Neoplasia
Nomenclature And Classification
Definition And Classification:
Table of Contents
A neoplasm or tumour is defined as a mass of tissue formed as a result of the abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells, even after the removal of the growth stimulus which caused it.
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The branch of science dealing with the study of neoplasms or tumours is called oncology (oncos=tumour, logos=study).
- Neoplasms may be ‘benign’ or innocent when they are slow-growing and localised without causing much difficulty to the host, or ‘malignant’ when they proliferate rapidly, spread throughout the body and may eventually cause death of the host.
- The common term used for all malignant tumours is ‘cancer’ meaning crab, thus reflecting the true character of cancer since ‘it sticks to the part stubbornly like a crab’.
All tumours, benign as well as malignant, have 2 basic components:
- ‘Parenchyma’ is comprised by proliferating tumour cells; parenchyma determines the nature and evolution of the tumour.
- ‘Supportive stroma’ is composed of fibrous connective tissue and blood vessels; it provides the framework on which the parenchymal tumour cells grow.
The tumours derive their nomenclature on the basis of the parenchymal component comprising them. The suffix ‘-oma’ is added to denote benign tumours.
- Malignant tumours of epithelial origin are called carcinomas, while malignant mesenchymal tumours are named sarcomas (sarcomas = fleshy). However, some cancers are composed of highly differentiated cells and are referred to as undifferentiated malignant tumours.
- Although this broad generalisation regarding nomenclature of tumours usually holds true in the majority of instances.
Some examples contrary to this concept are:
- Melanoma for carcinoma of the melanocytes,
- Hepatoma for carcinoma of the hepatocytes,
- Lymphoma for malignant tumour of the lymphoid tissue, and
- Seminoma for malignant tumour of the testis.
- Leukaemia is the term used for cancer of blood-forming cells.
Special Categories Of Tumours
Following examples of tumours have different nomenclature than the general scheme given above:
- Mixed tumours: When two types of tumours are combined in the same tumour, it is called a mixed tumour.
- For example: Adenosquamous carcinoma is the combination of adenocarcinoma and squamous cell carcinoma in the endometrium.
- Adenoacanthoma is the mixture of adenocarcinoma and benign squamous elements in the endometrium.
- Carcinosarcoma is the rare combination of malignant tumours of the epithelium (carcinoma) and of mesenchymal tissue (sarcoma) such as in the thyroid, and breast.
- Collision tumour is the term used for morphologically two different cancers in the same organ which do not mix with each other.
- Mixed tumour of the salivary gland (or pleomorphic adenoma) is the term used for a benign tumour having a combination of both epithelial and mesenchymal tissue elements. Similarly, mixed tumours also occur in the skin.
- Teratomas: These tumours are made up of a mixture of various tissue types arising from totipotent cells derived from the three germ cell layers—ectoderm, mesoderm and endoderm.
- Most common sites for teratomas are ovaries and testis (gonadal teratomas).
- But they occur at extra-gonadal sites as well, mainly in the midline of the body such as in the head and neck region, mediastinum, retroperitoneum, sacrococcygeal region etc.
- Teratomas may be benign or mature (most of the ovarian teratomas) or malignant or immature (most of the testicular teratomas).
- Blastomas (Embryomas): Blastomas or embryomas are a group of malignant tumours which arise from embryonal or partially differentiated cells which normally form blastema of the organs and tissue during embryogenesis.
- These tumours occur more frequently in infants and children (under 5 years of age).
- Some examples of such tumours in this age group are Neuroblastoma, nephroblastoma (Wilms’ tumour), hepatoblastoma, retinoblastoma, medulloblastoma, and pulmonary blastoma.
- Hamartoma: Hamartoma is a benign tumour which is made of mature but disorganised cells of tissues indigenous to the particular organ for example., hamartoma of the lung consists of mature cartilage, mature smooth muscle and epithelium. Thus, all mature differentiated tissue elements which comprise the bronchus are present in it but are jumbled up as a mass.
- Choristoma: Choristoma is the name given to the ectopic islands of normal tissue. Thus, choristoma is heterotopia but is not a true tumour, though it sounds like one.
Classification:
Currently, the classification of tumours is based on their histogenesis (i.e. cell of origin) and the anticipated behaviour. However, it must be mentioned here that the classification described here is only a summary.
Detailed classifications of benign and malignant tumours on different tissues and body systems along with morphologic features of specific tumours appear in the specific chapters of Systemic Pathology.
Nomenclature and Classification:
A neoplasm or tumour is a mass of tissue formed as a result of the abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells, even after the removal of the growth stimulus which caused it.
- Neoplasms may be ‘benign’ when they are slow-growing and localised without causing much difficulty to the host, or ‘malignant’ when they proliferate rapidly, spread throughout the body and may eventually cause death of the host.
- All tumours have 2 basic components: parenchyma comprised of proliferating tumour cells, and supportive stroma composed of fibrous connective tissue and blood vessels.
- The tumours are named with the suffix ‘ -oma’ to denote benign tumours. Malignant tumours of epithelial origin are called carcinomas, while malignant mesenchymal tumours are named sarcomas.
- A few examples of combinations of tumours are mixed tumours, teratoma, blastoma, hamartoma, and choristoma.
Characteristics Of Tumours
The majority of neoplasms can be categorised into benign and malignant on the basis of certain clinical features, biological behaviour and morphological characteristics.
- However, there are proportions that have some features suggesting innocent growth while other features point towards a more ominous behaviour.
- Therefore, it must be borne in mind that based on the characteristics of neoplasms, there may be 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:
- Rate of growth
- Cancer phenotype and stem cells
- Clinical and gross features
- Microscopic features
Based on these characteristics, contrasting features of benign and malignant tumours are
1. 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:
Classification of tumours based on histogenesis:
- Rate of cell production, growth fraction and rate of cell loss
- Degree of differentiation of the tumour.
Rate of cell production, growth fraction and rate of cell loss :
The rate of growth of a tumour depends upon 3 important parameters
- Doubling time of tumour cells (mitotic rate)
- Number of cells remaining in the proliferative pool (growth fraction), and
- Rate of loss of tumour cells by cell shedding (apoptosis).
In general, malignant tumour cells have increased mitotic rate (i.e. rapid doubling time) and slower death rate i.e. the cancer cells do not follow normal controls in the cell cycle and are immortal.
- If the rate of cell division is high, likely, that tumour cells in the centre of the tumour do not receive adequate nourishment and undergo ischaemic necrosis.
- During the relentless growth of malignant tumours, a larger proportion of tumour cells remain in a replicating pool in the cell cycle while other tumour cells are either lost by shedding due to lack of availability of adequate nourishment or leave the cell cycle.
- While dead tumour cells appear as ‘apoptotic’ 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.
Degree of differentiation:
Secondly, the rate of growth of malignant tumours is directly proportionate to the degree of dedifferentiation. Poorly-differentiated tumours show aggressive growth patterns as compared to well-differentiated tumours.
- Some tumours, after a period of slow growth, may suddenly show a spurt in their growth due to the development of an aggressive clone of malignant cells. On the other hand, some tumours may cease to grow after some time.
- Rarely, a malignant tumour may disappear spontaneously from the primary site, possibly due to necrosis caused by a good host immune attack, only to reappear as secondaries elsewhere in the body for example, Choriocarcinoma, malignant melanoma.
- The tumour growth and its microenvironment are influenced by several growth factors secreted by the tumour cells.
Out of various growth factors, important ones modulating tumour biology are listed below:
- Epidermal growth factor (EGF)
- Fibroblast growth factor (FGF)
- Platelet-derived growth factor (PDGF)
Contrasting features of benign and malignant tumours:
- Colony stimulating factor (CSF)
- Transforming growth factors – β (TGF-β)
- Vascular endothelial growth factor (VEGF)
- Hepatocyte growth factor (HGF)
2. 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 anti-social behaviour as under:
- Cancer cells disobey the growth-controlling signals in the body and thus proliferate rapidly.
- Cancer cells escape death signals and achieve immortality.
- The imbalance between cell proliferation and cell death in cancer causes excessive growth.
- Cancer cells lose properties of differentiation and thus perform little or no function.
- Due to the loss of growth controls, cancer cells are genetically unstable and develop newer mutations.
- Cancer cells over-run their neighbouring tissue and invade locally.
- Cancer cells can travel from the site of origin via blood, lymph or other body fluids to other sites in the body where they colonise and establish distant metastasis.
Cancer cells originate from the proliferation of a single clone of abnormal cells (monoclonality). There is evidence to suggest that cancer cells arise from stem cells which are normally present in the tissues in small numbers but 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 a few decades and they have now been found to be present in some other malignant tumours.
3. Clinical And Gross Features
- Clinically:
- Benign tumours are generally slow-growing, depending upon the location, may remain asymptomatic (for example Subcutaneous lipoma), or may produce serious symptoms (for example, 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 cachexia (weight loss, anorexia and anaemia), fever and paraneoplastic syndromes. Three cardinal clinical features of malignant tumours are Anaplasia, Invasiveness and Metastasis.
- Gross appearance: The appearance of benign and malignant tumours may be quite variable and the features may not be diagnostic based on gross appearance alone.
- However, certain distinctive features characterise almost all tumours compared to neighbouring normal tissue of origin — they have different colours, 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:
- Benign tumours are generally spherical or ovoid. They are encapsulated or well-circumscribed, freely movable, and more often firm and uniform unless secondary changes like haemorrhage or infarction supervene.
- 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
4. Microscopic Features
For recognising and classifying the tumours, the microscopic characteristics of tumour cells are of the greatest importance.
The following features are appreciated in histological sections of the tumours:
- Microscopic pattern
- Histomorphology of neoplastic cells (differentiation and anaplasia)
- Tumour angiogenesis and stroma
- Inflammatory reaction.
Microscopic Pattern:
The patterns or arrangements of tumour cells are best appreciated under low-power microscopic examination of the tissue section.
- Some of the common patterns in tumours are as under:
- The epithelial tumours generally consist of acini, sheets, columns or cords of epithelial tumour cells that may be arranged in a solid or papillary pattern.
- The mesenchymal tumours have often spindled tumour cells arranged as interlacing bundles, fascicles or whorls, lying separated from each other, usually by the intercellular matrix substance such as hyaline material in leiomyoma, cartilaginous matrix in chondroma, osteoid in osteosarcoma, reticulin network in soft tissue sarcomas etc.
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- Certain tumours have mixed patterns for example., teratoma arising from totipotent cells, pleomorphic adenoma of the 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.
- 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.
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: Differentiation is defined as the extent of the morphological and functional resemblance of parenchymal tumour cells to corresponding normal cells.
- If the deviation of neoplastic cells in structure and function is minimal as compared to normal cells, the tumour is described as ‘well differentiated’ such as most benign and low-grade malignant tumours.
- Terms such as ‘poorly differentiated’, ‘undifferentiated’ or ‘dedifferentiated’ tumours indicate poor structural and functional resemblance to corresponding normal cells.
- Anaplasia: Anaplasia is a 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 a high degree of anaplasia.
- As a result of anaplasia, noticeable morphological and functional alterations in the neoplastic cells are observed which are best appreciated under higher magnification of the microscope.
- These features are as follows and are diagrammatically depicted in:
- Loss of polarity: Normally, the nuclei of epithelial cells are oriented along the basement membrane which is termed 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.
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- Pleomorphism: The term pleomorphism means variation in the 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 for example in Small round cell malignant tumours.
- N: C ratio Generally: The nuclei of malignant tumour cells show more conspicuous changes. Nuclei are enlarged disproportionately to the cell size so that the nucleocytoplasmic ratio is increased from normal 1:5 to 1:1.
- Anisonucleosis: Just like cellular pleomorphism, the nuclei too, show variation in size and shape in malignant tumour cells.
- Hyperchromatism Characteristically: The nuclear chromatin of malignant cells is increased and coarsely clumped. This is due to an increase in the amount of nucleoprotein resulting in dark-staining nuclei, referred to as hyperchromatism.
- Nuclear shape may vary, a nuclear membrane may be irregular and nuclear chromatin is clumped along the nuclear membrane.
- Nucleolar changes: Malignant cells frequently have a prominent nucleolus or nucleoli in the nucleus reflecting increased nucleoprotein synthesis. This may be demonstrated as
- Nucleolar Organiser Region (NOR) by silver (Ag) staining called AgNOR material.
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- Mitotic: The parenchymal cells of poorly differentiated tumours often show a 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:
- Normal mitotic figures may be seen in some non-neoplastic proliferating cells, for example, 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 dark b and of equally divided 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.
- Tumour giant cells: Multinucleate tumour giant cells or giant cells containing a single large and bizarre nucleus, possessing nuclear characteristics of the adjacent tumour cells, are another important feature of anaplasia in malignant tumours.
- Functional (Cytoplasmic) changes: Structural anaplasia in tumours is accompanied by functional anaplasia as appreciated by 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 a quantitative abnormality in the product for example
- Large or small amount of collagen produced by benign tumours of fibrous tissue, and keratin formation in well-differentiated squamous cell carcinoma.
- In more anaplastic tumours, there is usually, a quantitative fall in the product made by the tumour cells for example, the Absence of keratin in anaplastic squamous cell carcinoma.
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- There may be both qualitative and quantitative abnormality of the cellular function in some anaplastic tumours, for example, 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 hormonelike substances may be produced by certain tumours quite unrelated to the endocrine glands.
- This property of tumours is called ectopic hormone production for example, 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 the kidneys, hepatocellular carcinoma and cerebellar haemangioblastoma.
- 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 the Philadelphia chromosome (named after the city in which it was first described) in 95% of 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.
Tumour Angiogenesis And Stroma:
The connective tissue along with its vascular network forms the supportive framework on which the parenchymal tumour cells grow and receive nourishment. In addition to a 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). Its mechanism and the role of angiogenic factors elaborated by tumour cells (for example, Vascular endothelium growth factor or VEGF) are discussed later under molecular pathogenesis of cancer.
- However, related morphologic features are as under:
- 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.
- Central necrosis: When the tumour outgrows its blood supply as occurs in rapidly growing tumours or when tumour angiogenesis fails, the central core of the tumour undergoes ischaemic necrosis.
- Tumour Stroma: The collagenous tissue in the stroma may be scanty or excessive. If it is scanty, the tumour is soft and fleshy (for example, In sarcomas, and lymphomas), while if it is excessive, the tumour is hard and gritty (for example, Infiltrating duct carcinoma breast). The growth of fibrous tissue in the tumour is stimulated by basic fibroblast growth factor (bFGF) elaborated by tumour cells.
- If the epithelial tumour is almost entirely composed of parenchymal cells with little stroma, it is called medullary for example, Medullary carcinoma of the breast, or 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 for example, Infiltrating duct carcinoma breast linitis plastica of the stomach.
Inflammatory Reaction:
At times, prominent inflammatory reactions are present in and around the tumours. It could be the result of ulceration in the cancer when there is a secondary infection. The inflammatory reaction in such instances may be acute or chronic.
However, some tumours show chronic inflammatory reactions, chiefly of lymphocytes, plasma cells and macrophages, and in some instances granulomatous reaction, as a part of the morphologic features of the tumour, 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.
Examples of such reactions are: Seminoma testis, Malignant melanoma of the skin, Medullary carcinoma of the breast, Choriocarcinoma, Lymphoepithelial carcinoma of the nasopharynx etc.
Characteristics of Tumours:
Neoplasms are categorised into benign and malignant on the basis of certain clinical and morphologic features. The tumour cells generally proliferate more rapidly than the normal cells; benign tumours grow slowly and malignant tumours rapidly.
- Tumour enlargement depends upon the rate of cell production, growth fraction, rate of cell loss and degree of differentiation of the tumour.
- Evidence suggests that cancer cells originate from the proliferation of a single clone of stem cells (monoclonality).
- Clinically, benign tumours are generally slow-growing and may remain asymptomatic while malignant tumours grow rapidly and may spread locally or to distant sites.
Grossly: Benign tumours are generally encapsulated or well-circumscribed, while malignant tumours are usually irregular in shape, poorly-circumscribed and extend into the adjacent tissues.
Microscopic features of tumours are more important for recognising and classifying tumours. These include:
- Microscopic pattern of tumour cells
- Histomorphology of neoplastic cells
- Tumour angiogenesis, and
- Stromal reaction.
The neoplastic cells are characterised by morphologic and functional alterations, the most significant of which are ‘Differentiation’ and ‘Anaplasia’.
- Differentiation is defined as the extent of the morphological and functional resemblance of parenchymal tumour cells to corresponding normal cells.
- Anaplasia is a lack of differentiation and is a characteristic feature of most malignant tumours.
Important features of anaplasia are:
- Loss of polarity
- Pleomorphism
- Increased N: C ratio
- Hyperchromatism
- Anisonucleosis
- Prominent nucleoli
- Abnormal mitotic figures
- Tumour giant cells
- Qualitative or quantitative cytoplasmic changes, and
- Chromosomal abnormalities.
Stromal features of significance in tumours are angiogenesis, collagenous stroma (desmoplasia) and inflammatory stromal reaction by the host.
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