Dysplasia and neoplasia

Cellular atypia and dysplasia

In the previous chapter, we considered cellular adaptations to a variety of stimuli resulting in alterations in their pattern of growth, whilst still achieving full differentiation/maturation. Occasionally, cells have an increased rate of division such that they do not have time to reach complete maturation (with full development of cytoplasmic specialisation) before another cycle of cell division supervenes. This leads to a population of cells that are structurally abnormal, having a high nuclear to cytoplasmic ratio with large nuclei containing abundant, dark-staining chromatin and prominent, occasionally multiple, nucleoli. These nuclear changes are associated with evidence of incomplete maturation of the cytoplasm, which may be lacking in the specialised structures normally seen in that cell type, such as mucin vacuoles or surface cilia. This is called failure of differentiation and the cells are said to show atypia .

Cellular atypia may be a consequence of rapid multiplication of cells as a response to cell destruction due to a persistent damaging stimulus. In this case, atypia is a result of the high turnover of cells attempting to regenerate damaged epithelium. When the damaging stimulus is removed, these abnormalities should revert to normal with full differentiation of the cells returning. However, sometimes the atypia is persistent and is not simply the result of regeneration. In these cases, the population of atypical cells may eventually be the focus from which invasive cancer develops. This type of persistent cellular atypia is called dysplasia ( Fig. 7.1 ). The problem for the pathologist is in distinguishing between cellular atypia, representing a reactive, regenerative response to tissue damage, and dysplasia, which is indicative of early pre-cancer. There is no simple answer.

Dysplasia often arises in metaplastic tissues and it is likely that the stimuli that cause dysplasia are also responsible for metaplastic change. Thus metaplastic epithelium in the cervix and Barrett’s oesophagus is at risk of dysplasia and subsequent neoplasia. In dysplastic cells, molecular biological techniques have demonstrated some of the genetic abnormalities found in invasive neoplasms. Because of the sinister association of dysplasia with the subsequent development of neoplasia, treatment of dysplastic conditions is undertaken to minimise the risk of subsequent development of a malignancy. Recognition of dysplastic changes by cytological examination of cervical smears forms the basis of screening for cancer of the cervix (see clinical box ‘Screening and pathology’ and Fig. 17.6 ).

Neoplasia

In a neoplasm, cellular proliferation and growth occur in the absence of any continuing external stimulus. Therefore, the term neoplasia (from the Greek for new growth) describes a state of autonomous cell division and the abnormal mass of cells that results is termed a neoplasm . The state of neoplastic growth contrasts with hyperplasia , discussed in Ch. 6 , where, although there is abnormal proliferation of cells, this ceases with removal of the causative stimulus.

As well as abnormal cell proliferation, neoplasia is characterised by abnormal maturation of cells. A feature of normal tissue growth is the maturation of constituent cells into a form adapted to a specific function. Such adaptation may involve the acquisition of specialised structures such as mucin vacuoles, neurosecretory granules, microvilli or cilia. This process of structural and functional maturation is called differentiation . A fully mature cell of any particular cell line is said to be highly differentiated , whereas its primitive precursor cells are described as being undifferentiated . In any given tissue, the normal cells have a characteristic state of differentiation. In contrast, neoplastic cells exhibit variable states of differentiation and commonly fail to achieve a highly differentiated state. Neoplasms are divided clinically into two main groups ( Table 7.1 ):

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  benign neoplasms grow slowly and remain localised to the site of origin

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  malignant neoplasms grow rapidly and may spread widely.

There is a broad correlation between histological appearances and biological behaviour, allowing prediction of the likely prognosis. In general, the cells of benign neoplasms are well differentiated. In the case of malignant neoplasms, there is a variable degree of differentiation. At one end of the spectrum, the constituent cells may closely resemble the tissue of origin, in which case the tumour is described as being a well differentiated malignancy . Alternatively, the constituent cells may bear little resemblance to the tissue of origin, in which case the neoplasm is described as being poorly differentiated . At the extreme end of the spectrum, neoplasms that exhibit no evidence of differentiation are termed anaplastic and, in many cases, it may not be possible to identify the cell of origin on morphological grounds alone. Generally, the degree of differentiation of a neoplasm is related to its behaviour. A poorly differentiated neoplasm tends to be more invasive and more aggressive than a well differentiated neoplasm.

Carcinoma in situ

The term carcinoma in situ is used when an epithelial tissue shows the cytological and histological features of carcinoma (architectural and cytological abnormalities such as cell crowding, pleomorphism, increased and abnormal mitotic activity, which may involve the full thickness of the epithelium), but there is no evidence that the basement membrane bounding the abnormal epithelial tissue has been breached and there is no encroachment of atypical cells into the underlying stroma. The process whereby tumour cells breach the basement membrane and extend into the surrounding tissues is described as invasion . Thus, with carcinoma in situ the epithelial cells show the cytological, but not the behavioural, characteristics of malignancy. However, many forms of carcinoma in situ will become invasive if left untreated.

Certain benign epithelial tumours may progress to form an invasive malignant tumour by development and selective persistence of mutations in key oncogenes. A sequence from benign neoplasm through increasing severity of dysplasia to carcinoma in situ and on to invasive carcinoma is well recognised in certain sites.

Carcinoma in situ is synonymous with severe/high grade dysplasia. However, terminology varies depending on the anatomical location. For example, the term carcinoma in situ is used in the skin (see Fig. 21.14 ) and bladder (see Fig. 15.21 ). At other sites such as the cervix, carcinoma in situ is called CIN3 (cervical intraepithelial neoplasia; see Fig. 17.7 ), in the vulva, VIN3 (vulval intraepithelial neoplasia) and in colonic adenomatous polyps, ‘high grade dysplasia’ (see Fig. 13.21 ). It also occurs in solid glandular organs, most notably the breast (ductal and lobular carcinoma in situ; see Figs. 18.9 and 18.11 ).

General characteristics of neoplasms

As mentioned before, the property whereby a malignant tumour can grow into the surrounding tissue is termed invasion. A further property of malignant neoplasms is distant spread of neoplastic cells away from the main neoplasm (the primary tumour ) to form subpopulations of neoplastic cells that are not in continuity with the primary tumour. Distant spread of tumour from a primary site is termed metastasis . The secondary tumours that result from this distant spread are termed metastases .

In general terms, a benign tumour will behave in a relatively innocuous manner and a malignant tumour will have deleterious effects, often leading to death. There are, however, exceptions to these generalisations and factors other than the biological growth pattern of a tumour may be important in influencing the outcome. Of these, the most notable is the location of the tumour. For example, a benign tumour of the brain stem may lead to rapid death, whereas a malignant tumour of the skin may progress slowly over many years.

In addition to local effects, malignant tumours can cause a variety of systemic symptoms such as weight loss (cachexia) , loss of appetite, fever and general malaise. In most cases, the pathophysiology is poorly understood, but includes effects of secreted cytokines such as tumour necrosis factor . Some tumours, benign and malignant, retain the function of their organ of origin. If this happens to be an endocrine function, then the tumour may exert harmful effects by secretion of excess hormone. Other tumours secrete hormones not usually secreted by that tissue, for example the secretion of parathyroid hormone by lung carcinomas. This is known as ectopic hormone secretion and the clinical manifestations are described as paraneoplastic syndromes (see clinical box ‘Paraneoplastic syndromes’).

Histological assessment of neoplasms

Histological assessment of a tumour provides a useful guide to its behaviour, i.e. whether the tumour is benign or malignant, and provides a rational basis for treatment. Histological assessment should establish the following features:

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  The type of tumour. This is based on the presumed tissue of origin and/or differentiation of the tumour.

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  The degree of differentiation ( Fig. 7.10 ). This is known as grading and takes into account some or all of the following features:

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    the similarity of the tumour to the supposed tissue of origin both architecturally and cytologically (differentiation)

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    the degree of variability of cellular shape and size (pleomorphism)

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    the proportion of mitotic figures (dividing cells).

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  The extent of spread of tumour (staging) is partly assessed histologically, particularly:

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    size of the primary tumour

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    histological assessment of local, vascular, lymphatic and perineural invasion

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    the presence of metastatic tumour deposits, for example in lymph nodes and bones.

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  The presence or absence of other prognostic factors. For instance, the presence of oestrogen receptors in breast carcinoma cells confers an improved prognosis. The expression of certain oncogenes is increasingly being related to prognosis in some tumours.

Tumour nomenclature and classification

The classification and nomenclature of neoplasms have developed from gross morphological, histological and behavioural observation. Ideally, the name given to a tumour should convey information about the cell of origin and the likely behaviour (either benign or malignant). While this is the case for the majority of tumours of epithelial and connective tissues, there are many tumours that are given eponymous or semi-descriptive names out of either poor understanding of pathogenesis or long-established tradition. Some tumours have several different names that are synonymous, but derive from different classifications.

Tumours of epithelial origin

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  Benign neoplasms of surface epithelia, for example skin, are termed papillomas. This term is preceded by the cell of origin, for example squamous papilloma of skin or larynx.

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  Benign neoplasms of both solid and surface glandular epithelia are termed adenomas . This is prefixed by the tissue of origin, for example thyroid adenoma, salivary gland adenoma. Frequently, a benign tumour of surface glandular epithelium (almost always in the large bowel) assumes a papillary growth pattern, termed a villous adenoma .

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  A malignant tumour of any epithelial origin is termed a carcinoma. Tumours of glandular epithelium (including that lining the gut) are termed adenocarcinomas . Tumours of other epithelia are preceded by the cell type of origin, for example squamous cell carcinoma and transitional cell carcinoma . To classify a carcinoma further, the tissue of origin is added, for example adenocarcinoma of prostate, adenocarcinoma of breast and squamous cell carcinoma of larynx.

The nomenclature of epithelial tumours is summarised in Table 7.2 .

Tumours of connective tissue origin

In connective tissues, there is a simpler and more descriptive classification of neoplasms. First, the tissue of origin is designated, with the addition of the suffix - oma for a benign tumour or - sarcoma for a malignant tumour. As an example, a benign tumour of adipose tissue is termed a lipoma, whilst a malignant tumour of the same origin is termed a liposarcoma. A summary of other connective tissue tumours is shown in Table 7.3 .

Nomenclature of other tumours

There are other neoplasms that do not fit into either the epithelial or the connective tissue category described above and these are grouped according to their tissue of origin. The main categories are as follows:

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  Melanoma: tumours of melanocytes ( Fig. 7.8 and Ch. 21)

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  Lymphomas: tumours of solid lymphoid tissue ( Fig. 7.7 and Ch. 16)

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  Leukaemias: tumours derived from haematopoietic elements that circulate in the blood and only rarely form tumour masses (see Ch. 16)

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  Gliomas: tumours derived from the non-neural support tissues of the brain (see Ch. 23)

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  Germ cell tumours: tumours derived from germ cells in the gonads ( Fig. 7.9 , Ch. 17 and Ch. 19)

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  Neuroendocrine tumours : tumours derived from cells of the neuroendocrine system. Examples include phaeochromocytoma (see Fig. 20.11), carcinoid tumour (see Fig. 12.22) and medullary carcinoma (see Fig. 20.7).

Finally, there is a group of tumour-like lesions known as hamartomas that represent non-neoplastic overgrowths of tissues indigenous to the site of their occurrence. These are thought to be developmental abnormalities. A common example is the ‘port-wine stain’ of the skin composed of blood vessels and known as a haemangioma . An example of a haemangioma in the liver is shown in Fig. 11.8.

Modes of spread of malignant neoplasms

There are four main modes of tumour spread:

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  Local invasion. Invasive tumours tend to spread into surrounding tissues by the most direct route. Examples include carcinoma of the breast invading overlying skin or deeply into underlying muscle and carcinoma of the cervix invading rectum or bladder.

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  Lymphatic spread. Tumours may spread via lymphatic vessels draining the site of the primary tumour. Neoplastic cells are conducted to local lymph nodes where they may form secondary tumours, e.g. breast cancer spreading to lymph nodes in the axilla or carcinoma of the tongue spreading to lymph nodes in the neck.

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  Vascular spread. Tumours can spread via the veins draining the primary site. Gut tumours tend to spread via the portal vein to the liver where secondary tumours are very common. In the systemic circulation, neoplastic cells may be trapped in the lung to form pulmonary metastases ( Fig. 7.16 ).

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  Transcoelomic spread. Certain tumours can spread directly across coelomic spaces, for example across the peritoneal or pleural cavities. Carcinoma of the ovary may spread transcoelomically to produce large numbers of metastatic deposits on the peritoneal surfaces.

Staging of malignant tumours

The extent of local, regional and distant tumour spread is an important determinant of tumour management and prognosis. Several systems have been devised for defining these characteristics in a standardised fashion; this is known as staging of a tumour. This is different from grading , described earlier in the chapter, which involves pathological assessment of the degree of differentiation of the tumour.

The TNM system is the most widely used method and involves scoring the extent of local T umour spread, regional lymph N ode involvement and the presence of distant M etastases. Despite advances in diagnostic techniques, the stage of a tumour is still a very good indicator of likely prognosis. Tumour stage assessment is also important in planning therapy. Tumours at an advanced stage (extensive spread) may require aggressive treatment, while early-stage tumours (localised) can be treatable by more conservative measures such as surgical excision alone. Staging is usually performed by a combination of histopathology, radiology and clinical assessments.

By way of example, the TNM (8 ^th Edition) for colonic cancer staging is illustrated in Table 7.4 .

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