Chapter 11 Carcinogenesis and neoplasia
GENERAL CHARACTERISTICS OF NEOPLASMS (TUMOURS)
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Incidence of tumours
Malignant neoplasms—those that invade and spread and are therefore of greater clinical importance—develop in approximately 25% of the human population. The risk increases with age, but tumours can occur even in infancy (Fig. 11.1). The mortality rate is high, despite modern therapy, so that cancer accounts for about one-fifth of all deaths in developed countries. However, the mortality rate varies considerably between specific tumour types.
The relative incidence by diagnosis of various common types of cancer is shown in Fig. 11.2. Lung cancer is the most frequent malignant neoplasm in the UK and USA, and its importance is compounded by the extremely poor prognosis. In other countries other cancers are more common, and these differences often provide important aetiological clues.
For various reasons most epidemiological data on cancer incidence probably underestimate the true incidence. Not all tumours become clinically evident and, unless a thorough autopsy is performed, may never be detected. For example, autopsy surveys have revealed a higher than expected incidence of occult carcinoma of the prostate in elderly men, although these often minute lesions are probably of little clinical consequence. Cancer incidence may also be underestimated due to a failure of detection or diagnosis in countries and communities with poor health care.
Structure of tumours
Solid tumours consist of neoplastic cells and stroma (see below and Fig. 11.3). The neoplastic cells reproduce to a variable extent the growth pattern and synthetic activity of the parent cell of origin. Depending on their functional resemblance to the parent tissue, they continue to synthesise and secrete cell products such as collagen, mucin or keratin; these often accumulate within the tumour where they are recognisable histologically. Other cell products may be secreted into the blood where they can be used clinically to monitor tumour growth and the effects of therapy (p. 234).
Stroma
The stroma always contains blood vessels which perfuse the tumour (Fig. 11.4). The growth of a tumour is dependent upon its ability to induce blood vessels to perfuse it, for unless it becomes permeated by a vascular supply its growth will be limited by the ability of nutrients to diffuse into it, and the tumour cells will cease growing when the nodule has attained a diameter of no more than 1–2mm (Fig. 11.5). Angiogenesis in tumours is induced by factors such as vascular endothelial growth factor (VEGF). This action is opposed by factors such as angiostatin and endostatin which have potential in cancer therapy.
Tumour shape and correlation with behaviour
The gross appearance of a tumour on a surface (e.g. gastrointestinal mucosa) may be described as sessile, polypoid, papillary, fungating, ulcerated or annular (Fig. 11.6). The behaviour of a tumour (i.e. whether it is benign or malignant) can often be deduced from its gross appearance: polypoid tumours are generally benign, i.e. unlikely to spread beyond the tissue of origin (Fig. 11.7); ulceration is more commonly associated with aggressive behaviour because invasion is the defining feature of malignancy (Fig. 11.8).
CLASSIFICATION OF TUMOURS
Tumours are classified according to their behaviour and histogenesis (cell of origin).
Behavioural classification
The behavioural classification divides tumours into:
The principal pathological criteria for classifying a tumour as benign or malignant are summarised in Table 11.1. Some tumours, such as some ovarian tumours, defy precise behavioural classification, because their histology is intermediate between that associated with benign and malignant tumours; these are often referred to as ‘borderline’ tumours.
Table 11.1 Principal characteristics of benign and malignant tumours
Feature | Benign | Malignant |
---|---|---|
Growth rate | Slow | Relatively rapid |
Mitoses | Infrequent | Frequent and often atypical |
Histological resemblance to normal tissue | Good | Variable, often poor |
Nuclear morphology | Often normal | Usually hyperchromatic, irregular outline, multiple nucleoli and pleomorphic |
Invasion | No | Yes |
Metastases | Never | Frequent |
Border | Often circumscribed or encapsulated | Often poorly defined or irregular |
Necrosis | Rare | Common |
Ulceration | Rare | Common on skin or mucosal surfaces |
Direction of growth on skin or mucosal surfaces | Often exophytic | Often endophytic |
Benign tumours
When a benign tumour arises in an epithelial or mucosal surface, the tumour grows away from the surface, because it cannot invade, often forming a polyp which may be either pedunculated (stalked) or sessile; this non-invasive outward direction of growth creates an exophytic lesion (Fig. 11.10). Histologically, benign tumours closely resemble the parent cell or tissue.
Malignant tumours
Malignant tumours are, by definition, invasive. They are typically rapidly growing and poorly circumscribed. Histologically, they resemble the parent cell or tissue to a lesser extent than do benign tumours. Malignant tumours encroach on and destroy the adjacent tissues (Fig. 11.10), enabling the neoplastic cells to penetrate the walls of blood vessels and lymphatic channels and thereby disseminate to other sites. This important process is called metastasis and the resulting secondary tumours are called metastases. Patients with widespread metastases are often said to have carcinomatosis.
Malignant tumours in solid organs tend to be poorly circumscribed, often with strands of neoplastic tissue penetrating adjacent normal structures. The resemblance of the cut surface of these lesions to a crab (Latin: cancer) gives the disease its popular name. Malignant tumours often show central necrosis because of inadequate vascular perfusion.
The considerable morbidity and mortality associated with malignant tumours may be due to:
Histogenetic classification
Histogenetic classification includes numerous subdivisions, but the major categories of origin are:
Although some general differences exist between the main groups of malignant tumours (Table 11.2), individual lesions have to be categorised more precisely both in clinical practice and for epidemiological purposes. It is inadequate to label the patient’s tumour as merely having an epithelial or connective tissue origin; efforts must be made to determine the precise cell type. The classification of individual tumours is vitally important. Thorough histological examination of the tumour, sometimes using special techniques like genetic analysis and immunocytochemistry, detects subtle features that betray its provenance.
Table 11.2 Principal characteristics of carcinomas and sarcomas
Feature | Carcinoma | Sarcoma |
---|---|---|
Origin | Epithelium | Connective tissues |
Behaviour | Malignant | Malignant |
Frequency | Common | Relatively rare |
Preferred route of metastasis | Lymph | Blood |
In situ phase | Yes | No |
Age group | Usually over 50 years | Usually below 50 years |
Histological grade (degree of differentiation)
The extent to which the tumour resembles histologically its cell or tissue of origin determines the tumour grade (Fig. 11.11) or degree of differentiation. Benign tumours are not usually further classified in this way because they nearly always closely resemble their parent tissue and grading the degree of differentiation offers no further clinical benefit in terms of choosing the most appropriate treatment. However, the degree of differentiation of malignant tumours is clinically useful both because it correlates strongly with patient survival (prognosis), and because it often indicates the most appropriate treatment. Thus, malignant tumours are usually graded either as well, moderately or poorly differentiated, or numerically, often by strict criteria, as grade 1, grade 2 or grade 3.
A few tumours are so poorly differentiated that they lack easily recognisable histogenetic features. There may even be great difficulty in deciding whether they are carcinomas or lymphomas, for example, although immunocytochemistry and genetic analysis often enable a distinction to be made. Tumours defying precise histogenetic classification are often referred to as ‘anaplastic’, or by some purely descriptive term such as ‘spindle cell’ or ‘small round cell’ tumour. Fortunately, advances in diagnostic histopathology have resulted in considerably fewer unclassifiable tumours and these descriptive terms are rapidly becoming obsolete.
NOMENCLATURE OF TUMOURS
There are exceptions to the rules of nomenclature that follow and these are a potential source of misunderstanding. For example, the words ‘melanoma’ and ‘lymphoma’ are both commonly used to refer to malignant tumours of melanocytes and lymphoid cells respectively, even though, from the rules of tumour nomenclature, these terms can be mistakenly interpreted as meaning benign lesions. To avoid confusion, which could be clinically disastrous, their names are often preceded by the word ‘malignant’. Similarly, a ‘myeloma’ is a malignant neoplasm of plasma cells.
Detailed descriptions of individual tumours are, in most instances, included in the relevant systematic chapters. Examples of tumour nomenclature are given below and, for reference, in Table 11.3.
Table 11.3 Examples of tumour nomenclature
Type | Benign | Malignant |
---|---|---|
Epithelial | ||
Squamous cell | Squamous cell papilloma | Squamous cell carcinoma |
Transitional | Transitional cell papilloma | Transitional cell carcinoma |
Basal cell | Basal cell papilloma | Basal cell carcinoma |
Glandular | Adenoma (e.g. thyroid adenoma) | Adenocarcinoma (e.g. adenocarcinoma of breast) |
Mesenchymal | ||
Smooth muscle | Leiomyoma | Leiomyosarcoma |
Striated muscle | Rhabdomyoma | Rhabdomyosarcoma |
Adipose tissue | Lipoma | Liposarcoma |
Blood vessels | Angioma | Angiosarcoma |
Bone | Osteoma | Osteosarcoma |
Cartilage | Chondroma | Chondrosarcoma |
Mesothelium | Benign mesothelioma | Malignant mesothelioma |
Synovium | Synovioma | Synovial sarcoma |
Epithelial tumours
Benign epithelial tumours
Benign epithelial tumours are either:
A papilloma is a benign tumour of non-glandular or non-secretory epithelium, such as transitional or stratified squamous epithelium (Fig. 11.12). An adenoma is a benign tumour of glandular or secretory epithelium (Fig. 11.13). The name of a papilloma or adenoma is incomplete unless prefixed by the name of the specific epithelial cell type or glandular origin; examples include squamous cell papilloma, transitional cell papilloma, colonic adenoma and thyroid adenoma.
Malignant epithelial tumours
Carcinoma in situ
The term carcinoma in situ refers to an epithelial neoplasm exhibiting all the cellular features associated with malignancy, but which has not yet invaded through the epithelial basement membrane separating it from potential routes of metastasis—blood vessels and lymphatics (Fig. 11.14). Complete excision at this very early stage will guarantee a cure. Detection of carcinomas at the in situ stage, or of their precursor lesions, is the aim of population screening programmes for cervical, breast and some other carcinomas. The phase of in situ growth may last for several years before invasion commences.
Connective tissue and other mesenchymal tumours
Eponymously named tumours
Miscellaneous tumours
Teratomas
A teratoma is a neoplasm formed of cells representing all three germ cell layers: ectoderm, mesoderm and endoderm. In their benign form, these cellular types are often easily recognised; the tumour may contain teeth and hair, and, on histology, respiratory epithelium, cartilage, muscle, neural tissue, etc. In their malignant form, these representatives of ectoderm, mesoderm and endoderm will be less easily identifiable.
Embryonal tumours: the ‘blastomas’
Mixed tumours
Carcinosarcomas combine the appearances of carcinoma and sarcoma in one tumour, as a result of either collision of adjacent carcinoma and sarcoma or divergent carcinomatous and sarcomatous differentiation from one original transformed cell.
Neuroendocrine tumours
Many neuroendocrine tumours are functionally active, and clinical syndromes often result from excessive secretion of their products (Table 11.4).
Table 11.4 Some neuroendocrine tumours and their associated clinical syndromes
Tumour | Clinical syndrome |
---|---|
Insulinoma | Episodes of hypoglycaemia |
Gastrinoma | Extensive peptic ulceration of the upper gut (Zollinger–Ellison syndrome) |
Phaeochromocytoma | Paroxysmal hypertension |
Carcinoid | If metastases are present, flushing, palpitations and pulmonary valve stenosis |
BIOLOGY OF TUMOUR CELLS
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Cellular immortalisation
Mitotic and apoptotic activity
Malignant tumours frequently exhibit more mitotic activity than the corresponding normal cell population. In histological sections, mitoses are abundant, and mitotic figures are often grossly abnormal, showing tripolar and other bizarre arrangements. Cellular proliferation can be estimated by mitosis counting, DNA measurements and determination of the frequency of expression of cell cycle-associated proteins (e.g. Ki-67 antigen). Prognostic information can be derived from these estimations: higher frequencies of cellular proliferation are associated with a worse prognosis.
Metabolic abnormalities
Tumour products
The major types of tumour product are:
Some tumour products are useful as markers for diagnosis or follow-up (Table 11.5). They can be detected in histological sections or their concentrations measured in the blood. Rising blood levels suggest the presence of tumour; falling levels indicate a sustained response to therapy (Fig. 11.16).
Table 11.5 Tumours secreting markers used in diagnosis or follow-up
Tumour | Marker | Comment |
---|---|---|
Myeloma | ||
Hepatocellular carcinoma | Alpha-fetoprotein (AFP) | Also associated with testicular teratoma |
Gastrointestinal adenocarcinomas | Carcinoembryonic antigen (CEA) | False positives occur in some non-neoplastic conditions |
Neuroendocrine tumours | Peptide hormones (e.g. insulin, gastrin) | Excessive hormone production may have clinical effects |
Phaeochromocytoma | Vanillyl mandelic acid (VMA) | Metabolite of catecholamines in urine |
Carcinoid | 5-Hydroxyindole-acetic acid (5-HIAA) | Metabolite of 5-hydroxytryptamine (5-HT) in urine |
Choriocarcinoma | Human chorionic gonadotrophin (hCG) | In blood or urine |
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