissues.

Lipoma

Circumscribed masses of fat are commonly found in the subcutaneous tissue of the arms, shoulders and buttocks. Less commonly they occur in the deep soft tissues of the limbs or retroperitoneum, but at these sites they must be carefully distinguished from low grade liposarcomas. Lipomas very rarely arise from the viscera.

Chondroma

A chondroma usually arises within the medullary cavity of the tubular bones of the hands and feet; it grows slowly, causing gradual expansion of the bone. Less commonly it occurs in long bones. Rarely multiple enchondromas appear in children and are associated with deformity: they occasionally become malignant.

Osteoma

This tumour is mainly found in the bones of the skull, although it may occur in long bones. Osteomas are relatively small but may produce severe symptoms because of their situation.

Leiomyoma (Fibroid)

The majority of benign smooth muscle tumours occur in the wall of the uterus where they are extremely common, but may lie within the uterine cavity or attached to the serosa. They are firm, rounded masses which usually begin in the myometrium.

Tumours of Fibrous Tissue

So-called fibromas are rare but tumour-like growths are fairly common. An example is a FIBROMATOSIS.

Palmar fibromatosis, at first nodular, causes flexion deformities of fingers (Dupuytren’s contracture) due to contraction of fibrous tissue within the palmar fascia. A similar condition may affect the plantar fascia. Deeply located fibromatoses behave in a locally aggressive manner.

Benign tumours of peripheral nerve and of vessels are described on pages 579 and 580.

Malignant Epithelial Tumours

Malignant epithelial tumours are known as CARCINOMAS (Greek ‘karkinos’: a crab), referring to the typical irregular jagged shape. This is due to invasion into adjacent normal tissues (p.135).

Types of Carcinoma

Like benign epithelial tumours, carcinomas can arise from squamous or glandular epithelium.

Squamous Cell Carcinoma

This is commonly found on the skin, especially exposed surfaces, but also develops in other sites covered by stratified squamous epithelium, e.g. lips, tongue, pharynx, oesophagus and vagina. In addition, it may occur on surfaces covered by glandular type epithelium through metaplastic transformation as in the bronchus, gall bladder and uterine cervix. It frequently arises from areas of carcinoma-in-situ (p.144).

1. It starts as a small papular mass

2. The surface breaks down and a characteristic irregular ulcer is produced.

Histologically, it is composed of irregular strands and columns of invading epithelium which infiltrate the underlying connective tissue. If well differentiated, the central cells of the invading masses show conversion into eosinophilic keratin, while the outer layer consists of young basophilic cells. In cross-section, the appearance is typical.

Squamous carcinoma of skin is typically well differentiated and slow growing. In contrast, uterine cervical carcinomas are poorly differentiated and spread early to draining lymph nodes.

Types of Carcinoma

Basal Cell Carcinoma (Rodent Ulcer)

This tumour may arise in any part of the skin but is most common in the face, near the eyes and nose.

First Stage

It starts as a flattened papilloma which slowly enlarges over months or perhaps a year or two.

Second Stage

The surface breaks down and a shallow, ragged ulcer with pearly edges is formed.

Usually the malignant tissue spreads slowly but progressively, mainly in a lateral direction. It is composed of cells resembling those of the basal layer of the skin; it has a characteristic histological appearance.

There are many histological variants. Sometimes they show pseudoglandular structures: melanin deposition occurs in some tumours.

Basal cell carcinoma is a locally invasive growth which can be extremely destructive (hence its name: Rodent ulcer). It almost never metastasises. Thus the two processes of local invasion and distant metastases are not necessarily linked.

Malignant Connective Tissue Tumours

Malignant connective tissue tumours are referred to as Sarcomas (Greek ‘sarkoma’: flesh). They arise in soft tissue, in bone and rarely in viscera.

Sarcomas are far less common than carcinomas, but are second in frequency to leukaemias and lymphomas in childhood and early adult life.

Unlike the ill-defined infiltrative carcinomas, sarcomas are large well defined fleshy tumours. Naked eye assessment suggests that they are encapsulated, but histology shows that this is a false impression. Malignant cells do infiltrate between normal tissues at the margin, so that surgical ‘shelling out’ is almost inevitably followed by local recurrence from aggregates of cells remaining in the tumour bed.

Most sarcomas consist of spindle shaped cells, although some are of round cell type. They are associated with the formation of many large thin walled blood vessels which are easily invaded by sarcoma cells. Blood borne metastases to lung are common. In contrast, lymph node involvement is rare in most types of sarcoma.

Sarcomas

Many different histological types of sarcoma have been described. The nomenclature is based on adding the suffix ‘sarcoma’ to the type of differentiation shown, e.g. chondrosarcoma, liposarcoma, leiomyosarcoma (cartilage, adipose tissue, smooth muscle).

In general, the grade of the tumour is of more prognostic importance than the precise histological type. Some of the commoner forms of sarcoma are described.

Liposarcoma

This tumour arises in soft tissues of the limbs and retroperitoneum. A number of sub types are described. Primitive fat containing cells (lipoblasts) are a feature.

Well differentiated liposarcoma has a good prognosis and rarely metastasises. Pleomorphic and round cell liposarcomas are highly aggressive tumours which metastasise early.

Synovial Sarcoma

Although a misnomer as the tumour does not arise from synovium, this has a typical microscopic appearance. Many tumours are biphasic – with both epithelioid and spindled forms.

Other Tumour Types

Teratoma

This is a tumour derived from totipotent germ cells. Most arise in the ovary (usually benign) and testis (almost always malignant): they may also occur at any site in the mid-line where germ cells have stopped in their migration to the gonads.

For example, Benign cystic teratoma is typically seen in the ovary.

It consists mainly of ectodermal structures such as skin and its appendages and neural tissue. Frequently respiratory epithelium, intestinal epithelium, bone and cartilage are present.

Testicular Teratomas are described on page 489.

Hamartoma

A hamartoma is a tumour-like but non-neoplastic malformation consisting of a mixture of tissues normally found at the particular site.

Haemangioma

Two main varieties exist:

1. Capillary angioma

These are common in the skin as ‘birth-marks’ which vary in size. Occasionally they may be found in internal organs. They are well defined, deep red or purple. A single artery provides a supply separate from the surrounding tissue.

2. Cavernous angioma

This type is usually confined to internal organs and quite often found in the liver. Like the capillary variety they are well defined and deep purple. Similar tumours are found involving the lymphatic system but less commonly.

Benign Pigmented Naevus (Melanocytic Naevus or Mole)

Benign pigmented naevus is extremely common. The term ‘naevus’ means a birthmark, but most naevi are acquired in childhood and adolescence.

During fetal life melanin-pigment-forming neuroectodermal cells migrate to the skin and are found in small numbers in the basal layer of the skin.

The common congenital pigmented mole is the result of an abnormality in migration, proliferation and maturation of these neuroectodermal cells. A continuous layer of pigmented cells is found adjacent to the basal epidermal cells.

The resulting naevi vary in size and appearance, varying from small flat macular brown areas or smooth papular lesions to warty hairy excrescences. Pigmentation is variable.

Blue naevus is another variation in which melanocytes are arrested in migration in the dermis.

Active proliferative activity may extend into adult life, but the great majority of these lesions undergo a degree of involution. One feature which differentiates them from malignant change is that the deeper the cells penetrate the dermis the smaller they become and the less active.

Malignant Melanoma

Malignant proliferation of melanocytes usually arises de novo but some melanomas arise from pre-existing naevi. Exposure to SUNLIGHT (the U.V. component) is the most important aetiological factor.

1. Chronic – over many years – especially relevant in the elderly.

2. Acute – causing burning. This is particularly important.

Sites

1. Skin of (a) face, soles of feet, palms of hands, nail beds, (b) legs (women) and (c) trunk (in men).

2. Mucous membranes of mouth, arms and genitalia – rare.

3. Eye and meninges – rare.

Some tumours are amelanotic (non-pigmented). The rate of growth is variable.

Four types of growth may occur:

1. Lentigo maligna – an ‘in situ’ lesion occurring on the face of the elderly. It may spread at one edge and regress at another. It may not reach the invasive stage before the patient dies of another disease.

2. Superficial spreading melanoma – occurs on female leg, male trunk. It accounts for 50% of all skin melanomas in northern countries.

3. Acral lentiginous melanoma – found on palms of hands, soles of feet and mucous membranes.

4. Nodular malignant melanoma – usually on trunk. It invades early and ulceration is common.

Types 2, 3 and 4 occur in younger adults, and all can have an in situ stage. The features of malignant melanoma are:

Spread of Tumours

Tumours spread by several routes.

1. Local invasion.

2. Lymphatic spread.

3. Blood (Haematogenous) spread.

4. Transcoelomic spread.

5. Perineural spread.

6. Intraepithelial spread.

Local Spread

The proliferating cells break through normal barriers.

Further spread is by penetration between normal tissues.

An important principle is that these permeating tumour cells take the line of least physical resistance.

Tumours may stimulate the production of new collagen fibres which are sometimes converted into dense fibrous tissue → contracts and fixes the growth to surrounding structures

The following diagram illustrates the basic mechanisms of cancer cell invasion.

Lymphatic Spread

This is the commonest mode of spread of carcinomas and melanomas, but rarely of sarcomas. Malignant cells easily invade lymphatic channels from the tissue spaces.

Groups of cells form emboli in the lymph stream and are carried to the nearest node (the sentinel node).

The emboli appear first in the subcapsular sinus, and then progressively invade the tissues of the node. Eventually they reach the medulla and grow into the efferent channel and produce metastases in other nodes. Invaded nodes are enlarged, firm and white.

Histological examination of the sentinel node is increasingly carried out to select the patients who require extensive lymph node dissection.

Blood Spread

Both carcinomas and sarcomas spread by the blood stream. The entry of malignant cells into the blood is via invasion of VENULES and by lymphatic embolism through the thoracic duct into the subclavian vein.

Via Larger Veins

Occasionally tumour thrombus is propagated from venules into larger veins. This is classically seen in RENAL CARCINOMA.

Rarely, a malignant process may be complicated by thrombosis of distant veins (thrombophlebitis migrans). This is not due to malignant invasion of the veins but is caused by the action of circulating thromboplastins formed by the tumour.

Arterial System

Direct invasion of arteries and arteriolar lumens is very rare because of the physical barrier provided by the thick muscular and elastic walls.

Destination of Emboli

This depends on the anatomical drainage of the vessel invaded.

Retrograde Venous Spread

As in lymphatics, growth of tumour within a vein may cause reversal of blood flow. In addition, reversal of flow is apt to happen in certain areas of the body where veins form a rich plexus and are deficient in valves, e.g. in the pelvis and around vertebrae. Changes in intra-abdominal and intrathoracic pressures easily induce changes in blood flow in these channels. It is for this reason that secondary tumours are relatively common in vertebral bodies.

Fate of Carcinomatous Emboli

SEED and SOIL ANALOGY

The distribution of carcinomatous emboli is determined in part by anatomy, but many complex factors both in the ‘seed’ (the cancer cell) and the ‘soil’ (the potential metastatic site) are at play in the establishment of metastases at particular sites. They include surface properties of the cancer cells e.g. increased expression of integrins and their receptors present in the endothelial cells at the metastatic site. Variation in the host IMMUNE RESPONSE is also important

Other Modes of Spread of Tumours

Transcoelomic Spread (via Serous Sacs)

This is an important and frequent route of spread in the peritoneal and pleural cavities. It also takes place in the pericardial sac.

As malignant cells sink in the peritoneal cavity, they will settle in various sites. They may cause an inflammatory reaction with fibrin formation. This can cause adhesions between organs, e.g. loops of bowel.

Gastric cancer can spread to both ovaries (so-called KRUKENBERG TUMOUR). An unusual but classic manifestation.

Intra-Epithelial Spread

This form of spread may occur where carcinoma develops in a gland or its duct, e.g. in the breast. Carcinoma cells spread in the areolar skin. (Paget’s disease of the nipple.)

Effects of Tumours

Benign Tumours

(a) The localised tumour mass may compress neighbouring structures causing loss of function and (b) benign endocrine tumours may produce excess hormones.

A Pituitary Adenoma is illustrative:

Non-Metastatic Complications

Patients with cancer often have severe weight loss (cachexia), loss of appetite and fever. These are probably due to release of cytokines (e.g. TUMOUR NECROSIS FACTOR) from tumour cells. Other complications include myopathy and neuropathy. Relapsing thrombosis of distant veins (thrombo-phlebitis migrans) is due to release of thromboplastins.

Tumour Markers

Tumour cells produce substances, many of which are proteins, which are helpful in diagnosis and monitoring of treatment.

(a) Product enters blood stream (and/or urine) where it can be measured.

(b) Histological diagnosis is improved by identifying the specific product using immuno-staining in the cytoplasm of the tumour cells.

Some examples are:

Tumour Marker	Tumour
Human chorionic gonadotrophin (HCG)	Choriocarcinoma, Teratoma of testis
αFeto-protein (αFP)	Hepatocellular carcinoma, Teratoma of testis
Prostate specific antigen, Prostatic acid phosphatase	Prostatic carcinoma
Carcino-embryonic antigen	Gastro-intestinal and other cancers
Calcitonin	Medullary thyroid carcinoma
5-hydroxyindole-acetic acid (5HIAA) in URINE (metabolite of 5-hydroxytryptamine (5HT-SEROTONIN))	Intestinal carcinoid

Monitoring Treatment

Blood levels of tumour markers reflect the effects of treatment. Example: Testicular teratoma

Diagnosis of Tumours Immunocytochemistry

Diagnosis of tumours is made by combining clinical information with pathological information of several types:

1. Gross Examination

2. Conventional Histological Assessment

3. Immunocytochemical staining

Different immunocytochemical panels are used to help address specific histological dilemmas.

Thus, for a metastatic adenocarcinoma of unknown origin, the pathologist may request:

Cytokeratin profiling	CK 7, 19, 20
Transcription factors	Wilms tumour 1 (WT1) Thyroid transcription factor 1 (TTF-1) CDX2
Hormone receptors	Oestogen (ER), progesterone (PR) receptors
‘Tumour markers’	Prostate specific antigen (PSA) Ca125 Carcinoembryonic antigen

An adenocarcinoma with this profile is likely to be of pulmonary origin

CK7 +, CK20 −
TTF1 +ve, WT1 −ve, CDX2 −ve
ER −ve, PR −ve
Ca125 −ve
PSA −ve

Pre-Malignancy

The pathological conditions which are associated with the development of malignancy fall into 3 groups: 1. Benign tumours, 2. Chronic inflammatory conditions and 3. Intraepithelial neoplasia.

1. MALIGNANT TRANSFORMATION OF BENIGN TUMOURS

(a) Colonic cancer is a good example in that most arise from a benign adenoma.

(b) In Familial adenomatous polyposis (Polyposis coli), transformation to cancer in one or more of the very numerous adenomas is inevitable (p.330).

2. CHRONIC INFLAMMATORY CONDITIONS

The inflammation has to be very long standing and transformation to cancer is RARE. Examples are:

(a) In Ulcerative colitis, repeated epithelial damage and repair increase the risk of cancer.

(b) In Hashimoto’s disease – an auto-immune thyroiditis – the uniformly enlarged thyroid contains many proliferating lymphoid follicles and lymphocytes.

3. INTRA-EPITHELIAL NEOPLASIA (carcinoma in situ) is common and a very important pre-cancerous condition at several sites.

Carcinoma in situ (Intraepithelial Neoplasia)

This represents an intermediate stage in the production of a cancer. All the cytological features of malignancy are present, but the cells have not invaded the surrounding tissues. It is frequently found in the cervix uteri at the junction of ecto and endocervix.

In the cervix, the abbreviation CIN (cervical intraepithelial neoplasia) is used. There are 3 grades of severity.

1. CIN 1 (mild dysplasia)

2. CIN 2 – appearances intermediate between Grades 1 and 3

3. CIN 3 (Carcinoma-in-situ)

These premalignant conditions may revert to normal, but most commonly they become truly malignant and invade the surrounding tissues.

The concept of progressive premalignant proliferation applies equally in other organs (e.g. breast, stomach, oesophagus, bronchus, prostate, mouth, vulva).

Carcinogenesis

Malignant tumours are due to UNCONTROLLED PROLIFERATION of cells. Most tumours are MONOCLONAL, i.e. are derived from a single transformed cell.

This concept is well illustrated in MULTIPLE MYELOMA – a malignant tumour of plasma cells.

Clonal Evolution

In time, some cells undergo further mutations which are passed on to their progeny. This is called clonal evolution or progression and explains the morphological variations seen in tumours. Some of the subclones grow more rapidly and metastasise more readily while others are so abnormal that proliferation is not possible and the clone dies out.

Nuclear Morphology and DNA Content

In histological sections these abnormalities are indicated by variations in nuclear density (usually increased), size and shape (i.e. pleomorphism).

The term ‘polyploidy’ is used when the nuclear DNA is increased by exact multiples of the normal.

‘aneuploidy’ indicates irregular increases in DNA content.→

A number of factors, both environmental and genetic, contribute to a cell undergoing malignant change. This should be regarded as a multistep sequence (see p.154).

Environmental Factors

The 3 major environmental factors which induce tumours are 1. Chemical carcinogens, 2. Radiation and 3. Viruses.

Chemical Carcinogenesis

Historically, chemical agents were the first to be associated with cancer. Now, many are recognised in (a) industrial processes, (b) social habits and (c) diet.

Industry	Tumour	Chemical Responsible
Aniline dyes	Bladder cancer	Naphthylamine
Insulation e.g. shipbuilding, building	Mesothelioma, lung, laryngeal cancer	Asbestos
Mineral oil and tar	Skin cancers	Benzpyrene and other hydrocarbons
Plastics	Angiosarcomas of liver	Vinyl chloride monomer
Wood dust	Cancer of nose and sinuses	?

Social Habits

Cigarette smoking is strongly associated with the development of many cancers, including lung, mouth, larynx and bladder. Chewing tobacco greatly increases the risk of oral cancer. It is likely that air pollution, e.g. combustion products of petrol and diesel, also contributes to carcinogenesis. Obesity is associated with an increased risk of cancer, e.g. of the uterus and colon.

Diet

Chemicals in food may be carcinogenic. Nitrosamines may be formed by the action of bacteria on ingested nitrites. AFLATOXINS are produced by fungi (Aspergillus flavus) and, by contaminating foodstuffs, may cause liver cancer.

Note: Chemical carcinogens may act in 2 ways:

1. Directly at the site of application or portal of entry, e.g. skin and lung cancers.

2. After modification, either at the sites of metabolism or excretion e.g. liver and urinary tract tumours.

This is a multistep process of long duration.

The stages of initiation and promotion are important and were identified in classic experiments of skin carcinogenesis.

The order of application of these agents is important. No tumour follows application of promotor alone, or promotor followed by initiator.

In rodents, these changes take months; in humans the time scale is years and is exemplified in the skin, cervix uteri, bronchus, urinary bladder, colon and breast.

Radiant Energy

The potential dangers from irradiation give much cause for concern.

Source of Radiation	Tumours	Type of Radiation
Sunlight	Melanoma, Carcinoma of skin	Ultraviolet (non-ionising)
Nuclear explosions (e.g. atom bombs, Chernobyl)	Leukaemia, carcinomas of lung, breast, thyroid	Ionising
Therapeutic irradiation	Various carcinomas, sarcomas, leukaemia	Ionising
Mining radioactive substances (e.g. uranium)	Lung carcinomas	Ionising
X-ray workers (historical)	Skin cancer, leukaemia	X-rays: Ionising

Effects of Irradiation on Cells

The ionising effect of radiation damages the cell’s DNA, especially during cell proliferation, ranging from single gene mutation to major chromosome damage, including breaks, deletions and translocations.

Proliferating cells are particularly vulnerable. Marrow and gastro-intestinal mucosa are highly sensitive.

Ultraviolet light is of low energy and mainly affects the skin. The ‘pyrimidine dimers’ formed by UV light are normally excised by DNA repair mechanisms. In xeroderma pigmentosum, these are deficient leading to numerous skin tumours.

Carcinogenesis – Viruses

Viruses have long been known to cause cancer in animals (e.g. Rous sarcoma virus and the mouse mammary tumour virus – the Bittner milk factor).

In recent years viruses have been shown to contribute to the development of some human cancers.

Virus	Type	Tumour type
Epstein-Barr (EBV)	DNA	Burkitt’s lymphoma, nasopharyngeal cancer, Hodgkin’s disease, post-transplantation lymphoma
Human herpes virus 8 (HHV-8)	DNA	Kaposi’s sarcoma
Hepatitis ‘B’	DNA	Hepatocellular carcinomas
Human papilloma virus (HPV)	DNA	Cervical, penile, anal carcinoma
Human ‘T’ cell leukaemia virus (HTLV-1)	RNA (Retrovirus)	T-lymphoblastic leukaemia

Mode of Action of Oncogenic Viruses

The essential feature is addition of new DNA to the nucleus of host cells resulting in mutants, but the way in which this is achieved differs in the two types of virus.

Carcinogenesis – Heredity

The inherited genetic influences in cancer are now well recognised.

1. There is a high risk of cancer in some uncommon syndromes inherited as Mendelian traits. Illustrative examples are:

(a) Familial adenomatous polyposis coli (APC). An autosomal dominant condition. Numerous polyps occur in the colon in late childhood (10–14 years) and inevitably lead to adenocarcinoma in early middle age (30–45 years). The APC gene responsible lies on chromosome 5.

(b) Xeroderma pigmentosum. An autosomal recessive trait where failure of DNA repair mechanism leads to skin cancer.

(c) Neurofibromatosis – multiple neurofibromas (NF) – with a 1% risk of sarcoma, is due to a defect of NF-1 gene on chromosome 17.

(d) Retinoblastoma – an autosomal dominant condition (Rb gene on chromosome 13), (p.153).

2. A less well defined, but strong familial tendency, is seen with some common tumours. For some the gene is identified, e.g. BRCA-1 gene, chromosome 17, – 60% risk of breast or ovarian cancer by 50 years.

3. In some families, there is a high risk of several types of cancer. In the rare Li-Fraumeni syndrome, childhood sarcomas, breast cancer in young women, and many other cancers are seen. This is due to a germ-line mutation of the p53 gene (p.153).

Illustrative Family Tree:

/ = denotes affected.

Oncogenes and Tumour Suppressor Genes

Cellular proto-oncogenes are NORMAL genes which STIMULATE cell division. Tumour suppressor genes are NORMAL genes which INHIBIT cell division. Their normal activity during somatic growth and in regeneration and repair takes place during the G₀–G₁ phase of the cell cycle and is strictly controlled.

In cancer cells the normal controls are defective so that the balance between factors stimulating and inhibiting cell growth is permanently lost, resulting in increased proliferation.

Cellular proto-oncogenes code for a number of proteins involved in cell proliferation:

In the cancer cell, these normal genes are permanently changed to oncogenes and proliferation is uncontrolled.

Mutation or overexpression of genes which normally control apoptosis (p.4) are increasingly recognised in many tumours, e.g. overexpression of bcl-2 inhibits apoptosis in follicular lymphoma (p.432).

Oncogenes

The production and activity of ONCOGENES is complex and there are many ways in which they are activated.

The following are examples.

1. Production of excess NORMAL protein

(a) Gene amplification, e.g. neuroblastoma (myc type gene)

(b) Increased mRNA transcription due to chromosomal translocation, e.g. in Burkitt’s LYMPHOMA chromosomes 8 and 14 are involved.

The myc oncogene is now under the influence of the Ig gene control and is permanently switched on.

2. Production of FUNCTIONALLY ABNORMAL PROTEIN

A point mutation of the proto-oncogene produces a protein with an altered function so that over-stimulation occurs.

Altered growth factor receptor function is an example.

Nuclear regulating protein is permanently ‘on’

Tumour Suppressor Genes

Tumour suppressor genes are normal genes which switch off cell proliferation by acting on the cell cycle in G₁. Their biological role is much broader than simply suppressing tumour function, but the name reflects how they have been discovered.

Loss of both copies of a tumour suppressor gene is required for cancer to develop. In contrast, only one copy of a given oncogene needs to be activated to cause excess proliferation.

Examples are:

Tumour suppressor gene	Chromosome	Tumours
p53	17	Carcinoma of lung and breast: sarcoma
Retinoblastoma (Rb)	13	Retinoblastoma, sarcoma: some carcinomas
NF1	17	Neurofibromas, malignant peripheral nerve tumours
APC	5	Colonic carcinoma
WT1	11	Wilms’ tumour, bladder cancer,