NEOPLASIA (CHARACTERISTICS OF TUMOURS)
CHARACTERISTICS OF TUMOURS
Majority of neoplasms can be categorised clinically and morphologically into benign and malignant on the basis of certain characteristics listed below. However, there are exceptions—a small proportion of tumours have some features suggesting innocent growth while other features point towards a more ominous behaviour. Therefore, it must be borne in mind that based characteristics of neoplasms,there is a wide variation in the degree of deviation from the normal in all the tumours.
The characteristics of tumours are described under the following headings:
I. Rate of growth
II. Cancer phenotype and stem cells
III. Clinical and gross features
IV. Microscopic features
V. Local invasion (Direct spread)
VI. Metastasis (Distant spread).
Based on these characteristics, contrasting features of benign and malignant tumours are summarised in Table and illustrated in Fig.
I. RATE OF GROWTH
The tumour cells generally proliferate more rapidly than the normal cells. In general, benign tumours grow slowly and malignant tumours rapidly. However, there are exceptions to this generalisation. The rate at which the tumour enlarges depends upon 2 main factors:
1. Rate of cell production, growth fraction and rate of cell loss
2. Degree of differentiation of the tumour.
1. Rate of cell production, growth fraction and rate of cell loss. Rate of growth of a tumour depends upon 3 important parameters:
i) doubling time of tumour cells,
ii) number of cells remaining in proliferative pool (growth fraction), and
iii) rate of loss of tumour cells by cell shedding.
In general, malignant tumour cells have increased mitotic rate (doubling time) and slower death rate i.e. the cancer cells do not follow normal controls in cell cycle and are immortal.If the rate of cell division is high, it is likely that tumour cells in the centre of the tumour do not receive adequate nourishment and undergo ischaemic necrosis. At a stage when malignant tumours grow relentlessly, they do so because a larger proportion of tumour cells remain in replicative pool but due to lack of availability of adequate nourishment, these tumour cells are either lost by shedding or leave the cell cycle to enter into G0 (resting phase) or G1 phase. While dead tumour cells appear as ‘apoptotic figures’ the dividing cells of tumours are seen as normal and abnormal ‘mitotic figures’ (discussed later). Ultimately,malignant tumours grow in size because the cell production exceeds the cell loss.
2. Degree of differentiation. Secondly, the rate of growth of malignant tumour is directly proportionate to the degree of differentiation. Poorly differentiated tumours show aggressive growth pattern as compared to better differentiated tumours. Some tumours, after a period of slow growth,may suddenly show spurt in their growth due to development of an aggressive clone of malignant cells. On the other hand, some tumours may cease to grow after sometime.Rarely, a malignant tumour may disappear spontaneously from the primary site, possibly due to necrosis caused by good host immune attack, only to reappear as secondaries elsewhere in the body e.g. choriocarcinoma, malignant melanoma.
The regulation of tumour growth is under the control of growth factors secreted by the tumour cells. Out of various growth factors, important ones modulating tumour biology are listed below and discussed later:
i) Epidermal growth factor (EGF)
ii) Fibroblast growth factor (FGF)
iii) Platelet-derived growth factor (PDGF)
iv) Colony stimulating factor (CSF)
v) Transforming growth factors-β (TGF-β)
vi) Interleukins (IL)
vii) Vascular endothelial growth factor (VEGF)
II. CANCER PHENOTYPE AND STEM CELLS
Normally growing cells in an organ are related to the neighbouring cells—they grow under normal growth controls, perform their assigned function and there is a balance between the rate of cell proliferation and the rate of cell death including cell suicide (i.e. apoptosis). Thus normal cells are socially desirable. However, cancer cells exhibit antisocial behaviour as under:
i) Cancer cells disobey the growth controlling signals in the body and thus proliferate rapidly.
ii) Cancer cells escape death signals and achieve immortality.
iii) Imbalance between cell proliferation and cell death in cancer causes excessive growth.
iv) Cancer cells lose properties of differentiation and thus perform little or no function.
v) Due to loss of growth controls, cancer cells are genetically unstable and develop newer mutations.
vi) Cancer cells overrun their neighbouring tissue and invade locally.
vii) Cancer cells have the ability to travel from the site of origin to other sites in the body where they colonise and establish distant metastasis.
Cancer cells originate by clonal prolferation of a single progeny of a cell (monoclonality). Cancer cells arise from stem cells normally present in the tissues in small number and are not readily identifiable. These stem cells have the properties of prolonged self-renewal, asymmetric replication and transdifferentiation (i.e. plasticity). These cancer stem cells are called tumour-initiating cells. Their definite existence in acute leukaemias has been known for sometime and have now been found to be present in some other malignant tumours.
III. CLINICAL AND GROSS FEATURES
Clinically, benign tumours are generally slow growing, and depending upon the location, may remain asymptomatic (e.g.subcutaneous lipoma), or may produce serious symptoms(e.g. meningioma in the nervous system). On the other hand,malignant tumours grow rapidly, may ulcerate on the surface, invade locally into deeper tissues, may spread to distant sites (metastasis), and also produce systemic features such as weight loss, anorexia and anemia. In fact, two of the cardinal clinical features of malignant tumours are:invasiveness and metastasis
Gross appearance of benign and malignant tumours may be quite variable and the features may not be diagnostic on the basis of gross appearance alone. However, certain distinctive features characterise almost all tumours compared to neighbouring normal tissue of origin—they have a different colour, texture and consistency. Gross terms such as papillary, fungating, infiltrating, haemorrhagic, ulcerative and cystic are used to describe the macroscopic appearance of the tumours. General gross features of benign and malignant tumours are as under(fig).
•Benign tumours are generally spherical or ovoid in shape.They are encapsulated or well-circumscribed, freely movable,more often firm and uniform, unless secondary changes like haemorrhage or infarction supervene (Fig.).
•Malignant tumours, on the other hand, are usually irregular in shape, poorly-circumscribed and extend into the adjacent tissues. Secondary changes like haemorrhage,infarction and ulceration are seen more often. Sarcomas typically have fish-flesh like consistency while carcinomas are generally firm (Fig.).
IV. MICROSCOPIC FEATURES
For recognising and classifying the tumours, the microscopic characteristics of tumour cells are of greatest importance.These features which are appreciated in histologic sections are as under:
1. microscopic pattern;
2. cytomorphology of neoplastic cells (differentiation and anaplasia);
3. tumour angiogenesis and stroma; and
4. inflammatory reaction.
1. Microscopic Pattern
The tumour cells may be arranged in a variety of patterns in different tumours as under:
•The epithelial tumours generally consist of acini, sheets,columns or cords of epithelial tumour cells that may be arranged in solid or papillary pattern (Fig.).
•The mesenchymal tumours have mesenchymal tumour cells arranged as interlacing bundles, fasicles or whorls, lying separated from each other usually by the intercellular matrix substance such as hyaline material in leiomyoma (Fig),cartilaginous matrix in chondroma, osteoid in osteosarcoma,reticulin network in soft tissue sarcomas etc (Fig).
•Certain tumours have mixed patterns e.g. teratoma arising from totipotent cells, pleomorphic adenoma of salivary gland(mixed salivary tumour), fibroadenoma of the breast,carcinosarcoma of the uterus and various other combinations of tumour types.
•Haematopoietic tumours such as leukaemias and lymphomas often have none or little stromal support.
•Generally, most benign tumours and low grade malignant tumours reduplicate the normal structure of origin more closely so that there is little difficulty in identifying and classifying such tumours (Fig). However, anaplastic tumours differ greatly from the arrangement in normal tissue of origin of the tumour and may occasionally pose problems in classifying the tumour.
2. Cytomorphology of Neoplastic Cells (Differentiation and Anaplasia)
The neoplastic cell is characterised by morphologic and functional alterations, the most significant of which are ‘differentiation’ and ‘anaplasia’.
•Differentiation is defined as the extent of morphological and functional resemblance of parenchymal tumour cells to corresponding normal cells. If the deviation of neoplastic cell in structure and function is minimal as compared to normal cell, the tumour is described as ‘well-differentiated’ such as most benign and low-grade malignant tumours. ‘Poorly differentiated’, ‘undifferentiated’ or ‘dedifferentiated’ are synonymous terms for poor structural and functional resemblance to corresponding normal cell.
•Anaplasia is lack of differentiation and is a characteristic feature of most malignant tumours. Depending upon the degree of differentiation, the extent of anaplasia is also variable i.e. poorly differentiated malignant tumours have high degree of anaplasia.
As a result of anaplasia, noticeable morphological and functional alterations in the neoplastic cells are observed. These are considered below and are diagrammatically illustrated in Fig:
i) Loss of polarity. Normally, the nuclei of epithelial cells are oriented along the basement membrane which is termed as basal polarity. This property is based on cell adhesion molecules, particularly selectins. Early in malignancy, tumour cells lose their basal polarity so that the nuclei tend to lie away from the basement membrane (Fig).
ii) Pleomorphism. The term pleomorphism means variation in size and shape of the tumour cells. The extent of cellular pleomorphism generally correlates with the degree of anaplasia. Tumour cells are often bigger than normal but in some tumours they can be of normal size or smaller than normal (Fig)
iii) N:C ratio. Generally, the nuclei of malignant tumour cells show more conspicuous changes. Nuclei are enlarged disproportionate to the cell size so that the nucleocytoplasmic ratio is increased from normal 1:5 to 1:1 (Fig).
iv) Anisonucleosis. Just like cellular pleomorphism, the nuclei too, show variation in size and shape in malignant tumour cells (Fig.).
v) Hyperchromatism. Characteristically, the nuclear chromatin of malignant cell is increased and coarsely clumped. This is due to increase in the amount of nucleoprotein resulting in dark-staining nuclei, referred to as hyperchromatism (Fig. 8.6). Nuclear shape may vary, nuclear membrane may be irregular and nuclear chromatin is clumped along the nuclear membrane.
vi) Nucleolar changes. Malignant cells frequently have a prominent nucleolus or nucleoli in the nucleus reflecting increased nucleoprotein synthesis (Fig.). This may be demonstrated as Nucleolar Organiser Region (NOR) by silver (Ag) staining called AgNOR material.
vii) Mitotic figures. The parenchymal cells of poorlydifferentiated tumours often show large number of mitoses as compared with benign tumours and well-differentiated malignant tumours. As stated above, these appear as either normal or abnormal mitotic figures (Fig):
•Normal mitotic figures may be seen in some non-neoplastic proliferating cells (e.g. haematopoietic cells of the bone marrow, intestinal epithelium, hepatocytes etc), in certain benign tumours and some low grade malignant tumours; in sections they are seen as a dark band of dividing chromatin at two poles of the nuclear spindle.
•Abnormal or atypical mitotic figures are more important in malignant tumours and are identified as tripolar, quadripolar and multipolar spindles in malignant tumour cells.
viii) Tumour giant cells. Multinucleate tumour giant cells or giant cells containing a single large and bizarre nucleus, possessing nuclear characters of the adjacent tumour cells, are another important feature of anaplasia in malignant tumours (Fig.).
ix) Functional (Cytoplasmic) changes. Structural anaplasia in tumours is accompanied with functional anaplasia as appreciated from the cytoplasmic constituents of the tumour cells. The functional abnormality in neoplasms may be quantitative, qualitative, or both.
•Generally, benign tumours and better-differentiated malignant tumours continue to function well qualitatively, though there may be quantitative abnormality in the product e.g. large or small amount of collagen produced by benign tumours of fibrous tissue, keratin formation in well differentiated squamous cell carcinoma. In more anaplastic tumours, there is usually quantitative fall in the product made by the tumour cells e.g. absence of keratin in anaplastic squamous cell carcinoma.
•There may be both qualitative and quantitative abnormality of the cellular function in some anaplastic tumours e.g. multiple myeloma producing abnormal immunoglobulin in large quantities.
•Endocrine tumours may cause excessive hormone production leading to characteristic clinical syndromes. Besides the production of hormones by endocrine tumours, hormones or hormone-like substances may be produced by certain tumours quite unrelated to the endocrine glands. This property of tumours is called ectopic hormone production e.g. oat cell carcinoma of the lung can secrete ACTH and ADH; less often it may produce gonadotropin, thyrotropin, parathormone, calcitonin and growth hormone. Ectopic erythropoietin may be produced by carcinoma of kidneys, hepatocellular carcinoma and cerebellar haemangioblastoma.
x) Chromosomal abnormalities. All tumour cells have abnormal genetic composition and on division they transmit the genetic abnormality to their progeny. The chromosomal abnormalities are more marked in more malignant tumours which include deviations in both morphology and number of chromosomes. Most malignant tumours show DNA aneuploidy, often in the form of an increase in the number of chromosomes, reflected morphologically by the increase in the size of nuclei.
One of the most important examples of a consistent chromosomal abnormality in human malignancy is the presence of Philadelphia chromosome (named after the city in which it was first described) in 95% cases of chronic myeloid leukaemia. In this, part of the long arm of chromosome 9 is translocated to part of the long arm of chromosome 22 (t 9; 22). Other examples of neoplasms showing chromosomal abnormalities are Burkitt’s lymphoma, acute lymphoid leukaemia, multiple myeloma, retinoblastoma, oat cell carcinoma, Wilms’ tumour etc.
3. Tumour Angiogenesis and Stroma
The connective tissue alongwith its vascular network forms the supportive framework on which the parenchymal tumour cells grow and receive nourishment. In addition to variable amount of connective tissue and vascularity, the stroma may have nerves and metaplastic bone or cartilage but no lymphatics.
TUMOUR ANGIOGENESIS. In order to provide nourishment to growing tumour, new blood vessels are formed from pre-existing ones (angiogenesis). How this takes place under the influence of angiogenic factors elaborated by tumour cells such as vascular endothelium growth factor (VEGF) is discussed later under molecular pathogenesis of cancer. However, related morphologic features are as under:
i) Microvascular density. The new capillaries add to the vascular density of the tumour which has been used as a marker to assess the rate of growth of tumours and hence grade the tumours. This is done by counting microvascular density in the section of the tumour.
ii) Central necrosis. However, if the tumour outgrows its blood supply as occurs in rapidly growing tumours or tumour angiogenesis fails, its core undergoes ischaemic necrosis.
TUMOUR STROMA. The collagenous tissue in the stroma may be scanty or excessive. In the former case, the tumour is soft and fleshy (e.g. in sarcomas, lymphomas), while in the latter case the tumour is hard and gritty (e.g. infiltrating duct carcinoma breast). Growth of fibrous tissue in tumour is stimulated by basic fibroblast growth factor (bFGF) elaborated by tumour cells.
•If the epithelial tumour is almost entirely composed of parenchymal cells, it is called medullary e.g. medullary carcinoma of the breast (Fig), medullary carcinoma of the thyroid.
•If there is excessive connective tissue stroma in the epithelial tumour, it is referred to as desmoplasia and the tumour is hard or scirrhous e.g. infiltrating duct carcinoma breast (Fig), linitis plastica of the stomach.
4. Inflammatory Reaction
At times, prominent inflammatory reaction is present in and around the tumours. It could be the result of ulceration in the cancer when there is secondary infection. The inflammatory reaction in such instances may be acute or chronic. However, some tumours show chronic inflammatory reaction, chiefly of lymphocytes, plasma cells and macrophages, and in some instances granulomatous reaction, in the absence of ulceration. This is due to cell-mediated immunologic response by the host in an attempt to destroy the tumour. In some cases, such an immune response improves the prognosis.
The examples of such reaction are: seminoma testis (Fig), malignant melanoma of the skin, lymphoepithelioma of the throat, medullary carcinoma of the breast, choriocarcinoma, Warthin’s tumour of salivary glands etc.
V. LOCAL INVASION (DIRECT SPREAD)
BENIGN TUMOURS. Most benign tumours form encapsulated or circumscribed masses that expand and push aside the surrounding normal tissues without actually invading, infiltrating or metastasising.
MALIGNANT TUMOURS. Malignant tumours also enlarge by expansion and some well-differentiated tumours may be partially encapsulated as well e.g. follicular carcinoma thyroid. But characteristically, they are distinguished from benign tumours by invasion, infiltration and destruction of the surrounding tissue, besides distant metastasis (described below). In general, tumours invade via the route of least resistance, though eventually most cancers recognise no anatomic boundaries. Often, cancers extend through tissue spaces, permeate lymphatics, blood vessels, perineural spaces and may penetrate a bone by growing through nutrient foramina. More commonly, the tumours invade thinwalled capillaries and veins than thick-walled arteries. Dense compact collagen, elastic tissue and cartilage are some of the tissues which are sufficiently resistant to invasion by tumours.
Mechanism of invasion of malignant tumours is discussed together with that of metastasis below.
VI. METASTASIS (DISTANT SPREAD)
Metastasis (meta = transformation, stasis = residence) is defined as spread of tumour by invasion in such a way that discontinuous secondary tumour mass/masses are formed at the site of lodgement. Metastasis and invasiveness are the two most important features to distinguish malignant from benign tumours: benign tumours do not metastasise while all the malignant tumours with a few exceptions like gliomas of the central nervous system and basal cell carcinoma of the skin, can metastasise. Generally, larger, more aggressive and rapidly-growing tumours are more likely to metastasise but there are numerous exceptions. About one-third of malignant tumours at presentation have evident metastatic deposits while another 20% have occult metastasis.
Routes of Metastasis
Cancers may spread to distant sites by following pathways:
1. Lymphatic spread
2. Haematogenous spread
3. Spread along body cavities and natural passages (Transcoelomic spread, along epithelium-lined surfaces, spread via cerebrospinal fluid, implantation).
1. LYMPHATIC SPREAD. In general, carcinomas metastasise by lymphatic route while sarcomas favour haematogenous route. However, sarcomas may also spread by lymphatic pathway. The involvement of lymph nodes by malignant cells may be of two forms:
i) Lymphatic permeation. The walls of lymphatics are readily invaded by cancer cells and may form a continuous growth in the lymphatic channels called lymphatic permeation.
ii) Lymphatic emboli. Alternatively, the malignant cells may detach to form tumour emboli so as to be carried along the lymph to the next draining lymph node. The tumour emboli enter the lymph node at its convex surface and are lodged in the subcapsular sinus where they start growing (Fig). Later, of course, the whole lymph node may be replaced and enlarged by the metastatic tumour (Fig).
•Generally, regional lymph nodes draining the tumour are invariably involved producing regional nodal metastasis e.g. from carcinoma breast to axillary lymph nodes, from carcinoma thyroid to lateral cervical lymph nodes, bronchogenic carcinoma to hilar and para-tracheal lymph nodes etc.
•However, all regional nodal enlargements are not due to nodal metastasis because necrotic products of tumour and antigens may also incite regional lymphadenitis of sinus histiocytosis.
•Sometimes lymphatic metastases do not develop first in the lymph node nearest to the tumour because of venouslymphatic anastomoses or due to obliteration of lymphatics by inflammation or radiation, so called skip metastasis.
•Other times, due to obstruction of the lymphatics by tumour cells, the lymph flow is disturbed and tumour cells spread against the flow of lymph causing retrograde metastases at unusual sites e.g. metastasis of carcinoma prostate to the supraclavicular lymph nodes, metastatic deposits from bronchogenic carcinoma to the axillary lymph nodes.
•Virchow’s lymph node is nodal metastasis preferentially to supraclavicular lymph node from cancers of abdominal organs e.g. cancer stomach, colon, and gall bladder.
It is believed that lymph nodes in the vicinity of tumour perform multiple roles—as initial barrier filter, and in destruction of tumour cells, while later provide fertile soil for growth of tumour cells.
Mechanism of lymphatic route of metastasis is discussed later under biology of invasion and metastasis.
2. HAEMATOGENOUS SPREAD. Blood-borne metastasis is the common route for sarcomas but certain carcinomas also frequently metastasise by this mode, especially those of the lung, breast, thyroid, kidney, liver, prostate and ovary. The sites where blood-borne metastasis commonly occurs are: the liver, lungs, brain, bones, kidney and adrenals, all of which provide ‘good soil’ for the growth of ‘good seeds’ (seed-soil theory). However, a few organs such as spleen, heart, and skeletal muscle generally do not allow tumour metastasis to grow. Spleen is unfavourable site due to open sinusoidal pattern which does not permit tumour cells to stay there long enough to produce metastasis. In general, only a proportion of cancer cells are capable of clonal proliferation in the proper environment; others die without establishing a metastasis.
•Systemic veins drain blood into vena cavae from limbs, head and neck and pelvis. Therefore, cancers of these sites more often metastasise to the lungs.
•Portal veins drain blood from the bowel, spleen and pancreas into the liver. Thus, tumours of these organs frequently have secondaries in the liver.
•Arterial spread of tumours is less likely because they are thick-walled and contain elastic tissue which is resistant to invasion. Nevertheless, arterial spread may occur when tumour cells pass through pulmonary capillary bed or through pulmonary arterial branches which have thin walls. Cancer of the lung may, however, metastasise by pulmonary arterial route to kidneys, adrenals, bones, brain etc.
•Retrograde spread by blood route may occur at unusual sites due to retrograde spread after venous obstruction, just as with lymphatic metastases. Important examples are vertebral metastases in cancers of the thyroid and prostate.
3. SPREAD ALONG BODY CAVITIES AND NATURAL PASSAGES. Uncommonly, some cancers may spread by seeding across body cavities and natural passages. These routes of distant spread are as under:
i) Transcoelomic spread. Certain cancers invade through the serosal wall of the coelomic cavity so that tumour fragments or clusters of tumour cells break off to be carried in the coelomic fluid and are implanted elsewhere in the body cavity. Peritoneal cavity is involved most often, but occasionally pleural and pericardial cavities are also affected.A few examples of transcoelomic spread are as follows:
a) Carcinoma of the stomach seeding to both ovaries(Krukenberg tumour).
b) Carcinoma of the ovary spreading to the entire peritoneal cavity without infiltrating the underlying organs.
c) Pseudomyxoma peritonei is the gelatinous coating of the peritoneum from mucin-secreting carcinoma of the ovary or apppendix.
d) Carcinoma of the bronchus and breast seeding to the pleura and pericardium.
ii) Spread along epithelium-lined surfaces. It is unusual for a malignant tumour to spread along the epithelium-lined surfaces because intact epithelium and mucus coat are quite resistant to penetration by tumour cells. However,exceptionally a malignant tumour may spread through:
a) the fallopian tube from the endometrium to the ovaries or vice-versa;
b) through the bronchus into alveoli; and
c) through the ureters from the kidneys into lower urinary tract.
iii) Spread via cerebrospinal fluid. Malignant tumour of the ependyma and leptomeninges may spread by release of tumour fragments and tumour cells into the CSF and produce metastases at other sites in the central nervous system.
iv) Implantation. Rarely, a tumour may spread by implantation by surgeon’s scalpel, needles, sutures, or may be implanted by direct contact such as transfer of cancer of the lower lip to the apposing upper lip.
MECHANISM AND BIOLOGY OF
INVASION AND METASTASIS
The process of local invasion and distant spread by lymphatic and haematogenous routes discussed above involves passage through barriers before gaining access to the vascular lumen.This includes making the passage by the cancer cells by dissolution of extracellular matrix (ECM) at three levels— at the basement membrane of tumour itself, at the level of interstitial connective tissue, and at the basement membrane of microvasculature. The following steps are involved at the molecular level which are schematically illustrated in Fig.
1. Aggressive clonal proliferation and angiogenesis. The first step in the spread of cancer cells is the development of rapidly proliferating clone of cancer cells. This is explained on the basis of tumour heterogeneity, i.e. in the population of monoclonal tumour cells, a subpopulation or clone of tumour cells has the right biologic characteristics to complete the steps involved in the development of metastasis. Tumour angiogenesis plays a very significant role in metastasis since the new vessels formed as part of growing tumour are more vulnerable to invasion as these evolving vessels are directly in contact with cancer cells.
2. Tumour cell loosening. Normal cells remain glued to each other due to presence of cell adhesion molecules (CAMs)i.e.E (epithelial) cadherin. In epithelial cancers, there is either loss or inactivation of E-cadherin and also other CAMs of immunoglobulin superfamily, all of which results in loosening of cancer cells.
3. Tumour cell-ECM interaction. Loosened cancer cells are now attached to ECM proteins, mainly laminin and fibronectin.This attachment is facilitated due to profoundness of receptors on the cancer cells for both these proteins. There is also loss of integrins, the transmembrane receptors, further favouring invasion
4. Degradation of ECM. Tumour cells overexpress proteases and matrix-degrading enzymes, metalloproteinases, that includes collagenases and gelatinase, while the inhibitors of metalloproteinases are decreased. Another protease, cathepsin D, is also increased in certain cancers. These enzymes bring about dissolution of ECM—firstly basement membrane of tumour itself, then make way for tumour cells through the interstitial matrix, and finally dissolve the basement membrane of the vessel wall.
5. Entry of tumour cells into capillary lumen. The tumour cells after degrading the basement membrane are ready to migrate into lumen of capillaries or venules for which the following mechanisms play a role:
i) Autocrine motility factor (AMF) is a cytokine derived from tumour cells and stimulates receptor-mediated motility of tumour cells.
ii) Cleavage products of matrix components which are formed following degradation of ECM have properties of tumour cell chemotaxis, growth promotion and angiogenesis in the cancer.
After the malignant cells have migrated through the breached basement membrane, these cells enter the lumen of lymphatic and capillary channels.
6. Thrombus formation. The tumour cells protruding in the lumen of the capillary are now covered with constituents of the circulating blood and form the thrombus. Thrombus provides nourishment to the tumour cells and also protects them from the immune attack by the circulating host cells. In fact, normally a large number of tumour cells are released into circulation but they are attacked by the host immune cells. Actually a very small proportion of malignant cells (less than 0.1%) in the blood stream survive to develop into metastasis.
7. Extravasation of tumour cells. Tumour cells in the circulation (capillaries, venules, lymphatics) may mechanically block these vascular channels and attach to vascular endothelium. In this way, the sequence similar to local invasion is repeated and the basement membrane in exposed.
8. Survival and growth of metastatic deposit. The extravasated malignant cells on lodgement in the right environment grow further under the influence of growth factors produced by host tissues, tumour cells and by cleavage products of matrix components. These growth factors in particular include: PDGF, FGF, TGF-β and VEGF. The metastatic deposits grow further if the host immune defense mechanism fails to eliminate it. Metastatic deposits may further metastasise to the same organ or to other sites by forming emboli.
PROGNOSTIC MARKERS
Metastasis is a common event in malignant tumours which greatly reduces the survival of patient. In the biology of tumour, metastasis is a form of unusual cell differentiation in which the tumour cells form disorderly masses at ectopic sites and start growing there. This random phenomenon takes place in a stepwise manner involving only a subpopulation of tumour cells selectively. The process is governed by inappropriate expression of genes which normally partake in physiologic processes i.e. it is a genetically programmed phenomenon.
Recent evidence has shown that in metastatic tumours, survival of host is correlated with some clinical and molecular features of tumours which act as prognostic markers. These are as under:
i) Clinical prognostic markers: Size, grade, vascular invasion and nodal involvement by the tumour.
ii) Molecular prognostic markers: Molecular markers indicative of poor prognosis in certain specific tumours are:
a) expression of an oncogene by tumour cells (C-met);
b) CD 44 molecule;
c) oestrogen receptors;
d) epidermal growth factor receptor;
e) angiogenesis factors and degree of neovascularisation; and
f) expression of metastasis associated gene or nucleic acid (MAGNA) in the DNA fragment in metastasising tumour.
GRADING AND STAGING OF CANCER
‘Grading’ and ‘staging’ are the two systems to predict tumour behaviour and guide therapy after a malignant tumour is detected. Grading is defined as the gross and microscopic degree of differentiation of the tumour, while staging means extent of spread of the tumour within the patient. Thus, grading is histologic while staging is clinical.
Grading
Cancers may be graded grossly and microscopically. Gross features like exophytic or fungating appearance are indicative of less malignant growth than diffusely infiltrating tumours. However, grading is largely based on 2 important histologic features: the degree of anaplasia, and the rate of growth. Based on these features, cancers are categorised from grade I as the most differentiated, to grade III or IV as the most undifferentiated or anaplastic. Many systems of grading have been proposed but the one described by Broders for dividing squamous cell carcinoma into 4 grades depending upon the degree of differentiation is followed for other malignant tumours as well. Broders’ grading is as under:
Grade I: Well-differentiated (less than 25% anaplastic cells).
Grade II: Moderately-differentiated (25-50% anaplastic cells).
Grade III: Moderately-differentiated (50-75% anaplastic cells).
Grade IV: Poorly-differentiated or anaplastic (more than 75% anaplastic cells).
However, grading of tumours has several shortcomings. It is subjective and the degree of differentiation may vary from one area of tumour to the other. Therefore, it is common practice with pathologists to grade cancers in descriptive terms (e.g. well-differentiated, undifferentiated, keratinising, non-keratinising etc) rather than giving the tumours grade numbers.
More objective criteria for histologic grading include useproliferatio of flow cytometry for mitotic cell counts, cell proliferation markers by immunohistochemistry, and by applying image morphometry for cancer cell and nuclear parameters.
Staging
The extent of spread of cancers can be assessed by 3 ways— by clinical examination, by investigations, and by pathologic examination of the tissue removed. Two important staging systems currently followed are: TNM staging and AJC staging.
TNM staging. (T for primary tumour, N for regional nodal involvement, and M for distant metastases) was developed by the UICC (Union Internationale Contre Cancer, Geneva). For each of the 3 components namely T, N and M, numbers are added to indicate the extent of involvement, as under:
T0 to T4: In situ lesion to largest and most extensive primary tumour.
N0 to N3: No nodal involvement to widespread lymph node involvement.
M0 to M2: No metastasis to disseminated haematogenous metastases.
AJC staging. American Joint Committee staging divides all cancers into stage 0 to IV, and takes into account all the 3 components of the preceding system (primary tumour, nodal involvement and distant metastases) in each stage.
TNM and AJC staging systems can be applied for staging most malignant tumours.
Currently, clinical staging of tumours does not rest on routine radiography (X-ray, ultrasound) and exploratory surgery but more modern techniques are available by which it is possible to ‘stage’ a malignant tumour by non-invasive techniques. These include use of computed tomography (CT) and magnetic resonance imaging (MRI) scan based on tissue density for locating the local extent of tumour and its spread to other organs. More recently, availability of positron emission tomography (PET) scan has overcome the limitation of CT and MRI scan because PET scan facilitates distinction of benign and malignant tumour on the basis of biochemical and molecular processes in tumours. Radioactive tracer studies in vivo such as use of iodine isotope 125 bound to specific tumour antibodies is another method by which small number of tumour cells in the body can be detected by imaging of tracer substance bound to specific tumour antigen.
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