Neoplasia - BPPT SY2021-2022 PDF

NEOPLASIA BPPT SY2021-2022 OLFU CPT AC Dr Sonnie P. Talavera DEFINITION OF NEOPLASIA “A NEOPLASM IS AN ABNORMAL MASS OF TISSUE, THE GROWTH OF WHICH EXCEEDS AND IS UNCOORDINATED WITH THAT OF THE NORMAL TISSUES AND PERSISTS IN THE SAME EXCESSIVE MANNER AFTER CESSATION OF THE STIMULI WHICH E...

NEOPLASIA BPPT SY2021-2022 OLFU CPT AC Dr Sonnie P. Talavera DEFINITION OF NEOPLASIA “A NEOPLASM IS AN ABNORMAL MASS OF TISSUE, THE GROWTH OF WHICH EXCEEDS AND IS UNCOORDINATED WITH THAT OF THE NORMAL TISSUES AND PERSISTS IN THE SAME EXCESSIVE MANNER AFTER CESSATION OF THE STIMULI WHICH EVOKED THE CHANGE” - WILLIS GENETIC CHANGES AUTONOMOUS CLONAL CARCINOGENESIS - OVERVIEW NEOPLASIA IS AN ABNORMALITY OF CELL GROWTH AND MULTIPLICATION CHARACTERISED BY AT CELLULAR LEVEL EXCESSIVE CELLULAR PROLIFERATION UNCOORDINATED GROWTH TISSUE INFILTRATION AT MOLECULAR LEVEL DISORDER OF GROWTH REGULATORY GENES DEVELOPS IN A MULTISTEP FASHION  Naming Cancers Cancer Prefixes Point to Location Prefix Meaning adeno- gland chondro- cartilage erythro- red blood cell hemangio- blood vessels hepato- liver lipo- fat lympho- lymphocyte melano- pigment cell myelo- bone marrow myo- muscle osteo- bone NOMENCLATURE – BENIGN TUMORS -OMA = BENIGN NEOPLASM MESENCHYMAL TUMORS CHRONDROMA: CARTILAGINOUS TUMOR FIBROMA: FIBROUS TUMOR OSTEOMA: BONE TUMOR EPITHELIAL TUMOR ADENOMA: TUMOR FORMING GLANDS PAPILLOMA: TUMOR WITH FINGER LIKE PROJECTIONS PAPILLARY CYSTADENOMA: PAPILLALRY AND CYSTIC TUMOR FORMING GLANDS POLYP: A TUMOR THAT PROJECTS ABOVE A MUCOSAL SURFACE CHONDROMA LEIOMYOMA THYROID ADENOMA OVARIAN CYSTADENOMA THYROID ADENOMA Normal thyroid Papillary adenoma of colon ORAL PAPILLOMA Colon polyp NOMENCLATURE – MALIGNANT TUMORS SARCOMAS: MESENCHYMAL TUMOR CHRONDROSARCOMA: CARTILAGINOUS TUMOR FIBROSARCOMAMA: FIBROUS TUMOR OSTEOSARCOMA: BONE TUMOR CARCINOMAS: EPITHELIAL TUMORS ADENOCARCINOMA: GLAND FORMING TUMOR SQUAMOUS CELL CARCINOMA: SQUAMOUS DIFFERENTIATION UNDIFFERENTIATED CARCINOMA: NO DIFFERENTIATION NOTE: CARCINOMAS CAN ARISE FROM ECTODERM, MESODERM, OR ENDODERM CHONDROSARCOMA RHABDMYOSARCOMA ANGIOSARCOMA ADENOCARCINOMA SQUAMOUS CELL CARCINOMA Adenocarcinoma Undifferentiated Large Cell Carcinoma of the Lung  TUMORS WITH MIXED DIFFERENTIATION MIXED TUMORS: E.G. PLEOMORPHIC ADENOMA OF SALIVARY GLAND CARCINOSARCOMA TERATOMA TUMOR COMPRISED OF CELLS FROM MORE THAN ONE GERM LAYER ARISE FROM TOTIPOTENT CELLS (USUALLY GONADS) BENIGN CYSTIC TERATOMA OF OVARY IS THE MOST COMMON TERATOMA ABERRANT DIFFERENTIATION (NOT TRUE NEOPLASMS) HAMARTOMA: DISORGANIZED MASS OF TISSUE WHOSE CELL TYPES ARE INDIGINOUS TO THE SITE OF THE LESION, E.G., LUNG CHORIOSTOMA: ECTOPIC FOCUS OF NORMAL TISSUE (HETEROTOPIA), E.G., PANCREAS, PERHAPS ENDOMETRIOSIS TOO MISNOMERS HEPATOMA: MALIGNANT LIVER TUMOR MELANOMA: MALIGNANT SKIN TUMOR SEMINOMA: MALIGNANT TESTICULAR TUMOR LYMPHOMA: MALIGNANT TUMOR OF LYMPHOCYTES  1. MALIGNANT CHANGE IN THE TARGET CELL, REFERRED NATURAL TO AS TRANSFORMATION HISTORY OF 2. GROWTH OF THE MALIGNANT TRANSFORMED CELLS TUMORS 3. LOCAL INVASION 4. DISTANT METASTASES.  WELL DIFFERENTIATED NEOPLASM RESEMBLES MATURE CELLS OF TISSUE OF ORIGIN POORLY DIFFENTIATED NEOPLASM COMPOSED OF PRIMITIVE CELLS WITH LITTLE DIFFRERENTIATION DIFFERENTIATION UNDIFFERENTIATED OR “ANAPLASTIC” TUMOR CORRELATION WITH BIOLOGIC BEHAVIOR BENIGN TUMORS ARE WELL DIFFERENTIATED POORLY DIFFERENTIATED MALIGNANT TUMORS USUALLY HAVE WORSE PROGNOSIS  PLEOMORPHISM SIZE SHAPE ABNORMAL NUCLEAR MORPHOLOGY HYPERCHROMASIA “ANAPLASIA” HIGH NUCLEAR CYTOPLASMIC RATIO CANCER CHROMATIN CLUMPING PROMINENT NUCLEOLI MITOSES MITOTIC RATE LOCATION OF MITOSES LOSS OF POLARITY  LITERALLY MEANS ABNORMAL GROWTH MALIGNANT TRANSFORMATION IS A MULTISTEP PROCESS IN DYSPLASIA SOME BUT NOT ALL OF THE FEATURES OF MALIGNANCY ARE PRESENT, MICROSCOPICALLY DYSPLASIA MAY DEVELOP INTO DYSPLASIA MALIGNANCY UTERINE CERVIX COLON POLYPS GRADED AS LOW-GRADE OR HIGH- GRADE, OFTEN PROMPTING DIFFERENT CLINICAL DECISIONS DYSPLASIA MAY NOT DEVELOP INTO MALIGNANCY HIGH GRADE DYSPLASIA OFTEN CLASSIFIED WITH CIS  DOUBLING TIME OF TUMOR CELLS ✓ LENGTHENS AS TUMOR GROWS ✓ 30 DOUBLINGS (109 CELLS) = 1 G (MONTHS TO YEARS) ✓ 10 MORE DOUBLINGS (1 KG) = LETHAL BURDEN TUMOR FRACTION OF TUMOR CELLS IN REPLICATIVE POOL GROWTH ✓ MAY BE ONLY 20% EVEN IN RAPIDLY RATE GROWING TUMORS ✓ TUMOR STEM CELLS RATE AT WHICH TUMOR CELLS ARE SHED OR LOST ✓ APOPTOSIS ✓ MATURATION IMPLICATIONS FOR THERAPY “clonal” Schematic Representation Of Tumor Growth  CELLULAR FEATURES LOCAL INVASION CAPSULE FEATURES OF BASEMENT MEMBRANE MALIGNANT METASTASIS TUMORS UNEQUIVOCAL SIGN OF MALIGNANCY SEEDING OF BODY CAVITIES LYMPHATIC HEMATOGENOUS  EXAMPLE OF BREAST CANCER HALSTED RADICAL MASTECTOMY SENTINEL NODE BIOPSY PROGNOSTIC SIGNIFICANCE NUMBER OF INVOLVED NODES IS OF NODAL AN IMPORTANT COMPONENT OF TNM STAGING SYSTEM METS THERAPEUTIC OVERALL RISK OF RECURRENCE EXTENT OF NODAL INVOLVEMENT HISTOLOGIC GRADE AND OTHER CONSIDERATIONS “ADJUVANT” CHEMOTHERAPY  BENIGN VS MALIGNANT FEATURES Feature Benign Malignant Rate of growth Progressive but Variable. Mitoses slow. Mitoses few more frequent and and normal may be abnormal Differentiation Well differentiated Some degree of anaplasia Cohesive growth. Poorly cohesive LOCAL Capsule & BM and INVASION not breached infiltrative! Metastasis Absent May occur  Loss of Normal Growth Control Normal cell division Cell Suicide or Apoptosis Cell damage— no repair Cancer cell division First Second Third Fourth or mutation mutation mutation later mutation Uncontrolled growth  SUN EXPOSURE MELANOMAS 6X INCIDENCE NEW ZEALAND VS ICELAND BLACKS HAVE LOW INCIDENCE OF MELANOMA, SO DO NORMALLY PIGMENTED AREAS LIKE AREOLAE ON WHITE PEOPLE SMOKING AND ALCOHOL ABUSE BODY MASS GEOGRAPHIC & OVERWEIGHT = 50% INCREASE IN CANCER ENVIRONMENTAL ENVIRONMENTAL VS RACIAL FACTORS JAPANESE IMMIGRANTS TO USA VIRAL EXPOSURE HUMAN PAPILLOMA VIRUS (HPV) AND CERVICAL CANCER HEPATITIS B VIRUS (HBV) AND LIVER CANCER (AFRICA, ASIA) EPSTEIN-BARR VIRUS (EBV) AND LYMPHOMA Avoid Carcinogens at Work  AGE MOST CANCERS OCCUR IN PERSONS ≥ 55 YEARS CHILDHOOD CANCERS LEUKEMIAS & CNS NEOPLASMS PREDISPOSING BONE TUMORS FACTORS FOR GENETIC PREDISPOSTION CANCER FAMILIAL CANCER SYNDROMES EARLY AGE AT ONSET TWO OR MORE PRIMARY RELATIVES WITH THE CANCER MULTIPLE OR BILATERAL TUMORS POLYMORPHISMS THAT METABOLIZE PROCARCINOGENS, E.G., NITRITES  NONHEREDITARY PREDISPOSING CONDITIONS CHRONIC INFLAMMATION? PRECANCEROUS CONDITIONS PREDISPOSING CHRONIC ULCERATIVE COLITIS FACTORS FOR CANCER ATROPHIC GASTRITIS OF PERNICIOUS ANEMIA LEUKOPLAKIA OF MUCOUS MEMBRANES IMMUNE COLLAPSE?  CHRONIC ATROPHIC GASTRITIS OF PERNICIOUS ANEMIA SOLAR KERATOSIS OF THE PRECANCEROUS SKIN CONDITIONS. CHRONIC ULCERATIVE COLITIS LEUKOPLAKIA OF THE ORAL CAVITY, VULVA, AND PENIS  1. PERMANENT CELLS- OUT OF THE CELL CYCLE NEURONS, CARDIAC MUSCLE CELL 2. STABLE CELLS- DORMANT/RESTING NORMAL (G0) CELL LIVER, KIDNEY CYCLE 3. LABILE CELLS- CONTINUOUSLY DIVIDING GIT CELLS, SKIN, ENDOMETRIUM , BLOOD CELLS CELL CYCLE G0------------------G1→S→G2→M G0- DORMANT OR RESTING G1- NORMAL CELL ACTIVITIES S- DNA SYNTHESIS G2- PRE-MITOTIC, SYNTHESIS OF PROTEINS FOR CELLULAR DIVISION M- MITOTIC PHASE (I-P-M-A-T)  PROPOSED MOLECULAR CAUSE OF CANCER: CHANGE IN THE DNA STRUCTURE → ALTERED DNA FUNCTION → CELLULAR ABERRATION CANCER → CELLULAR DEATH → NEOPLASTIC CHANGE GENES IN THE DNA “PROTO-ONCOGENE” AND “ANTI- ONCOGENE”  ULTIMATE OUTCOME OF ALL GROWTH-PROMOTING STIMULI -- CELL CYCLE. CYCLINS CANCERS GROW AND AUTONOMOUSLY CYCLIN- GENES THAT DRIVE THE CELL DEPENDENT CYCLE BECOME DYSREGULATED KINASES. MUTATIONS OR AMPLIFICATION. MUTATIONS THAT DYSREGULATE THE ACTIVITY OF CYCLINS AND CDKS FAVOR CELL PROLIFERATION. NORMAL CELL CYCLE PHASES INHIBITORS: Cip/Kip, INK4/ARF Tumor (really growth) suppressor genes: p53  G1/S CHECKPOINT CHECKS FOR DNA DAMAGE IF DAMAGE IS PRESENT DNA-REPAIR MACHINERY AND CYCLINS MECHANISMS THAT ARREST THE CELL CYCLE ARE PUT IN MOTION---DNA AND REPAIR IF THE DAMAGE IS NOT REPAIRABLE CYCLIN- APOPTOTIC PATHWAYS ARE ACTIVATED DEPENDENT TO KILL THE CELL. KINASES. PREVENTS THE REPLICATION OF CELLS THAT HAVE DEFECTS IN DNA PERPETUATED AS MUTATIONS OR CHROMOSOMAL BREAKS DNA DAMAGED AFTER ITS REPLICATION REPAIRED AS LONG AS THE CHROMATIDS HAVE NOT SEPARATED  G2/M CHECKPOINT MONITORS THE COMPLETION OF DNA REPLICATION CYCLINS CHECKS -- CELL CAN SAFELY AND INITIATE MITOSIS AND SEPARATE SISTER CHROMATIDS. CYCLIN- DEPENDENT IMPORTANT IN CELLS EXPOSED TO IONIZING RADIATION KINASES. ACTIVATE THE G2/M CHECKPOINT AND ARREST IN G2 DEFECTS IN THIS CHECKPOINT GIVE RISE TO CHROMOSOMAL ABNORMALITIES  CHECKPOINT EFFECTOR MOLECULES DIFFER, DEPENDING ON THE CELL CYCLINS CYCLE STAGE AT WHICH THEY ACT AND G1/S CHECKPOINT CYCLIN- P53---INDUCES THE CELL CYCLE INHIBITOR P21 DEPENDENT G2/M CHECKPOINT KINASES. P53-DEPENDENT AND P53- INDEPENDENT MECHANISMS DEFECTS IN CELL CYCLE CHECKPOINT COMPONENTS MAJOR CAUSE OF GENETIC INSTABILITY IN CANCER CELLS.  NON-LETHAL GENETIC DAMAGE A TUMOR IS FORMED BY THE CLONAL EXPANSION OF A SINGLE PRECURSOR CELL MOLECULAR (MONOCLONAL) BASIS FOUR CLASSES OF NORMAL OF REGULATORY GENES CANCER PROTO-ONCOGENES ONCOGENES→ ONCOPROTEINS DNA REPAIR GENES APOPTOSIS GENES CARCINOGENESIS IS A MULTISTEP PROCESS  ARE MUTATIONS OF NORMAL GENES (PROTO- ONCOGENES) GROWTH FACTORS GROWTH FACTOR RECEPTORS ONCOGENES SIGNAL TRANSDUCTION PROTEINS (RAS) NUCLEAR REGULATORY PROTEINS CELL CYCLE REGULATORS ONCOGENES CODE FOR ➔ ONCOPROTEINS NORMAL CELL Growth factor Growth factor receptor cytoplasm Signal transduction Activation of transcription nucleus  point mutation HOW DOES PROTO- ONCOGENE GET translocation ACTIVATED? gene amplification  PROTO- Mode of Associated Human Category Oncogene Activation Tumor GFs PDGF-β chain SIS Overexpression Astrocytoma Osteosarcoma Fibroblast HST-1 Overexpression Stomach cancer growth factors INT-2 Amplification Bladder cancer Breast cancer Melanoma TGFα TGFα Overexpression Astrocytomas Hepatocellular  PROTO- Mode of Associated Human Category Oncogene Activation Tumor GF Receptors EGF-receptor ERB-B1 Overexpression Squamous cell carcinomas of family (ECFR) lung, gliomas ERB-B2 Amplification Breast and ovarian cancers CSF-1 receptor FMS Point mutation Leukemia Receptor for RET Point mutation Multiple endocrine neoplasia 2A neurotrophic and B, familial medullary thyroid factors carcinomas PDGF receptor PDGF-R Overexpression Gliomas Receptor for stem KIT Point mutation Gastrointestinal stromal tumors cell (steel) factor and other soft tissue tumors  PROTO- Mode of Associated Human Category Oncogene Activation Tumor Signal Transduction Proteins GTP-binding K-RAS Point mutation Colon, lung, and pancreatic tumors H-RAS Point mutation Bladder and kidney tumors N-RAS Point mutation Melanomas, hematologic malignancies Nonreceptor ABL Translocation Chronic myeloid leukemia tyrosine kinase Acute lymphoblastic leukemia RAS signal BRAF Point mutation Melanomas transduction WNT signal β-catenin Point mutation Hepatoblastomas, transduction hepatocellular carcinoma  Mode of PROTO- Activation Associated Human Category Oncogene Tumor Nuclear Regulatory Proteins Transcrip. C-MYC Translocation Burkitt lymphoma activators N-MYC Amplification Neuroblastoma, small cell carcinoma of lung L-MYC Amplification Small cell carcinoma of lung  Encodes for transcription factors MYC Also involved with apoptosis P53 AND RAS P53 RAS ACTIVATES DNA REPAIR H, N, K, ETC., VARIETIES PROTEINS SINGLE MOST COMMON SENTINEL OF G1/S ABNORMALITY OF TRANSITION DOMINANT ONCOGENES IN HUMAN TUMORS INITIATES APOPTOSIS MUTATED IN MORE THAN PRESENT IN ABOUT 1/3 OF ALL HUMAN 50% OF ALL HUMAN CANCERS CANCERS  TGF-Β → COLON E-CADHERIN → STOMACH NF-1,2 → NEURAL TUMORS TUMOR APC/Β-CADHERIN → GI, MELANOMA (REALLY SMADS → GI “GROWTH”) RB → RETINOBLASTOMA SUPPRESSOR P53 → EVERYTHING!! GENES WT-1 → WILMS TUMOR P16 (INK4A) → GI, BREAST (MM IF INHERITED) BRCA-1,2 → BREAST KLF6 → PROSTATE  BCL-2 EVASION OF APOPTOSIS p53 MYC  DNA REPAIR IS LIKE A SPELL CHECKER HNPCC (HEREDITARY NON-POLYPOSIS COLON CANCER): TGF-Β, Β-CATENIN, DNA BAX REPAIR XERODERMA PIGMENTOSUM: UV FIXING GENE GENE ATAXIA TELANGIECTASIA: ATM GENE DEFECTS BLOOM SYNDROME: DEFECTIVE HELICASE FANCONI ANEMIA  TELOMERES determine the limited number of duplications a cell will have, like a cat with nine LIMITLESS lives. REPLICATIVE POTENTIAL TELOMERASE, present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential TRANSFORMATION & PROGRESSION SELF-SUFFICIENCY IN GROWTH SIGNALS INSENSITIVITY TO GROWTH-INHIBITING SIGNALS EVASION OF APOPTOSIS DEFECTS IN DNA REPAIR: “SPELL CHECKER” LIMITLESS REPLICATIVE POTENTIAL: TELOMERASE ANGIOGENESIS INVASIVE ABILITY METASTATIC ABILITY  HOW CLOSE TO A BLOOD VESSEL MUST A CELL BE? 1-2 MM TUMOR ACTIVATION OF VEGF AND FGF-B ANGIOGENESIS TUMOR SIZE IS REGULATED (ALLOWED) BY ANGIOGENESIS/ANTI- ANGIOGENESIS BALANCE TRANSFORMATION→ GROWTH→ BM INVASION→ ANGIOGENESIS→ INTRAVASATION→ EMBOLIZATION→ ADHESION→ EXTRAVASATION→ METASTATIC GROWTH→ ETC.  DETACHMENT ("LOOSENING UP") OF THE TUMOR CELLS FROM EACH OTHER INVASION ATTACHMENT TO MATRIX COMPONENTS FACTORS DEGRADATION OF ECM, E.G., COLLAGENASE, ETC. MIGRATION OF TUMOR CELLS  NM23 METASTATIC GENES? KAI-1 KISS CHROMOSOME CHANGES IN CANCER TRANSLOCATIONS AND INVERSIONS OCCUR IN MOST LYMPHOMAS/LEUKEMIAS OCCUR IN MANY (AND GROWING NUMBERS) OF NON-HEMATOLOGIC MALIGNANCIES ALSO Malignancy Translocation Affected Genes Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34 bcr 22q11 Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21 MLL 11q23 (6;11)(q27;q23) AF6 6q27 MLL 11q23 Burkitt lymphoma (8;14)(q24;q32) c-myc 8q24 IgH 14q32 Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13 IgH 14q32 Follicular lymphoma (14;18)(q32;q21) IgH 14q32 bcl-2 18q21 T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc 8q24 TCR-α 14q11 (10;14)(q24;q11) Hox 11 10q24 TCR-α 14q11 Ewing sarcoma (11;22)(q24;q12) Fl-1 11q24  NO SINGLE ONCOGENE CAUSES CANCER BOTH SEVERAL ONCOGENES AND SEVERAL TUMOR SUPPRESSOR GENES MUST BE INVOLVED CARCINOGENESIS GATEKEEPER/CARETAKER CONCEPT IS “MULTISTEP” GATEKEEPERS: ONCOGENES AND TUMOR SUPPRESSOR GENES CARETAKERS: DNA REPAIR GENES TUMOR “PROGRESSION” ANGIOGENESIS HETEROGENEITY FROM ORIGINAL SINGLE CELL  FAILURE OF IMMUNE SURVEILLANCE CONCEPTS NEOPLASTIC CHANGES FREQUENTLY OCCUR IN CELLS CARCINOGENESIS HYPOTHESES OF THE ALTERED DNA RESULT IN ORIGIN OF PRODUCTION OF NEOANTIGENS & NEOPLASIA TUMOR-ASSOCIATED ANTIGENS IMMUNE RESPONSE (CYTOTOXIC) TO NEOANTIGENS AS FOREIGN ANTIGENS NEOPLASTIC CELLS ESCAPING RECOGNITION AND DESTRUCTION BECOME CLINICAL CANCERS  1. T CELL SYSTEM/ CELLULAR IMMUNITY CYTOTOXIC T CELLS KILL TUMOR BODY CELLS DEFENSES 2. B CELL SYSTEM/ HUMORAL IMMUNITY AGAINST B CELLS CAN PRODUCE ANTIBODY TUMOR 3. PHAGOCYTIC CELLS MACROPHAGES CAN ENGULF CANCER CELL DEBRIS  IMMUNE SURVEILLENCE CONCEPT CD8+ T-Cells HOST NK cells DEFENSES MACROPHAGES ANTIBODIES CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells  MUTATION, LIKE MICROBES ↓ MHC MOLECULES ON TUMOR CELL SURFACE LACK OF CO-STIMULATION HOW DO TUMOR CELLS MOLECULES, E.G., (CD28, ESCAPE IMMUNE ICOS), NOT JUST AG-AB SURVEILLANCE? RECOGNITION IMMUNOSUPPRESSIVE AGENTS ANTIGEN MASKING APOPTOSIS OF CYTOTOXIC T- CELLS (CD8), I.E., THE DAMN TUMOR CELL KILLS THE T-CELL!  INITIATION/PROMOTION CONCEPT: BOTH INITIATORS AND PROMOTORS ARE NEEDED NEITHER CAN CAUSE CANCER BY CARCINOGENESIS: ITSELF THE USUAL (3) SUSPECTS INITIATORS (CARCINOGENS) CAUSE MUTATIONS PROMOTORS ARE NOT CARCINOGENIC BY THEMSELVES, AND MUST TAKE EFFECT AFTER INITIATION, NOT BEFORE PROMOTORS ENHANCE THE PROLIFERATION OF INITIATED CELLS  CHEMICAL CARCINOGENESIS TYPES PROXIMATE OR DIRECT-ACTING CARCINOGENESIS : ACT LOCALLY WITHOUT AGENTS CAUSING METABOLIC CHANGE NEOPLASM INDIRECT ACTING : CARCINOGENIC ONLY AFTER BEING METABOLISED INTO ACTIVE COMPOUNDS (PROCARCINOGEN → ULTIMATE CARCINOGEN)  CHEMICAL CARCINOGENS: INITIATORS DIRECT “PRO”CARCINOGENS POLYCYCLIC AND HETEROCYCLIC AROMATIC Β-PROPIOLACTONE HYDROCARBONS DIMETH. SULFATE AROMATIC AMINES, AMIDES, AZO DYES DIEPOXYBUTANE NATURAL PLANT AND MICROBIAL PRODUCTS ANTICANCER DRUGS (CYCLOPHOSPHAMIDE, AFLATOXIN B1→ HEPATOMAS CHLORAMBUCIL, NITROSOUREAS, AND OTHERS) GRISEOFULVIN→ ANTIFUNGAL ACYLATING AGENTS CYCASIN→ FROM CYCADS 1-ACETYL-IMIDAZOLE SAFROLE→ FROM SASSAFRAS DIMETHYLCARBAMYL CHLORIDE BETEL NUTS→ ORAL SCC  OTHERS NITROSAMINE AND AMIDES (TAR, NITRITES) VINYL CHLORIDE→ ANGIOSARCOMA IN KENTUCKY NICKEL CHEMICAL CHROMIUM CARCINOGENS INSECTICIDES : INITIATORS FUNGICIDES POLYCHLORINATED BIPHENYLS (PCBS)  HORMONES PHORBOL ESTERS (TPA), ACTIVATE KINASE C CHEMICAL CARCINOGENS: PHENOLS PROMOTORS DRUGS, MANY “Initiated” cells respond and proliferate FASTER to promotors than normal cells  UV: BCC, SCC, MM (I.E., ALL 3) IONIZING: PHOTONS AND PARTICULATE HEMATOPOETIC AND THYROID RADIATION (90%/15YRS) TUMORS IN FALLOUT CARCINOGENS VICTIMS SOLID TUMORS EITHER LESS SUSCEPTIBLE OR REQUIRE A LONGER LATENCY PERIOD THAN LEUK/LYMPH BCCS IN THERAPEUTIC RADIATION  RADIATION TYPES OF ONCOGENIC RADIATION ULTRAVIOLET CARCINOGENESIS X-RAY AGENTS CAUSING RADIOISOTOPES NEOPLASM NUCLEAR FALLOUT MODE OF ONCOGENESIS DIRECT EFFECT ON DNA ACTIVATION OF CELLULAR ONCOGENES  UV RADIATION SOLAR UV RADIATION ASSOCIATED WITH SKIN CANCERS – SQUAMOUS CA, BASAL CELL CA, CARCINOGENESIS MALIGNANT MELANOMA AGENTS CAUSING NEOPLASM FAIR-SKINNED AND ELDERLY ARE SUSCEPTIBLE UV LIGHT IS BELIEVED TO INDUCE CROSS-LINKAGES BETWEEN DNA MOLECULES AND CA OCCURS WHEN REPAIR MECHANISMS ARE NOT EFFICIENT  X-RAY RADIATION EARLIER USE OF X-RAYS CAUSED SKIN CANCER, LEUKEMIA AND PAPILLARY THYROID CA CARCINOGENESIS RADIOTHERAPY CAUSES RADITATION- AGENTS CAUSING INDUCED MALIGNANCY 10-30 YRS NEOPLASM LATER – USUALLY SARCOMAS DIAGNOSTIC X-RAYS ARE CONSIDERED TO HAVE NO INCREASED RISK EXCEPT IN ABDOMINAL X-RAYS WHICH INCREASE INCIDENCE OF LEUKEMIA IN THE FETUS  RADIOISOTOPES OSTEOSARCOMA COMMON AMONG FACTORY WORKERS WHO USE RADIUM- CONTAINING PAINTS RADIOACTIVE MINERAL MINING IN CARCINOGENESIS AGENTS CAUSING EUROPE AND USA ASSOCIATED WITH NEOPLASM LUNG CANCER THORIUM INCREASES RISK OF LIVER CANCER – HEPATOCELLULAR, ANGIOSARCOMA, CHOLANGIOCARCINOMA RADIOACTIVE IODINE – INCREASED RISK OF CANCER 15-25 YEARS LATER  NUCLEAR FALLOUT HIROSHIMA, NAGASAKI (ATOMIC BLASTS) CARCINOGENESIS MARSHALL ISLANDS AGENTS CAUSING NEOPLASM (ATMOSPHERIC TESTING OF NUCLEAR DIVIDE CONTAINING RADIOACTIVE IODINE) CHERNOBYL, 1986 CARCINOGENESIS AGENTS CAUSING NEOPLASM VIRAL ONCOGENESIS TYPES ONCOGENIC RNA VIRUSES ONCOGENIC DNA VIRUSES MODE OF ONCOGENESIS RNA VIRUS DNA VIRUS  VIRAL ONCOGENE HYPOTHESIS RNA RETROVIRUS – PRODUCES DNA PROVIRUS DNA PROVIRUS CONTAINING VIRAL ONCOGENE (V-ONC) IS INTRODUCED IN CARCINOGENESIS HOST CELL DNA HYPOTHESES OF THE RNA VIRUSES IS THOUGHT TO HAVE ORIGIN OF ACQUIRED V-ONC SEQUENCE BY NEOPLASIA RECOMBINANT MECHANISM FROM ANIMAL CELLS DNA VIRUS DO NOT CONTAIN VIRAL ONCOGENES ACT BY BLOCKING SUPPRESSOR GENE PRODUCTS EXAMPLES – HPV, EBV,HBV  HPV→ SCC EBV→ BURKITT LYMPHOMA VIRAL CARCINOGENESIS HBV→ HEPATOCELLULAR CARCINOMA (HEPATOMA) HTLV1→ T-CELL MALIGNANCIES KSHV→ KAPOSI SARCOMA  DETECTION OF VIRAL GENOME IDENTIFICATION OF VIRAL-SPECIFIC NUCLEIC ACID SEQUENCES BY CARCINOGENESIS HYBRIDISATION WITH DNA/RNA AGENTS CAUSING PROBES NEOPLASM RECOGNITION OF VIRUS-SPECIFIC ANTIGENS ON INFECTED CELLS DETECTION OF VIRUS-SPECIFIC MRNA  100% OF GASTRIC LYMPHOMAS (I.E., M.A.L.T.-OMAS) H. PYLORI CARCINOGENESIS GASTRIC CARCINOMAS  HORMONAL DEPENDENCE OF NEOPLASMS NEOPLASM NOT CAUSED BY HORMONES BUT DEPEND ON HORMONES FOR OPTIMAL GROWTH CARCINOGENESIS NEOPLASTIC CELLS POSSESS AGENTS CAUSING RECEPTORS FOR BINDING NEOPLASM HORMONE LOSS OF HORMONAL STIMULATION SLOW BUT DOES NOT HALT GROWTH EXAMPLES PROSTATE CA BREAST CA THYROID CA  HORMONAL ONCOGENESIS TYPES INDUCTION OF NEOPLASMS BY CARCINOGENESIS HORMONES AGENTS CAUSING NEOPLASM DEPENDENCE OF NEOPLASMS ON HORMONES HORMONES INDUCING NEOPLASMS ESTROGEN – BREAST CA DIETHYLSTILBESTROL (DES) – VAGINAL AND UTERINE CA  6 - GENETIC ONCOGENESIS (ROLE OF INHERITANCE) TYPES CARCINOGENESIS MENDELIAN INHERITANCE AGENTS CAUSING NEOPLASM POLYGENIC INHERITANCE ASSOCIATION WITH INHERITED DISEASES MENDELIAN INHERITANCE DOMINANT RECESSIVE  POLYGENIC INHERITANCE CARCINOGENESIS NEOPLASMS OCCURING IN AGENTS CAUSING RELATED INDIVIDUALS MORE NEOPLASM OFTEN THAN EXPECTED ON THE BASIS OF CHANCE BREAST CA COLON CA  EXAMPLES RETINOBLASTOMA WILM’S TUMOR CARCINOGENESIS AGENTS CAUSING OTHERS NEOPLASM NEUROFIBROMATOSIS (TYPE 1 VON RECKLINGHAUSEN’S DISEASE) MULTIPLE ENDOCRINE ADENOMATOSIS (MEN) FAMILIAL POLYPOSIS COLI NEVOID BASAL CELL CARCINOMA SYNDROME  ASSOCIATION WITH INHERITED DISEASES MANY INHERITED DISEASES ARE CARCINOGENESIS AGENTS CAUSING ASSOCIATED WITH HIGHER RISK OF NEOPLASM NEOPLASIA TYPES : SYNDROMES CHARACTERISED BY INCREASED CHROMOSOMAL FRAGILITY SYNDROMES OF IMMUNODEFICIENCY  CLINICAL MANIFESTATION AND CANCER STAGING  LOCATION→ ANATOMIC ENCROACHMENT EFFECTS HORMONE PRODUCTION OF TUMOR BLEEDING, INFECTION ON THE ACUTE SYMPTOMS, E.G., HOST RUPTURE, INFARCTION METASTASES CACHEXIA REDUCED DIET: FAT LOSS>MUSCLE LOSS CACHEXIA: FAT LOSS AND MUSCLE LOSS TNF (Α BY DEFAULT) IL-1 PIF (PROTEOLYSIS INDUCING FACTOR)  PARA-NEOPLASTIC SYNDROMES ENDOCRINE NERVE/MUSCLE, E.G., MYASTHENIA W. LUNG CA. SKIN: E.G., ACANTHOSIS NIGRICANS, DERMATOMYOSITIS BONE/JOINT/SOFT TISSUE: HPOA (HYPERTROPHIC PULMONARY OSTEOARTHROPATHY) VASCULAR: TROUSSEAU, ENDOCARDITIS HEMATOLOGIC: ANEMIAS RENAL: E.G., NEPHROTIC SYNDROME  ENDOCRINE Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance Pancreatic carcinoma Neural tumors Syndrome of inappropriate Small cell carcinoma of lung; Antidiuretic hormone or atrial antidiuretic hormone intracranial neoplasms natriuretic hormones secretion Parathyroid hormone-related protein Hypercalcemia Squamous cell carcinoma of lung (PTHRP), TGF-α, TNF, IL-1 Breast carcinoma Renal carcinoma Adult T-cell leukemia/lymphoma Ovarian carcinoma Hypoglycemia Fibrosarcoma Insulin or insulin-like substance Other mesenchymal sarcomas Hepatocellular carcinoma Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin Pancreatic carcinoma Gastric carcinoma Polycythemia Renal carcinoma Erythropoietin Cerebellar hemangioma Hepatocellular carcinoma GRADING/STAGING GRADING: HOW “DIFFERENTIATED” ARE THE CELLS? STAGING: HOW MUCH ANATOMIC EXTENSION? TNM WHICH ONE OF THE ABOVE DO YOU THINK IS MORE IMPORTANT?  WELL? (pearls) MODERATE? (intercellular bridges) POOR? (WTF!?!) GRADING for Squamous Cell Carcinoma ADENOCARCINOMA GRADING LET’S HAVE SOME FUN!  COMPLETE DIAGNOSTIC EVALUATION INCLUDES IDENTIFYING STAGE AND GRADE OF THE TUMOR. TUMOR ACCOMPLISHED PRIOR TO TREATMENT TO PROVIDE STAGING BASELINE DATA FOR EVALUATING AND OUTCOMES OF THERAPY GRADING MAINTAIN A SYSTEMATIC AND CONSISTENT APPROACH TO ONGOING DIAGNOSIS AND TREATMENT. TREATMENT OPTIONS AND PROGNOSIS ARE BASED ON STAGING AND GRADING.  TUMOR, NODES, AND METASTASIS (TNM) SYSTEM (AMERICAN JOINT COMMITTEE ON CANCER, 2006) STAGING PROVIDE A CONVENIENT SHORTHAND NOTATION COMPARISONS OF TREATMENTS AND PROGNOSES  TX PRIMARY TUMOR CANNOT BE ASSESSED T0 NO EVIDENCE OF PRIMARY TUMOR PRIMARY TIS CARCINOMA IN SITU TUMOR (T) T1, T2, T3, T4 INCREASING SIZE AND/OR LOCAL EXTENT OF THE PRIMARY TUMOR  NX REGIONAL LYMPH NODES CANNOT BE ASSESSED N0 NO REGIONAL LYMPH NODE METASTASIS REGIONAL N2, N2, N3 INCREASING INVOLVEMENT OF REGIONAL LYMPH LYMPH NOTES NODES (N) NOTE: DIRECT EXTENSION OF THE PRIMARY TUMOR INTO A LYMPH NODE(S) IS CLASSIFIED AS A LYMPH NODE METASTASIS. NOTE: METASTASIS IN ANY LYMPH NODE OTHER THAN REGIONAL IS CLASSIFIED AS A DISTANT METASTASIS.  MX DISTANT METASTASIS CANNOT BE ASSESSED DISTANT METASTASIS M0 NO DISTANT METASTASIS (M) M1 DISTANT METASTASIS  REFERS TO THE CLASSIFICATION OF THE TUMOR CELLS. DEFINE THE TYPE OF TISSUE FROM WHICH THE TUMOR ORIGINATED AND THE DEGREE GRADING TO WHICH THE TUMOR CELLS RETAIN THE FUNCTIONAL AND HISTOLOGIC CHARACTERISTICS OF THE TISSUE OF ORIGIN (DIFFERENTIATION).  NUMERIC VALUE RANGING FROM I TO IV. GRADE I WELL-DIFFERENTIATED TUMORS, CLOSELY RESEMBLE THE TISSUE OF ORIGIN IN STRUCTURE AND FUNCTION. GRADING GRADE IV. TUMORS THAT DO NOT CLEARLY RESEMBLE THE TISSUE OF ORIGIN IN STRUCTURE OR FUNCTION POORLY DIFFERENTIATED OR UNDIFFERENTIATED AND ARE ASSIGNED MORE AGGRESSIVE AND LESS RESPONSIVE TO TREATMENT THAN WELL-DIFFERENTIATED TUMORS.  GX GRADE CANNOT BE ASSESSED G1 WELL DIFFERENTIATED G2 MODERATELY DIFFERENTIATED HISTOLOGIC G3 POORLY DIFFERENTIATED GRADE (G) G4 UNDIFFERENTIATED  BASED ON ASSESSMENT OF PHYSIOLOGIC AND FUNCTIONAL CHANGES AND RESULTS OF THE DIAGNOSTIC EVALUATION. PATIENTS WITH SUSPECTED CANCER UNDERGO EXTENSIVE TESTING TO (1) DETERMINE THE PRESENCE AND EXTENT CANCER OF TUMOR, DIAGNOSIS (2) IDENTIFY POSSIBLE SPREAD (METASTASIS) OF DISEASE OR INVASION OF OTHER BODY TISSUES, (3) EVALUATE THE FUNCTION OF INVOLVED AND UNINVOLVED BODY SYSTEMS AND ORGANS (4) OBTAIN TISSUE AND CELLS FOR ANALYSIS, INCLUDING EVALUATION OF TUMOR STAGE AND GRADE.  1. BIOPSY THE MOST DEFINITIVE CANCER DIAGNOSIS 2. CT, MRI 3. TUMOR MARKERS 4. MOLECULAR  BIOPSY LAB CYTOLOGY: (EXFOLIATIVE) DIAGNOSIS CYTOLOGY: (FNA, FINE NEEDLE ASPIRATE)  ANALYSIS OF SUBSTANCES FOUND IN TUMOR BODY—TISSUES, BLOOD, OR OTHER MARKER BODY FLUIDS THAT ARE MADE BY THE TUMOR OR BY THE BODY IN IDENTIFIC RESPONSE TO THE TUMOR ATION BREAST, COLON, LUNG, OVARIAN, TESTICULAR, PROSTATE CANCERS  CATEGORIZATION OF UNDIFFERENTIATED TUMORS IMMUNOHIST LEUKEMIAS/LYMPHOMAS OCHEMISTRY SITE OF ORIGIN RECEPTORS, E.G., ERA, PRA  HORMONES: (PARANEOPLASTIC SYNDROMES) “ONCO”FETAL: AFP, CEA ISOENZYMES: PAP, NSE PROTEINS: PSA, PSMA TUMOR (“M” = “MEMBRANE”) MARKERS GLYCOPROTEINS: CA-125, CA-19-5, CA-15-3 MOLECULAR: P53, RAS NOTE: These SAME substances which can be measured in the blood, also can be stained by immunochemical methods in tissue  FOR THE PRESENCE OF MUTATIONS (ALTERATIONS) IN, GENES FOUND IN TUMORS OR BODY TISSUES. ASSISTS IN RESPONSE TO THERAPY, GENETIC AND RISK OF PROGRESSION OR PROFILING SELECTION OF TREATMENT, PREDICTION ANALYSIS OF CONSIDERED INVESTIGATIONAL) BREAST, LUNG, KIDNEY, OVARIAN, BRAIN CANCERS, LEUKEMIA AND LYMPHOMA (MANY USES OF GENETIC PROFILING ARE DIAGNOSIS, MICRO-ARRAYS THOUSANDS of genes identified from tumors give the cells their own identity and FINGERPRINT and may give important prognostic information as well as guidelines for therapy. Some say this may replace standard histopathologic identifications of tumors. What do you think?  MAMMOGRAPHY USE OF X-RAY IMAGES OF THE BREAST BREAST CANCER MAGNETIC RESONANCE IMAGING (MRI) USE OF MAGNETIC FIELDS AND RADIOFREQUENCY SIGNALS TO CREATE SECTIONED IMAGES OF VARIOUS BODY STRUCTURES NEUROLOGIC, PELVIC, ABDOMINAL, THORACIC, BREAST CANCERS  COMPUTED TOMOGRAPHY (CT) USE OF NARROW-BEAM X-RAY TO SCAN SUCCESSIVE LAYERS OF TISSUE FOR A CROSS-SECTIONAL VIEW NEUROLOGIC, PELVIC, SKELETAL, ABDOMINAL, THORACIC CANCERS FLUOROSCOPY USE OF X-RAYS THAT IDENTIFY CONTRASTS IN BODY TISSUE DENSITIES; MAY INVOLVE THE USE OF CONTRAST AGENTS SKELETAL, LUNG, GASTROINTESTINAL CANCERS  ULTRASONOGRAPHY (ULTRASOUND) HIGH-FREQUENCY SOUND WAVES ECHOING OFF BODY TISSUES ARE CONVERTED ELECTRONICALLY INTO IMAGES; USED TO ASSESS TISSUES DEEP WITHIN THE BODY ABDOMINAL AND PELVIC CANCERS ENDOSCOPY DIRECT VISUALIZATION OF A BODY CAVITY OR PASSAGEWAY BY INSERTION OF AN ENDOSCOPE INTO A BODY CAVITY OR OPENING; ALLOWS TISSUE BIOPSY, FLUID ASPIRATION, AND EXCISION OF SMALL TUMORS. USED FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES BRONCHIAL, GASTROINTESTINAL CANCERS  NUCLEAR MEDICINE IMAGING USES INTRAVENOUS INJECTION OR INGESTION OF RADIOISOTOPE SUBSTANCES FOLLOWED BY IMAGING OF TISSUES THAT HAVE CONCENTRATED THE RADIOISOTOPES BONE, LIVER, KIDNEY, SPLEEN, BRAIN, THYROID CANCERS POSITRON EMISSION TOMOGRAPHY (PET) THROUGH THE USE OF A TRACER, PROVIDES BLACK AND WHITE OR COLOR-CODED IMAGES OF THE BIOLOGIC ACTIVITY OF A PARTICULAR AREA, RATHER THAN ITS STRUCTURE. USED IN DETECTION OF CANCER OR ITS RESPONSE TO TREATMENT LUNG, COLON, LIVER, PANCREATIC, HEAD AND NECK CANCERS;HODGKIN AND NON- HODGKIN LYMPHOMA AND MELANOMA  PET FUSION USE OF A PET SCANNER AND A CT SCANNER IN ONE MACHINE TO PROVIDE AN IMAGE COMBINING ANATOMIC DETAIL, SPATIAL RESOLUTION, AND FUNCTIONAL METABOLIC ABNORMALITIES SEE PET RADIOIMMUNOCONJUGATES MONOCLONAL ANTIBODIES ARE LABELED WITH A RADIOISOTOPE AND INJECTED INTRAVENOUSLY INTO THE PATIENT; THE ANTIBODIES THAT AGGREGATE AT THE TUMOR SITE ARE VISUALIZED WITH SCANNERS COLORECTAL, BREAST, OVARIAN, HEAD AND NECK CANCERS;LYMPHOMA AND MELANOMA