[WinFlash] Q1=What is Krukenberg's tumor? ^ A1=A classic example of metastatic gastrointestinal neoplasia to the ovaries is termed Krukenberg's tumor, which are bilateral metastases composed of mucin-producing, signet-ring cancer cells, most often of gastric origin. Q2=What is a Lisch nodule? ^ A2=Iris hamartomas typically seen in type 1 neurofibromatosis. Q3=Leiomyoma ^ A3=Benign smooth muscle tumors, often arise in the uterus, where they represent the most common neoplasm in the female Leiomyomas may also arise in the walls of blood vessels, in deep soft tissue, and in the skin and subcutis from the arrector pili muscles found in the skin, nipples, scrotum, and labia (genital leiomyomas). Those arising in the arrector muscles (pilar leiomyomas) are frequently multiple and painful. The tendency to multiple lesions is thought to be hereditary and transmitted as an autosomal dominant trait. In whatever setting, these lesions tend to occur in adolescence and early adult life. ^The most common benign mesenchymal tumors arising in the bladder and tend to grow as isolated, intramural, encapsulated, oval-to-spherical masses, varying in diameter up to several centimeter Q4=What is the number one most common malignancy? ^ A4=Malignant melanoma, Australia is number one. Q5=What is a neoplasm forming fibrosis tissue commonly in the breast (hard mass)? ^ A5=Desmoplasia: Hyperplasia of fibroblasts and disproportionate formation of fibrous connective tissue, especially in the stroma of a carcinoma. Parenchymal cells stimulating the formation of an abundant collagenous stroma called desmoplasia. Q6=Adenoma ^ A6=An ordinarily benign neoplasm of epithelial tissue in which the tumor cells form glands or glandlike structures in the stroma; usually well circumscribed, tending to compress rather than infiltrate or invade adjacent tissue. Q7=Papilloma ^ A7=A circumscribed benign epithelial tumor projecting from the surrounding surface; more precisely, a benign epithelial neoplasm consisting of villous( finger like growth) or arborescent outgrowths of fibrovascular stroma covered by neoplastic cells. Q8=Condylomma accuminatum ^ A8=a contagious projecting warty growth on the external genitals or at the anus, consisting of fibrous overgrowths covered by thickened epithelium showing koilocytosis, due to sexual contact with infection by human papilloma virus; it is usually benign, although malignant change has been reported, associated with particular types of the virus. Q9=Cystadenomas ^ A9=Adenomas that form large cystic masses, as in the ovary, are referred to as cystadenomas. Classic lesions occuring in the ovary: Ovarian neoplasm's which are unilateral and occur in younger women < 40-45 usually BENIGN but in older women are bilateral and malignant: most of ovarian neoplasm have a cystic component to it as well as glandular component which is why they are called cystadenoma. Q10=Carcinoma ^ A10=Any of the various types of malignant neoplasm derived from epithelial tissue in several sites, occurring more frequently in the skin and large intestine in both sexes, the lung and prostate gland in men, and the lung and breast in women. Carcinomas are identified histologically on the basis of invasiveness and the changes that indicate anaplasia, i.e., loss of polarity of nuclei, loss of orderly maturation of cells (especially in squamous cell type), variation in the size and shape of cells, hyperchromatism of nuclei (with clumping of chromatin), and increase in the nuclear-cytoplasmic ratio. Carcinomas may be undifferentiated, or the neoplastic tissue may resemble (to varying degree) one of the types of normal epithelium. Q11=What is a malignant neoplasm of mesoderm? Give examples. ^ A11=Sarcoma: e.g.,1) striated muscle leads to rhabdomyosarcoma 2) fibrous tissue leads to fibrosarcoma 3) bone leads to osteogenicsarcoma ^imp. to know if have carcinoma or sarcoma because carcinomas in contrast to sarcomas usually have better prognosis Q12=Rhabdomyosarcoma ^ A12=Rabid dog biting into a child's skeletal muscle. ^A malignant neoplasm derived from skeletal (striated) muscle, occurring in children or, less commonly, in adults; classified as embryonal alveolar (composed of loose aggregates of small round cells), or pleomorphic (containing rhabdomyoblasts). Q13=What are three types of Rhabdomyosarcomas? ^ A13=Rabid dog biting into a child's skeletal muscle. ^Embryonal rhabdomyosarcoma appears as a soft gray infiltrative mass. Most when first seen are many centimeters in size. The tumor cells mimic skeletal muscle in its various stages of embryogenesis and consist of sheets of both malignant round and spindled cells in a variably myxoid stroma. Sarcoma botryoides grows in a polypoid fashion, producing the appearance of a cluster of grapes protruding into a hollow structure, such as the bladder or vagina. Where the tumor abuts the mucosa of an organ, the tumor cells form a submucosal zone of hypercellularity known as the cambium layer. Rhabdomyoblasts with visible cross striations are present in most cases. ^2)Alveolar rhabdomyosarcoma occurs in early to middle adolescence and commonly arises in the deep musculature of the extremities.78 The tumor is traversed by a network of fibrous septae that divide the cells into clusters or aggregates; as the central cells become necrotic and drop out, a crude resemblance to pulmonary alveoli is created. The tumor cells are discohesive and moderate in size, and many have little cytoplasm. Cells with cross striations are identified in only about 30% of cases. Cytogenetic studies have shown a translocation between chromosomes 2 and 13 (q35-37; q14) in this type of rhabdomyosarcoma.79 ^3)Pleomorphic rhabdomyosarcoma is characterized by numerous large, sometimes multinucleated, bizarre tumor cells. This variant is uncommon, has a tendency to arise in the deep soft tissue of adults, and can be confused histologically with malignant fibrous histiocytoma. Q14=Osteosarcoma ^ A14=Osteosarcoma is defined as a malignant mesenchymal tumor in which the cancerous cells produce bone matrix. It is the most common primary malignant tumor of bone exclusive of myeloma and lymphoma and accounts for approximately 20% of primary bone cancers. About 1000 cases are newly diagnosed each year in the United States. Osteosarcoma occurs in all age groups but has a bimodal age distribution. Approximately 75% occur in patients younger than 20 years of age.27 The smaller second peak (secondary osteosarcoma) occurs in the elderly, who frequently suffer from conditions known to be associated with the development of osteosarcoma (Paget's disease, bone infarcts, and prior irradiation). Hereditary osteochondromas, enchondromas, and fibrous dysplasia are also sometimes complicated by osteosarcomas. Overall, males are more commonly affected than females (1.6:1). The tumors usually arise in the metaphyseal region of the long bones of the extremities, and almost 60% occur about the knee. Their locations in descending order of frequency are the distal femur, proximal tibia, proximal humerus, and proximal femur ny bone may be involved, however, and in persons beyond the age of 25, the incidence in flat bones and long bones is almost equal. Q15=Fibrosarcoma ^ A15=Fibrosarcoma is composed of malignant fibroblasts arranged in a "herringbone pattern." The level of differentiation determines the amount of collagen produced and degree of cytologic atypia. Bizarre multinucleated cells are not common, and most fibrosarcomas have the appearance of a low-to-intermediate grade malignancy. Malignant fibrous histiocytoma consists of a background of spindled fibroblasts in a storiform pattern admixed with large, ovoid, bizarre, multinucleated tumor giant cells. Morphologically some tumor cells resemble neoplastic histiocytes; however, the evidence shows they are actually fibroblasts. Malignant fibrous histiocytoma is generally a high-grade pleomorphic tumor. Q16=Which have better prognosis, sarcomas or carcinomas? ^ A16=Carcinoma Q17=What are the genetic alterations in an adematous polyp of the colon? ^ A17=patients (with familial adenomatous polyposis) are born with loss of one copy of the APC gene, on chromosome 5q. All their cells are deficient in one of the two copies of the APC gene Q18=What features distinguish a benign from a malignant growth in the colonic mucosa? ^ A18=Benign tumors are well circumscribed, slow growing, well differentiated, and non-invasive, and they do not metastasize. Malignant tumors are invasive, and they may metastasize. They may be well differentiated or poorly differentiated. Because of invasion, their margins are irregular. Q19=What term is used to describe the intense staining of the adenoma cells? ^ A19=Hyperchromatic staining. Q20=To what organ(s) might Colon carcinoma metastasize? ^ A20=Colon carcinoma may spread by lymphatics to the regional lymph nodes or by the blood stream to liver. Eventually, spread may occur into the lungs. Intraperitoneal spread may also occur in the peritoneal cavity. Q21=What tumor markers are associated with Adenocarcinoma of the Colon ^ A21=Carcinoma of the colon is associated with the presence of carcinoembryonic antigen (CEA) in the serum. However, this is not specific for colon carcinoma. CEA may also be present in the serum in patients with gastric cancer or breast cancer. Some non-neoplastic conditions may also be associated with CEA in the serum. Q22=What term is used to describe cells and nuclei with irregular sizes and shapes? ^ A22=Pleomorphism Q23=How frequently are mutations in p53, ras, and APC seen in other types of malignancies? ^ A23=p53 is the most common gene mutated in human cancer. It is mutated in over 50% of all malignant tumors. Ras is the most commonly mutated protooncogene in human cancer. It is mutated in about 25-30% of malignancies. APC mutation is seen in very few other tumors (e.g. gastric and esophageal cancers). Q24=What is the most commonly mutated gene in human cancer? ^ A24=p53 Q25=What is the most commonly mutated protooncogene in human cancer? What frequency? ^ A25=Ras, It is mutated in about 25-30% of malignancies Q26=What type of mutation is seen in gastric and esophageal cancers? ^ A26=APC mutation Q27=What are the functions of p53 and ras in normal cells? ^ A27=p53 is called "guardian of the genome." When cells experience DNA damage, the normal p53 gene causes cell cycle arrest in G1, providing time for repair of DNA damage. If repair is successful, cells enter the cycle again; if not successful, the p53 gene causes cell death by apoptosis. Ras in normal cells is a signal-transduction molecule. When cells receive a growth-promoting stimulus, ras GDP is converted to ras GTP. The latter is the active form of ras, and it sends growth-promoting signals to the nucleus. However, normally the ras GTP is rapidly converted to its inactive form by hydrolysis of GTP to GDP. Q28=What is the relationship between cirrhosis of the liver and primary liver cell cancer? ^ A28=Cirrhosis, regardless of its etiology, is a very important risk factor for liver cancer. This association is believed to result from the extensive regeneration of liver cells that characterizes cirrhosis. The dividing cells are at an increased risk of mutation Q29=What determines the homing of cancer cells into various organs? ^ A29=Why certain cancer cells metastasize to specific organs is not entirely clear. Certainly anatomic considerations are important, e.g., cancer of the breast usually spreads first to the draining lymph nodes. But other factors that are specific to the tissues are also important. For example, tumor cells may bear receptors for molecules on the endothelial cells specific to a given organ. Alternatively, certain tissues may not favor metastases because their microenvironment may inhibit the proteolytic enzymes needed for invasion by the tumor cells. Q30=What is the biochemical function of NF-1? ^ A30=NF-1 encodes a GTPase activating protein (GAP) that facilitates the inactivation of ras by converting ras GTP to ras GDP. Thus, NF-1 downregulates the function of ras. Q31=What are characteristic clinical feature of neurofibromatosis, type 1? ^ A31=Cafe' au lait spots. These spots on the skin (macules) display light brown pigmentation. Iris hamartomas called Lisch nodules. Q32=What route of metastasis is commonly used by sarcomas? ^ A32=Sarcomas typically spread by the vascular route. Q33=How might estrogen receptor expression be involved in the etiology of a tumor? ^ A33=Estrogen may bind to the receptors on the tumor cells and promote their growth. Estrogen is not mutagenic, so it is a tumor promoter, not a tumor initiator. Q34=What is the significance of the intense erbB2 staining in presumed cancer cells? ^ A34=erbB2 is a dominant proto-oncogene. It is a cell surface receptor with intrinsic tyrosine kinase activity with homology to the EGF receptor. Binding of erbB2 to its ligand, heregulin, results in proliferation of the target cell. It is thought that the overexpression of erbB2, found in many mammary carcinomas, results in the constitutive activation of this growth-stimulatory pathway. This is considered a sign of a poor prognosis. Q35=How does the presence of carcinoma cells in the cerebrospinal fluid influence tumor staging? How does it influence grading? ^ A35=The presence of cells in the CSF indicates distant ^metastases and hence the tumor stage is increased to IV. Because the cells still appear to have a differentiated feature (secreting mucin), the grade is not affected by this finding. Q36=How do carcinomas spread? ^ A36=Carcinomas spread via lymphatic channels and go to central Lymph nodes then via a particular lymphatic channel (LC) --> bilateral slow growing neoplasm --> have better prognosis in general, But if carcinoma go to LC will eventually go to THORACIC DUCT, which will empty into venous system and spread through out body, which is advanced stage of disease. Q37=Mixed tumors ^ A37=have both carcinoma and sarcoma or have a benign mix tumor. For example,glandular neoplasm along with mesodermal neoplasm. Also carcinosarcoma or a mixed mesodermal tumor of the endometrium. Q38=Teratoma: ^ A38=neoplasm of 3 germ layers: e.g., neoplasm of ovary --> cysticteratoma: usually most of germ layer is ectodermal Q39=Choristoma or heterotopia ^ A39=The term heterotopia (or choristoma) is applied to microscopically normal cells or tissues that are present in abnormal locations. Examples of heterotopias include a rest of pancreatic tissue found in the wall of the stomach or small intestine, or a small mass of adrenal cells found in the kidney, lungs, ovaries, or elsewhere. The heterotopic rests are usually of little significance, but they can be confused clinically with neoplasms. Rarely, they are sites of origin of true neoplasms, producing the paradox of an adrenal carcinoma arising in the ovary. Q40=What is a benign tumor of connective tissue called? ^ A40=Fibroma Q41=What is a benign tumor of fatty tissue called? ^ A41=Lipoma Q42=What is a benign tumor of cartilage called? ^ A42=Chondroma Q43=What is a benign tumor of bone called? ^ A43=Osteoma Q44=What is a malignant tumor of connective tissue called? ^ A44=Fibrosarcoma Q45=What is a malignant tumor of fatty tissue called? ^ A45=Liposarcoma Q46=What is a malignant tumor of cartilage called? ^ A46=Chondrosarcoma Q47=What is a malignant tumor of bone called? ^ A47=Osteosarcoma Q48=Tumors of vascular cells and related tissues. ^ A48=Vascular tumors constitute a spectrum-from the benign hemangiomas to intermediate lesions that are locally aggressive but infrequently metastasize, to relatively rare, highly malignant angiosarcomas. In addition, congenital malformations, such as those that occur in the Sturge-Weber syndrome, may present as tumor-like lesions, as do some non-neoplastic inflammatory vascular proliferations, such as the granuloma pyogenicum of pregnancy. For these reasons, vascular neoplasms are difficult to categorize clinically and histologically. Here we describe only those lesions that are common or clinically important. Vascular neoplasms are divided into benign, intermediate, and malignant based on two major anatomic characteristics: (1) the degree to which the neoplasm is composed of well-formed vascular channels and (2) the extent and regularity of the endothelial cell proliferation (see Table 11.8 ). In general, benign neoplasms are made up largely of well-formed vessels with well-differentiated endothelial cell proliferation; in contrast, frankly malignant tumors are solidly cellular and anaplastic, with scant numbers of only poorly developed vascular channels. The endothelial nature of neoplastic proliferations that do not form distinct vascular lumina can sometimes be confirmed by endothelial cell-specific markers such as vWF by immunohistochemical techniques (see earlier in this chapter). Because these lesions constitute abnormalities of unregulated vascular proliferation, a particularly exciting possibility is that of controlling such growth by agents that inhibit blood vessel formation (antiangiogenic factors). Q49=Hemangioendothelioma ^ A49=Hemangioendothelioma is used to denote a true neoplasm of vascular origin composed predominantly of masses of endothelial cells growing in and about vascular lumina. The hemangioendothelioma represents an intermediate grade between the well-differentiated hemangiomas and the frankly anaplastic, totally cellular angiosarcomas. It is most frequently encountered in the skin but may affect the spleen and liver. Histologically, vascular channels are evident, with masses and sheets of spindle-shaped cells, occasionally with mitotic figures and some pleomorphism. The chief importance of this tumor lies in its differentiation from the more ominous angiosarcoma. The clinical setting is critical. Borderline lesions that are present at birth often mature eventually, but in the setting of chronic lymphedema they should cause concern. ^Epithelioid hemangioendothelioma is a unique vascular tumor occurring around medium-sized and large veins in the soft tissue of adults. In such tumors, well-defined vascular channels are inconspicuous, and the tumor cells are plump and often cuboidal, thus resembling epithelial cells. Occurring in the lung as a so-called intravascular bronchoalveolar tumor, such a tumor can be misdiagnosed as metastatic carcinoma. Clinical behavior is variable; most are cured by excision, but up to 40% recur, and 20% eventually metastasize. Q50=Sturge-Weber syndrome (also called encephalotrigeminal angiomatosis) ^ A50=Port-wine stains in the distribution of the trigeminal nerve may be associated with the Sturge-Weber syndrome (also called encephalotrigeminal angiomatosis). An extremely uncommon congenital disorder attributed to faulty development of certain mesodermal and ectodermal elements, it is characterized by venous angiomatous masses in the leptomeninges over the cortex and by ipsilateral port-wine nevi of the face. Because it is often associated with mental retardation, seizures, hemiplegia, and radiopacities in the skull, a large vascular malformation in the face may well be more than a coincidence in a child who exhibits some evidence of mental deficiency.( congenital cutaneous angioma (flame nevus) in the distribution of the trigeminal nerve, usually unilateral; 2) homolateral meningeal angioma with intracranial calcification and neurologic signs; and 3) angioma of the choroid, often with secondary glaucoma.) Q51=Von Hippel-Lindau Disease ^ A51=This disorder is inherited in an autosomal dominant pattern and includes the predilection to develop characteristic tumors within the cerebellar hemispheres (capillary hemangioblastomas), retina, and, less commonly, the brain stem and spinal cord. Patients may also have cysts involving the pancreas, liver, and kidneys and have a strong propensity to develop renal cell carcinoma of the kidney. The gene, a tumor suppressor gene, is located on chromosome 3p25-26. Therapy is directed at the symptomatic neoplasms, including resection of the cerebellar hemangioblastomas and laser therapy for retinal lesions. Partial nephrectomies may be performed for renal carcinomas when these malignancies are bilateral. Polycythemia is associated with the presence of a hemangioblastoma in about 10% of cases; the tumor has been shown to be a source of erythropoietin in these cases, although the cell origin of the growth factor is not known. Q52=Nevus Flammeus ^ A52=This is a "ten-dollar" term for the ordinary birthmark. Most commonly on the head and neck, they range in color from light pink to deep purple and are ordinarily flat. Histologically, they show only dilatation of vessels in the dermis. The vast majority ultimately fade and regress. A special form of nevus flammeus, the so-called port-wine stain, may grow proportionately with a child, thicken the skin surface, and become unsightly. Port-wine stains in the distribution of the trigeminal nerve may be associated with the Sturge-Weber syndrome (also called encephalotrigeminal angiomatosis). An extremely uncommon congenital disorder attributed to faulty development of certain mesodermal and ectodermal elements, it is characterized by venous angiomatous masses in the leptomeninges over the cortex and by ipsilateral port-wine nevi of the face. Because it is often associated with mental retardation, seizures, hemiplegia, and radiopacities in the skull, a large vascular malformation in the face may well be more than a coincidence in a child who exhibits some evidence of mental deficiency. Q53=lymphangioma ^ A53=A fairly well-circumscribed nodule or mass of lymphatic vessels or channels that vary in size, are usually greatly dilated, and are lined with normal endothelial cells; lymphoid tissue is usually present in the peripheral portions of the lesions, which are present at birth, or shortly thereafter, and probably represent anomalous development of lymphatic vessels (rather than true neoplasms); they occur most frequently in the neck and axilla, but may also develop in the arm, mesentery, retroperitoneum, and other sites. Syn: angioma lymphaticum. Q54=Simple (Capillary) Lymphangioma ^ A54=Lymphangioma Simple (Capillary) Lymphangioma These masses, composed of small lymphatic channels, tend to occur subcutaneously in the head and neck region and in the axilla. Rarely, they are found in the trunk, within internal organs, or in the connective tissue in and about the abdominal or thoracic cavities.On body surfaces, they are slightly elevated or sometimes pedunculated lesions, 1 to 2 cm in diameter. Histologically, they are composed of a network of endothelium-lined lymph spaces that can be differentiated from capillary channels only by the absence of blood cells. Sometimes the lining cells hypertrophy, become cuboidal, and take on the appearance of glandular epithelium. These tumors are completely benign clinically. Q55=Lymphangiosarcoma ^ A55=Lymphangiosarcoma is a rare tumor that develops after prolonged lymphatic obstruction with lymphedema. Most cases occur in the edematous arms of patients treated by radical mastectomy for carcinoma of the breast. Clinically the edematous arm may undergo acute swelling followed by the appearance of subcutaneous nodules, hemorrhage, and skin ulceration. The nodules are frequently multiple, but they later become confluent, forming a large mass. On the average, they appear about 10 years after the mastectomy and have a very poor prognosis. They may also develop after prolonged lymphedema in the lower legs. Histologically, the tumor is composed of channels lined by anaplastic endothelial cells. Q56=meningioma ^ A56=A benign, encapsulated neoplasm of arachnoidal origin, occurring most frequently in adults; most frequent form consists of elongated, fusiform cells in whorls and pseudolobules with psammoma bodies frequently present; meningioma's tend to occur along the superior sagittal sinus, along the sphenoid ridge, or in the vicinity of the optic chiasm; in addition to meningothelial meningioma, angiomatous, chondromatous, osteomatous, lipomatous, melanotic, fibroblastic and transitional varieties are recognized. Q57=Psammoma bodies ^ A57=Mineralized body's occurring in the meninges, choroid plexus, and in certain meningiomas; composed usually of a central capillary surrounded by concentric whorls of meningocytes in various stages of hyaline change and mineralization; can also occur in benign and malignant epithelial tumors (often papillary) or with chronic inflammation; Syn: sand bodies. Q58=Meningiomas Morphology ^ A58=Grossly, meningiomas tend to be rounded masses with a well-defined dural base that compress underlying brain but are easily separated from it. Extension into the overlying bone is not uncommon. The surface of the mass is usually encapsulated with thin, fibrous tissue and may have a bosselated or polypoid appearance. Another characteristic growth pattern is the en plaque variant, in which the tumor spreads in a sheet-like fashion along the surface of the dura. This form is commonly associated with hyperostotic reactive changes in the overlying bone. The lesions may have a finely gritty consistency, reflecting few calcifications, or they may be extremely calcified with psammoma bodies or even contain metaplastic bone. In the absence of these types of changes, the lesions are usually firm to fibrous and lack evidence of necrosis or extensive hemorrhage.Traditionally, several histologic patterns have been recognized, although it is now felt that most of these carry little prognostic significance. Among the histologic patterns found in meningiomas are syncytial, appropriately named for the whorled clusters of cells which sit in tight groups without visible cell membranes; fibroblastic, with elongated cells and abundant collagen deposition between them; transitional, which shares features of the syncytial and fibroblastic types; psammomatous, with a dominant pattern of psammoma bodies, apparently forming from calcification of the syncytial nests of meningothelial cells; secretory, with PAS-positive intracytoplasmic droplets and intracellular lumina by electron microscopy; and microcystic, with a loose, spongy appearance. One histologic pattern is associated with a worse prognosis: the papillary variant, which has pleomorphic cells arranged around fibrovascular cores. Tumors may have a mixture of these histologic types as well. Some recognize a group of angioblastic meningiomas; others feel that they constitute a distinct population of neoplasms, as discussed later. Immunohistochemical studies of meningiomas have revealed them to be positive for epithelial membrane antigen (EMA), in distinction to other tumors arising in this region. Keratin staining is usually restricted to lesions with the secretory pattern, and these tumors are also positive for carcinoembryonic antigen (CEA). Xanthomatous degeneration, metaplasia, and moderate nuclear pleomorphism, are common in meningiomas. These findings are of no prognostic significance. Malignant meningiomas are extremely unusual tumors and may be difficult to recognize histologically. Features that support this diagnosis include single cell infiltration of underlying brain and abundant mitoses with atypical forms. Q59=Which neoplasm is positive for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA). ^ A59=Meningioma Q60=What is the second most common neoplasm? ^ A60=Leiomyoma of the uterus. Q61=Which is more amenable to chemotherapy, sarcomas or carcinomas? ^ A61=Carcinoma Q62=Benign Epithelial Tumors ^ A62=Epithelial cysts are common lesions formed by the downgrowth and cystic expansion of the epidermis or of the epithelium forming the hair follicle. The lay term "wen" derives from the Anglo-Saxon wenn, meaning a lump or tumor. These cysts are filled with keratin and variable amounts of admixed, lipid-containing debris derived from sebaceous secretions. Clinically, they are dermal or subcutaneous, well-circumscribed, firm, and often moveable nodules. When large, they may be dome-shaped and flesh-colored and often become painful upon traumatic rupture Q63=Squamous cell carcinoma ^ A63=Squamous cell carcinoma is the most common tumor arising on sun-exposed sites in older people. Except for lesions on the lower legs, these tumors have a higher incidence in men than in women. Implicated as predisposing factors, in addition to sunlight, are industrial carcinogens (tars and oils), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation, and in the oral cavity tobacco and betel nut chewing. Patients with xeroderma pigmentosum, and immunosuppressed individuals also have a high incidence of this neoplasm. Squamous cell carcinomas that have not invaded through the basement membrane of the dermoepidermal junction (in situ carcinoma) appear as sharply defined, red scaling plaques. More advanced, invasive lesions are nodular, show variable keratin production appreciated clinically as hyperkeratosis, and may ulcerate. Well-differentiated lesions may be indistinguishable from keratoacanthoma. When the mucosa is involved, a zone of white thickening is seen, an appearance caused by a variety of disorders and referred to clinically as leukoplakia. Q64=Basal cell carcinoma ^ A64=(should be called basal cell epithelioma b/c basal cell cancers which can occur usually @ some exposed areas of face in particular, they don't metastasize.) ^Basal cell carcinomas are common, slow-growing tumors that rarely metastasize. They have a tendency to occur at sites subject to chronic sun exposure and in lightly pigmented people. As with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with immunosuppression and in patients with inherited defects in DNA replication or repair (xeroderm pigmentosum ). The rare, dominantly inherited basal cell nevus syndrome is associated with the development of numerous basal cell carcinomas in early life and with abnormalities of bone, nervous system, eyes, and reproductive organs. Clinically, these tumors present as pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias). Some tumors contain melanin pigment and, thus, appear similar to nevocellular nevi or melanomas. Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur after many years of neglect or in unusually aggressive tumors, justifying the past designation "rodent ulcers. Q65=Which type of neoplasm can be cauterized and should not be referred to as a neoplasm when consulted by a patient? ^ A65=Basal cell carcinoma because it is easily removed and rarely metastasizes. Q66=What is a tumor/neoplasm of endodermal origin? ^ A66=Adenoma: glandular neoplasm: usually a polyp , always going to occur in colon, 5% of adenomas of colon would eventually turn into adenocarcinoma of colon (quiet common neoplasm), 50% of adenomas of colon can be reached by an examining finger (rectal exam): adenocarcinoma : most common carcinoma of intestinal tract most common benign lesion of intestinal tract Q67=What is the most common benign lesion of the intestinal tract? ^ A67=Adenocarcinoma Q68=Adenocarcinomas arising in Barrett's esophagus ^ A68=Adenocarcinomas arising in Barrett's esophagus chiefly occur in patients older than 40 years of age, with a median age in the sixth decade. In keeping with Barrett's esophagus, adenocarcinoma is more common in men than in women, and whites are affected more frequently than are blacks, in contrast to squamous cell carcinomas. As in other forms of esophageal carcinoma, patients usually present because of dysphagia, progressive weight loss, bleeding, chest pain, and vomiting. Long-term symptoms of heartburn, regurgitation, and epigastric pain that are related to concurrent gastroesophageal reflux disease (and sliding hiatal hernias) are present in fewer than half of newly diagnosed patients. ^The prognosis of esophageal adenocarcinoma is as poor as that for other forms of esophageal cancer, with a less than 15% 5-year survival rate. Early diagnosis with definitive resection improves 5-year survival to more than 50%. No medical therapy has been shown to decrease the risk of esophageal cancer in patients with Barrett's esophagus. In fact, medical therapy rarely if ever causes disappearance of Barrett's mucosa.5 Although dysplasia appears to be a requisite precursor for the development of adenocarcinoma, patients with low-grade dysplasia may not progress to cancer over long periods of follow-up, and regression may occ Q69=Papillary carcinoma ^ A69=common @ rectal area: may look like and behave like papilloma and looks good in biopsy, but in core have adenocarcinoma in 1/3 of cases à have benign lesion with malignancy in it Q70=Cystadenocarcinoma ^ A70=A malignant neoplasm derived from glandular epithelium, in which cystic accumulations of retained secretions are formed; the neoplastic cells manifest varying degrees of anaplasia and invasiveness, and local extension and metastases occur; cystadenocarcinoma's develop frequently in the ovaries, where pseudomucinous and serous types are recognized. Q71=Bronchogenic Carcinoma ^ A71=In industrialized nations, "public enemy number one" among cancers is bronchogenic carcinoma. It is the most common visceral malignancy in males; it alone accounts for approximately one-third of all cancer deaths in males and over 7% of all deaths in both sexes. The incidence is increasing dramatically in women, and lung cancer has passed breast carcinoma as a cause of cancer death in women. Overall, lung cancer is the most frequent fatal malignancy. The annual number of deaths from lung cancer in the United States increased from 18,000 in 1950 to an estimated 153,000 in 1994.78 The age-adjusted death rate from cancer of the lung since 1950 has more than trebled in males, rising from 19.9 to an outstanding 74 per 100,000 population. The death rate in females since 1950 has risen from 4.5 to 31 per 100,000, almost certainly the delayed consequence of increased cigarette smoking among women. Cancer of the lung now accounts for 16% of all cancers in males and 13% in females. In 1994 there will be an estimated 150,000 new cases of lung cancer. Cancer of the lung occurs most often between ages 40 and 70 years, with a peak incidence in the sixth or seventh decade. Only 2% of all cases appear before the age of 40. Q72=Which broncogenic carcinomas are associated with smoking? ^ A72=Squamous cell carcinoma and small cell carcinoma Q73=What are the classifications of bronchogenic carcinoma? ^ A73=Numerous histologic classifications of bronchogenic carcinoma have been proposed, but the currently popular ones, based on classifications of the World Health Organization, divide these tumors into four major categories: squamous cell carcinoma, and adenocarcinoma of approximately equal frequency, 25 to 40% each; small cell carcinoma, 20 to 25%; and large cell carcinoma, 10 to 15%. There may be mixtures of histologic patterns, even in the same cancer. Thus, combined types of squamous cell carcinoma and adenocarcinoma or of small cell and squamous cell carcinoma are not infrequent. Another classification in common clinical use is based on response to available therapies: small cell carcinomas (high initial response to chemotherapy) versus non-small cell carcinomas (less responsive. The strongest relationship to smoking is with squamous cell and small cell carcinoma. From a histogenetic point of view, it seems most likely that all histologic variants of bronchogenic carcinoma, including small cell carcinoma as well as the bronchial carcinoid, to be described later, are derived from endoderm or a derivative-a view consistent with the frequency of tumors with mixed histologic patterns. Q74=Squamous Cell Carcinoma morphlogy ^ A74=This type is most commonly found in men and is closely correlated with a smoking history. The microscopic features are familiar in the form of production of keratin and intercellular bridges in the well-differentiated forms, but many less well-differentiated squamous cell tumors are encountered that begin to merge with the undifferentiated large cell pattern. This tumor arises in the larger, more central bronchi, tends to spread locally, and metastasizes somewhat later than the other patterns, but its rate of growth in its site of origin is usually more rapid than that of other types. Squamous metaplasia, epithelial dysplasia, and foci of frank carcinoma in situ are sometimes present in bronchial epithelium adjacent to the tumor mass. Q75=Adenocarcinoma morphology ^ A75=Histologic classifications of adenocarcinomas include at least two forms: (1) the usual bronchial-derived adenocarcinoma; and (2) a somewhat distinctive type termed bronchioloalveolar carcinoma, which probably arises from terminal bronchioles or alveolar walls. There may be overlap between these two forms, but the bronchioloalveolar carcinoma has sufficiently distinctive gross, microscopic, and epidemiologic features to be discussed later. Adenocarcinoma is the most common type of lung cancer in women and nonsmokers. The lesions are usually more peripherally located, tend to be smaller, and vary histologically from well-differentiated tumors with obvious glandular elements to papillary lesions resembling other papillary carcinomas, to solid masses with only occasional mucin-producing glands and cells. About 80% contain mucin. Adenocarcinomas grow more slowly than squamous cell carcinomas. Peripheral adenocarcinomas are sometimes associated with areas of scarring (see above). Adenocarcinomas, including bronchioloalveolar carcinomas, are less frequently associated with a history of smoking than are squamous or small cell carcinomas. Q76=Small Cell Carcinoma ^ A76=This highly malignant tumor has a distinctive cell type. The epithelial cells are generally small, have little cytoplasm and are round or oval and, occasionally, lymphocyte-like (although they are about twice the size of a lymphocyte). This is the classic "oat cell" (see Figure 15.43 ). Other small cell carcinomas have spindle-shaped or polygonal cells and may be thus classified (spindle or polygonal small cell carcinoma). The cells grow in clusters that exhibit neither glandular nor squamous organization. Electron microscopic studies show dense-core neurosecretory granules in some of these tumor cells. The granules are similar to those found in the neuroendocrine argentaffin (Kulchitsky's) cells present along the bronchial epithelium, particularly in the fetus and neonate. The occurrence of neurosecretory granules, the ability of some of these tumors to secrete polypeptide hormones, and the presence (ascertained by immunohistochemical stains) of neuroendocrine markers such as neuron-specific enolase and parathormone-like and other hormonally active products suggest derivation of this tumor from neuroendocrine cells of the lining bronchial epithelium. Small cell carcinomas have a strong relationship to cigarette smoking; only about 1% occur in nonsmokers. Most often hilar or central, they are the most aggressive of lung tumors, metastasize widely, and are virtually incurable by surgical means. They are the most common pattern associated with ectopic hormone production (see later). ^Large Cell Carcinoma. This anaplastic carcinoma has larger, more polygonal cells and vesicular nuclei. Large cell carcinomas probably represent those squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they can no longer be recognized. Some of these large cell carcinomas contain intracellular mucin, some exhibit larger numbers of multinucleate cells (giant cell carcinoma), some have cleared cells and are termed clear cell carcinoma, and some have a distinctly spindly histologic appearance (spindle cell carcinoma). Q77=Kulchitsky cells. ^ A77=enteroendocrine cells: cell's with granules that may be either argentaffinic or argyrophilic; the cell's, scattered throughout the digestive tract, are of several varieties and are believed to produce at least 20 different gastrointestinal hormones and neurotransmitters. Syn: enterochromaffin cells, Kulchitsky cells. Q78=Secondary Pathology of Bronchogenic carcinomas ^ A78=Secondary Pathology. Bronchogenic carcinomas cause related anatomic changes in the lung substance distal to the point of bronchial involvement. Partial obstruction may cause marked focal emphysema; total obstruction may lead to atelectasis. The impaired drainage of the airways is a common cause for severe suppurative or ulcerative bronchitis or bronchiectasis. Pulmonary abscesses sometimes call attention to a silent carcinoma that has initiated the chronic suppuration. Compression or invasion of the superior vena cava can cause venous congestion, dusky head and arm edema, and, ultimately, circulatory compromise, the superior vena cava syndrome. Extension to the pericardial or pleural sacs may cause pericarditis (see Chapter 12: Consequences and Complications of Myocardial Infarction ) or pleuritis with significant effusions. Q79=Bronchogenic carcinomas morphology: ^ A79=Bronchogenic carcinomas arise most often in and about the hilus of the lung. About three-fourths of the lesions take origin from first-, second-, and third-order bronchi. A small number of primary carcinomas of the lung arise in the periphery of the lung substance from the alveolar septal cells or terminal bronchioles. These are predominantly adenocarcinomas, including those of the bronchioloalveolar type, to be discussed separately. ^Carcinoma of the lung begins as an area of in situ cytologic atypia that, over an unknown interval of time, yields a small area of thickening or piling up of bronchial mucosa. With progression, this small focus, usually less than 1 cm2 in area, assumes the appearance of an irregular, warty excrescence that elevates or erodes the lining epithelium (see Figure 15.42 ). The tumor may then follow a variety of paths. It may continue to fungate into the bronchial lumen to produce an intraluminal mass. It can also rapidly penetrate the wall of the bronchus to infiltrate along the peribronchial tissue (see Figure 15.42 ) into the adjacent region of the carina or mediastinum. In other instances, the tumor grows along a broad front to produce a cauliflower-like intraparenchymal mass that appears to push lung substance ahead of it. In almost all patterns, the neoplastic tissue is gray-white and firm to hard. Especially when the tumors are bulky, focal areas of hemorrhage or necrosis may appear to produce yellow-white mottling and softening. Sometimes these necrotic foci cavitate. ^Extension may occur to the pleural surface and then within the pleural cavity or into the pericardium. Spread to the tracheal, bronchial, and mediastinal nodes can be found in most cases. The frequency of nodal involvement varies slightly with the histologic pattern but averages over 50%. More distant spread of bronchogenic carcinoma occurs through both lymphatic and hematogenous pathways. These tumors have a distressing habit of spreading widely throughout the body and at an early stage in their evolution. Often the metastasis presents as the first manifestation of the underlying occult bronchogenic lesion. No organ or tissue is spared in the spread of these lesions, but the adrenals, for obscure reasons, are involved in more than half the cases. The liver (30 to 50%), brain (20%), and bone (20%) are additional favored sites of metastases. ^Bronchogenic carcinomas arise most often in and about the hilus of the lung. About three-fourths of the lesions take origin from first-, second-, and third-order bronchi. A small number of primary carcinomas of the lung arise in the periphery of the lung substance from the alveolar septal cells or terminal bronchioles. These are predominantly adenocarcinomas, including those of the bronchioloalveolar type, to be discussed separately. ^Carcinoma of the lung begins as an area of in situ cytologic atypia that, over an unknown interval of time, yields a small area of thickening or piling up of bronchial mucosa. With progression, this small focus, usually less than 1 cm2 in area, assumes the appearance of an irregular, warty excrescence that elevates or erodes the lining epithelium (see Figure 15.42 ). The tumor may then follow a variety of paths. It may continue to fungate into the bronchial lumen to produce an intraluminal mass. It can also rapidly penetrate the wall of the bronchus to infiltrate along the peribronchial tissue (see Figure 15.42 ) into the adjacent region of the carina or mediastinum. In other instances, the tumor grows along a broad front to produce a cauliflower-like intraparenchymal mass that appears to push lung substance ahead of it. In almost all patterns, the neoplastic tissue is gray-white and firm to hard. Especially when the tumors are bulky, focal areas of hemorrhage or necrosis may appear to produce yellow-white mottling and softening. Sometimes these necrotic foci cavitate. Extension may occur to the pleural surface and then within the pleural cavity or into the pericardium. Spread to the tracheal, bronchial, and mediastinal nodes can be found in most cases. The frequency of nodal involvement varies slightly with the histologic pattern but averages over 50%. ^More distant spread of bronchogenic carcinoma occurs through both lymphatic and hematogenous pathways. These tumors have a distressing habit of spreading widely throughout the body and at an early stage in their evolution. Often the metastasis presents as the first manifestation of the underlying occult bronchogenic lesion. No organ or tissue is spared in the spread of these lesions, but the adrenals, for obscure reasons, are involved in more than half the cases. The liver (30 to 50%), brain (20%), and bone (20%) are additional favored sites of metastases. Q80=What type of cells are bronchial adenoma or carcinoid tumor associated with? ^ A80=Kulchitsky cells present lining the respiratory passages which when metastasize will produce 5-HT e.g., patient's ovary palpated and they presents with flushed, wheezing, and diarrhea due to production of 5-HT release Q81=A patients ovary is palpated and they present with flushing or wheezing, why? ^ A81=Serotonin released from metastasized Kulchitsky cells in ovary causes this response. Q82=What are characteristics of a benign neoplasm? ^ A82=Structures mimic parent tissues Q83=Giant cell tumors ^ A83=Giant cell tumor is so named because it contains a profusion of multinucleated, osteoclast-type giant cells, giving rise to the synonym "osteoclastoma." Giant cell tumor is a relatively uncommon benign but locally aggressive neoplasm. It usually arises during the third to fifth decades, and there is a slight female predominance. Giant cell tumors are postulated to have a monocyte-macrophage lineage,42 and the giant cells are believed to form via fusion of mononuclear cells. Morphology: ^Giant cell tumors in adults involve both the epiphyses and the metaphyses, but in adolescents they are confined proximally by the growth plate and are limited to the metaphysis. The majority of giant cell tumors arise around the knee (distal femur and proximal tibia), but virtually any bone may be involved, including the sacrum, pelvis, and small bones of the hands and feet. The location of these tumors in the ends of bones near joints frequently causes patients to complain of arthritic symptoms. Occasionally they present as pathologic fractures. Most are solitary; however, multiple or multicentric tumors do occur, especially in the distal extremities. Radiographically, giant cell tumors are large, purely lytic, and eccentric and erode into the subchondral bone plate (see Figure 27.38 ). The overlying cortex is frequently destroyed, producing a bulging soft tissue mass delineated by a thin shell of reactive bone. The margins with the adjacent bone are fairly circumscribed but seldom sclerotic. The biologic unpredictability of these neoplasms complicates their management. Conservative surgery such as curettage is associated with a 40 to 60% recurrence rate. Giant cell tumors are histologically benign; up to 4%, however, metastasize to the lungs usually after prior surgery, suggesting dislodgement of tumor emboli. The metastatic deposits have the same morphology as the primary tumor. Sarcomatous transformation of a giant cell tumor, either de novo or following previous treatment, is a rare event. Q84=What type of tumor is also called an osteoclastoma? ^ A84=Giant cell tumor. Q85=Ewing's Sarcoma and Primitive Neuroectodermal Tumor ^ A85=Ewing's sarcoma is a primary malignant small round cell tumor of bone. It has long posed a difficult diagnostic problem because by light microscopy Ewing's cells resemble those of lymphoma, rhabdomyosarcoma, neuroblastoma, and small cell carcinoma of the lung. Originally classified as an endothelial neoplasm, current evidence indicates that many Ewing's sarcomas exhibit a primitive neural phenotype. The identification of an 11;22 chromosomal translocation in both Ewing's sarcoma and primitive neuroectodermal tumors of soft tissue further supports this contention.39 The translocation results in the production of a fusion protein in which the carboxy-terminus of the protein EWS (for Ewing's sarcoma), which normally contains an RNA binding domain, is replaced by a DNA binding transcription factor termed FLI-1. The functions of both the native EWS protein and the EWS-FLI-1 fusion protein are as yet undetermined. It is now believed that Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related tumors that differ in their degree of differentiation. Diagnostically, tumors that demonstrate neural differentiation by light microscopy, immunohistochemistry, or electron microscopy are labeled primitive neuroectodermal tumors, and those that are undifferentiated by these analyses are diagnosed as Ewing's sarcoma.41 Ewing's sarcoma is the term used to represent these two tumors in this discussion. ^Ewing's sarcoma accounts for approximately 6 to 10% of primary malignant bone tumors and follows osteosarcoma as the second most common bone sarcoma in children. Of all bone sarcomas, Ewing's sarcoma has the youngest average age at presentation: most patients are 10 to 15 years old, and approximately 80% are younger than 20 years. Males are affected slightly more frequently than females, and there is a striking predilection for whites; blacks are rarely afflicted. ^Morphology: ^Ewing's sarcoma usually arises in the diaphysis of long tubular bones, especially the femur and the flat bones of the pelvis. It presents as a painful enlarging mass, and the affected site is frequently tender, warm, and swollen. Interestingly some patients have systemic findings, including fever, elevated sedimentation rate, anemia, and leukocytosis, which mimic infection. Plain x-ray films show a destructive lytic tumor that has permeative margins. The characteristic periosteal reaction produces layers of reactive bone deposited in an "onionskin" fashion. The diagnosis often depends on the identification of the characteristic 11;22 translocation and glycogen within the tumor cells. The treatment of Ewing's sarcoma includes chemotherapy and surgery with or without radiation. The advent of effective chemotherapy has dramatically improved the prognosis from a dismal 5 to 15% to a 75% 5-year survival rate; 50% are long-term cures. Q86=What are characteristics of a malignant neoplasm? ^ A86=Is dedifferentiated, looking less and less like the parent tissue. Q87=What is the grading system for a malignant CNS neoplasm? ^ A87=Grade system for CNS lesion: Grade 1 looks like parent tissue. Grade 4 doesn't look like parent and dead by 7 months Q88=Do the most important malignant neoplasm's grow slow or fast? ^ A88=Slow Q89=Are benign neoplasms encapsulated? ^ A89=NOT encapsulated except lipomas which grow by expansion and compress the surrounding fibrous tissue ^e.g., Leiomyoma of uterus - when looking at gross picture, looks looks well circumscribed. Can be removed relatively easily without dissection. Slow growing but can compress surrounding tissue causing nerve or vascular impingement. Q90=What is an example of implanted benign neoplasm due to rupture of an organ? ^ A90=Splenosis (ruptured spleen) Q91=What is the normal nucleus to cytoplasm ratio? ^ A91=1:6 or 1:4 Q92=What is the average size of a cell nucleus? ^ A92=8-10 microns (slightly larger than an RBC) Q93=What is the nucleus to cytoplasm ratio of a neoplastic cell? ^ A93=1:2 Q94=How does normal hypertrophy compare to neoplastic hypertrophy? ^ A94=In normal hypertrophy, there is a proportional enlargement of cell keeping the nucleus/cytoplasmic ratio In malignant or neoplastic hypertrophy, the cell grows and the ratio is disproportionate. Q95=What is a characteristic neoplastic cell with disproportionately large nucleus? ^ A95=Small cell neoplasm of lung is a common lesion (smokers). If measured will have larger nuclei than body and occupies tremendous proportion of total cell area Q96=What are some morphological signs of malignancy in the nucleus? ^ A96=X, Y, swastika, or O shaped nuclei. Q97=Is tritiated thymadine uptake necessarily a sign of malignancy? ^ A97=No, although malignant cells have a high turnover, other normal cells in the body such as GI epithelial cells also have high turnover (16% at any given time). Q98=Which neoplasm seems to be under hormonal control in that it shrinks once the hormone is not present? ^ A98=Leiomyoma is active in menstruating women but shrinks and disappears after menopause when estrogen is no longer present. Q99=In which type of neoplasm do Homer Wright rosettes occur? ^ A99=Neuroblastoma Q100=In which type of neoplasm do 1p deletion DNA hyperdiploidy, Neurosecretory granules by electron microscopy, n-myc amplification, Clinical elevation in level of urinary catecholamines occur? † ^ A100=Neuroblastoma Q101=Give an example of spontaneous disappearance of a neoplasm: ^ A101=hypernephromas : malignancy of kidney ^malignant melanoma serous cancer of ovary ^:occur in adrenal medulla is a neuroblastoma which occur in very young and if neural cell maturation. If (TRKA) factor present in high amount, this neoplasm can mature down to a neuroma. Q102=in situ neoplasm ^ A102=Some cancers seem to evolve from a preinvasive stage referred to as carcinoma in situ. These often grow intraepithelially. This is best illustrated by carcinoma of the uterine cervix type of Squamous Cell Carcinoma ). In situ cancers display the cytologic features of malignancy without invasion of the basement membrane. They may be considered one step removed from invasive cancer, and indeed with time most penetrate the basement membrane and invade the subepithelial stroma. Q103=What virus is definitely associated with an in situ neoplasm? ^ A103=HPV 16, 18 Q104=What can happen to in situ cancers? ^ A104=They can become dysplastic and invade tissues as is the case with HPV type 6 and 11 Q105=What is the progression of a benign lesion becoming malignant? ^ A105=It can take decades, for instance in the cervix, dysplasia can occur at 27 years of age leading to insitu cancer, then pre-malignancy and finally malignancy. Q106=What happens to an in situ cancer of the bowel if left alone? ^ A106=It can lead to adenocarcinoma. Q107=How does cohesiveness in cancer versus normal cells compare? ^ A107=It is well known that cancer cells have decrease cohesiveness between cells contrast to normal cells. Using this criteria one can exfoliate and do an endocervical smear for example. ^(study @ Mayo clinic --> ID early malignancies of large bowel by DNA) malignant cells exfoliate more readily than normal cells can diagnose bronchogenic carcinoma via sputum sample because of low adherence Q108=What are some of the pathways to the spread of cancer? ^ A108=1)Seeding: ^Lymphatic spread ^Hematogenous spread Q109=Lymphatic Spread. ^ A109=Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas, but it should be remembered that sarcomas may also use this route. The emphasis on lymphatic spread for carcinomas and hematogenous spread for sarcomas is misleading because ultimately there are numerous interconnections between the vascular and lymphatic systems. The pattern of lymph node involvement follows the natural routes of drainage. Because carcinomas of the breast usually arise in the upper outer quadrants, they generally disseminate first to the axillary lymph nodes. Cancers of the inner quadrant may drain through lymphatics to the nodes within the chest along the internal mammary arteries. Thereafter the infraclavicular and supraclavicular nodes may become involved. Carcinomas of the lung arising in the major respiratory passages metastasize first to the perihilar tracheobronchial and mediastinal nodes. Local lymph nodes, however, may be bypassed-"skip metastasis"-because of venous-lymphatic anastomoses or because inflammation or radiation has obliterated channels. In many cases, the regional nodes serve as effective barriers to further dissemination of the tumor, at least for a time. Conceivably the cells, after arrest within the node, may be destroyed. A tumor-specific immune response may participate in this cell destruction. Drainage of tumor cell debris or tumor antigens, or both, also induces reactive changes within nodes. Thus, enlargement of nodes may be caused by (1) the spread and growth of cancer cells or (2) reactive hyperplasia (as ^in-Hodgkin's Lymphomas (NHL) ). It should be noted therefore that nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion. Q110=Metastatic spread by seeding to body cavities. ^ A110=This may occur whenever a malignant neoplasm penetrates into a natural "open field." Most often involved is the peritoneal cavity, but any other cavity-pleural, pericardial, subarachnoid, and joint spaces-may be affected. Such seeding is particularly characteristic of carcinomas arising in the ovaries, when, not infrequently, all peritoneal surfaces become coated with a heavy layer of cancerous glaze. Remarkably the tumor cells may remain confined to the surface of the coated abdominal viscera without penetrating into the substance. Sometimes mucus-secreting ovarian and appendiceal carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei. Q111=Hematogenous Spreading of metastasis. ^ A111=This pathway is typical of sarcomas but is also used by carcinomas. Arteries, with their thicker walls, are less readily penetrated than are veins. Arterial spread, however, may occur when tumor cells pass through the pulmonary capillary beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves give rise to additional tumor emboli. In such arterial spread, a number of factors (to be discussed) condition the patterns of distribution of the metastases. With venous invasion, the blood-borne cells follow the venous flow, draining the site of the neoplasm. Understandably the liver and lungs are most frequently involved secondarily in such hematogenous dissemination. All portal area drainage flows to the liver, and all caval blood flows to the lungs. Cancers arising in close proximity to the vertebral column often embolize through the paravertebral plexus, and this pathway is probably involved in the frequent vertebral metastases of carcinomas of the thyroid and prostate. ^Certain cancers have a propensity for invasion of veins. Renal cell carcinoma often invades the branches of the renal vein and then the renal vein itself to grow in a snake-like fashion up the inferior vena cava, sometimes reaching the right side of the heart. Hepatocarcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels. Remarkably such intravenous growth may not be accompanied by widespread dissemination. Histologic evidence of penetration of small vessels at the site of the primary neoplasm is obviously an ominous feature. Such changes, however, must be viewed guardedly because, for reasons discussed later, they do not indicate the inevitable development of metastases. ^With this background on the structure and behavior of neoplasms, we now discuss the origin of tumors, starting with insights gained from the epidemiology of cancer and followed by the molecular basis of transformation. Q112=How does a hypernephroma/renal cell carcinoma spread? ^ A112=Renal vein to vena cava to lung. Q113=What are two organs that are favorite sites of Metastatic cancer spread? ^ A113=Lung and liver. Q114=What is the grading and staging of cancer according to the Union Internationale Contre Cancer (UICC)? ^ A114=The staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases. Two major staging systems are currently in use, one developed by the Union Internationale Contre Cancer (UICC) and the other by the American Joint Committee (AJC) on Cancer Staging. The UICC employs a so-called TNM system-T for primary tumor, N for regional lymph node involvement, and M for metastases. The TNM staging varies for each specific form of cancer, but there are general principles. With increasing size, the primary lesion is characterized as T1 to T4. T0 is added to indicate an in situ lesion, N0 would mean no nodal involvement, whereas N1-N3 would denote involvement of an increasing number and range of nodes. M0 signifies no distant metastases, whereas M1 or sometimes M2 indicates the presence of blood-borne metastases and some judgment as to their number. Q115=What would T0 connote? ^ A115=In situ carcinoma. Q116=What is the grading and staging of cancer according to the American Joint Committee (AJC) on Cancer Staging? ^ A116=The AJC employs a somewhat different nomenclature and divides all cancers into stages 0 to IV, incorporating within each of these stages the size of the primary lesion as well as the presence of nodal spread and distant metastases. Q117=When does a neuroblastoma have a good prognosis? ^ A117=Diploid and triploid have poorer prognosis than tetraploid.2) Those with cell maturation factor (TRKA) have very good prognosis and those without do not. Q118=What are the four phases of tumor growth? ^ A118=1) Transformation 2) Growth 3) Invasion 4) Metastases Q119=What is an example of a polyclonal neoplasm? ^ A119=Chronic Myelogenous Leukemia with the Philadelphia chromosome. Q120=What is a good example of a monoclonal neoplasm? ^ A120=Cervical cancer arises from a single cell and takes decades and 30 doublings --> cell loss and cell growth --> neoplasm grows when cell growth exceeds cell loss --> takes more time for clinical growth to occur --> 1gm (smallest clinically detectable mass) --> 1 Kg (person can't live with) Q121=What kind of cancer killed Jackie O? ^ A121=NHL, it became resistant to chemotherapy. Q122=What is an example of exogenous hormone administration causing neoplasia? ^ A122=Substitute estrogens (diethylstilbestrol, but not steroid hormones), once used during pregnancy for threatened abortion, produced in some female offspring in their second to third decades of life vaginal adenosis and, very rarely, superimposed clear cell adenocarcinoma Q123=What is the danger of diethylstilbestrol administration to pregnant mothers? ^ A123=Substitute estrogens (diethylstilbestrol, but not steroid hormones), once used during pregnancy for threatened abortion, produced in some female offspring in their second to third decades of life vaginal adenosis and, very rarely, superimposed clear cell adenocarcinoma Q124=Why do small neoplasms have a better prognosis? ^ A124=Start with single cell it takes time to get heterogeneity and if have small neoplasm it is usually younger and does not have the heterogeneity that a large neoplasm has. Q125=What is the difference between grade and stage of a lesion? ^ A125=Grade is histological severity of lesion Stage is clinical extent of lesion best index of prognosis If have to chose one or other, choose stage Q126=What is the best index of prognosis, grade or stage? ^Why? ^ A126=Stage because it is the clinical extent of the lesion Q127=What is the after 5 year survival rate of endometrial cancer? Pancreatic? ^ A127=Pancreatic= 3%,Endometrial= 86% Q128=What is the process of neoplasm growth (metastatic cascade)? ^ A128=Primary neoplasm: cells expansion, grow, diversification Metastatic subclone will adhere to basement membrane via the laminin receptor. It will selectively clip BM and use pseudopodia to enter vascular space. It may be detected and destroyed by NK cells (sometimes this forms a microembolus). Or it can travel through the vasculature to distant sites, then extravasate and use its collagenases to get into an organ and set up shop. Q129=What is the relationship of thrombocytes to the systemic dissemination of a neoplasm? ^ A129=Having too many platelets augments the malignant neoplastic cells capability to disseminate and extravasate. ^Possibly by mediation of the upregulation of adhesion molecules and the contribution to generalized raised blood viscosity and relative stasis. Q130=How can one help to eradicate a neoplasm by altering platelet numbers? ^ A130=Thrombocytopenia is a means of reducing the propensity for systemic dissemination of a malignant tumor so drugs inducing this state can be a means of slowing the spread and atopping it. Q131=What is the chromosomal pattern of CML? ^ A131=T(9,22) Q132=What is the chromosomal pattern of ALL? ^ A132=L1, L2 lead to t(9, 22), L3 leads to t(8, 14) Q133=What is the most common cancer in the adult male? ^ A133=Prostate. Q134=What is the risk of cancer if a member of the family has it? ^ A134=Three times more common. Q135=Give an example of a hereditary neoplasm: ^ A135=40% of retinoblastoma before age 3 is familial ^associated with Rb gene Q136=Give an example of Predisposition to malignancy ^ A136=People with. Xeroderma pigmentosum have unstable DNA so they get lesions all over face due to young age. This can lead to malignant melanoma, basal cell epithelioma, squamous cancer Q137=Von Recklinghausen Disease ^ A137=Neurofibromatosis type 1 ^Neurofibromatosis-1 is a relatively common disorder with a frequency of almost 1 in 3000. Although approximately 50% of the patients have a definite family history consistent with autosomal dominant transmission, the remainder appear to represent new mutations. In familial cases, the expressivity of the disorder is extremely variable, but the penetrance is 100%. Neurofibromatosis-1 has three major features: (1) multiple neural tumors dispersed anywhere on or in the body; (2) numerous pigmented skin lesions, some of which are "café au lait" spots; and (3) pigmented iris hamartomas, also called Lisch nodules. A bewildering assortment of other abnormalities (cited later) may accompany these cardinal manifestations Q138=Post-menopausal bleeding: ^ A138=women with post-menopausal bleeding should always be considered to have endometrial adenocarcinoma until proven otherwise. 5% is the frequency. Q139=What type of deficiency can mimic a cervical dysplasia? ^ A139=Folate. Q140=What is the number one cancer worldwide and why? ^ A140=Hepatocellular carcinoma is #1 cancer worldwide because of high incidence of Hepatitis B in underdeveloped countries Q141=What are some of the precancerous conditions? ^ A141=Certain non-neoplastic disorders-the chronic atrophic gastritis of pernicious anemia; solar keratosis of the skin; chronic ulcerative colitis; and leukoplakia of the oral cavity, vulva, and penis-have such a well-defined association with cancer that they have been termed "precancerous conditions." This designation is somewhat unfortunate because in the great majority of instances no malignant neoplasm emerges. Nonetheless, the term persists because it calls attention to the increased risk. Analogously certain forms of benign neoplasia also constitute "precancerous conditions." The villous adenoma of the colon, as it increases in size, develops cancerous change in up to 50% of cases. It might be asked: Is there not a risk with all benign neoplasms? Although some risk may be inherent, a large cumulative experience indicates that most benign neoplasms do not become cancerous. Nonetheless, numerous examples could be offered of cancers arising, albeit rarely, in benign tumors: for example, a leiomyosarcoma beginning in a leiomyoma, and carcinoma appearing in long-standing pleomorphic adenomas. Generalization is impossible because each type of benign neoplasm is associated with a particular level of risk ranging from virtually never to frequently. Only follow-up studies of large series of each neoplasm can establish the level of risk, and always the question remains: Was the tumor an indolent form of cancer from the outset, or was there a malignant focus in the benign tumor? Q142=Acquired pre-neoplastic disorder progress to cancer unless treated early. ^ A142=The only certain way of avoiding cancer is not to be born; to live is to incur the risk. The risk is greater than average, however, under many circumstances, as is evident from the predisposing influences discussed earlier. Certain clinical conditions are also of importance. Because cell replication is involved in cancerous transformation, regenerative, hyperplastic, and dysplastic proliferations are fertile soil for the origin of a malignant neoplasm. There is a well-defined association between certain forms of endometrial hyperplasia and endometrial carcinoma and between cervical dysplasia and cervical carcinoma (Cervical Intraepithelial Neoplasia ). The bronchial mucosal metaplasia and dysplasia of habitual cigarette smokers are ominous antecedents of bronchogenic carcinoma. About 80% of hepatocellular carcinomas arise in cirrhotic livers, which are characterized by active parenchymal regeneration. Other examples could be offered, but although these settings constitute important predispositions, it must be appreciated that in the great majority of instances they are not complicated by neoplasia. Certain non-neoplastic disorders-the chronic atrophic gastritis of pernicious anemia; solar keratosis of the skin; chronic ulcerative colitis; and leukoplakia of the oral cavity, vulva, and penis-have such a well-defined association with cancer that they have been termed "precancerous conditions." This designation is somewhat unfortunate because in the great majority of instances no malignant neoplasm emerges. Nonetheless, the term persists because it calls attention to the increased risk. Analogously certain forms of benign neoplasia also constitute "precancerous conditions." The villous adenoma of the colon, as it increases in size, develops cancerous change in up to 50% of cases. It might be asked: Is there not a risk with all benign neoplasms? Although some risk may be inherent, a large cumulative experience indicates that most benign neoplasms do not become cancerous. Nonetheless, numerous examples could be offered of cancers arising, albeit rarely, in benign tumors: for example, a leiomyosarcoma beginning in a leiomyoma, and carcinoma appearing in long-standing pleomorphic adenomas. Generalization is impossible because each type of benign neoplasm is associated with a particular level of risk ranging from virtually never to frequently. Only follow-up studies of large series of each neoplasm can establish the level of risk, and always the question remains: Was the tumor an indolent form of cancer from the outset, or was there a malignant focus in the benign tumor? Q143=What type of cancer cell is mucin producing and what is it associated with? ^ A143=Signet-ring cell. A classic example of metastatic gastrointestinal neoplasia to the ovaries is termed Krukenberg's tumor, which are bilateral metastases composed of mucin-producing, signet-ring cancer cells, most often of gastric origin Q144=Leukoplakia ^ A144=The term "leukoplakia" means simply "white plaque." It may be produced by several conditions, including epidermal proliferations-benign to malignant, tobacco or snuff-pouch keratosis, chronic cheek bite, lichen planus, palatitis nicotina, and candidiasis as well as other rarer lesions. However, 85 to 90% of all white plaques are caused by epidermal proliferations, and so most experts recommend the following definition: Leukoplakia is a white plaque on the oral mucous membranes that cannot be removed by scraping and cannot be classified clinically or microscopically as another disease entity.2 All other white lesions are specified as to cause (e.g., lichen planus, candidal membrane). Thus defined, leukoplakic plaques range from completely benign epithelial thickenings to highly atypical lesions with dysplastic changes that merge with carcinoma in situ. Thus, it must be emphasized that leukoplakia is a clinical term; until proved otherwise it must be considered precancerous. ^Related to leukoplakia, but much less common and much more ominous, is erythroplakia (dysplastic leukoplakia). It represents a red, velvety, possibly eroded area within the oral cavity that usually remains level with or may be slightly depressed in relation to the surrounding mucosa. The epithelial changes in such lesions tend to be markedly atypical, incurring a much higher risk of malignant transformation than that with leukoplakia. Occasionally, intermediate forms are encountered that have the characteristics of both leukoplakia and erythroplakia, termed speckled leukoerythroplakia. ^Both leukoplakia and erythroplakia may be encountered in adults at any age, but they are usually found between the ages of 40 and 70, with a 2-to-1 male preponderance. Although these lesions have multifactorial origins, the use of tobacco (cigarettes, pipes, cigars, and particularly chewing tobacco and buccal pouches) is the most common antecedent. Other potentiating influences are alcohol, ill-fitting dentures, and chronic exposure to persistent irritants (lovers of hot pizza take note). HPV sequences, particularly serotype 16, have been identified in more than half of these lesions.3 ^Morphology: The frequency of carcinoma in situ or overt cancerous changes in leukoplakia varies among reports from 1 to 16%, but a reasonable average is 5 to 6%.4 Ominous features are a speckled appearance, warty or verrucous thickening, and occurrence in "high-risk sites" (e.g., floor of the mouth and ventral surface of the tongue); hence the need for biopsy of persistent lesions that fail to respond to such simple measures as avoidance of tobacco and alcohol. In the case of erythroplakia, the malignant transformation rate is about 50% (some would say higher). Q145=What percent of colonic polyps will turn into malignany? ^ A145=5% Q146=What is p53 and what is its role? ^ A146=P53 ap53: Located on chromosome 17p13.1, the p53 gene is the single most common target for genetic alterations in human cancer. Homozygous loss of the p53 gene is found in 70% of colon cancers, 30 to 50% of breast cancers, and 50% of lung cancers-the three "biggies" in the cancer parade. Mutations of p53 are not restricted to epithelial tumors-they have been found in a diverse array of neoplasms, including leukemias, lymphomas, sarcomas, and neurogenic tumors. Although in most instances p53 mutations are acquired in somatic cells, inherited forms of p53 alterations have also been described. As with the Rb gene, inheritance of a mutant p53 allele in the Li-Fraumeni syndrome predisposes individuals to the development of cancers. In contrast to those who inherit a defective Rb gene, however, patients with the Li-Fraumeni syndrome are at a high risk of developing a wide range of tumors, including breast carcinomas, sarcomas, and brain tumors. The central role played by the p53 tumor suppressor gene in the origin of human tumors has been confirmed by studies in p53 knockout mice. With homozygous loss of both p53 alleles, these mice develop a variety of tumors in young adulthood. Q147=What is a protooncogene? ^ A147=Cellular genes that promote normal growth and differentiation. Q148=What is an oncogene? ^ A148=Any of a family of genes which under normal circumstances code for proteins involved in cell growth or regulation (e.g., protein kinases, GTPases, nuclear proteins, growth factors) but may foster malignant processes if mutated or activated by contact with retroviruses. Identified oncogenes include the ras, originally associated with bladder tumors, and the p53, a mutated version of a gene on chromosome 17 which normally corrects for mutations caused by ultraviolet radiation. p53 now has been shown to be involved in cancers of the breast, cervix, ovary, and lung, among others. Oncogenes often work in concert to produce cancer, and their action may be exacerbated by retroviruses, jumping genes, or inherited genetic mutations. See: antioncogene. 2. Found in certain DNA tumor viruses. It is required for viral replication. Syn: transforming gene Q149=What is v-onc? ^ A149=These are unique transforming sequences found in the genome of acute transforming viruses. These retroviruses cause rapid induction of tumors in animals and can transform animal cells in vitro. Q150=What is c-onc? ^ A150=Cellular oncogene.. It is important to note that v-oncs are not present in several cancer-causing RNA viruses. One such example is a group of so-called slow transforming viruses that cause leukemias in rodents after a long latent period. The mechanism by which they cause neoplastic transformation implicates, once again, proto-oncogenes. Molecular dissection of the cells transformed by these leukemia viruses has revealed that the proviral DNA is always found to be integrated (inserted) near a proto-oncogene. One consequence of proviral insertion near a proto-oncogene is to induce a structural change in the cellular gene, thus converting it into a c-onc. Alternatively, strong retroviral promoters inserted in the vicinity of the proto-oncogenes lead to dysregulated expression of the cellular gene. This mode of proto-oncogene activation is called insertional mutagenesis. Q151=Summarize v-onc and c-onc: ^ A151=To summarize, proto-oncogenes may become oncogenic by retroviral transduction (v-oncs) or by influences that alter their behavior in situ, thereby converting them into cellular oncogenes (c-oncs). Q152= (1) What are the functions of oncogene products? ^ A152=Oncogenes encode proteins called oncoproteins which resemble the normal products of proto-oncogenes, with the exception that oncoproteins are devoid of important regulatory elements and their production in the transformed cells does not depend on growth factors or other external signals. To aid in the understanding of the nature and functions of oncoproteins, it is necessary to review briefly the sequence of events that characterize normal cell proliferation. Control of Cell Growth . Under physiologic conditions, cell proliferation can be readily resolved into the following steps: ^The binding of a growth factor to its specific receptor on the cell membrane ^Transient and limited activation of the growth factor receptor, which in turn activates several signal-transducing proteins on the inner leaflet of the plasma membrane ^Transmission of the transduced signal across the cytosol to the nucleus via second messengers ^Induction and activation of nuclear regulatory factors that initiate DNA transcription and ultimately cell division ^With this background, we can readily identify oncogenes and oncoproteins as altered versions of their normal counterparts and group them on the basis of their role in the signal transduction cascade Q153= (2) How do the normally "civilized" proto-oncogenes turn into "enemies within"? ^ A153=Changes in the structure of the gene, resulting in the synthesis of an abnormal gene product (oncoprotein) having an aberrant function ^Changes in regulation of gene expression, resulting in enhanced or inappropriate production of the structurally normal growth-promoting protein Q154=What are the specific lesions that lead to structural and regulatory changes that affect proto-oncogenes? ^ A154= 1)Point Mutations: The ras oncogene represents the best example of activation by point mutations. Dramatica reduction of the GTPase activity of the ras proteins. As mentioned in an earlier section, the intrinsic GTPase activity of normal ras proteins is augmented greatly by GAPs; in contrast, the GTPase activity of mutant ras proteins is poorly stimulated by GAPs. The mutant ras thus remains in the active GTP bound form. ^2)Chromosomal Translocations such as in Burkitt's lymphoma ^3)Gene Amplification: Activation of proto-oncogenes associated with overexpression of their products may result from reduplication and manifold amplification of their DNA sequences. The most interesting cases of amplification involve N-myc in neuroblastoma and c-erb B2 in breast cancers. These genes are amplified in 30 to 40% of these two tumors, and in both settings this amplification is associated with poor prognosis.24 Similarly amplification of L-myc and N-myc correlates strongly with disease progression in small cell cancer of the lung. Q155=Direct acting chemical carcinogen ^ A155=Anti-cancer drugs: ^When an individual has malignancy that is in remission, cells can be damaged by chemotherapeutic agent therefore increasing suceptability to new malignancy 2-3 fold. ^Polycyclic aromatic hydrocarbons in cigarette smoking, industrial effluents, auto emissions, and animal fats can contribute to transformation to cancer. ^Aromatic amines and Azodyes can get into urinary system and when excreted by urinary bladder lead to high incidence of transitional cell carcinoma of uroepithelium. ^ Transitional cell carcinoma occurs in renal pelvis, ureter, urinary bladder, and is often multiple Q156=Clinical course of bladder cancer ^ A156=All bladder tumors classically produce painless hematuria. This is their dominant and sometimes only clinical manifestation. Occasionally, frequency, urgency, and dysuria accompany the hematuria. When the ureteral orifice is involved, pyelonephritis or hydronephrosis may follow. About 60% neoplasms, when first discovered, are single, and 70% localized to the bladder. ^All transitional cell cancers, whatever their grade, have a tendency to recur following excision, and usually the recurrence exhibits greater anaplasia. Overall, about 60% of grade I papillary carcinomas recur, in contrast to 80 to 90% of grade III lesions. In many instances, the recurrence is seen at a different site, and the question of a new primary tumor must be entertained. The prognosis depends on the histologic pattern, on the grade of the tumor, and principally on the stage when first diagnosed. Grade I TCCs yield a 98% 10-year survival rate regardless of the number of recurrences. Only a few patients with this grade of carcinoma have progression of their disease to a grade III lesion. In contrast, only about 30% of individuals with a grade III cancer survive 10 years; the tumor is progressive in 65%. Approximately 70% of patients with squamous cell carcinomas are dead within the year. Other factors may influence the prognosis. The expression of blood group antigens by tumor cells has proved to be a useful indicator of tumor behavior. Tumor cells that express A, B, and H antigens have a better prognosis than those that do not or lose this capacity. Analogously, the detection of a T antigen, increased c-myc expression, and multiple chromosomal mutations (cited earlier) all worsen the outlook. Almost half of all high-grade TCCs elaborate human chorionic gonadotropin even though the tumors show no chorionic differentiation. The finding of this hormone in the urine is thus a marker of an aggressive tumor. The clinical challenge with these neoplasms is early detection. Although cytoscopy and biopsy are the mainstays of diagnosis, preneoplastic dysplasia, carcinoma in situ producing no or only subtle gross mucosal changes, and early small papillary lesions may be difficult to detect. Of value in these circumstances are cytologic examinations and flow cytometric analyses of urinary sediment. These diagnostic approaches are about 85% effective in detecting grade III TCC and squamous cell carcinomas and are almost as effective with carcinoma in situ. However, grade I TCC and some carcinoma in situ tumors are diploid and have only subtle anaplastic changes, reducing the effectiveness of cytologic and cytometric evaluations.12 The perfect method of detecting all bladder cancers has yet to be discovered. Q157=What are two naturally occurring carcinogens? ^ A157=Aflatoxin B1: Among the approximately 30 known chemical carcinogens produced by plants and microorganisms, the potent hepatic carcinogen aflatoxin B1 is most important. It is produced by some strains of Aspergillus flavus that thrive on improperly stored grains and peanuts. A strong correlation has been found between the dietary level of this hepatocarcinogen and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East. It may be noted that infection with hepatitis B virus has also been strongly correlated with these cancers, raising the possibility that the aflatoxin and the virus collaborate in the production of this form of neoplasia. ^ ^Nitrosamines and Amides: ^These carcinogens are of interest because of the possibility that they are formed in the gastrointestinal tract of humans and so may contribute to the induction of some forms of cancer, particularly gastric carcinoma. Similar to most other carcinogens, the nitroso-compounds require activation, which again involves the microsomal P-450 system. Q158=Aromatic Amines and Azo Dyes ^ A158=The carcinogenicity of most aromatic amines and azo dyes is exerted mainly in the liver, where the "ultimate carcinogen" is formed by the intermediation of the cytochrome P-450 oxygenase systems. Thus, fed to rats, acetylaminofluorene and the azo dyes induce hepatocellular carcinomas but not cancers of the gastrointestinal tract. An agent implicated in human cancers, beta-naphthylamine, is an exception. In the past, it has been responsible for a 50-fold increased incidence of bladder cancer in heavily exposed workers in aniline dye and rubber industries.80 After absorption, it is hydroxylated into an active form and then detoxified by conjugation with glucuronic acid. When excreted in the urine, the nontoxic conjugate is split by the urinary enzyme glucuronidase to release the electrophilic reactant again, thus inducing bladder cancer. Regrettably humans are one of the few species to possess the urinary glucuronidase. Some of the azo dyes were developed to color food, e.g., butter yellow to give margarine the appearance of butter and scarlet red to impart the seductive coloration of certain foods such as maraschino cherries. These dyes are now federally regulated in the United States because of the fear that they may be dangerous to humans. Q159=Nitrosamines and Amides ^ A159=These carcinogens are of interest because of the possibility that they are formed in the gastrointestinal tract of humans and so may contribute to the induction of some forms of cancer, particularly gastric carcinoma. Similar to most other carcinogens, the nitroso-compounds require activation, which again involves the microsomal P-450 system. Q160=Polycyclic Aromatic Hydrocarbons ^ A160=These agents represent some of the most potent carcinogens known. They require metabolic activation and can induce tumors in a wide variety of tissues and species. Painted on the skin, they cause skin cancers; injected subcutaneously, they evoke sarcomas; introduced into a specific organ, they cause cancers locally. The polycyclic hydrocarbons are of particular interest as carcinogens because they are produced in the combustion of tobacco, particularly with cigarette smoking, and may well contribute to the causation of lung cancer. They are also produced from animal fats in the process of broiling meats and are present in smoked meats and fish. Q161=Direct-Acting Alkylating Agents ^ A161=These agents are activation independent, and in general they are weak carcinogens. Nonetheless, they have importance because many therapeutic agents (e.g., cyclophosphamide, chlorambucil, busulfan, melphalan, and others) fall into this category. These are used as anticancer drugs but regrettably have been documented to induce lymphoid neoplasms, leukemia, and other forms of cancer. Some alkylating agents, such as cyclophosphamide, are also powerful immunosuppressive agents and are therefore used in treatment of immunologic disorders, including rheumatoid arthritis and Wegener's granulomatosis. Although the risk of induced cancer with these agents is low, judicious use of them is indicated. Alkylating agents appear to exert their therapeutic effects by interacting with and damaging DNA, but it is precisely these actions that render them also carcinogenic. Q162=Promoters of Chemical Carcinogenesis ^ A162=Certain promoters may contribute to cancers in humans. It has been argued that promoters are at least as important as initiating chemicals because cells initiated by exposure to environmental carcinogens are innocuous unless subjected to repeated assault by promoters. Saccharin and cyclamates have been shown to promote the induction of bladder cancer in rats previously given marginal doses of carcinogens. Whether these artificial sweeteners are also initiators or promoters in humans in a hotly debated issue. Epidemiologic studies, although yielding conflicting results, disclose no solid evidence of carcinogenicity in the dosages customarily used by humans. Hormones such as estrogens serve in animals as promoters of liver tumors. The prolonged use of diethylstilbestrol is implicated in the production of postmenopausal endometrial carcinoma and in the causation of vaginal cancer in offspring exposed in utero, as discussed in Chapter 23: Premalignant and Malignant Neoplasms . Intake of high levels of dietary fat has been associated with increased risk of colon cancer. This may be related to an increase in synthesis of bile acids, which have been shown to act as promoters in experimental models of colon cancer. Q163=Carcinogenic Chemicals Miscellaneous Agents ^ A163=Scores of other chemicals have been indicted as carcinogens. Only a few that represent important industrial hazards are mentioned. Occupational exposure to asbestos has been associated with an increased incidence of bronchogenic carcinomas, mesotheliomas, and gastrointestinal cancers. Concomitant cigarette smoking heightens the risk of bronchogenic carcinoma manyfold. Vinyl chloride is the monomer from which the polymer polyvinyl chloride is fabricated. It was first identified as a carcinogen in animals, but investigations soon disclosed a scattered incidence of the extremely rare hemangiosarcoma of the liver among workers exposed to this chemical. Chromium, nickel, and other metals, when volatilized and inhaled in industrial environments, have caused cancer of the lung. Skin cancer associated with arsenic is also well established. Similarly, there is reasonable evidence that many insecticides, such as aldrin, dieldrin, and chlordane and the polychlorinated biphenyls, are carcinogenic in animals, and the unpleasant citations could be continued Q164=Which chemical can cause a rare hemangiosarcoma of the liver? ^ A164=Vinyl chloride Q165=Exposure to what chemical can give skin cancers? ^ A165=Arsenic. Q166=Exposure to what chemical concomitantly with cigarette smoke increases the rate of bronchogenic carcinomas, mesotheliomas, and gastrointestinal cancers? ^ A166=Asbestos Q167=What is the most important risk for getting mesotheliomas? ^ A167=Asbestos Q168=Radiation Carcinogenesis due to Ultraviolet Rays: ^ ^ ^ A168=There is ample evidence from epidemiologic studies that ultraviolet rays derived from the sun induce an increased incidence of squamous cell carcinoma, basal cell carcinoma, and melanocarcinoma of the skin.84 The degree of risk depends on the type of ultraviolet rays, the intensity of exposure, and the quantity of light-absorbing "protective mantle" of melanin in the skin. Persons of European origin who have fair skin that repeatedly gets sunburned but stalwartly refuses to tan and who live in locales receiving a great deal of sunlight (for example, Queensland, Australia, close to the equator) have the highest incidence of melanoma. The ultraviolet portion of the solar spectrum can be divided into three wavelength ranges: UVA (320 to 400 nm), UVB (280 to 320 nm), and UVC (200 to 280 nm). Of these, UVB is believed to be responsible for the induction of cutaneous cancers. UVC, although a potent mutagen, is not considered significant because it is filtered out by the ozone shield around the earth (hence the concern about ozone depletion). UVA, until recently considered harmless, has now been determined to cause cancer in animals, and therefore there is renewed interest in its role in human cancer. ^Ultraviolet rays have a number of effects on cells, including inhibition of cell division, inactivation of enzymes, induction of mutations, and in sufficient dosage, killing of cells. The carcinogenicity of UVB light is attributed to its formation of pyrimidine dimers in DNA. When unrepaired, these dimers lead to larger transcriptional errors and, in some instances, cancer. Studies in mice suggest that more is involved than ultraviolet-induced mutations alone. The ultraviolet light simultaneously impairs cell-mediated immunity.85 Whether these findings apply to humans is not documented, but it is likely that ultraviolet-induced mutations serve as the initiating mechanism and the immune changes as either potentiators or promoters. Q169=Radiation Carcinogenesis due to Ionizing Radiation: ^ ^ A169=Electromagnetic (x-rays, gamma rays) and particulate (alpha particles, beta particles, protons, neutrons) radiations are all carcinogenic.83 The evidence is so voluminous that only a few examples will suffice. Many of the pioneers in the development of roentgen rays developed skin cancers. Miners of radioactive elements in central Europe and the Rocky Mountain region of the United States have suffered a tenfold increased incidence of lung cancers. Most telling is the followup of survivors of the atomic bombs dropped on Hiroshima and Nagasaki. Initially, there was a marked increase in the incidence of leukemias-principally acute and chronic myelocytic leukemia -after an average latent period of about 7 years. Subsequently, the incidence of many solid tumors with longer latent periods (e.g., breast, colon, thyroid, and lung) has increased. ^Even therapeutic irradiation has been documented to be carcinogenic. Thyroid cancers have developed in approximately 9% of those exposed during infancy and childhood to head and neck radiation. The previous practice of treating a form of arthritis of the spine known as ankylosing spondylitis with therapeutic irradiation has yielded a 10- to 12-fold increase in the incidence of leukemia years later. ^To conclude this doleful litany, mention should be made of the residents of the Marshall Islands, who were exposed on one occasion to accidental fallout from a hydrogen bomb test that contained thyroid-seeking radioactive iodines. As many as 90% of the children under the age of ten years on Rongelap Island developed thyroid nodules within 15 years, and it is significant that about 5% of these nodules proved to be thyroid carcinomas. It is evident that radiant energy-whether absorbed in the pleasant form of sunlight, through the best intentions of a physician, or by tragic exposure to an atomic bomb blast-has awesome carcinogenic potential. In humans, there is a hierarchy of vulnerability to radiation-induced cancers. Most frequent are the leukemias, save for chronic lymphocytic leukemia, which, for unknown reasons, almost never follows radiation injury. Cancer of the thyroid follows closely but only in the young. In the intermediate category are cancers of the breast, lungs, and salivary glands. In contrast, skin, bone, and the gastrointestinal tract are relatively resistant to radiation-induced neoplasia, even though the gastrointestinal mucosal cells are vulnerable to the cellkilling effects of radiation and the skin is in the pathway of all external radiation. Nonetheless, the physician dare not forget: Any cell can be transformed into a cancer cell by sufficient exposure to radiant energy. Q170= Radiation Carcinogenesis and DNA Repair Defects: ^ A170=Important insights into the molecular processes that affect the response of cells to radiations have been provided by the study of rare inherited diseases characterized by defects in DNA repair.87 These autosomal recessive disorders include xeroderma pigmentosum, Bloom's syndrome, ataxia-telangiectasia, and Fanconi's anemia. Together they are characterized by hypersensitivity to one or more DNA-damaging agents and by a predisposition to cancer. Patients with xeroderma pigmentosum have extreme photosensitivity, a very high incidence of cancers in sun-exposed skin, and, in some cases, neurologic abnormalities. The molecular basis of degenerative changes in sun-exposed skin and occurrence of cutaneous tumors rests on an inherited inability to repair ultraviolet light-induced DNA damage. As mentioned earlier, ultraviolet light causes formation of pyrimidine dimers; cells from patients with xeroderma pigmentosum are markedly deficient in the excision repair of pyrimidine dimers. Xeroderma pigmentosum is genetically heterogeneous-with at least seven different variants. Each of these forms is caused by a mutation in one of several genes involved in nucleotide excision repair.88 Ataxia-telangiectasia, in contrast to xeroderma pigmentosum, is associated with defective response to damage induced by ionizing radiation and a greatly increased risk of developing lymphoid malignancies. In addition, as the name indicates, these patients have progressive cerebellar ataxia and oculocutaneous telangiectasia. They are also immunodeficient and susceptible to recurrent sinopulmonary infection. Like xeroderma pigmentosum, ataxia-telangiectasia is also genetically heterogeneous, with at least six molecular variants. Patients with Fanconi's anemia have a predisposition to leukemias, progressive aplastic anemia (see Chapter 13: Aplastic Anemia ), and congenital malformations. Their cells are extremely sensitive to DNA cross-linking agents, presumably as a result of a deficiency of enzymes that eliminate interstrand cross-links that form after exposure to genotoxic agents. Bloom's syndrome differs from all other disorders in this group because patients with this disease seem to be hypersensitive to a variety of different DNA-damaging agents (e.g., ultraviolet light, irradiation). Thus, it appears that they have a more generalized DNA repair defect. Cytologically, cells from these patients are characterized by a greatly increased frequency of apparently spontaneous sister-chromatid exchange, resulting presumably from some defect in DNA ligation. Clinically, patients with Bloom's syndrome have severe immunodeficiency, growth retardation, and predisposition to several types of cancers. Because these syndromes are inherited as autosomal recessives, it can be concluded that both copies of the relevant DNA repair genes are mutated or inactivated in these cancer-prone patients. In this respect, genes involved in DNA repair may be considered tumor suppressor genes. Q171=What are the three discussed agents of viral carcinogenesis? ^ A171=1)HPV: A DNA virus that can cause papillary lesions such as condylomma acuminatum. These do not become malignant. This virus can also be associated with dysplasia of the cervix which may progress to malignancy by way of an in situ cancer. ^2) EBV: This virus, a member of the herpes family, has been implicated in the pathogenesis of four types of human tumors: the African form of Burkitt's lymphoma; B-cell lymphomas in immunosuppressed individuals, particularly after human immunodeficiency virus (HIV) infection and organ transplantation; some cases of Hodgkin's disease; and nasopharyngeal carcinomas. ^3) Hepatitis B: Epidemiology , strongly suggest a close association between HBV infection and the occurrence of liver cancer (hepatocellular carcinoma). HBV is endemic in countries of the Far East and Africa, and correspondingly these areas have the highest incidence of hepatocellular carcinoma. For example, in Taiwan, those who are infected with HBV have a greater than 200-fold increased risk of developing liver cancer as compared with uninfected individuals in the same area. Studies in experimental animals also support a role for HBV in the development of liver cancer. First, by causing chronic liver cell injury and accompanying regenerative hyperplasia, HBV expands the pool of cells at risk for subsequent genetic changes. In the mitotically active liver cells, mutations may arise spontaneously or be inflicted by environmental agents, such as dietary aflatoxins. Mutational inactivation of p53 is noted in areas of the world where exposure to HBV as well as aflatoxins is endemic. Second, HBV encodes a regulatory element called HBx protein that disrupts normal growth control of infected liver cells by transcriptional activation of several host cell proto-oncogenes. Third, the HBx protein activates protein. kinase C, a critical component of several signal transduction pathways, and thus mimics the action of the tumor promoter TPA.98 The important role played by HBx in the pathogenesis of liver cell cancers is buttressed by the observation that mice transgenic for the HBx gene develop hepatic cancers. Q172=Describe the action of the RNA Oncogenic Virus Human T-Cell Leukemia Virus Type 1 (HTLV-1) ^ A172=HTLV-1 is associated with a form of T-cell leukemia/lymphoma that is endemic in certain parts of Japan and the Caribbean basin but is found sporadically elsewhere, including the United States. Similar to the AIDS virus, HTLV-1 has tropism for CD4+ T cells, and hence this subset of T cells is the major target for neoplastic transformation. Human infection requires transmission of infected T cells via sexual intercourse, blood products, or breastfeeding. Leukemia develops in only about 1% of the infected individuals after a long latent period of 20 to 30 years. In addition to leukemia, HTLV-1 is also associated with a demyelinating neurologic disorder called tropical spastic paraparesis Q173=PIP2 pathway -the way proto-oncogene works ^ A173=Growth Factor binds to receptor and activates a tyrosine kinase. This is essential for signal transduction, and thus phosphorylation of tyrosine residues on one or more target proteins is a critical event in the transfer of extracellular signals to cell proliferation. A series of proteins strategically located on or close to the inner surface of the cell membrane play a role in such signaling. The initial activation of these signaling proteins appears to result from the binding of specific domains (called (SH2), for src homology) to the phosphotyrosine of the activated receptor. The signaling proteins include the following: ^1)Phospholipase C catalyzes the degradation of phosphatidylinositol-4,5-biphosphate (PIP2), resulting in the generation of two second messengers: inositol-1,4,5-triphosphate (IP3), which releases intracellular calcium stores, and diacylglycerol (DAG). ^2) DAG, in turn, activates protein kinase C (PKC), a member of a family of serine threonine kinases that are bound to the plasma membrane and are thus in the same perimembrane region as the kinases of the receptors. ^3) PKC phosphorylates cytoplasmic second messengers that translocate to the nucleus and induce DNA alterations. Q174=What is the most common gene in the body associated with malignant neoplasms? ^ A174=Ras: The ras signal transduction pathway. The phosphorylated receptor tyrosine kinase binds to a bridging protein complex which converts inactive ras GDP to active ras GTP. The ras GTP activates raf-1, which in turn phosphorylates a series of other mitogen-induced protein kinases (MAPKs), leading to activation of nuclear transcription factors. GAP, also phosphorylated by receptor-ligand binding, counteracts ras activation.