5Tumorigenesis initiation promotion progression Initiating events such as gain of function of oncogenespromotionloss of function of tumor-suppressor genes may lead a single cell to acquire a distinct growth advantageprogressiondisease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior.Most tumors go through a progression from benign lesions to in situ tumors to invasive cancersMutations in at least four or five genes are required for formation of a malignant tumor, whereas fewer changes suffice for formation of a benign tumor
6OncogenesDesignated by three-letter abbreviations, such as myc or ras.Oncogenes are further designated by the prefix "v-" for virus or "c-" for cell or chromosome, corresponding to the origin of the oncogene when it was first detected.Oncogenes may begrowth factors - platelet-derived growth factorgrowth factor receptors - HER2intracellular signal transduction molecules - rasnuclear transcription factors - c-myc
7Oncogenes ras (k-ras) ret – medullary CA of thyroid erb B G Protein defectColon cancer, pancreatic cancerret – medullary CA of thyroiderb Bepidermal growth factor receptorBreast cancermyc (c-myc, n-myc, l-myc)Transcription factorsBurkitt’s lymphoma, nasopharyngeal CAc-kit – CML, Gastric leiomyoma (GIST)src- tyrosine kinase defectsis- PDGF receptor
11Cancer Invasionin situ cancer vs invasive cancer - tumors that breach the basement membraneglycoproteins of the ECM bind to tumor cell integrin receptorsSerine, cysteine, and aspartic proteinases and MMPsMMPs comprise a family of metal-dependent endopeptidasesActive in alsmost every cancer type
13Metastasis Metastasis is an inefficient process Must establish vascularization to sustain the new tumorOnly a small subset of cancer cells is able to initiate micrometastases, even smaller - macrometastases.
16Selected Genes/Cancers Hereditary Retinoblastoma (Rb1)led to the theory that a single mutation is not sufficient for tumorigenesis.hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutationsKnudson's "two-hit" hypothesis.A "hit" may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene.
17BRCA1, BRCA2Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in BRCA1 or BRCA2.Higher in patients such as in the Ashkenazi Jewish population.Cumulative risks of developing breast cancer and ovarian cancerBRCA 1– 87% and 44%BRCA 2- 84% and 27%Responsible for male breast CA
18APC Gene and Familial Adenomatous Polyposis Hundreds to thousands of polyps in the colon and rectum.Appear in adolescence progress to colorectal cancer.FAP is associated with benign extracolonic manifestationscongenital hypertrophyretinal pigment epitheliumepidermoid cysts, and osteomas.Also at risk forupper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer),hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma),thyroid carcinomas, desmoid tumors, and medulloblastomas.Gardner’s and Turcot’s
19Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis.DNA mismatch repair genesHNPCC consists of at least two syndromes:Lynch syndrome 1- colorectal cancerLynch syndrome 2- colorectal cancer + carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.Amsterdam Criteria
20Amsterdam Criteria (3-2-1 rule) At least 3 relatives with an HNPCC-associated cancer: colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis.At least two successive generations should be affectedAt least one tumor should be diagnosed <50 years of age
26Cancer Diagnosis Fine-needle aspiration Core-needle biopsy is easy and relatively safedisadvantage of not giving information on tissue architecture. Cannot differentiate between an invasive and noninvasive tumorCore-needle biopsyis more advantageous when the histologic findings will affect the recommended therapy.performed either by direct palpation or can be guided by an imaging studydisadvantage of introducing sampling errorOpen biopsieshave the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure.Incisional biopsies are reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy.Excisional biopsies are performed for lesions for which either core biopsy is not possible or the results are nondiagnostic. Should be performed with curative intent.
27Staging TNM staging For Absite, review: Breast Cancer Colon Cancer MelanomaLung cancer
29Prostate-Specific Antigen PSA is the best serum marker available with highest sensitivityPSA levels may be elevated in benign prostate conditions such as prostatitis and benign prostatic hyperplasia, as well as in men with prostate cancer.useful in evaluating treatment and monitoring for recurrence after therapy. In monitoring for recurrence, a trend of increasing levels is more significant than a single absolute elevated value.American Urologic Association and the American Cancer Society both recommend yearly PSA testing for men aged 50 years and oldertotal serum PSA level of 4 ng/mL should be used as a threshold for performing a prostate biopsy
30Surgical Management of Primary Tumors The goal of surgical therapy for cancer is to achieve oncologic cure.A curative operation presupposes that the tumor is confined to the organ of originPatients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease.The operability of primary tumors is best determined with imaging studies that can define the extent of local-regional disease.Primary tumors can be resected for palliative reasons, such as improving the quality of life by alleviating pain, infection, or bleeding.
31Surgical Management of Lymph Nodes Unlike most carcinomas, soft tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore lymph node surgery usually is not necessary.generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancersOn the other hand, there have been opposing opposing views regarding the role of lymphadenectomy in survival of cancer patients.
32Surgical Management of Lymph Nodes Relatively new developmentLymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by Cabanas for penile cancerLymphatic mappingisosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combination of both techniques to detect sentinel nodes.***There is no role for sentinel LN BX for clinically palpable nodes
33Surgical Management of Distant Metastases depends on the number and sites of metastases, the cancer type, the rate of tumor growthsuch therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain.25% 5 year survival for a single colonic met to liver if successfully resected.
34ChemotherapyClassified according to the phase of the cell cycle during which they are effective.Cell-cycle phase–nonspecific agents have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug.Cell-cycle phase–specific drugs have a plateau, and cell kill will not increase with further increases in drug doseMethotrexate and 5-FU are cell cycle specific, all others are non-specific
35Drug Mech of action Side FX Methotrexate Inhibits dihydrofolate reductaseinhibiting purine synthesisRenal toxicity5-Flourouracil(5-FU)Inhibits thymidylate synthesisCyclophosphamideAlkylating agentGonad dysfxn, SIADH, hemorrhagic cystitisIsofosfamideBisulfanPulmonary fibrosisCisplatinPlatinum alkylating agentNephro, neuro, ototoxicCarboplatinBone marrow surpressionVincristineMicrotubule inhibitorNeurotoxicVinblastineTaxolMicrotubule stabilizerEtopsideInhibits topoisomeraseBleomycinAntitumor antibioticDoxorubicin(O2 radical formation)Heart toxicitiyLevamisoleAntihelminthic drug, stimulates immune system
36Radiation TherapyM phase is most vunerable stage of cell cycle for XRTMost damage to DNA is done by formation of oxygen radicals with H2O2 intermediateMore oxygenated tumor = more damageLarge tumors less responsiveTo a lesser extent, ionizing radiation itself can cause direct DNA damageMost is external beam radiationBrachytherapy: source of radiation delivered directory into operative bed using catheters. Allows high concentrated radiation with fewer side effects.
37Radiation Therapy Fractional Doses Radiosensitive tumors: Allows repair of normal cellsAllows reoxygenation of tumorAllows redistribution of tumor cells in cell cycleRadiosensitive tumors:Seminomas, lymphomasRadioresistant tumorsEpithelial, Sarcomas