NEOPLASIA NOTES (BS)

Nomenclature 1. Benign and malignant tumors are composed of parenchyma consisting of proliferating cells and supporting stroma made up of connective tissue, blood vessels and sometimes lymphatics. * the parenchymal component determines its behavior and the name of the tumor. 2. Benign tumors are composed of parenchymal cells that closely resemble the tissue of origin and are frequently classified by adding the suffix oma to the cell type (e.g. lipoma, fibroma, chondroma). * benign tumors of epithelial origin are called adenomas, if they arise from glandular epithelium (e.g. follicular adenoma of the thyroid; adrenal adenoma) or papillomas if they have a papillary (frond-like) appearance (e.g. squamous papilloma). 3. Malignant tumors arising from epithelial origin are called carcinomas. * the epithelium can be derived from ectoderm (squamous carcinoma, transitional cell carcinoma), endoderm (colon adenocarcinoma) or mesoderm (e.g. renal adenocarcinoma). * adenosquamous carcinomas imply that both squamous and glandular components are present. * secondary descriptors further classify the lesion as follows: . papillary (e.g. papillary adenocarcinoma of the thyroid). . medullary implies a soft tumor (e.g. medullary carcinoma of the breast). . scirrhous refers to a hard textured tumor (e.g. scirrhous carcinoma of the breast; another term for scirrhous is desmoplastic). . mucinous implies mucin production by the neoplastic cells (e.g. mucinous carcinoma of the breast). . comedo refers to necrotic material resembling a comedone or pimple (e.g. comedocarcinoma of the breast). 4. Sarcomas are malignant tumors of mesenchymal origin. * Sarcomas of . bone - - - osteogenic sarcoma . cartilage - - - Chondrosarcoma . adipose - - - liposarcoma . vessel endothelium - - - angiosarcoma . fibroblasts - - - fibrosarcoma . striated muscle - - - rhabdomyosarcoma . smooth muscle - - - leiomyosarcoma * they differ from carcinomas in that they . arise from mesenchymal cells. . are very fast growing. . are usually bulky. . frequently undergo necrosis by outgrowing their blood supply. . metastasize most commonly to the lungs rather than lymph nodes . usually prefer hematogenous routes (blood vessel) of metastasis rather than lymphatic.

* the malignant fibrous histiocytoma is the most common adult sarcoma and the embryonal rhabdomyosarcoma (derived from muscle) is the most common childhood sarcoma. 5. Hamartomas are not true tumors. * they are an overgrowth of tissue that is normally present in the organ (e.g. a bronchial hamartoma of the lung composed of mature cartilage). 6. Choristomas, or heterotopic rests, are not true tumors. * they represent normal tissue in a foreign location (e.g. benign pancreatic tissue in the wall of the stomach). 7. Mixed tumors have two different morphologic patterns that are derived from the same germ layer. * the mixed tumor of the parotid gland is the most common overall salivary gland tumor. 8. Teratomas are tumors that derive from all three germ cell layers. * ectoderm - - - skin and sebaceous glands * endoderm - - - glandular epithelium * mesoderm - - - cartilage, bone, etc. * an ovarian cystic teratoma frequently demonstrates teeth and bone on x-ray. * teratomas are also germ cell tumors (see below) 9. Leukemias are tumors of hematopoietic cells arising in the bone marrow. * leukemia can arise for WBCs (lymphoblastic leukemia, monocytic leukemia, granulocytic [myelogenous] leukemia), RBCs, or megakaryocytes . there are no benign leukemias. * an acute leukemia contains more than 30% blasts (e.g. myeloblasts; lymphoblasts) in the marrow. . an acute lymphoblastic leukemia is the most common overall cancer and leukemia in children. . an acute myelogenous leukemia is the most common acute leukemia of young to middle aged adults. * a chronic leukemia shows some element of maturation and has less than 30% blasts (e.g. myeloblasts) in the marrow . chronic lymphocytic leukemia is the most common leukemia in the elderly population. 10. A malignant lymphoma is a solid tumor arising from lymphoid tissue (lymph nodes most commonly). * a nodular poorly differentiated lymphocytic lymphoma is the most common adult B cell lymphoma. * extranodal lymphomas arise form lymphoid tissue outside the lymph nodes (e.g. Peyers patches, tonsils) . the stomach is the MC extranodal site for lymphomas. 11. Tumors arising from germinal (totipotential) epithelium are called germ cell tumors. * germ cell tumors are totipotential (able to develop into any cell type). * teratomas are the most common germ cell tumor. * other examples include the . the ovarian dysgerminoma . the seminoma (testicular tumor) in males . trophoblastic tumors (e.g. choriocarcinoma)

12. Tumors of neuroglial elements include * astrocytoma (most common primary brain tumor), which derive from astrocytes. * oligodendrogliomas, which derive from oligodendrocytes. * ependymomas, which derive from oligodendrocytes. 13. Tumors of embryonic origin are pluripotential ( primitive cells that can develop into multiple cell types having a maximum of 2 germ layers). * the Wilms tumor in children arises from the primitive renal anlage and characteristically has abortive appearing glomeruli and striated muscle intermixed with primitive appearing cells. 14. Sounds benign tumors that are really malignant include * hepatoma (hepatocellular carcinoma). * melanoma (malignant melanoma). * lymphoma (malignant lymphoma). * astrocytoma (a low grade neuroglial tumor). * carcinoid (a malignant that can either be low grade or high grade depending on size and location). 15. Pathology procedure that are used to diagnose tumors include * immediate frozen sections of tissue removed during surgery (freeze the tissue, make thin sections on a microtome, and stain in less than 3 minutes. * routine tissue sections *usually use hematoxylin-eosin stain). * cytology (needle aspirations), needle biopsies, incisional biopsies (piece of the tumor), excisional biopsies (entire lesion). * immunohistochemistry (use monoclonal antibodies against antigens in tissue That can be identified as color changes in the tissue). * DNA probes. * electron microscopy is useful in identifying the following tumors: . tonofilaments - - - indicate an epithelial tumor . angiosarcoma - - - demonstration of Weibel Palade bodies. . small cell carcinoma of the lung, neuroblastomas and carcinoid tumors - - - neurosecretory granules . rhabdomyosarcomas - - - thick and thin myofilaments . histiocytosis X (malignant histiocytic tumor) - - - Birbeck Granules in Langerhans cells (histiocytes) * histochemical stains of importance include: . cytokeratin - - - separates a carcinoma (positive) from a malignant lymphoma (negative) and a mesothelioma (positive) from an adenocarcinoma (negative) . S 100 - - - positive in malignant melanoma and neuroblastomas . factor VIII related antigen - - - positive in vascular tumors. . carcinoembryonic antigen (CEA) - - - negative in mesothelioma and positive in adenocarcinoma . desmin - - - positive in muscle sarcomas * Southern blot assays involve the extraction of DNA from cells. * Northern blot assays involve the extraction of RNA from cells.

Biologic Behavior of Tumors 1. Benign tumors * benign tumors are . usually encapsulated; exceptions - leiomyomas of the uterus (MC benign tumor in women) - dermatofibroma . well differentiated (resemble their parent tissue). . have normal mitotic spindles (not tetraploid, etc.) . are non-invasive; exceptions - dermatofibroma - invasive mole (trophoblastic tumor) . do not metastasize; exception - invasive mole can metastasize to lung, but does not kill the patient. . often cease to enlarge. . can sometimes secrete hormones, if they arise in an endocrine organ; examples; - adrenal adenoma - - - hypercortisolism, hyperaldosteronism - parathyroid adenoma - - - hyperparathyroidism with hypercalcemia - prolactinoma (MC pituitary tumor) - - - secretes prolactin . are rarely fatal; exception - meningioma arising from arachnoid granulations can potentially kill a person by virtue of its location next to the brain. 2. Malignant tumors * malignant tumors are . usually nonencapsulated; exception - renal adenocarcinoma frequently look like they have a capsule (incomplete capsule). . less differentiated than benign tumors . have abundant abnormal mitotic spindles (see diagram later). . characteristically have a rapid growth rate. . generally invasive . have the potential to metastasize; exceptions - basal cell carcinomas of the skin (MC skin cancer) - astrocytomas . usually fatal if left untreated * size alone may sometimes be a criteria of malignancy . carcinoid tumors of the small bowel (> 2 cm) are usually malignant . renal adenocarcinoma vs renal adenoma (>3 cm) is likely to be malignant; < 2 cm usually adenoma. * in general, malignant cells have a longer cell cycle than their normal counterpart . acute leukemia and small cell carcinoma of the lung are exceptions - - short cell cycles . malignancy is a problem with greater accumulation rather than removal of malignant cells (more cells produced than cells that die). . the majority (97%) of the proliferating cells die.

malignant cells have increased DNA, which can be quantitated by flow cytometry for prognosis purposes. . diploid cells (multiples of 23 chromosomes) have a better prognosis than aneuploid cells (uneven multiples). individual characteristics of malignant cells . have simple biochemical systems (anaerobic metabolism). . lack cohesiveness, which is the reason why they shed easily when doing a Pap smear. . are not contact inhibited (pie up on each other) . they can be transplanted . they are immortal in culture. . commonly lose their surface ABO antigens - loss of ABO antigens is used as a prognostic indicator of tumor aggressiveness. it takes at least 30 doubling times for a malignant tumor to become clinically detectable (1 cm). . 1 cm3 = 108 109 cells. not all tumor cells are in the proliferative pool. . malignant lymphomas, leukemias and small cell carcinomas of the lung have very high proliferation rates. malignant cells are predominantly monoclonal but exhibit considerable heterogeneity within the tumor . some cells have the capacity to metastasize, while others do not. nuclear cytologic features of malignant cells include . an increased nuclear/cytoplasmic (N/C) ratio. . irregular nuclear membranes . hyperchromatic nuclei with parachromatin clearing . large irregular nucleoli . atypical mitotic spindles (see schematic).

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cytoplasmic features that help differentiate the source (not the malignant potential) of the malignant cell are . keratin (squamous origin) . vacuoles with mucin material (adenocarcinoma) . in a Pap smear, keratin stains a bright red in the cytoplasm Invasion * malignant cells invade tissue in the following manner . cancer cells capable of invading express surface receptors that attach to laminin and fibronectin receptors in tissue - . they release type IV collagenases (dissolves basement membrane) and proteases to locally destroy tissue and basement membranes - and . they have the capacity to move through the tissue - - and

once in a vessel channel, they embolize to a target organ (metastasis) - - - and . attach to receptors on the endothelium and - - - and . repeat to above process homing devices used by tumor cells include . special adhesion molecules on the endothelial surfaces in the target tissue and/or . chemotactic agents emitted by the target tissue that attract the tumor emboli metastasis is defined as the discontinuous spread of malignant cells from one organ to another. metastasis is the single best criterion for malignancy. . breast, prostate and thyroid cancers commonly metastasize to bone. . lung cancer commonly metastases to the brain . gastrointestinal cancers commonly metastasize to the liver, since they drain into the portal vein most patients die from their metastases rather than the primary tumor most patients already have metastasis when thr tumor is first discovered. dissemination of tumor occurs by seeding within body cavities, lymphatic spread or hematogenous spread. seeding is commonly seen with colorectal cancers and ovarian cancers, which seed tiny implants of tumor over the peritoneum . tumor implants are capable of invading the bowel and are also capable of forming bowel adhesions with subsequent obstruction. . the rectal pouch of Douglas (anterior to the rectum and posterior to the uterus) in women is a common site for seeding to occur lymphatic invasion is more common in carcinomas than sarcomas, although this distinction is no longer of any consequence because lymphatics eventually empty into the systemic circulation. . lymphatic spread initially goes to the regional lymph nodes (subcapsular sinus first site of metastasis) and from there into the systemic circulation via the thoracic duct. hematogenous spread is favored by sarcomas (not exclusively) with spread to the lungs and liver as a common finding . carcinomas with a propensity for hematogenous invasion are - renal adenocarcinomas invading the renal vein - hepatocellular carcinomas invading the hepatic and portal veins - follicular carcinomas of the thyroid, which commonly by pass the cervical lymph nodes and metastasize to the lungs and bone. . tumors draining into the portal vein (e.g. colon, stomach, pancreas) spread to the liver, while those draining into the vena cava involve the lung (e.g. low lying rectal carcinoma). skip metastases not following the usual lymphatic drainage are seen with . testicular tumors (seminoma), which commonly go to the paraaortic nodes first (follow the same route the testicles used in descending into the scrotum)

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stomach cancers, which often involve Virchows node in the left supraclavicular chain . cervical cancer, which can also spread to the left supraclavicular nodes. * metastasis is more common than a primary cancer in the . lymph nodes (MC organ metastasized to) . lung . liver . bone . adrenals * osteoblastic metastases cause densities in bone on x-ray and elevate the serum alkaline phosphatase (present in osteoblasts). . prostate cancer (most common) . follicular carcinoma of the thyroid . breast cancer . carcinoid tumors * osteolytic metastases cause lucencies in bone on x-ray . breast cancer - - - both lytic and blastic . osteolytic metastases are frequently the site of a pathologic fracture of bone. Examples of extremely aggressive malignancies include * anaplastic carcinoma of the thyroid * non-gestational derived (not associated with pregnancy) choriocarcinoma * acute leukemias * glioblastoma multiforme (a highly malignant brain tumor of astrocyte origin) * small cell carcinomas of the lung. Choriocarcinoma in a woman is an excellent example of a highly malignant tumor that has responded most to chemotherapy (e.g. methotrexate and chlorambucil) even in the presence of multiple metastases.

ONCOGENESIS 1. Protooncogenes are regulatory genes that encode for growth promoting factors (e.g. growth factors, growth factor receptors, etc.) * suppressor genes (anti-oncogenes) regulate cell growth. * cancer is best viewd as a multistep process involving multiple mutational events that activate a series of different protooncogenes into cellular oncogenes, or c-oncs, or inactivate different suppressor genes. * in either situation, this leads to unrestricted cell division, which can be enhanced in some cases by growth promoters (hormones), chemicals (phorbol esters), or drugs. * protooncogenes are involved in all the stages of normal cell growth. . these stages include - the synthesis of growth factors (1) - the synthesis of their receptors (2) - receptors stimulate production of second messengers (3) which are phosphorylated proteins - second messengers stimulate DNA transcription and mitosis (4)

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protooncogenes, such as the sis oncogene, code for growth factors like fibroblast growth factor, platelet derived growth factor, and epidermal derived growth factor. . activation of these oncogenes (e.g by gene amplification) leads to overexpression of these gene products with subsequent increase in mutational activity. . cancer associations involving this particular mechanism include astrocytoma, osteogenic sarcomas, and various carcinomas. * protooncogenes such as neu [erb2] code for growth factor receptors, which either have their own intrinsic tryosine kinase activity or stimulate other protein systems (e.g. GDP system) to produce phosphorylated proteins that act as second messengers. . activation of these oncogenes does not require the presence of growth factors to stimulate cell division. . cancer associations with this mechanism include glioblastoma multiforme and various carcinomas (breast, colon, stomach cancers). * signals from activated receptors are sent to protooncogenes involved with non-receptor associated tyrosine kinase (e.g. abl oncogene) or to oncogenes that activate GDP - - - GTP (e.g. ras oncogene), both of which produce phosphorylated second messengers (e.g. cAMP from the GDP - GTP system). . chronic granulocytic leukemia is associated with activation of the abl oncogene. . cancers such as pancreas, colon, thyroid, and leukemia are associated with activation of the ras oncogene. * protooncogenes are also involved in regulating DNA transcription (e.g. myc and N-myc oncogenes), which, ultimately, produces cell division. . Burkitts lymphoma and neuroblastoma are associated with activation of myc and N-myc oncogenes, respectively. Processes that acivate protoonocogenes include point mutations (e.g. activation of the ras oncogene), chromosomal translocations (e.g. activation of the able [t9;22] and myc [t8;14] oncogenes), and gene amplification leading to overexpression of the gene products (e.g. neu [erb2]). * carcinogenic agents such as chemicals, viruses, and radiation work through these mechanisms. * types of mutations that activate protooncogenes include . balanced translocations (t8;14; t9;22) . gene deletions (e.g. 5q) . gene amplification (increase the number of copies of a gene). * in the t8;14 balanced translocation of Burkitts lymphoma, the myc oncogene on chromosome 8 is translocated next to the mu heavy chain region on chromosome 14. . this activates DNA transcription and cell mitoses leading to Burkitts lymphoma. . EBV is though to play a role by first infecting B cells and then causing polyclonal activation of the B cells that are predisposed to the t8;14 translocation. * in the t9;22 balanced translocation of chronic granulocytic leukemia (CGL), the translocated abl oncogen (#9) fuses with the break cluster region (bcr) of chromosome 22 (Philadelphis chromosome) forming a

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tyrosine kinase, which in turn produces second messengers that ultimately cause the cell proliferation of CGL. Inactivation of suppressor genes leads to unrestricted cell divisions. * inactivation of the Rb gene on chromosome 13 causing retinoblastoma is the best example of this form of oncogenesis. * he Rb gene normally inhibits retinal cells from entering the cell cycle. * in sporadic retinoblastoma (non-genetic), 2 separate mutations in the Rb locus on both chromosomes are required before retinoblastoma develops. * in autosomal dominate retinoblastoma, 1 mutation inactivating the Rb locus is already present and only 1 more is needed to produce overt retinoblastoma. Once a tumor has developed, its growth is dependent on various cell cycle events (previously discussed), tumor angiogenesis, and tumor progression. * regarding tumor angiogenesis, angiogenesis factors are released from both tumor cells and host cells (macrophages tumor necrosis factor alpha). * tumor progression relates to multiple mutational events that lead to the formation of heterogeneous subpopulations of cells with different functions. . some of the cells are capable of metastasizing, others invade, and still others are resistant to therapy. In summary, the clinically important c-oncs involved in neoplasia include * the c-abl oncogene of chronic myelogenous leukemia (translocated from chromosome 9 to chromosome 22 [Philadelphia chromosome]). * the c-myc oncogene of Burkitts lymphoma (translocated from chromosome 8 to chromosome 14). * the N-myc oncogene of neuroblastoma. * the c-neu (erb2) oncogene in breast cancer. * the c-ras oncogene associated with pancreatic, colon, and thyroid carcinomas and leukemia.

Chemical Carcinogenesis 1. In some cases of chemical carcinogenesis, the transformation of a cell into a malignant cell is due to the process of initiation followed by promotion (think of a fraternity or sorority - - you must be initiated before you get promoted). * initiation is the first step in the transformation of a cell, where the protooncotgen becomes activated into a c-onc (e.g. ras oncogene has a point mutation and becomes c-ras). . initiation - is rapid - prefers rapidly dividing cells - has memory - is additive - produces a permanent mutational change in the cells DNA. * promotion must always follow initiation . promotion - is slow - is reversible in the early stages - is non-additive

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causes the initiated cells to replicate (growth promoter - estrogen), so the mutational event can be passed on to future generations of cells. . repeated mitoses predispose to additional mutations, which ultimately transforms the cell. * most carcinogens are complete carcinogens meaning that they both initiate and promote a cell (e.g. asbestos is both an initiator and promoter). Chemicals are either transformed by the microsomal P-450 system of the liver into carcinogens (indirect acting) or are direct acting carcinogens (e.g. alkylating chemotherapy agents). * the mutagenicity of chemical carcinogens is evaluated with the Ames test. . in this test, Salmonella that is not able to synthesize histidine is mixed with the chemical in question and liver microsomes (convert chemical to mutagen). . they are cultured on histidine free media . if Salmonella does not grow, the chemical is not a mutagen. If Salmonella does grow, the chemical is a mutagen.

Carcinogen Aniline dyes Benzidine Cyclophosphamide Phenacetin Vinyl chloride Thorotrast Arsenic Asbestos Polycyclic hydrocarbons (smoking)

Chromium Nickel Chewing tobacco Alkylating agents Benzene Oral contraceptives Aflatoxins Diethylstilbestrol Nitrosamines Cadmium Tars, soots, oils

Tumor Association(s) Bladder cancer (transitional) Bladder cancer (transitional) Bladder cancer (transitional) Bladder cancer (transitional) Angiosarcoma of the liver Angiosarcoma of the liver, hepatocellular carcinoma Angiosarcoma of the liver, squamous carcinoma of the skin, lung cancer Lung cancer (most common), mesothelioma Lung cancer (squamous and small cell); squamous cancers of the oral pharynx, esophagus, larynx; adenocarcinomas of stomach and pancreas; bladder (transitional); cervical carcinoma Lung, nasal cavity Lung, nasal cavity Verrucous carcinoma of the mouth Acute leukemia/lymphoma Acute leukemia (also aplastic anemia) Liver adenomas, hepatocellular carcinoma Hepatocellular carcinoma Clear cell adenocarcinoma of the vagina Esophageal and gastric cancers Prostate and lung cancers Squamous carcinoma of the skin

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Chemical induced tumors have tumor antigens that are different in all of the tumors (no 2 tumors are alike).

Viruses 1. Viruses are potential carcinogens. * acute transforming retroviruses (RNA viruses) already have activated oncogenes (v-oncs) in their genome. . these represent captured protooncogenes from a host cell that have been activated such that their reintroduction into a host cells genome results in a transformed cell. 2. Both RNA and DNA viruses have been implicated in cancer. 3. Important putative virus cancer relationships are listed in the following Table. * to date, no viruses are unequivocal carcinogens. RNA viruses HTLV 1 HTLV II HIV DNA viruses HBV (HCV / DNA) EBV HPV Cancer relationship adult T cell leukemia/lymphoma ? hairy cell leukemia ? Kaposi sarcoma

hepatocellular carcinoma Burkitts lymphoma, nasopharyngeal carcinoma, polyclonal malignant lymphoma squamous carcinoma of the cervix, vagina, and vulva, anus in homosexuals; ? Kaposi sarcoma

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Retroviruses are RNA viruses that have reverse transcriptase (an RNAdependent DNA polymerase). * reverse transcriptase does the reverse of DNA by taking the viruss RNA and synthesizing DNA, so the viral genome becomes part of the host cells genome. * some retroviruses are able to both integrate themselves into the host cells DNA and replicate themselves without killing the host cell. * acute transforming retroviruses have activated oncogenes (v-oncs) that directly transform a cell when it is infected. * slow transforming virus4s do not have v-oncs. . some of them activate protooncogene in the host cell by inserting their genome above or below a proto-oncogene causing them to become activated and to over express their gene product (gene amplification). . sometimes they inactivate suppressor genes. * HTLV-1 retroviruses are associated with T cell leukemia/lymphomas. . once integrated into the T cell genome, they code for a gene product that stimulates the formation of interleukin 2 and granulocyte/macrophage colony stimulating factors. . this results in T cell proliferation and increases the chances of a mutational event leading to full blown T cell leukemia/lymphoma. * HPV apparently inactivates suppressor genes, leading to squamous cell carcinoma.

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DNA viruses differ from retroviruses in that they do not require reverse transcriptase. * they cannot both integrate and replicate themselves at the same time without killing the cell. * DNA viruses cause the hosts integrated genome to synthesize T antigen, which is the key component for transforming (initiating) the cell. * these work by either inactivating a suppressor gene or activating a protooncogene. Unlike chemically induced tumors, virally induced tumors have tumor antigens that are the same in all the tumors.

Radiation 1. In radiation carcinogenesis, ionizing particles (e.g. alpha and beta particles), gamma rays and x-rays hydrolyze water into free radicals, which are mutagenic to DNA by activating protoonocogenes to form c-oncs. * ultraviolet light induces the formation of thymidine dimers, which distort the DNA molecule. . if DNA repair cannot keep pace with dimer production, the cell is transformed. . in patients with xeroderma pigmentosum, a DNA repair enzyme deficiency state, UV light induced skin cancers occur at an early age (e.g. squamous cell carcinoma, basal cell carcinoma and malignant melanoma). 2. Examples of radiation induced cancers are as follows: * leukemia - - - the most common overall radiation induced cancer and the one most frequently observed in the atomic bomb victims (most developed chronic myelogenous leukemia). * papillary carcinoma of the thyroid in children irradiated in the head and neck area. * lung cancer in uranium miners. * breast cancer * osteogenic sarcoma * angiosarcoma of the liver in those patients exposed in the past to thorotrast dye * squamous and basal cell cancers in those with beta irradiation of the skin Grade and Stage Cancer 1. The grade of a tumor is based primarily on the degree of differentiation of the tumor and on the amount of mitotic activity, which indirectly indicates its growth rate. * grading terms include . low grade - - - well differentiated - - - can tell that the tumor is squamous (e.g. keratin present) transitional, or an adenocarcinoma (e.g. glands with mucin) . intermediate grade . high grade - - poorly differentiated, anaplastic - - - cannot tell whether the tumor is squamous, glandular, sarcomatous, etc. . 2. tumor stage is based on the size of the primary tumor and the presence or absence of lymph nodal or hematogenous dissemination. * the prognosis is closely related to the grade and stage (mosst important factor of the two) of the cancer.

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the TNM system is frequently used for staging. . T stands for characteristics of the primary tumor (e.g. size, skin involvement, etc.). . N refers to the lymph node status and the localization of those involved (e.g. mediastinal, axillary, etc.) . M refers to distant metastasis. * there are other staging systems utilized including the modified Dukes classification for colon cancer or the Columbia system for breast cancer. Other studies that have prognostic significance include * tumor markers (discussed later). * ERA-PRA receptor studies in breast cancer. * DNA flow cytometry to determine ploidy (diploid is good and aneuploid is bad). * detection of certain activated oncogenes (e.g. c-neu [erb2] for breast cancer).

Host Defenses Against Cancer 1. Host defense against tumors is both humoral and cellular, the latter being the most effective. * cancer cells frequently exhibit altered class I surface antigens to which antibodies and certain types of T cells and natural killer cells can react. * examples of immune mechanisms used in destroying cancer cells include . cytotoxic T cells that recognize altered class 1 antigen sites on neoplastic cells and kill the cells (Type IV hypersensitivity). . killer cells, which recognize antibody coated tumor cells and hook into the antibody with their Fc receptor and kill the cell (ADCC type II hypersensitivity). . natural killer cells, which directly kill the cell with or without an antibody. . macrophages activated by gamma interferon that attack and kill tumor cells with cytolytic enzymes. . antibody and complement that attach to tumor cells and kill them (Type II hypersensitivity). 2. Tumor cells attempt to escape destruction by * shedding their antigens * forming immune complexes with cytotoxic antibodies * stimulating CD8 T suppressor cells to inhibit cellular immunity. Tumor Versus Host Reactions 1. Cachexia refers to the progressive weakness, malaise, anorexia and muscle wasting associated with and often predating the presence of a malignancy. * tumor necrosis factor alpha (cachectin) released by tumor cells and macrophages has been implicated. * no universally effective therapeutic modalities appear to be able to reverse cachexia. 2. Anemia is commonly present in cancer * it usually the anemia of chronic disease and/or iron deficiency * additional causes of anemia include: . metastasis to the marrow (myelophthisic) with subsequent secondary fibrosis. . marrow hypoplasia secondary to chemotherapy

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. rapid tumor proliferation, which uses up existing stores of folate (macrocytic anemia). . autoimmune hemolytic anemia (frequently associated with chronic lymphocytic leukemia). A leukoerythroblastic peripheral blood picture (immature myeloid cells and nucleated RBCs), is due to bone marrow invasion by tumor (breast cancer). Coagulation abnormalities associated with cancer include: * thrombocytosis (increase in platelets). * thrombocytopenia due to marrow replacement by tumor, chemotherapy or autoimmune destruction. * hypercoagulable state (increased fibrinogen, V, and VIII) with subsequent venous thrombosis and the potential for pulmonary embolization. * Trousseaus sign which is a migratory superficial thrombophlebitis that often accompanies pancreatic cancer Infections frequently complicate malignancy * they are due to defective host immunity as a result of hypogammaglobulinemia and/or poor cellular immunity * opportunisti9c infections are common (e.g. cryptococcosis; Pneumocystis) in malignancy * fever of unknown origin in a patient with a malignancy is infection first until proven otherwise * fever unassociated with infection is sometimes seen in . Hodgkins disease (Pel Ebsteins fever) . renal adenocarcinoma . osteogenic sarcomas Various paraneoplastic syndromes can occur (10-15%) which indicate the presence of an underlying cancer. * paraneoplastic syndromes are not due to the effects of tumor invasion or metastasis. * hypercalcemia in the hospitalized patient is most commonly due to malignancy. . a number of different mechanisms have been implicated in the hypercalcemia of malignancy including - bone metastases with lysis of bone by the tumor itself (not paraneoplastic). - Secretion of PTH-like substances (paraneoplastic) - Generation of osteoclast activating factor (IL-1) by the tumor (not paraneoplastic). - Release of prostaglandins by tumor (not paraneoplastic). * the Eaton-Lambert syndrome refers to a patient with myasthenia gravislike features. . it is most commonly associated with small cell carcinomas of the lung . it differs from myasthenia in that - strength increases with exercise - there is a poor response to Tensilon (edrophonium). * subacute motor neuropathy with lo9wer motor neuron weakness. * dermatologic syndromes associated with cancer include . acanthosis nigricans as a phenotypic marker for gastric carcinoma

dermatomyositis and its association with lung and breast carcinomas. . crops of seborrheic keratoses (Leser-T relat sign) and gastrointestinal cancer a musculoskeletal syndrome is hypertrophic osteoarthritis of the fingers and toes (with or without clubbing) which is most commonly associated with lung cancer. hematologic syndromes include . venous thromboses (Trousseaus sign). . anemia . leukemoid reaction (increased WBC count looking like a leukemia). . marantic vegetations on the mitral value (sterile vegetations that are thought to be due to a hypercoagulable state). miscellaneous syndromes include . nephrotic syndrome due to immune complex deposition in the glomerulus (membranous type of glomerulonephritis). . subacute cerebellar degeneration often associated with dementia and dysarthria in lung, prostate and colorectal cancers. ectopic hormones are frequently secreted by tumors. Tumor small cell carcinoma lung Small cell carcinoma lung Squamous carcinoma lung Renal adenocarcinoma Renal adenocarcinoma Hepatocellular carcinoma Cerebellar hemangioblastoma (increased incidence of renal adenocarcinoma, leiomyoma of uterus (compression of ureters), renal cysts hepatocellular carcinoma Retroperitoneal tumors Carcinoid tumor (small bowel most common) Choriocarcinoma Syndrome hyponatremia hypercortisolism hypercalcemia Secondary polycythemia

Ectopic hormone ADH ACTH (most common) PTH-like peptide Erythropoietin

Insulin-like factor Serotonin Beta hCG

hypoglycemia Flushing, diarrhea (carcinoid syndrome) Hyperthyroidism, gynecomastia hypocalcemia

Calcitonin Medullary carcinoma thyroid Tumor Markers 1. A tumor marker is a biochemical indicator or the presence of a neoplastic process * they can be used as a screen for cancer but are more commonly used to follow the disease for recurrences.

Tumor Antigen Carcinoembryonic antigen (CEA) Alpha fetoprotein (AFP) Beta hCG CA 125 CA 19-9 CA 15-3 Prostatic acid phosphatase (PAP) Prostate specific antigen (PSA)

Cancer Association Colorectal, pancreatic, breast and small cell cancer Hepatocellular carcinoma, testicular cancer Trophoblastic cancers (choriocarcinoma) Ovarian cancer Pancreatic cancer Breast cancer Prostate adenocarcinoma Prostate adenocarcinoma

Neuron specific enolase Small cell carcinoma lung, neuroblastoma Cancer Epidemiology 1. Cancer is the second most common cause of death in this country. * over two-thirds of cancer deaths occur in people over 65. * cancer deaths are least in Utah and greatest in the District of Columbia * mortality and incidence rates are higher for blacks than for whites. * poor people have higher overall cancer rates. 2. Important statistics on cancer based on different cancer sites are ad follows: * cancer of the cervix is on the decline (endometrial less so) due to cytological screening. . endometrial cancer is more common than cervical cancer, because the sensitivity of a Pap smear is only 50% versus 80% in diagnosing cervical cancer. * ovarian cancer has the highest mortality among the gynecologic cancers. * Stomach cancer is on the decline in the United States. . this is most likely related to the refrigeration of meats, which decreases conversion of nitrates to nitrites. . blood group A individuals have a higher incidence of stomach cancer than blood group O patients. * pancreatic cancer is increasing in the United States (? Increased smoking). * lung cancer is increasing in women due to an increase in smoking and is decreasing in men. . MCC of cancer death in both males and females. * cancer of the colon-rectum is second in incidence in women and third in men. * breast cancer is the MC cancer in women . approximately 1 in 10 women will develop breast cancer at some time during their lives. * prostate caner is the MC cancer in males (if skin cancer is excluded). . approximately 1 in 10 men will develop prostate caner at some time during their lives. . MC in black than whites. * skin cancers most commonly relate to ultraviolet exposure (squamous, basal cell, malignant melanoma). . malignant melanomas are one of the most rapidly increasing cancers in the United States. . Blacks rarely develop skin cancers related to ultraviolet light exposure

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Ethnic relationships and cancer are important. * Burkitts lymphoma, due to the EBV virus, is endemic in certain parts of Africa. * hepatocellular carcinoma is common in the Far East and correlates with HBV hepatitis and aflatoxins. * nasopharyngeal carcinoma due to EBV virus is common in China * stomach cancer is the leading cause of cancer death in Japan (nitrosamines in smoked fish have been implicated). * esophageal cancer in China and Russia * choriocarcinoma in Orient due to increase in molar (trophoblastic) disease. the top three (3) cancers in incidence (number of new cases over a specified time period) in females in order of decreasing frequency are * prostate * lung * colorectal cancer The top three (3) cancers in incidence (number of new cases ocer a specified time period) in females in order of decreasing frequency are * breast * colorectal * lung cancer the top three (3) cancers in mortality in descending order of frequency in males are * lung * prostate * colorectal cancer The top three (3) cancers in mortality in females in descending order of frequency are * lung * breast * colorectal cancer

Factors Predisposing to Cancer 1. Genetic abnormalities associated with an increased incidence of cancer are listed in a Table. * in autosomal dominant conditions, tumors invariably develop in all the patients * in autosomal recessive states, the expression of the cancer is influenced by exposure to certain environmental factors (e.g. sunlight in xeroderma pigmentosum).

Genetic Condition Autosomal Dominant * MEN syndromes

Types of Tumor

* Retinoblastoma * Wilms tumor * Familial polyposis * Gardners syndrome (tumors and * Family cancer syndrome * Osler Weber Rendu * Peutz Jeghers syndrome * Sturge Webers syndrome * Tuberous sclerosis

* Neurofibromatosis * Neuroblastoma * von Hippel Lindau Autosomal Recessive * Xeroderma pigmentosum * Blooms syndrome * Fanconis syndrome * Ataxia telangiectasia * Turcots syndrome

MEN I: pituitary tumor, parathyroid adenoma (hyperparathyroidism), pancreatic tumor (Zollinger Ellison); MEN IIa: medullary carcinoma of thyroid, pheochromocytoma, parathyroid adenoma (hyperparathyroidism); MEN IIb: medullary carcinoma of the thyroid, pheochromocytoma. Retinoblastoma; predisposition for osteogenic sarcoma Wilms tumor Colon adenocarcinoma Colon adenocarcinoma and soft tissue (desmoid benign bone tumors (osteomas). Cancers of the breast, endometrium, lung and colon. Angiomas of the eye and colon Hamartomatous polyps; predisposition for ovarian tumors. Angiomas of the leptomeninges Glial tumors, rhabdomyoma of the heart, angiomyolipoma of the kidney (hamartoma), adenoma sebaceum of the skin. Neurofibromas, neurofibrosarcoma, pheochromocytoma, optic nerve glioma. Neuroblastoma Cerebellar hemangioblastoma, renal adenocarcinoma

Squamous cell carcinoma of the skin, basal cell carcinoma of the skin, malignant melanoma Chromosome instability syndrome: acute leukemia, colon adenocarcinoma Chromosome instability syndrome: acute leukemia Chromosome instability syndrome: malignant lymphoma Familial polyposis syndrome: Colon adenocarcinoma, glial tumors

Chromosome Number Disorders * Klinefelters syndrome * Turners syndrome * Downs syndrome

Breast cancer Ovarian cance : dysgerminoma and gonadoblastoma Acute leukemia

Sex Linked Recessive * Wiskott-Aldrich syndrome Malignant lymphoma * Sex-linked lymphoproliferative Malignant lymphoma disorder (EBV)

2.

Pancancerous conditions by system are summarized on the following pages.

Respiratory System nasopharyngeal carcinoma: EBV, chromium, nickel squamous carcinoma of the larynx: smoking, asbestos, alcohol lung cancer: smoking, arsenic, chromium, nickel, uranium, cadmium, asbestosis + smoking mesothelioma: asbestos Gastrointestinal System squamous carcinoma in the oral cavity: smoking, chewing tobacco (verrucous), leukoplakia and erythroleukoplakia, alcohol esophageal squamous carcinoma: achalasia, lye strictures, diverticular diseases, esophageal webs, smoking, alcohol, nitrosamines esophageal adenocarcinoma: Barretts esophagus stomach adenocarcinoma: atrophic gastritis related to pernicious anemia, adenomatous polyps, smoking, nitrosamines, blood group A, gastric stump, intestinal metaplasia, smoking intestinal malignant lymphoma: IgA heavy chain disease, celiac disease, Crohns disease colon adenocarcinoma: low fiber/high fat diet, polyposis syndromes, ulcerative colitis, Crohns disease, villous adenoma, cancer family syndrome anal squamous carcinoma: HPV in homosexuals Hepatobiliary/Pancreas System hepatocellular carcinoma: HBV, HCV, aflatoxins, thorotrast, cirrhosis, oral contraceptive cholangiocarcinoma: Clonorchis sinensis angiosarcoma: mnemonic VAT for vinyl chloride, arsenic, thorotrast gallbladder adenocarcinoma: porcelain gallbladder, cholelithiasis pancreatic adenocarcinoma: diabetes, smoking, familial relapsing pancreatitis, chronic pancreatis Genitourinary System transitional cell carcinoma: phenacetin, aniline dyes, smoking, cyclophosphamide, benzidine squamous cell carcinoma of the bladder: Schistosoma hematobium adenocarcinoma of the bladder: urachal remnants, cystitis glandularis, Eagles syndrome penile squamous carcinoma: erythroplasia of Queyrat, Bowens disease, balanitis xerotica obliterans, uncircumcised testicular seminoma: cryptorchid testis, testicular feminization prostate adenocarcinoma: family history, cadmium, ras oncogene renal adenocarcinoma: Lindau von Hippel, smoking vulva squamous carcinoma: HPV 16 and 18, hyperplastic dystrophy, Bowens immunosuppression vaginal squamous cancer: HPV types 16 and 18 vaginal clear cell carcinoma: diethylstilbestrol therapy cervical carcinoma: HPV types 16 and 18, early onset of sexual intercourse, multiple partners, immunosuppression by drugs, smoking endometrial adenocarcinoma: diabetes, obesity, hypertension, nulliparity, unopposed estrogen (oral, granulosa cell tumor, polycystic ovarian

syndrome, early menarche), familial cancer syndrome, history of breast cancer uterine mixed tumors: irradiation dysgerminoma and gonadoblastoma of the ovary: Turners syndrome endometrioid carcinoma of the ovary: endometriosis Integumentary System squamous and basal cell carcinoma of the skin: ultraviolet light, irradiation, arsenic, tars/soots/oils, xeroderma pigmentosum, immunosuppression malignant melanoma: ultraviolet light, xeroderma pigmentosum, dysplastic nevus syndrome, cellular blue nevus Kaposi sarcoma: ? HIV, ? HPV (putative) Breast adenocarcinoma: family history first generation, history of endometrial cancer, irradiation, family cancer syndrome, early menarche, late menopause, epithelial hyperplasia, lobular neoplasia, Klinefelters syndrome Musculoskeletal Syndrome osteogenic sarcoma: irradiation, Pagets disease, retinoblastoma chondrosarcoma: enchondromatosis lung cancer: dermatomyositis Central Nervous System / Special Senses astrocytoma: Turcots syndrome, tuberous sclerosis neurofibromas and meningiomas: neurofibromatosis retinoblastoma: deletion # 13 malignant lymphoma Hematopoietic System acute leukemia: irradiation, alkylating agents, Downs syndrome, chromosome instability syndromes chronic myelogenous leukemia: t9;22 (translocation); irradiation hairy cell leukemia : HTLV II T cell leukemia/lymphoma : HTLV I Burkitts lymphoma: t 8;14 (translocation); EBV Endocrine System pheochromocytoma: neurofibromatosis, Lindau von Hippel, MEN IIa and IIb parathyroid adenoma: MEN I and MEN IIa papillary carcinoma of the thyroid: irradiation pituitary adenoma: MEN I medullary carcinoma of the thyroid: MEN IIa and IIb malignant lymphoma of thyroid: Hashimotos thyroiditis NEOPLASIA REVIEW QUESTIONS 1. All of the following are examples of a hamartoma, EXCEPT: a. polyps in Peuta-Jeghers syndrome b. capillary hemangioma c. solitary nodule in the lung composed of benign cartilage d. benign pancreatic tissue in the wall of the stomach.

2.

Which of the following relationships is INCORRECT? a. Lymphoma - - malignant tumor originating from lymph nodes or lymphoid tissue. b. Seminoma - - germ cell tumor c. Mixed tumor - - two types of tissue in the tumor derived from two different cell layers d. Teratomas - - germ cell tumor with tissue derived from all three cell layers. e. Leukemia - - cancer arising from hematopoietic elements in the marrow. All of the following characterize a benign tumor EXCEPT: a. usually encapsulated b. well differentiated c. do not invade tissue d. do not metastasize e. loss of cell cohesiveness All of the following characterize a carcinoma EXCEPT: a. derive from epithelial structures b. more common than sarcomas c. metastasize hematogenously d. involve lymph nodes draining the tumor All of the following characterize sarcomas, EXCEPT: a. malignant tumor of mesenchymal origin b. metastasize to lymph nodes c. large, bulky tumors d. generally radioresistant Which one of the following putative virus - - cancer relationships is not completely correct? a. human papilloma virus - - cervical and anal squamous carcinoma b. Epstein Barr virus - - Burkitts lymphoma, nasopharyngeal carcinoma c. Hepatitis B virus - - hepatocellular carcinoma and angiosarcoma d. Hepatitis C virus - - hepatocellular carcinoma e. Human immunodeficiency virus - - Kaposi All of the following predispose to transitional cell carcinoma of the bladder EXCEPT: a. aniline dyes b. cyclophosphamide c. chromium d. smoking e. phenacetin All of the following predispose to angiosarcoma EXCEPT: a. birth control pills b. arsenic c. thorotrast d. vinyl chloride

3.

4.

5.

6.

7.

8.

9.

All of the following predispose to lung cancer EXCEPT: a. nickel b. uranium c. arsenic d. polycyclic hydrocarbons e. carbon monoxide Tobacco related products predispose to all of the following cancers, EXCEPT: a. pancreatic adenocarcinoma b. cervical carcinoma c. laryngeal carcinoma d. colon cancer e. verrucous cancer in the mouth Immunosuppression therapy for transplant patients frequently predisposes to: a. non-Hodgkins lymphoma b. squamous cancers c. both d. neither Parathormone secreting tumors include all of the following EXCEPT: a. renal adenocarcinoma b. hepatocellular carcinoma c. squamous carcinoma of the lung Increased erythropoietin is associated with all of the following EXCEPT: a. small cell carcinoma of the lung b. hepatocellular carcinoma c. cerebellar hemangioblastoma d. renal adenocarcinoma e. uterine leiomyomas An increase in beta hCG can be associated with all of the following EXCEPT: a. testicular tumors b. hydatidiform moles c. choriocarcinoma d. renal adenocarcinoma An increase in ACTH can be associated with all of the following EXCEPT: a. small cell carcinoma of the lung b. adrenal carcinoma c. medullary carcinoma of the thyroid Which of the following tumor marker relationships is INCORRECT? a. CEA - - recurrent colon cancer b. Calcitonin - - parathyroid carcinoma c. Alpha fetoprotein - - hepatocellular carcinoma and testicular tumors d. CA 19 9 - - pancreatic carcinoma e. CA 125 - - ovarian carcinoma Which one of the following oncogene relationships is INCORRECT?

10.

11.

12.

13.

14.

15.

16.

17.

a. b. c. d. 18.

c erb B-2 - - breast cancer n myc - - neuroblastoma c myc - - T cell leukemia c abl - - chronic myelogenous leukemia

Which of the following cancer types would you expect to be most common as a primary malignancy arising from the germinal follicles of a lymph node? a. T cell malignant lymphoma b. B cell malignant lymphoma c. Histiocytic lymphoma d. T cell leukemia e. B cell leukemia

19. A 15 year-old girl complains of abdominal pain. An x-ray of the abdomen reveals calcifications in the pelvic region. Which of the following tumors is MOST LIKELY responsible for the findings in this patient? a. Hamartoma b. Choristoma c. Teratoma d. Mixed tumor e. Sarcoma 20. All of the following characterize a malignant cell EXCEPT: a. abnormal mitotic spindles b. increased cell cohesion c. simple biochemical pathways d. irregular nuclear membranes e. lack of contact inhibition A pathologist described a tumor of the pancreas as follows . . .individual cells exhibit enlarged, hyperchromatic nuclei with prominent, irregular nucleoli. The cytoplasm of many of the cells contain a single, large vacuole, which pushes the nucleus to the periphery. Occasional cells infiltrate the perineural space. The surrounding stroma is desmoplastic. A single lymph node contains metastatic disease. Which of the following statements is INCORRECT concerning this report? a. The tumor is malignant b. The tumor most likely has a soft consistency c. The tumor is glandular in origin d. Staging information is provided in the report e. Grading information is provided in the report. Which of the following parameters is the BEST criteria of malignancy? a. Mitotic rate b. Size of the tumor c. Metastasis d. Degree of local invasion e. Ectopic hormone production

21.

22.

23.

Metastasis is more common than a primary cancer in all of the following sites EXCEPT: a. lung b. liver c. bone d. lymph node e. brain All of the following statements are true concerning MOST oncogenic retroviruses, EXCEPT: a. they contain reverse transcriptase b. they cannot both integrate and replicate in a cell without killing the cell c. they are RNA viruses All of the following statements are true concerning initiation of a tumor in chemical carcinogenesis, EXCEPT: a. it must precede promotion of a cell b. it is irreversible c. it produces a mutational event in the cell d. it causes proliferation of the transformed cell. All of the following are capable of killing neoplastic cells EXCEPT: a. natural killer cells b. cytotoxic T cells c. antibodies alone d. activated macrophages e. antibodies plus complement

24.

25.

26.

27. An elderly male has a hard mass palpated anteriorly on rectal exam. He complains of back pain and difficulty with voiding. The patient has a mild anemia, multiple densities in the vertebral column on x-ray, and an elevated acid phosphatase and alkaline phosphatase. Which of the following statements BEST explain (s) the findings in this patient? a. Prostate cancer b. Osteolytic metastases to bone c. Both statements are correct d. Neither statement is correct 28. The presence of both immature white blood cells and nucleated RBCs in the peripheral blood of a woman with known breast cancer is MOST LIKELY due to: a. ectopic secretion of erythropoietin by the tumor b. metastasis to bone c. a normal response of the marrow to cancer d. release of interleukin 1 by tumor cells.

29. All of the following statements characterize cachexia in a cancer patient, EXCEPT: A. muscle wasting b. reversibility with improced diet c. secretin of tumor necrosisi factor, alfa

d. 30.

generalized catabolic state

Which of the is/are true of most DNA oncogenic viruses? a. They can both integrate and replicate in a cell without killing the cell b. they induce host DNA to generate T antigen c. Both statements are true d. Neither statement is ture Which of the following cancers is Least likely to be associated with radiation exposure? a. Leukemia b. Squamous carcinoma of the skin c. Thyroid cancer d. Breast cancer e. Pancreatic cancer Which of the following cancers is frequently associated with gynecomastia in a male? a. small cell (oat cell) carcinoma of the lung b. Squamous cell carcinoma of the lung c. Choriocarcinoma d. Hepatocellular carcinoma e. Medullary carcinoma of the thyroid Coagulation abnormalities that may be associated with cancer include all of the following EXCEPT: a. an increase in platelets (thrombocytosis). b. venous thromboses c. a decrease in platelets (thrombocytopenia). d. disseminated intravascular coagulation e. loss of von Willebrands factor Hypercalcemia in a hospitalized patient is MOST COMMONLY due to a. primary hyperparathyroidism b. vitamin D intoxication c. malignancy d. sarcoidosis e. multiple myeloma Which of the following characterized carcinogenesis associated with heavy exposure to ultraviolet light? a. Formation of pyrimidine dimers in the DNA b. Chromosome deletions c. Inactivation of DNA repair enzymes d. Chromosome translocations e. Inactivation of suppressor genes Which of the following cancer groupings are properly listed in descending order of frequency of mortality in males? a. Prostate-lung colon b. Lung-colon-prostate

31.

32.

33.

34.

35.

36.

c. d. e. 37.

Prostate colon lung Lung prostate colon Colon lung prostate

Which of the following cancer groupings are properly listed in descending order of frequency of mortality in females? a. Breast lung colon b. Lung breast colon c. Breast colon lung d. Lung colon breast e. Colon lung prostate Which of the following tests is MOST responsible for a decline in cancer in women in the United States? a. Mammography b. Pap smear in females c. Chest x-ray d. CT scan e. Stool for occult blood. Which of the following statements apply (ies) to oncogenes? a. They can become activated by viruses, radiation, chemicals and translocations b. They frequently code fro growth factors or their receptors c. They are primarily located in the nucleus d. They are only found in individuals who are predisposed to cancer Anemia in malignancy could be the result of a. iron deficiency b. metastasis to the bone marrow c. chronic disease d. therapy Which of the following is/are paraneoplastic markers for an underlying malignancy? a. Secondary polycythemia b. Myasthenia-like syndrome c. Dermatomyositis d. Hypercalcemia Which of the following cancers characteristically spread (s) by peritoneal seeding? a. Acute leukemia b. Colon/appendiceal carcinoma c. Malignant melanoma d. Ovarian carcinoma

38.

39.

40.

41.

42.

1.

Answer: D - - choristoma, or heterotopic rests, refer to normal tissue in a place it should not be. It is not neoplastic. Hamartomas are a localized overgrowth of tissue normally present in the area. It is not neoplastic Answer: C - - mixed tumors have two types of tissue that derive from the same cell layer. Lymphomas are the most common primary cancer of lymphoid tissue. Germ cell tumors are totipotential tumors, meaning that they have the ability to develop into ectodermal, endodermal, or mesodermal tissue, as in a teratoma. As a rule, they are very radiosensitive tumors. Answer: E - -Loss of cell cohesiveness is a malignant feature Answer: C - -carcinomas metastasize by lymphatics, which drain into the lymph nodes. Sarcomas metastasize by invasion of vessels. Answer: B - - Sarcomas metastasize hematogenously to the lung, bone, etc. Answer: C - - HBV does not predispose to angiosarcoma Answer: C - - Chromium predisposes to nasopharyngeal carcinoma and lung cancer. Answer: A - - BCPs predispose to hepatocellular carcinoma, liver adenomas and focal nodular hyperplasia of the liver. Answer: E - - CO poisoning does not predispose to cancer. Answer: D - - to date, there is no relationship of smoking with colon cancer., Chewing tobacco predisposes to verrucous cancer in the mouth. Answer: C - - squamous cancers can be on the skin, cervix or other sites. Most lymphomas are of the immunoblastic type. Answer: B - -hepatocellular carcinomas ectopically secrete erythropoietin and an insulin like peptide Answer: A - - small cell carcinomas commonly secrete ADH and ACTH Answer: D - - renal adenocarcinomas secrete erythropoietin, PTH, renin, and gonadotropins. Answer: B - - adrenal carcinomas can secrete cortisol or 17-ketosteroids. Answer: B - - Calcitonin is a marker of medullary carcinoma of the thyroid, which is part of the MEN IIa and IIb syndrome. Answer: C - - the c-myc oncogene is associated with Burkitts lymphoma. Answer: B - - B cell malignant lymphoma - - B cells are in germinal follicles. T cell lymphomas arise from paracortical tissue. Leukemias originate from the hematopoietic tissue in the marrow, not lymph nodes.

2.

3. 4.

5. 6. 7.

8.

9. 10.

11.

12.

13. 14.

15. 16.

17. 18.

19.

Answer: C - - cystic teratomas commonly make teeth or bone, useful markers for the tumor. Answer: B - - cell cohesion is decreased, which accounts for their willingness to exfoliate in a smear (e.g. Pap smear) Answer: B - - desmoplasia indicates a fibroblastic response to the presence of tumor, so it would be hard and indurated. Perineural invasion and lymph node involvement provides staging information, while the presence of vacuoles indicates the grade as well to moderately well differentiated. Answer: C - - metastasis is unequivocal evidence of malignancy Answer: E - - in most series, only 25% of brain cancers are metastatic. Lymph nodes are the most common organ metastasized to. The subcapsular sinus is the first location for metastasis in the node. Answer: b - -as a rule, retroviruses can both integrate and replicate within a cell without killing it. This is not true of the HIV virus which kills the CD4 T helper cells. However, it can live and replicate in macrophages, its human reservoir. Answer: D - - promotion refers to proliferation of a transformed cell. Estrogen is a promoter. Answer: C - - antibodies without complement or an effector cell cannot kill neoplastic cells.

20.

21.

22. 23.

24.

25.

26.

27.

Answer: A - - osteoblastic metastases increase alkaline phosphatase because osteoblasts contain the enzyme, not osteoclasts. Answer: B - - this called leukoerythroblastic smear, meaning that both immature WBCs and nucleated RBCs are present in the smear. Answer: B - - this is considered an irreversible process Answer: B - - DNA viruses classically kill cells if they begin to replicate. Retroviruses, or RNA viruses, contain reverse transcriptase, since they must change their RNA into DNA. T antigen is the initiator of DNA viruses. Answer: E - - pancreatic cancer is unrelated to radiation exposure. Answer: c - - choriocarcinomas secrete beta hCG, which causes gynecomastia Answer: E von Willebrands factor is normal in malignancy. Most cancer patients are thrombogenic due to elevation of coagulation factors and platelets. Thrombocytopenia is most commonly due to chemotherapy, radiation, or metastasis of the tumor to the marrow. Any adult patient with unexplained thrombocytosis is suspect for malignancy.

28.

29. 30.

31. 32. 33.

34.

Answer: C - - there are 4 proposed mechanisms for hypercalcemia in malignancy - - secretion of a PTH like peptide (most common - - not the same as PTH; it does stimulate osteoclasts but does not produce the other effects such as a low phosphorous and bicarbonate); secretion of osteoclast activating factor by the tumor (really is interleukin 1); lysis of bone by the tumor itself; and secretion of prostaglandins, which mobilize calcium from bone. Answer: A - - this differs from other types of radiation, which produce free radicals that cause mutations in DNA Answer: D - - prostate cancer recently surpassed colon cancer for the number 2 position (14% vs 13%). Answer: B - - self explanatory Answer: B - - Cervical cancer is on the decline in the United States due to Pap smears. Endometrial cancers, however, are more common than cervical cancers, since they are more difficult to recognize than cervical cancer. Answer: A - - proto-oncogenes are found in all individuals and have normal functions. When they become activated, they become c-oncogenes, or cancer producing oncogenes. Answer: E - - all of the above - - self explanatory Answer: E - - all of the above are examples of paraneoplastic syndromes that frequently predate the clinical recognition of cancer. Answer: C - - tumors in cavities can spread by seeding if they break through the serosa (colon/appendix) or ovarian capsule.

35.

36.

37. 38.

39.

40. 41.

42.

CHEMOTHERAPY AGENTS (STUDY FOR BOARD) A. Antimetabolites 1. methotrexate is an antagonist of folic acid and inhibits dihydrofolate reductase a. effective in the S phase b. leucovorin rescue bypasses blocked dihydrofolate reductase to rebuild folate stored c. urine must be kept alkaline to avoid renal toxicity and crystalluria d. can produce a megaloblastic anemia; liver toxicity (fibrosis) e. resistance to the drug is enhanced by amplification of the gene that increases the synthesis of dihydrofolate reductase (most important), modifying the enzyme, a change in the carrier-mediated transport system of the drug into neoplastic cells. f. useful in the treatment of acute lymphoblastic leukemia, choriocarcinoma (single agent therapy), rheumatoid arthritis, and psoriasis. 2. 6-mercaptopurine is a purine analog that blocks purine synthesis a. effective in the S phase b. it exacerbates allopurinol toxicity c. converted into a nucleotide d. useful in the maintenance of remission of ALL 3. 5-fluorouracil is a pyrimidine analog that blocks the formation of thymidylic acid a. effective in the S phase and throughout the cell cycle b. commonly used in the therapy of colon cancer c. bone marrow suppression, mucositis, and diarrhea 4. cytarabine (ara C) is a pyrimidine antagonist that blocks DNA and RNA a. effective in the S phase b. primarily used in the therapy of acute myelogenous leukemia c. severe myelosuppression B. Antibiotics 1. dactinomycin, or actinomycin D, interferes with DNA synthesis a. effective in the S phase b. used in the treatment of Wilms tumor and choriocarcinoma c. severe myelosuppression 2. doxorubicin (Adriamycin) produces single strand breaks n DNA a. effective in S phase b. dose related cardiotoxicity (congestive cardiomyopathy) in 10% which is best evaluated by measuring the left ventricular ejection fraction. c. mitomycin potentiates its cardiotoxicity d. used in the treatment of ALL, breast and ling cancer, and Hodgkins disease 3. bleomycin breaks DNA by an oxidative process a. effective in the G2 phase b. pulmonary fibrosis is a side effect that is best monitored with CO diffusion studies. c. pulmonary hypersensitivity reaction

d. used in the treatment of testicular tumors e. not toxic to the marrow 4. plicamycin (mithramycin) restricts the function of DNA a. it is toxic to osteoclasts and lowers the serum calcium b. it produces a hemorrhagic diathesis 5. mitomycin restricts the function of DNA a. it can produce a microangiopathic hemolytic anemia, circulating immune complexes, and renal failure. b. it potentiates the action of doxorubicin c. it is used in the treatment of carious solid tumors C. Alkylating agents 1. mechlorethamine (nitrogen mustard) alkylates the guanine bases in DNA a. it was initially developed for chemical warfare b. it is part of the MOPP regimen for the treatment of Hodgkins disease (m for mustard) c. severe vomiting and marrow suppression occur 2. tamoxifen is an estrogen antagonist that binds to the estrogen receptor and thwarts its action in promoting RNA synthesis a. it is used in the treatment of breast cancer b. its side effects are similar to those of estrogen due to a mild estrogenic effect. 3. diethylstilbestrol is an estrogen compound that is used in the treatment of prostate cancer a. it competes with androgens for intracellular receptor sites, thus blocking the growth promoting activity of androgens on prostatic cancer b. it can produce gynecomastia and thromboembolic episodes 4. leuprolide is an analog of GnRH that inhibits the release of FSH and LH, thus reducing androgen synthesis a. it is used in the treatment of prostate cancer F. Interferons 1. interferons have the following functions a. they increase T cell activity b. they increase natural killer cells c. they increase macrophage killing d. they increase HLA expression and tumor associated antigens for easier recognition e. they decrease cell proliferation f. they decrease oncogene expression g. they decrease angiogenesis by tumor 2. interleukin 2 increases T cell proliferation, increases lymphokine activated killer cells. 3. alpha interferon is extremely useful in the treatment of hairy cell leukemia, Kaposi sarcoma, condyloma acuminata (veneraeal warts) and chronic viral hepatitis (particularly HCV). 4. gamma interferons are used to stimulate natural killer cells 5. tumor necrosis factor from macrophages inhibits the proliferation of tumor cells.

G. Monoclonal antibodies (MAB) 1. MABs are used in the diagnosis of tumors in surgical pathology and the therapy of tumors by antibody dependent cytotoxicity or as a vehicle for selective delivery of isotopes or toxic molecules to the site of tumor H. Cisplatin 1. cisplatin inhibits both DNA and RNA a. it is effective in G1 and S phases b. it is used in the treatment of testicular and bladder cancers c. it is nephrotoxic and is a magnesium waste in the urine d. it potentiates the nephrotoxic activity of the aminoglycosides I. Procarbazine 1. procarbazine inhibits DNA and RNA synthesis a. it is part of the MOPP regimen for Hodgkins disease b. it is mutagenic, teratogenic, and causes sterility c. it is contraindicated when taken with foods containing tyramine like cheese and wine (fermentative sources). J. L-Asparaginase 1. L-asparaginase hydrolyses blood asparagine so tumor cells are deprived of the nutrient for protein synthesis a. it lacks myelosuppression b. it is used to treat ALL along with prednisone and vincristine c. allergic reactions and fever occur K. Etoposide 1. Etoposide is a semisynthetic plant alkaloid that breaks DNA strands a. it block cells in late S-G2 phase b. it is used in the therapy of refractory testicular cancer and in small cell carcinoma of the lung L. Interleukins 1. interleukin 2 (from helper T cells) is used in treating metastatic renal adenocarcinoma 2. interleukin 3 (stimulates hematopoiesis) is useful in treating pure RBC aplasia (Blackfan Diamond syndrome), aplastic anemia and myelodysplastic syndrome. M. Colony stimulating factors 1. granulocyte colony stimulating factor is used for treating cyclic neutropenia and is also used in treating neutropenia in AIDS. 2. granulocyte-macrophage stimulating factor is used for myeloid reconstitution after autologous bone marrow transplantation or bone marrow transplantation failure.