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Pathology 1
Neoplasia
| Question | Answer |
|---|---|
| ______ rarely metastasizes; _______ is usually metastatic when first diagnosesd | basal cell carcinoma; osteosarcoma |
| 3 main routes of metastatic dissemination with most common examples for each | (1) SEEDING WITHIN BODY CAVITIES (ovarian and colon CA-->periotnal); 2. LYMPH (epithelial origin); 3. HEMATOGENOUS (most frequent for sarcomas; usually involves liver from abdominal organs and lung from head and neck |
| The US leads the world in incidence of _____ cancer. | colon |
| HCC is most common in ______ or where ____ infection is common, with likely contributing factors:_______ | far east/sub sah Africa; Hepatitis B; iron overlaod and aflatoxin |
| The incidence of prostate cancer is highest/lowest in... | highest (AA), lowest (Japanese men) |
| mesothelioma is caused by | asbestos |
| lung cancer can be caused by what 2 agents in occupational areas | asbestos and berylium |
| what can cause prostate and testicular cancer in occupational environments | cadmium |
| exposure to refrigerant or plastic adhesive can cause tumor of the ________ by what agent | tumors of liver, angiosarcoma, due to vinyl chloride |
| exposure to batteries which contain cadmium can cause | prostate or testicular cancer |
| missle fuel contains ____ which can cause? | berylium, lung cancer |
| angiosarcoma can be caused by exposure to what agent? | vinyl chloride |
| What cancers are more frequent in children? | Wilms tumor, osteosarcoma, astrocytomas, lymphoblastic lymphoma, acute leukemia (WOALA) |
| What cancers typically affect older people? | prostate cancer, follicular lymphoma, prostate cancer (PFChangs) |
| What are some of the herediatary neoplasms that are inherited as germ line mutations? | Rb, Familial adenomatous polyposis coli, multiple endocrine neoplasia 1 and 2, Li-Fraumeni syndrome (all Auto Dom) |
| What are some of the hereditary preneoplastic conditions? | aut recessive (precancerous): defective DNA repair |
| Features of Retinoblastoma | AD: bilateral retinoblastoma |
| Features of Familial adenomatous polyposis coli | AD: polyps and colon cancer |
| Features of multople endocrine neoplasia I and II | AD: endocrine gland adenomas |
| Features of LiFreumeni syndrome | AD: multiple cancers |
| Features of Defective DNA Repair (Hered Preneoplastic conditions) | AR: skin carcinoma |
| ___% of Rb's are familial? | 40% |
| Multiple Endocrine Neoplasia Syndrome Type 1 | adenomas of pituitary, parathyroids, pancreatic islets |
| Multiple Endocrine Neoplasia Syndrome Type 2 | parathyroids, medullary thyroid CA, pheochromocytoma |
| Multiple Endocrine Neoplasia Syndrome Type 2b | like 2, but parathyroid involvement is less common, and ganglioneuromas stud the GI tract |
| Von Recklinghausen's Neurofibromatosis | AD: nerve tumors, pheochromocytoma |
| pheochromocytomas associated with which 2 hereditary AD conditons: | von recklinghausens' NF, type 2 MENS |
| AR Hereditary prenoplastic defect in DNA repair mechanisms include | Xeroderma pigmentosum, predisposing for melanoma and basal cell carcinoma; Fanconi Anemia, Bloom Syndrome |
| Xeroderma pigmentosum predisposes for | melanoma and basal cell carcinoma |
| Acquired Preneoplastic disorders include | chronic skin fistula--> SCC; cirrhosis-->HCC, endometrial hyperplasia-->endomet adenocarcinoma; atrophic gastritis-->gastric sarcoma; villous adenoma--> colonic adenocarcinoma |
| Tumor progression refers to both: | growth and distant spread of CA, and how the front line cells become more aggressive and more resistant to therapy |
| How can clonality of a tumor be assessed? | In women, polymorphic markers can be used (XL marker G6PD or RFLP also X linked. |
| What are the 4 principal targets of genetic damage causing tumors? | protooncogenes, TSG's, apoptotic genes, DNA repair genes |
| oncogen-sis... | growth factor, overexpression, astrocytoma |
| oncogen-neu | growth factor receptor, amplification, breast and ovarian CA |
| oncogen-ras | signal transduction, point mutation, lung and colon CA |
| oncogen-abl | signal transduction, transloation, chronic myeloid leukemia |
| oncogen: c-myc | transcription factor, translocation, Burkitt's Lymphoma |
| oncogen: N-myc | transcription factor: amplification, neuroblastoma |
| oncogen cyclin D | cyclins, amplification, breast cancer |
| what does sis do? | it codes for the beta chain of PDGF which activates fibroblasts normally, the oncogen causes astrocytoma |
| growth factor receptor Neu (c-erb-B-2) is elevated in what? | 80% lung carcinomas, 30% breast cancers |
| What are the tyrosine kinase oncogene prototypes | ras and abl |
| what is the mechanism of disruption caused by ras? | most oncogenic ras mutations are point mutations in position 12, 13, or 61 that destroy GTPase activity and keep GTP binding activity locked on |
| what is the philadelphia chromosome | t(9,22) occuring in chronic myelocytic leukemia; c-abl is translocated from chromosome 9 to the bcr (breakpt cluster reg) of chr 22, and a chimeric bcr-abl protein is produced which has TK activity |
| the nuclear transcription factor oncogenes include: | myc, myb, jun, and fos, which have protein products that are intranuclear and bind DNA |
| t(8:14)c-myc is moved from 8 to Ig gene on 22 causing | Burkitt's Lymphoma |
| N-myc amplification is associated with waht | NF |
| cyclins are for promoting quiescent cell growth, which is ochrestrated by CDK; which is constituitively expressed? | CDK |
| explain the process of breast cancer or mantle cell lymphoma in association with Cyclin D and the retinoblastoma protein | at the beginning of the cell cycle cyclin D is produced which binds to CDK which phosphorylates Rb, which allows progression of cyclel ; overexpression of Cyclin D thus causes excessive cell cycle |
| How are protooncogenes transformed to oncogenes? | point mutations (ras), chromosomal translocations (BL c-myc; CML bcr-abl), gene amplification (of one gene) |
| how are gene amplifications seen by cytogeneticists? | homogenous staining or double minutes (Nueuroblastoma N-myc and Her2/neu amplification in 30% of breast carcinomas) |
| proto-oncogenes become oncogenes with ---mutations and TSG become oncogenic with ----. | 1, 2 |
| Knudson's 2 hit hypothesis: | 2 hits to TSG makes it carcinogenic; you can be born with 1 hit and then acquire the other, or acquire both after birth |
| What is the prototype of TSG? | Rb gene |
| what is the Rb susceptibility locus | RB1 in chromosome 13q14 |
| What is the difference between familial RB and sporadic retinoblastoma? | FRB is one germline mutation followed by a somatic mutation in the retina, SRB is 2 hits after birth (2 somatic mutations) |
| Loss of RB gene can be associated with? | RB (familial or sporadic), breast CA, osteosarcoma |
| Protein products of TSG's include? | Growth Inhibitory Factors (BRCA1), CELL Adhesion REg molecules (DCC, Ecadherin, APC), Molecules that reg ST (NF1 inactivates ras), Molecules that regulate nuclear transcription and cell cycle (Rb) |
| BRCA 1 ? | growth inhib factor gene, germline mutations in this gene are associated with 10% of all breast carcinomas (familal breast cancer) |
| DCC? | "deleted in colon carcinoma" gene that is infactivated in colon cancer, inolving cell2cell interaction and allows normal differentiation and development |
| Ecadherin? | involved in formation of intercellular junctions and is mutation in GASTRIC CARCINOMA |
| APC? | Adenomatous Polyposis Coli protein is linked to Ecadherin and patients with mutation in APC develop colonic adenomas, some of which turn malignant with a second hit |
| NF1? | encodes a GTPase enzyme that inactivates RAS thus controlling signal transduction |
| HPV? | forms transforming proteins believed to play a role in carcinoma of the cervix by binding to hypophosphorylated Rb and thus avoid that needs to bind transcription factors which remain free to cause cell division |
| what is the most common defective gene linked to many human cancers, including lung, breast, and colon? where is it located? | tp53, located on chr 17p13.1 |
| You have a young patient with cancer. What would you first suspect is the mutation? | mutation in p53 |
| In the Li-Fraumeni syndrome, what cancers are normally associated? | breast and sarcomas |
| tp53 is involved in most cancers, including LiFreumeni syndrome, what is the difference | in most cancers, both hits are most likely somatic, where in LiFreumeni one is germline |
| What is the function of tp53 gene product? | the sequence-specific binder to DNA that prevents mitosis during times of cell injury (mutagens, rad, chemical), allowing more time for DNA repair, this causes incr in p21, which inhibits CDK and arrests cells in the G1 phase; if DNA repair fails-apoptos |
| when tp53 accumulates what happens? | due to cell injury, p21 is formed, inhibits CDK, arrests cells in G1, signals repair, if no repair, tp53 stimulates apoptosis |
| DCC: subcellular location, function, associated tumor, germ line mutations cause? | cell surface, cell2cell intrx, colon/pancreas, ? |
| APC: subcellular location, function, associated tumor, germ line mutations cause? | under cell mem, stomach/colon, familial adenomatosis coli |
| NF: subcellular location, function, associated tumor, germ line mutations cause? | cytoplasm, unknown, schwannomas, NF |
| Rb:subcellular location, function, associated tumor, germ line mutations cause? | nucleus, cell cycle, RB, familial retinoblastoma |
| tp53: subcellular location, function, associated tumor, germ line mutations cause? | nucleus, cell cycle, most types of tumors, Li-Fraumeni |
| What are the genes that mediate apoptosis? | bcl-2, bax, bcl-x |
| what is the prototype of anti-apoptosis gene? | bcl-2 |
| follicular center cell lymphoma? | translocation of t(14;18) activating Bcl-2 |
| bcl-2 action promotes cell survival, what opposes bcl-2, promoting cell death | bax |
| how does tp53 cause apoptosis if DNA repair mechanisms fail? | by increasing expression of bax (pro-apoptotic) protein, which antagonizes bcl-2 |
| What are some examples of cancers that develop as a result of failed DNA repair mechanisms? | HNPCC (mismatch rep genes such as msh-2 proofread DNA misalignments and correct); Xeroderma Pigmentosum (nucleotide excision repair mechanism is lost and the crosslinking of pyrimidines caused by UV light prevents normal rep causing skin ca); bloom and FA |
| describe the order of proposed mutations in morphogenic and molecular changes in colon cancer? | initial event is homozygous loss and inactivation of APC (cells look normal), mutation and activation of ras (adenoma), homozygous loss of DCC (larger adenoma), and finally homozyg loss of tp53 (invasive carcinoma) |
| many cancers can by detected karyotypically. if it can be detected this way, they fall into 3 categories: | 1. balanced translocations, deletions, gene amplification |
| Karyotypic changes associated with balanced translocations invovle? | t(9;22) the philadelphia chr in CML and t(8;14) in BL [hematopoietic tumors] |
| Karyotypic changes associated with deletions invovle? | del 13q14 RB; del 3p in renal cell carcinoma, and small cell carcinoma; del 11p in Wilms tumor [solid tumors] |
| Karyotypic changes associated with gene amplification involve? | N-myc in neuroblastoma and her2.neu in breast cancer |
| which cancers can be detected karyotypically? | CML, BL, retinoblastoma, renal cell carc, small cell carc, breast cancer, neuroblastoma |
| what determines tumor kinetics? | doubling time, growth fraction, cell production and loss |
| why is it impt to determine the growth fraction of tumor cells? | because some antineoplastic drugs are more effective on dividing cells |
| What is special about BL treatment? | they are quickly dividing, so they're rapidly responsive to trx |
| Sometimes a combined modality treatment is necessary. What is an example? | colon cancer; tumor removal which stimulates remaining cells to move into G1, where drugs may work |
| Tumor cells usually secrete angiogenic factors. What is the most impt one? | bFGG (basic fibroblastic growth factor) and VEGF; which promotes matastisis |
| Explain the process of local and distant spread of a tumor? | INVASION of ECM (detach, loss of adh mol like ecadherin, attach to ECm laminin recep, degradation by MP/collagenase, migration by chemotaxis; VASC dissm (form emboli adhere and exit thru BM), HOMING usually to liver and lung |
| 3 categories of cancer etiologic agents? | chemicals, radiant energy, and oncogenic viruses |
| definition of carcinogen? | something missing an electron that can react with DNA and RNA |
| What are the major chemical carcingoens? | DIRECT (alkylating agents:antineo durgs: cyclophosphamide, chlorambucil, nitrosureas); PROCARC (req met act) polycyclinc aromatic hydrocarbons (benzathracene/benzopyrene; aromatic amines (naphylamine); natural plants (aflatoxin B1;aspergillus); others |
| polycyclic aromatic hydrocarbons | benzathracene, benzopyrene, present in fossil fuel and cigarette smoke [procarcinogens] |
| aromatic amines, amides, and azo dies | napthylamine (present in aniline dye |
| natural plants and microbial products? | alfatoxina B1 (produced by mold Aspergillus) |
| What procarcinogens cause lung cancer? | benzathracene, benzyopyrene |
| waht procarcinogens cause increase in bladder cancer | aromatic amines, amides and azo dyes (like naphylene) |
| What is the suspected mode of problem in chemical carcinogenesis? | disruption of ras, but others subsequently |
| Aflotoxin B is associated with? | HCC |
| what are the sources of carcinogenic radiation? | UV light, Xrays, nuclear fission, radionucleotides |
| UV light? | causes pyrimidine dimers (CC>TT) which are repaired unless of XP, causing skin ca (melanoma, sq cell carcinoma, and basal cell carcinoma) |
| RNA oncogenic viruses | HTLV-1 (only oncogenic retrovirus) associated with a T cell lymphoma endemic to Japan and Caribean basin Tropism for CD4 T cells |
| DNA oncogenic viruses | HPV (16, 18, genes E6E7; E7 binds to Rb; E6 inact p53 2 hits, but req more), EBV (BL, Bcell Lymp in AIDS, Hodgkins ds, nasophar carc), HBV(no transforming proteins, incudes liver regeneration, multifactorial) |
| What are the host defenses that protect against tumorogenesis? | (1) tumor ag (tum specific/tumor associated ag's); (2)Antitumor effectors (CTL-virus induced tumors, NK--kill without sensitization, Macr) (3) Immunsurveillance (most ca occur in IS people, so in healthy most tumors select non-immunogenic clones/decr MHC |
| Example of a tumor specific antigen | MEGA1 melanoma |
| Example of a tumor associated antigen | PSA in prostic carcinoma |
| What is the most likely explanantion for cancer pain? | bone invasion causing microfractures |
| What causes colicky pain? | obstruction of a hollow organ (ureter, gut) by a tumor |
| Nerve plexus association with tumors is less common, but which cancer does this the most? and what nerves does it affect? | pancreatic cancer, celiac plexus |
| What is cancer cachexia? | loss of body fat and lean body mass associated with weakness, anorexia, and anemia; usually more severe when metast (incr metab unlike starv); TNFa suppresses appetite |
| Paraneoplastic syndromes | syndromes that may develop from a tumor but hard to explain as a direct effect, maybe due to ectopic production of hormone or unknown immunologic mechanism (15% of pts with cancer develop paraneoplastic syndromes) |
| What are the most common paraneoplastic syndromes? | hypercalcemia and Cushing's syndrome |
| What are the most common neoplasms associated with paraneoplastic syndromes? | bronchogenic carcinoma and breat carcinoma, and hematologic malignancies |
| which has increased expression of collagenase? | benign breast tumors or breast carcinomas |
| Lung cancer can cause which paraneoplastic syndromes? | cushings syndrome, hypercalcemia, hypertrophic osteoarthropathy (unknown) |
| Renal cell carcinoma can cause what Paraneoplastic syndrome? | polycythemia (erythropoietin) |
| thymoma can cause what paraneoplastic syndrome? | myasthenia gravis (immne?) |
| pancreatic carcinoma can cause what paraneoplastic syndrome? | venous thrombosis (hypercoag) |
| Cushing's syndrome is associated with ectopic production of ? | ACTH |
| Hypercalcemia is associated with ectopic production of? | PTH |
| What finally kills the ca pt? | pneumonia (most common) usually by neutropenia (by tumor occupying BM or other immunosuprresion) Tumor nodules in the lung may also cause atelectasis, pleural effusion; sepsis is also common; hemorrhage, pulmonary thromboemboli (bedridden) |
| What is the tumor grade? | the degree of differentiation of a cancer cell, determined by the pathologist |
| Grading a tumor usually encompasses 3 levels: | Karyotypic changes associated with |
| What is staging a cancer? | defining how extensive or how widespread the tumor is--TNM system |
| What does TNM stand for in staging of cancer? | T (tumor: T1-->T4 for increasing size); N (node; N0-->N3); M (metasisis; M0-M1 indicating presence or absence of distant metastasis) |
| the TNM for a large lung cancer with metastasis to 2 nearby lymphnodes, metastasis to the brain might be? | T3N1M1 |
| Which is more clinical staging or grading? | staging |
Created by:
HSF2