Neoplasia

Dr suvarna nalapat

Definition
Neoplasia is new, uncontrolled growth; a

"tumor" or "mass lesion" is simply a "growth" or "enlargement" which may not be neoplastic (such as a granuloma). The term "cancer" implies malignancy, but neoplasms can be subclassified as either benign or malignant. Sir rupert willisneoplasm is an abnormal mass of tissue ,the growth of which exceeds and is uncoordinated with that of normal tissue and persists after cessation of the stimuli

Normal vs neoplastic cells

Autonomous independent of growth factors and regulatory mechanisms Excessive Disorganised Key words-tumour (swelling)-benign ,malignant Cancer-malignant tumour Oncology oncos-greek for the latin tumour-the scince dealing with study of tumours.

Benign Neoplasms
slow growth, resemblance to tissue of origin (well

differentiated), circumscription, lack of invasion or metastases. solitary (e.g., lipoma of colon, meningioma of dura), but may be multiple (e.g., leiomyomata of uterus, intradermal nevi on skin). cause problems through mass effect, particularly in tight quarters (pituitary adenoma in sella turcica). hamartoma benign ,localized but haphazard growth of tissues normally found at a given site (pulmonary hamartoma has jumbled cartilage, bronchial epithelium, and connective tissue).another eg a mole choristoma benign tissue not normal to the site of origin (e.g., salivary gland choristoma of the middle ear,pancreatic choristoma in stomach or liver,ectopic brain tissue in nasal cavity.

Malignant Neoplasms
rapid increase in size, lack of differentiation

(anaplasia), tendency to spread by invasion or metastases. Cytologic features of malignant neoplasms increased nuclear size (with increased nuclear/cytoplasmic ratio-N/C ratio). variation in nuclear or cell size (pleomorphism). lack of differentiation (anaplasia). increased nuclear DNA content with subsequent dark staining on H and E slides (hyperchromatism). prominent nucleoli within the nuclei. mitoses (especially irregular or bizarre mitoses). All of these features are "atypical". Atypia implies a change for the worse from normal.

Spread of Malignant Neoplasms

By direct extension (invasion) into surrounding tissues. Through lymph channels to lymph nodes (lymphatic spread)--typical of carcinomas. Via the bloodstream (hematogenous spread)-typical of carcinomas or sarcomas. Within body cavities (seeding)--typical of neoplasms in peritoneal cavity

The spread of malignant neoplasms determines the stage

In-situ (refers to epithelial malignancies confined to just the epithelium without going throug the basement membrane). Microinvasion (spread of epithelial malignancies just beyond the point of origin through the basement membrane).

Local invasion (spread within the organ of origin or to contiguous structures). Local metastases (noncontiguous spread of the neoplasm within the organ of origin or to the lymph nodes closest to the organ of origin). Distant metastases (spread to other organs or to far away lymph nodes)

 The indicators that a neoplasm is malignant are: Metastases (best indicator) and Invasion (next best indicator

Grading of neoplasms
Based upon: differentiation (the degree to which the

neoplasm resembles the tissue of origin) along with the degree of atypia. well-differentiated--looks very similar to normal tissue moderately differentiated--looks something like normal poorly differentiated--hardly looks like normal tissue anaplastic--virtually no similarity to normal tissue Both staging and grading schemes are devised to classify malignant neoplasms for determining appropriate treatment and to try and determine the prognosis. In general, the higher the stage or the higher the grade, the worse the prognosis.

Appearances of Neoplasms
Desmoplasia the proliferation of non-neoplastic

connective tissue in association with neoplasia (gives tumors a firm, fibrous, "scirrhous" appearance) and may distort surrounding tissues. Neoplasms mimic tissue of origin, but not always. Larger masses tend to undergo central necrosis. Metastases usually look similar to primary, but not always. primary site is ususally a single large mass in an organ, while multiple masses in an organ usually indicate metastases. It is not always possible to tell benign from malignant based upon histologic or cytologic criteria alone. biologic behavior of neoplasm may not always correlate with appearance, making choice of treatment more difficult.

Oncogenesis

The process of

neoplasia is represented symbolically

Nomenclature of Neoplasia
Based upon origin: Maligant neoplasms arising from tissue

embryologically derived from ectoderm or endoderm are usually carcinomas. Examples include: Squamous cell carcinoma of cervix Adenocarcinoma of stomach Hepatocellular carcinoma Renal cell carcinoma

 Malignancies arising from mesoderm are usually sarcomas. Examples include: Leiomyosarcoma Chondrosarcoma Osteosarcoma Liposarcoma

 Neoplasms with more than one cell type but

arising from only one germ layer are called "mixed tumors". The best example is the benign mixed tumor (also called pleomorphic adenoma) of salivary gland. Neoplasms with more than one cell type and arising from more than one germ layer are called teratomas. Such neoplasms are common in the ovary.

Neoplasms ending in "blastoma"

resemble primitive embryonic tissues: Retinoblastoma Neuroblastoma Hepatoblastoma Medulloblastoma

 Not all malignant neoplasms have benign counterparts: Hematopoietic and lymphoid cells (as in bone marrow and lymph node) give rise to leukemias and lymphomas. They have no benign counterpart. Gliomas (astrocytomas, oligodengrogliomas, glioblastoma multiforme, etc) arise from glial cells in the CNS. They have no benign counterpart

Carcinomas
Arise from epithelial surfaces (in gastrointestinal tract,

in respiratory tract, in urogenital tract, in biliary tract, in skin) and in organs with epithelial-lined ducts (breast, pancreas, salivary gland, liver). Endocrine glands, including testis and ovary, may also give rise to carcinomas. In general, carcinomas are composed of polygonal-shaped cells. Carcinomas that form glandular configurations are called adenocarcinomas. Carcinomas that form solid nests of cells with distinct borders, intercellular bridges, and pink keratinized cytoplasm are called squamous cell carcinomas.

Sarcomas
Arise from soft tissues (connective tissues

such as cartilage, bone, or fascia, smooth or skeletal muscle, blood vessels, lymph vessels, coverings of organs such as mesothelium). In general, sarcomas are composed of very pleomorphic spindle-shaped cells. Sarcomas are generally big and bad.

 Biology of Neoplasia
This subject attempts to determine what gives

rise to neoplasms and what controls their growth.

Causes of Neoplasia
The origin for many neoplasms is obscure.

However, there are several theories of origin

Environmental causes:
Chemicals (aniline dyes and bladder cancer), drugs

(cigarette smoke and lung cancer), and natural compounds (aflatoxins and liver cancer) carcinogenic. Oncogenic viruses human papillomavirus (HPV) implicated in most squamous cell carcinomas of cervix and anogenital squamous papillomas, EpsteinBarr virus (EBV) implicated in African Burkitt's lymphoma, and hepatitis B virus (HBV) implicated in development of hepatocellular carcinomas. Radiation (such as ultraviolet light and skin cancers; gamma radiation and leukemia, thyroid, lung, colon, and breast cancers). Ultraviolet light induces pyrimidine dimers in DNA. Ionizing radiation induces mutations in DNA

Hereditary causes:
Chromosomes which have absent or defective anti-

oncogenes that control growth (retinoblastoma results from defective chromosome 13) Obscure defects: racial predilections (American women have breast cancer more often than Japanese women; Japanese men have stomach cancer far more often than American men). Age: older persons have a greater propensity to develop neoplasms from lack of effective control mechanisms.

Altered DNA:
All the above mediated by the cause, producing a

mutation in, or damage to, cell DNA mutations involving tumor suppressor genes (such as p53),. The majority of human neoplasms probably arise via this mechanism. In some cases these mutations are probably mediated by proto-oncogenes (genes which control cellular growth) that undergo mutation to oncogenes which give rise to neoplasia. Proto-oncogenes can be activated by point mutations, translocations, and by gene amplification

 An example of this is chronic myelogenous leukemia

(CML) which is a neoplastic proliferation of white blood cells. All cases of CML have the "Philadelphia chromosome" which is a translocation between chromosomes 9 and 22. This translocation juxtaposes the proto-oncogene ABL with the breakpoint cluster region (BCR) on chromosome 22. The chimeric ABLBCR gene leads to production of a mutant protein with enhanced tyrosine kinase activity. This protein may play a role in regulation of cell growth in CML.

 About 15 to 20% of human cancers have been linked

to oncogenic activity. The ras oncogene is the transforming gene found most frequently in human cancers. Oncogenic viruses may bring oncogenes with them, so-called viral oncogenes (typical of RNA containing "retroviruses" such as human T-lymphotropic viruses (HTLV's). Growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1) assist oncogene activity. Transforming growth factor (TGF-alpha) also promotes tumor growth.

Tissue evidence of carcinogenic factors at work

Metaplasia: an initial change from normal cells to a different cell type (such as chronic irritation of cigarette smoke causing ciliated pseudostratified epithelium to be replaced by squamous epithelium more able to withstand the insult Dysplasia: an increasing degree of disordered growth or maturation of the tissue (often thought to precede neoplasia) such as cervical dysplasia as a result of human papillomavirus infection. Dysplasia is still a reversible process. However, once the transformation to neoplasia has been made, the process is not reversible ).

Metaplasia - dysplasia Neoplasia. best evidenced in uterine cervix and respiratory tract

Chemical carcinogenesis initiation and promotion

initiating carcinogenic agent irreversibly damages cell

DNA (mutagenic). Examples : alkylating agents like cyclophosphamide, polycyclic aromatic hydrocarbons like epoxides found in smoked foods, aromatic amines or azo dyes used in food coloring, aflatoxins in moldy peanuts, nitrosamines in pickled foods. promoting agent (may be the same as the carcinogen) then acts (reversibly) to cause proliferation of neoplastic cell clone, but there appears to be a "dosethreshold" concentration of promoter below which neoplasia will not occur. Examples of promoters include: hormones such as estrogen, drugs such as diethylstibesterol, and chemicals such as cyclamates used as sweeteners

Cellular Transformation Some factor, causes a cell to be transformed to a neoplastic cell not controlled by normal body processes. most transformed cells die because they are too abnormal to function or are abnormal enough for the body's immune system to destroy them. if factors promoting neoplasia persist, transformed cell give rise to clone that continue to grow

 Malignant neoplasms do not tend to arise from benign neoplasms (e.g., malignant melanomas do not come from benign nevi) though in some cases such as adenomas of the colon, the appearance of the benign neoplasm is a step toward possible malignancy. There are "pre-cancerous" conditions in which malignant neoplasia is more likely to occur (but not in every case): liver cirrhosis, chronic ulcerative colitis, atrophic gastritis, epidermal actinic keratosis, oral leukoplakia

Clonality
Neoplastic cells tend to be monoclonal, or similar in genetic makeup, indicating origin from a transformed cell. Non-neoplastic proliferations (such as reactions to inflammation) have cells that are polyclonal in origin. The concept of "tumor progression" holds that subclones may arise over time from the original malignant clone. These subclones may differ from the original clone in characteristics such as invasiveness, metastatic potential, and response to therapy

Tumor Genetics
Neoplasms have a greater tendency to

karyotypic abnormalities such as translocations, deletions, and gene amplifications (which are also activators of proto-oncogenes). Leukemias and lymphomas are famous for this, as with the Philadelphia (Ph1) chromosome of chronic myelogenous leukemia and the t(8:14) translocation in Burkitt's lymphomas

Tumor growth
less differentiated a neoplasm, faster it grows. cell cycle of neoplastic cells is not shortened, rather the growth fraction of cells proliferating is increased. This is offset by neoplastic cell death. Tumor growth is expressed as a "doubling time" or the time to increase twice in volume (e.g., from 1 to 1.3 cm diameter). An aggressive malignant neoplasm doubles in 1 to 3 months, while benign neoplasms double in years.

 Some neoplastic growth is influenced by host factors. Estrogenic hormones aid growth of breast fibroadenomas or carcinomas and uterine leiomyomas because the tumor cells have hormone receptors. Growth is also dependent upon the ability of the tumor to develop a blood supply. Factors secreted by neoplastic cells promote angiogenesis and fibroblast proliferation.

Characteristics of Transformed (Neoplastic) Cells

Neoplastic cell growth is not inhibited by contact with surrounding cells and is not dependent on anchorage to a solid surface. Neoplastic cells may attain "immortality" or the ability to keep dividing indefinitely. They are discohesive and transplantable-favoring invasion and metastasis. Tumor cells can bind to laminin and fibronectin in connective tissues, then secrete collagenases or proteases, and then invade

Epidemiology of Neoplasia
Neoplasms can be characterized by: Their incidence (how often they occur). Their death rate (how many deaths are caused

by them). A neoplasm such as basal cell carcinoma of the skin can be quite common, yet it almost never kills the patient. On the other hand, gliomas of the brain are uncommon but virtually always kill the patient. One in 5 Americans dies of cancer.

Incidence of Neoplasia (estimated new cases for 1996 for malignant neoplasms in the U.S.)

Men Prostate Lung Colon-rectum Bladder Lymphomas 317,000 112,000 68,000 38,000 35,000 Breast

Women 184,000 82,000 78,000 34,000 26,000

Colon-rectum Lung Endometrium Lymphomas

Deaths from Neoplasia (top death-causing malignant neoplasms in the U.S. estimated for 1996)

Men Lung Prostate Colon-Rectum Pancreas Lymphomas 94,000 41,000 27,000 14,000 13,000 Lung Breast

Women 64,000 44,000 28,000 15,000 14,000

Colon-Rectum Ovary Pancreas

 These data indicate that some cancers such as prostate

and breast are more amenable to therapy than lung or pancreas. Another measure of therapeutic effectiveness is the so-called "5-year survival". Treatments can be compared based upon who survived the longest. The incidence of some tumors in the U.S. is increasing (lung) while others are decreasing (stomach). Environmental factors influence incidences from location to location and race to race.

Important to remember:
the incidence of cancer varies greatly with age.

Testicular cancers and Hodgkin's disease are seen mostly in young adult males, while prostate cancers are more frequent in older men. Of malignant neoplasms in children, leukemias and brain tumors are most frequent.

Effects of neoplasia on the body

Mass effect: impinging on a vital area (airway, nerve, blood vessel, hollow viscus) to obstruct or destroy it, or lead to infarction or infection. Local destruction: invasion or lysis of epithelial surfaces or vascular channels, leading to ulceration, bleeding, and infection. Cachexia: either caloric intake is decreased (lack of appetite or inability to eat) or the neoplasm alters normal metabolism (tumor necrosis factor); cancers do not "eat" the calories themselves.

 Functional activity: production of a hormone or substance that has an untoward effect. Many of these are so-called "paraneoplastic" syndromes (such as an oat cell lung cancer secreting ACTH or a renal cell carcinoma secreting erythropoietin or an islet cell tumor producing insulin). Hypercalcemia often accompanies cancers and is due either to: (1) osteolysis from metastases to bone or (2) production of parathormone-like substance (often in squamous cell carcinomas).

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