NEOPLASIA General pathomorphology of neoplasia

The term neoplasia means new growth; the new growth produced is called neoplasm or tumor. However, all new growth is not neoplasms since examples of new growth of tissues and cells also exist in the processes of embriogenesis, regeneration on repair, hyperplasia and hormonal stimulation. Neoplastic cells lose control and regulation of replication and form an abnormal mass of tissue. Satisfactory definition of neoplasm or tumor is a mass of tissue formed as a result of abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells. The tumors are classified according to histogenetic principles with the account of their morphological structure, localization,

peculiarity of their structure in a definite organ, benign or malignant character. The classification was suggested as an international one by the Committee on Tumor Nomenclature of the International Anticancer Union. According to this classification, there are 7 groups of tumors; their total number exceeds 200. 1. Epithelial tumors without specific localization (nonorganspecific). 2. Tumors of endocrine and exocrine, glands as well as epithelial integument (organspecific). 3. Mesenchymal tumors. 4. Tumors of melanin-forming tissue. 5. Tumors of nervous system and brain membranes. 6. Tumors of blood system. 7. Teratomas. The suffix -oma is added to denote benign tumors. Malignant tumors of epithelial origin are called carcinomas, while malignant mesenchymal tumors are named sarcomas (sarcos = fleshy). Some examples

contrary to this concept are: melanoma for carcinoma of the melanocytes, hepatoma for carcinoma of the hepatocytes, lymphoma for malignant tumor of the lymphoid tissue, and seminoma for malignant tumor of the testis. Tumors composed of a single type of parenchymal cells that differentiate towards more than one cell line are called mixed tumors. Teratomas, on the other hand, are made up of a number of parenchymal cell types arising from totipotent cells derived from more than one germ cell layer. Choristoma refers to the ectopic rests of normal tissue. Hamartoma is a mass of disorganised-but mature cells of tissues indigenous to the particular site. The currently used classification of tumors is based on the histogenesis (i.e. tissue of origin) and on the anticipated behavior. Characteristics of tumors The characteristics of tumors are described under: I. Macroscopic features. II. Microscopic features.

III. Growth rate. IV. Local invasion (Direct spread). V. Metastasis (Distant spread). Based on these characteristics, contrasting features of benign and malignant tumors are summarized in Table 6. I. Macroscopic features Almost all tumors have a different color, texture and consistency as compared to the surrounding tissue of origin. Gross terms such as papillary, fungati, infiltrating, hemorrhagic, ulcerative and cystic are used to describe the macroscopic appearance of the tumors.
Benign tumors are generally spherical or ovoid in shape. They are encapsulated or wellcircumscribed, freely movable, more often firm and uniform, unless secondary changes like hemorrhage or infarction supervene. Malignant tumors are usually irregular in shape, poorly-circumscribed and extend into the adjacent tissues. Secondary changes like hemorrhage, infarction and ulceration are seen more often. Sarcomas typically have fish-flesh

like consistency while carcinomas are generally firm. II. Microscopic features: These are: microscopic pattern, cytomorphology of neoplastic cell (differentiation and anaplasia), angiogenesis and tumor stroma, and inflammatory reaction. 1. Microscopic patten: The tumor cells may be arranged in a variety of patterns in tumors, e.g. The epithelial tumors generally consist of acini, sheets, columns or cords of epithelial tumor cells that may be arranged in solid or papillary pattern. The mesenchymal tumors have mesenchymal tumor cells lying separated from each other usually by the intercellular substance such as cartilaginous matrix in chondroma, osteoid in osteosarcoma, reticulin network in soft tissue sarcomas etc. Hematopoetic tumors such as leukemias and lymphomas often have none or little stromal support. Generally, most benign tumors and low-grade malignant tumors reduplicate the normal structure of origin more closely.

Other cellular deviations from the normal cellular arrangement in malignant tumors are: loss of basal orientation (polarity), altered alignment of tumor cells to each other, and stromal invasion by tumor cells. 2. Tumor Cytomorphology (Differentiation and Anaplasia) Differentiation is defined as the extent of morphological and functional resemblance of parenchymal tumor cells to corresponding normal cells. If the deviation of neoplastic cell in structure and function is minimal as compared to normal cell, the tumor is described as well-differentiated such as most benign and low-grade malignant tumors. 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 tumors.

As a result of anaplasia, following noticeable morphological and functional alterations in the neoplastic cells are observed: 1) Pleomorphism means variation in size and shape of the tumor cells. The extent of cellular pleomorphism generally correlates with the degree of anaplasia. 2) Nucleocytoplasmic changes. These are as under: Generally, the nuclei of malignant tumor cells are enlarged, so that the nucleocytoplasmic ratio is increased. The nuclei too, show variation in size (anisonucleosis) and shape in malignant tumor cells. Characteristically, the nuclear chromatin of malignant cell is increased and coarsely clumped, referred to as hyperchromatism. Besides, a prominent nucleolus or nucleoli may be present in these nuclei reflecting increased nucleoprotein synthesis. It is most important to identify abnormal and atypical mitotic figures such as tripolar,

quadripolar and multipolar spindles in malignant tumour cells because increased number of normal mitoses may be present in non-neoplastic proliferations such as in hematopoietic cells of the bone marrow, intestinal epithelium, hepatocytes etc.

The cytoplasm of tumor cells in betterdifferentiated cancers and in benign tumors may show the normal constituents from which the tumor is derived. But the more anaplastic tumor cells lose such features. 3) Genetic abnormalities. All tumor cells have abnormal genetic composition and on division they transmit the genetic abnormality to their progeny. Most malignant tumors show aneuploidy. 4) Functional changes. Structural anaplasia in tumors is accompanied with functional anaplasia. The functional abnormality in neoplasms may be quantitative, qualitative, or both. Generally, benign tumors and betterdifferentiated malignant tumors continue to

Multinucleate tumor giant cells or giant cells containing a single large and bizarre nucleus, possessing nuclear characters of the adjacent tumor cells, are another important feature of anaplasia.

function well qualitatively, though there may be quantitative abnormality in the product, e.g. large or small amount of collagen produced by benign tumors of fibrous tissue, keratin formation in well-differentiated squamous cell carcinoma. In more anaplastic tumors, there is usually quantitative fall in the product made by the tumor cells, e.g. absence of keratin in anaplastic squamous cell carcinoma. Hormones or hormone-like substances may be produced by certain tumors quite unrelated to the endocrine glands, called ectopic hormone production, e.g. oat cell carcinoma of the lung can secrete ACTH and ADH. 3. Angiogenesis and Tumor Stroma. The connective tissue along with its blood supply forms the supportive framework on which the parenchymal tumor cells grow and receive nourishment. In order to provide nourishment to growing tumor, new blood vessels are formed from pre-existing ones (angiogenesis) that is probably stimulated by secretion of tumor angiogenesis factors from the parenchymal tumor cells such as vascular endothelial growth factor (VEGF). However, if the tumor outgrows its blood supply as occurs in

rapidly growing tumors, its core undergoes ischemic necrosis. If the tumor is almost entirely composed of parenchymal cells, it is called medullary, if there is excessive connective tissue stroma, it is referred to as desmoplasia and the tumor is hard or scirrhous. 4. Inflammatory Reaction. At times, prominent inflammatory reaction is present in and around the tumors. It could be the result of ulceration in the cancer when there is secondary infection. However, some tumors show chronic inflammatory reaction, chiefly of lymphocytes, plasma cells and macrophages, and in some instances, granulomatous reaction, due to cell-mediated immunologic response by the host in an attempt to destroy the tumor, e.g. seminoma testis, malignant melanoma of the skin, lymphoepithelioma of the throat, medullary carcinoma of the breast, Warthins tumor of salivary glands etc. TABLE 6: Contrasting Features of Benign and Malignant Tumors. FEATURE BENIGN MALIGNANT S (DIFFERENTI (UNDIFFERENT ATED) IATED)

MACROSC OPIC FEATURE S 1. Encapsulated Boundaries or wellcircumscribed 2. Often Surroundin compressed g tissue 3. Size Usually small 4. Occur less Secondary often changes II. MICROSC OPIC FEATURE S 1. Pattern Usually resembles the tissue of origin closely 2. Basal Retained polarity 3. Usually not

Poorlycircumscribed and irregular Usually invaded Often larger Occur more often

Often poor resemblance to tissue of origin Often lost Often present

Pleomorphi sm 4. Nucleocytoplasmic ratio 5. Anisonucle osis 6. Hyperchro matism 7. Mitoses

present Normal Increased

Absent Absent

Generally present Often present

8. Tumor giant cells 9. Cytoplasm 10. Function

May be present Mitotic figures but are always increased and are typical mitoses generally atypical and abnormal May be present Present with but without nuclear atypia nuclear atypia May show Normal normal cytopiasmic constituents elements are reduced or lost Usually well May be retained, maintained lost or become abnormal

III. Usually slow GROWTH RATE IV. LOCAL Often INVASION compresses the surrounding tissues without invading or infiltrating them V. Absent METASTA SIS

Usually rapid Usually infiltrates and invades the adjacent tissues

Frequently present

III. Growth rate The tumor cells generally proliferate more rapidly than the normal cells. In general, benign tumors grow slowly and malignant tumors rapidly. The rate at which the tumor enlarges depends upon 3 main factors: 1. Rate of division and destruction of tumor cells. The rate of division of tumor cells depends upon 2 factors - proportion of cells undergoing mitosis (milotic index), and the duration taken to complete the mitotic cell cycle.

2. Non-neoplastic elements within the tumors. These are the connective tissue stroma, abundant mucoid material, cartilaginous matrix etc all of which add to the bulk of the tumors. 3. Degree of differentiation. In general, rate of growth of malignant tumor is directly proportionate to the degree of differentiation. Rarely, a malignant tumor such as choriocarcinoma and malignant melanoma 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. The regulation of tumor growth is under the control of growth factors secreted by the tumor cells. Depending on the degree of the tumor differentiation, there are different types of its growth: expansive, apposition, infiltrating (invasive). At expansive growth the tumor grows from itself moving away the surrounding tissues. This type of growth is slow, and is characteristic benign tumors. Apposition growth is due to transformation of normal cells to tumor ones.

In infiltrating growth the cells of the tumor invade normal tissues and destroy them (so called destructive growth). In relation to the lumen of the hollow organ, the growth of the tumor may be endophytic or exophytic. Endophytic growth is infiltrating growth of the tumor deep into the wall of the organ. Exophytic growth is expansive growth of the tumor to the cavity of the organ. According to the number of foci of tumor development, they can be unicenter (one focus) and multicenter (several foci). IV. Local invasion (direct spread) Most benign tumors form encapsulated or circumscribed masses that push aside the surrounding normal tissues without actually invading, infiltrating or metastasising. Malignant tumors also enlarge by expansion. But, they are distinguished from benign tumors by invasion, infiltration and destruction of the surrounding tissue, besides distant metastasis. Often, cancers extend through tissue spaces, permeate lymphatics, blood vessels, and perineural spaces and may penetrate a bone by growing through nutrient foramina. More

commonly, the tumors invade thin-walled capillaries and veins than thick-walled arteries. V. Metastasis (distant spread) Metastasis is defined as spread of tumor by invasion in such a way that discontinuous secondary tumor mass/masses are formed at the site of lodgement. Metastasis is the most important feature to distinguish malignant from benign tumors. Benign tumors do not metastasize while all the malignant tumors with a few exceptions like gliomas of the central nervous system and basal cell carcinoma of the skin, can metastasize. Routes of metastasis: 1. Lymphatic spread. 2. Hematogenous spread. 3. Other routes (spread along epithelium-lined surfaces, spread via cerebrospinal fluid, implantation). 1. Lymphatic spread. In general, carcinomas metastasize by lymphatic route while sarcomas favour hematogenous route. The walls of lymphatics are readily invaded by cancer cells and may form a continuous growth in the lymphatic channels called lymphatic permeation, or may detach to form tumour

emboli. The tumor emboli enter the lymph node at its convex surface and are lodged in the subcapsular sinus. Later, of course, the whole lymph node may be replaced and enlarged by the metastatic tumor. Sometimes lymphatic metastases do not develop first in the lymph node nearest to the tumor because of venouslymphatic anastomoses or due to obliteration of lymphatics by inflammation or radiation, so called stop metastasis. Other times, due to obstruction of the lymphatics by tumor cells, the lymph flow is disturbed and retrograde metastases may be seen at unusual sites, e.g. metastasis of carcinoma prostate or stomach to the supraclavicular lymph nodes, metastatic deposits in the adrenals from carcinoma lung etc. 2. Hematogenous spread. Metastasis through blood vessels is the common route for sarcomas but certain carcinomas also frequently metastasize by this mode, especially those of the lung, breast, thyroid, kidney and prostate. The common sites for blood-borne metastasis are the liver, lungs, kidneys, brain and bones, all of which provide good soil for the growth of good seeds (seed-soil theory) than are the

unfavourable sites like the spleen and muscles. The cancer cells readily invade the walls of capillaries, venules and veins than the arteries which are thick-walled and contain elastic tissue resistant to invasion. Cancers of the organs draining into portal veins frequently establish metastasis in the liver, while cancers of organs draining into caval veins metastasize to the lungs. Etiology and pathogenesis of neoplasia The etiology of tumors is various, 4 theories are recognized. 1. Virogenetic theory. It states integration of the genomes of the virus and the normal cell that is combination of nucleic acid of the virus with genetic apparatus of the cell, which turns into tumor ceil. Oncogenic viruses are those containing DNA and RNA (Epstein-barr virus, herpes virus, hepatitis B- Virus, etc.). 2. Physicochemical theory suggests that tumor appears under the influence of different physical and chemical substances, so called carcinogens. 3. Dysontogenetic theory was created by J. Cohnheim; According to his theory, tumors appear from embryonic tissue and abnormally

developed tissues under the influence of different causative agents. 4. Polyetiological theory emphasizes the importance of different factors, i.e. chemical, physical, viral, parasite, dyshormonal. Based on the current state of knowledge, these factors are broadly described under 2 main headings: I. Predisposing epidemiologic factors, which include a number of endogenous host factors and exogenous environmental factors. II. Carcinogenesis, that encompasses exogenous agents like chemical, physical, hormonal and biological substances. Carcinogenesis Carcinogenesis means inductions of tumors; agents, which can induce tumors, are called carcinogens. Carcinogens are a variety of extrinsic agents, which are broadly divided into 4 groups: 1. Chemical carcinogens. 2. Physical carcinogens (mainly radiation). 3. Hormonal carcinogens. 4. Biologic carcinogens (chiefly viruses). Clinical aspects of neoplasia

Two major aspects of clinical significance in assessing the course and management of neoplasia are tumor-host inter-relationship and laboratory diagnosis of cancer. Effect of tumor on host Malignant tumors produce more ill effects than the benign tumors. 1. Local effects. Both benign and malignant tumors cause local effects on the host due to their size or location. Some of the local effects of tumors are as under Compression. Mechanical obstruction. Tissue destruction. Infarction, ulceration, hemorrhage. 2. Cancer cachexia. Patients with advanced and disseminated cancers terminally have asthenia (emaciation), and anorexia, together referred to as cancer cachexia. 3. Fever. Fever of unexplained origin may be presenting feature in some malignancies such as in Hodgkins disease, adenocarcinoma kidney, osteogenic sarcoma and many other tumors. The exact mechanism of tumor-associated fever is not known but probably the tumor cells themselves elaborate pyrogens.

4. Paraneoplastic syndromes. Paraneoplastic syndromes (PNS) are a group of conditions developing in patients with advanced cancer, which are not explained by direct and distant spread of the tumor (endocrine, neuromuscular, hematologic, gastrointestinal, renal syndromes, amyloidosis). 5. Secondary changes in the tumor result from disturbances of blood circulation, from chemo*or radiotherapy. They manifest by foci of necrosis, hemorrhages, inflammation, formation of mucus, calcification. Diagnosis of cancer. The most certain and reliable method which has stood the test of time is the histological examination of biopsy, cytological methods, histochemistry and cytochemistry, immunohistochemistry. EPITHELIAL TUMORS Benign epithelial tumors Benign epithelial tumors are subdivided according to their origin from different types of epithelium into the tumors of integumentary epithelium (papillomas), tumors of glandular epithelium (adenomas). Papilloma has following features Bening tumor.

Origin from the skin and mucous membranes. It looks like a ledge or a bush of branching papillae. Exophytic tumor. Slow growth. The base of the tumor consists of connective tissue containing blood vessels. It is a continuation of subepithelial connective tissue covered with epithelium like. May be hard of soft. Hard papillomas locate on the skin and mucous membranes covered with multilayer squamous epithelium (mouth, larynx, pharynx). Soft papillomas consist of thin fibers with thinwalled vessels. They are covered with cylindrical transition or ciliated epithelium, their thin branching papillae can be easily injured and bleed. They grow quickly. They often become malignant turning into cancer. These papillomas are mainly found in the neck of the urinary bladder and in the region of the triangle. Adenoma Benign epithelial tumor from the epithelium of the glands and glandular organs.

More often they can be found in the breast, thyroid gland, liver, ovaries, prostatic gland, gastrointestinal tract. According to the histological composition adenoma may be tubular and alveolar. In tubular adenoma, there are glandular cavities resembling tubes in the connective tissue with vessels. In alveolar adenoma, numerous bubbles bedded with cylindrical or cubic epithelium are observed in the connective tissue with vessels. Adenomas from compact organs (liver, adrenal gland) can be made of groups of respective cells separated from each other by a thin layer of stroma. Thus, the structure of adenomas is similar to that of the original organ, which is the cause of their functional similarity (ability of adenoma cells to produce respective secretes) e.g. adenomas of mucous membranes - mucus, adenomas of eosinophilic cell of the anterior lobe of pituitary - somatotropic hormone, medullar layer of adrenal gland - noradrenaline, beta cells of pancreas - insulin, etc. Adenomas have atypical structure, which manifests in absence of ducts, variety of shape,

size and location, parenchyma and stroma ratio (fibroadenoma, adenofibroma) in the glandular tubules and vesicles. In some adenomas glandular cavities are widened and form large cavities, cysts filled with serous fluid or mucus. These cyst-like adenomas are called cystoadenomas. Sometimes epithelial growth is so intensive that the papillae invade the walls of flie cyst, involve the peritoneum, produce metastases, relapse, cause cachexia and may cause sever consequences. These adenomas are termed papillary adenocystomas. They develop in ovaries, thyroid gland. Adenocystomas may become malignant more frequently than the other adenomas. Malignant epithelial tumors Immature, or malignant, tumors of epithelium are also called carcinoma. The term came to us from the time of Hippocrates and Galen. Precancerous states: defects of development, including lost embryonic germs, chronic inflammatory diseases, chronic ulcers, disturbed tissue regeneration (abundant granulation, metaplasia, displasia), hormonal hyperplasias,

polyposis of mucous membrane, and leukoplakias of the mucous membrane. The morphological classification is based on differentiation of the tumor cells. According to it all cancers can be divided into 3 groups: 1) Poorly-differentiated: small-cell or large-cell, medullar, scirrhus, solid. 2) Well-differentiated: squamous-cell, with keratinization, without keratinization, adenocarcinoma (trabecular, alveolar, papillary, mucous. 3) Special kinds: chorionepithelioma, seminoma, hypernephroid cancer. As to metastases, it is important to know that invasion of the tumor cells in the veins is difficult because they become narrowed. Blood vessels in the tumors look differently. Usually they have the structure of capillaries. As a rule, vessels in tumors are new structures but they are connected with general circulation. The tumors may be connected with the sources of nutrition in different ways. The more directly they contact, the more intensive is the growth of the tumor, the more rapidly it produces metastases

(e.g., chorionepithelioma, seminoma, hypernephroid cancer). If both stroma and parenchyma of the tumor are anaplastic, they characterize combination tumors, termed sarcocarcinomas or carcinosarcomas. Together with tissue and cellular atypism, malignant tumors are characterized by infiltrating tumor growth. Clinical-anatomical practice suggests that tumor, as a rule, does not appear at once, its development is preceded by different processes characterized by: 1) prolonged chronic course, 2) association with cell multiplying, 3) failure of conservative treatment.