Topic

Immune System Cellular Aberration

NEOPLASIA - is the uncontrolled, disorderly proliferation of cells, resulting in a benign or malignant tumor, or neoplasm. A. Dysplasia a. Is a reversible change b. Often precedes malignancy c. Morphologically manifests by disorderly maturation and spatial arrangement of cells, marked variability in nuclear size and shape (pleomorphism), and increased, often abnormal, mitosis. d. Is exemplified by dysplasia of squamous epithelium of the cervix, which often is a precursor of malignancy. B. Neoplasms a. If the resemblance to tissue of origin is close, the neoplasm is termed well-differentiated; if little resemblance to the tissue of origin is seen, it is poorly differentiated. b. Neoplasms grow at the expense of function and vitality of normal tissue without benefit to the host and are largely independent of host control mechanisms. Classification and Nomenclature of Tumors Neoplasms are classified as either malignant or benign, based on their behavior. They are also described by terms derived from the appearance of the neoplasm, tissue of origin, or degree of differentiation.

A. Malignant Tumors (Cancer) a. Are capable of invasion (spread of the neoplasm into adjacent structures) and metastasis (implantation of the neoplasm into noncontiguous sites); this is the most important defining characteristic of malignancy, although there are some malignant tumors, such as basal cell carcinoma of the skin, that rarely metastasize. b. Are usually less differentiated than benign tumors c. Are marked by anaplasia, in which tumor cells are very poorly differentiated and exhibit pleomorphism, hyperchromatism (dark-staining nuclei), an increased nuclear-cytoplasmic ratio, abnormal mitoses, cellular dyspolarity, and often prominent nucleoli. In general, highly anaplastic tumors are very aggressive, and well-differentiated tumors are less aggressive. 1. Carcinoma - is a malignant tumor of epithelial origin and can be seen in the following variations: a. Squamous Cell Carcinoma o Originates from stratified squamous epithelium of the skin, mouth, esophagus, and vagina, as well as from areas of squamous metaplasia, as in the bronchi or the squamocolumnar junction of the uterine cervix. o Is marked by the production of keratin b. Transitional Cell Carcinoma o Arises from the transitional cell epithelium of the urinary tract. c. Adenocarcinoma o Is carcinoma of glandular epithelium and includes malignant tumors of the gastrointestinal mucosa, endometrium, and pancreas. o Is often associated with desmoplasia, tumor-induced proliferation of non-neoplastic fibrous connective tissue, particularly in adenocarcinoma of the breast, pancreas, and prostate. 2. Sarcoma - is a malignant tumor of mesenchymal origin. - Is often used with prefix that denotes the tissue of origin of the tumor, as in osteosarcoma (bone), rhabdomyosarcoma (skeletal muscle), leiomyosarcoma (smooth muscle), and liposarcoma (fatty tissue). 3. Eponycally Named Tumors - includes Burkitts lymphoma, Hodgkins disease, and Wilms Tumor. 4. APUDoma

is a tumor characterized by amine precursor uptake and decarboxylation (APUD) and the resultant production of hormone-like substances.

5. Teratoma - is a neoplasm derived from all three germ cell layers, which may contain structures such as skin, bone cartilage, teeth, and intestinal epithelium. - May be either malignant or benign - It usually arises in the ovaries or testes B. Benign Tumors are usually well-differentiated, closely resembling the tissue of origin. Do not metastasize and grow slowly. They can be harmful if their growth compresses adjacent tissues. Example. Benign intracranial tumors can be more lethal than some malignant skin tumors. Tend to become encapsulated Are denoted by the suffix oma, as in lipoma and fibroma. However, this suffix is also supplied to some malignant neoplasms, such as hepatoma, melanoma, lymphoma, and mesothelioma, as well as several nonneoplastic swellings, including granuloma and hematoma.

1. Papilloma o is a benign neoplasm most often arising from surface epithelium such as squamous epithelium of the skin, larynx, or tongue. o Is composed of delicate finger-like epithelial processes overlying a core of connective tissue stroma that contains blood vessels. o May also develop from transitional epithelium of the urinary bladder, ureter, or renal pelvis. 2. Adenoma o is a benign neoplasm of glandular epithelium that occurs in several variants: a. Papillary Cystadenoma is characterized by adenomatous papillary processes that extend into cystic spaces, as in cystadenoma of the ovary. b. Fibroadenoma is marked by proliferation of connective tissue surrounding neoplastic glandular epithelium; for example, fibroadenoma of the breast 3. Benign Tumors of Mesenchymal origin o are most often named by the tissue of origin; for example, leiomyoma, rhabdomyoma, lipoma, fibroma, and chondroma. o Include the most common neoplasm of women, the uterine leiomyoma or fibroid tumor. 4. Choristoma o is a small non-neoplastic area of normal tissue misplaced within another organ, such as pancreatic tissue within the wall of the stomach. 5. Hamartoma o is a non-neoplastic, disorganized, tumor-like overgrowth of cell types that are regularly found within the affected organ; hemangioma, or irregular accumulation of blood vessels. Properties of Neoplasms A. Properties of Transformed Cells - Include the following characteristic changes, which are observed in vitro in tissue culture. These changes may reflect the altered biology of cancer cells. 1. Loss of contact inhibition o in contrast to nontransformed cells, transformed cells continue to grow even when touching other cells. 2. Loss of adhesion o Transformed cells tend to grow separately rather than in clusters, perhaps partly due to faulty cytoskeletal structure. 3. Loss of anchorage dependence

Transformed cells will often grow in soft agar, in contrast to most normal cells, which must be anchored to a solid surface.

4. Expression of cell-surface proteases o this change may facilitate invasiveness 5. Increased expression of laminin receptors o these specific glycoprotein receptors may facilitate attachment of malignant cells to basement membranes 6. Marked reduction of cell-surface fibronectin o fibronectin may play role in contact-mediated growth control in normal cells, and reduced levels may be partially responsible for the uncontrolled growth of cancer cells. 7. Increased agglutinability by lectins 8. Chromosomal aneuploidy with increased DNA content B. Tumor-Specific Antigens (TSA) are cellular proteins characteristic of some tumors that are demonstrable immunologically. Include the following types:

1. TSAs induced by oncogenic viruses o often represent expression of viral proteins, and remain the same regardless of the tissue infected by the virus. 2. TSAs induced by chemical carcinogenesis o tend to be highly variable from tissue to tissue 3. Normal tissue proteins o apparently become accessible to immunologic probes because of conformational changes in the cell surface. 4. Proteins normally expressed only in fetal or embryonic life o are termed oncofetal antigens; their expression by neoplastic cells is considered a manifestation of these cells lack of differentiation. o Include carcinoembryonic antigen (CEA), associated with colon cancer and other cancers and preneoplastic processes, and alpha-fetoprotein, which is associated with hepatocellular carcinoma and many germ cell tumors. Invasion and Metastasis 1. Invasion - is aggressive infiltration of adjacent tissues by a malignant tumor. - Often extends into lymphatics and blood vessels, with the formation of tumor emboli that may be carried to distal sites. Not all tumor emboli result in metastatic tumor implants, and the presence of tumor cells within blood vessels or lymphatics indicates only the penetration of basement membranes and is not synonymous with metastasis. 2. Metastasis - is implantation in distal sites a. Process i. Growth and vascularization of the primary tumor ii. Invasiveness and penetration of basement membranes into lymphatics or blood vessels. iii. Transport and survival of tumor cells in the circulation iv. Arrest of tumor emboli in the target tissue v. Overcoming of target tissue defense mechanism vi. Development of successful metastatic implants b. Routes of Metastasis i. Carcinomas tend to metastasize via lymphatic spread ii. Sarcomas tend to invade blood vessels early resulting in widespread hematogenous dissemination

c. Target Organs i. Most commonly the liver, lungs, brain, adrenal glands, lymph nodes, and bone marrow. ii. Rarely include skeletal muscle of the spleen Manifestations of Malignancy: are mediated by mechanisms other than invasion and metastasis

1. Cachexia and Wasting o characterized by weakness, weight loss, anorexia, anemia, infection, and hypermetabolism o be mediated in part by cachectin (TNF-a), a product of macrophages that promotes catabolism of fatty tissue 2. Pituitary Abnormalities i. Prolactinoma, leading to amenorrhea, infertility, and sometimes, galactorrhea ii. Somatotropic adenoma, leading to gigantism in children and acromegaly in adults iii. Corticotropic adenoma, leading to Cushings disease iv. Adrenocortical Abnormalities includes Conns syndrome, adrenogenital syndrome, Cushings syndrome resulting from adrenal cortex tumors v. Ovarian abnormalities includes Granulosa-theca cell tumors, Sertoli-Leydig cell tumor leading to excess androgen production vi. Trophoblastic tissue abnormalities, include hyperproduction of human chorionic gonadotropin from H-mole or choriocarcinoma 3. Paraneoplastic Syndromes a. Endocrinpathies are causes by ectopic production of hormones or chemically unrelated substances inducing effects similar to those of a given hormone. i. Cushings Syndrome is caused by production of ACTH-like substances by small (oat cell) carcinoma of the lung ii. Inappropriate secretion of antidiuretic hormone, most commonly small cell carcinoma of the lung iii. Hypercalcemia caused by metastatic disease in bone, secretion of a substance similar to parathormone by squamous cell bronchogenic carcinoma, or secretion of a substance similar to osteoclast-activating factor by the malignant plasma cells of multiple myeloma iv. Hypoglycemia caused by secretion of insulin-like substances by hepatocellular carcinomas, mesotheliomas, and some sarcomas. v. Polycythemia caused by elaboration of erythropoietin by renal tumors and other neoplasms vi. Hyperthyroidism caused by production of substances like thyroid-stimulating hormone by hydatidiform moles, choriocarcinomas, and other lung tumors b. Neurologic Abnormalities - may occur in the absence of metastatic disease and include degenerative cerebral changes with dementia, cerebellar changes with resultant gait dysfunction, and peripheral neuropathies c. Skin lesions may be associated with visceral malignancies and include acanthosis nigricans and dermatomyositis d. Coagulation Abnormalities include migratiory thrombophlebitis associate with carcinoma of the pancreas and other visceral malignancies (Trousseaus Phenomenon), and disseminated intravascular coagulation associated with a variety of neoplasms. Carcinogenesis and Etiology the transformation of normal to neoplastic cells is caused by both endogenous and exogenous factors, including chemical and physical agents, viruses, activation of cancer-promoting genes, and inhibition of cancer-suppressing genes.

1. Types of carcinogens a. Direct-reacting carcinogens need not be chemically altered to act b. Indirect-reacting carcinogens require metabolic conversion from procarcinogens to active ultimate carcinogens. For example, a muclosa glucuronidase in the urinary bladder converts B-naphthylamine glucoronide to the carcinogen B-naphthylamine 2. Exposure to ultraviolet radiation form of sunlight.

3. Ionizing Radiation is a classic cause of cancer, exemplified by the increased incidence of cancers in those exposed to radiation. 4. Virus Carcinogens a. DNA viruses integrate viral DNA into host genomes perhaps resulting in host cell expression of viral mRNA coding for specific proteins. It includes HPV, EBV, HSV-2, and Hepatitis B virus as prominent suspects that play a role in human carcinogenesis. b. Retroviruses are marked by transcription of viral genomic RNA sequences into DNA by action of viral reverse transcriptase. 5. Stages a. Initiation i. Is the first critical carcinogenic event and it is usually a reaction between a carcinogen and DNA. b. Promotion i. Is induced by a stimulator of cell proliferation and enhances the carcinogenic process. A promoter, not carcinogenic in itself, enhances other agents carcinogenicity. Epidemiology Important epidemiologic factors include geographic and racial differences, heredity, age, sex and hormonal differences, dietary factors, environmental toxins, and infection

Grading and Staging 1. Grading - is histopathologic evaluation of the lesion based on the degree of cellular differentiation 2. Staging is clinical assessment of the degree of localization or spread of the tumor Generally correlates better with prognosis than does histopathologic grading. Exemplified by the generalized TNM system which evaluates size and extent of tumor (T), lymph node involvement (N), and metastasis (M). Is sometimes oriented toward specific tumors, as exemplified by the Dukes System for colorectal carcinoma and the Ann Arbor System for Hodgkins disease and Non-Hodgkins lymphomas.