Minarcik robbins 2013_ch7-neoplasm
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NeoplasiaNeoplasia
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NEOPLASIA (TUMORS)NEOPLASIA (TUMORS) DefinitionsDefinitions NomenclatureNomenclature Biology of Tumor GrowthBiology of Tumor Growth EpidemiologyEpidemiology Molecular Basis of CancerMolecular Basis of Cancer Molecular Basis of CarcinogenesisMolecular Basis of Carcinogenesis Agents (The Usual Suspects)Agents (The Usual Suspects) Host Defense (Tumor Immunity)Host Defense (Tumor Immunity) Clinical Features of TumorsClinical Features of Tumors
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Defnition of NeoplasiaDefnition 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
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Nomenclature – Benign TumorsNomenclature – Benign Tumors -oma = benign neoplasm (-oma = benign neoplasm (NOTNOT carcin-, sarc-, lymph-, carcin-, sarc-, lymph-,
or melan-)or melan-) Mesenchymal tumors (mesodermal derived)Mesenchymal tumors (mesodermal derived)
chrondroma: cartilaginous tumorchrondroma: cartilaginous tumor fibroma: fibrous tumorfibroma: fibrous tumor osteoma: bone tumorosteoma: bone tumor
Epithelial tumor (ecto- or endo- derived)Epithelial tumor (ecto- or endo- derived) adenoma: tumor forming glandsadenoma: tumor forming glands papilloma: tumor with finger like projectionspapilloma: tumor with finger like projections papillary cystadenoma: papillary and cystic tumor forming papillary cystadenoma: papillary and cystic tumor forming
glandsglands polyp: a “tumor” that projects above a mucosal surfacepolyp: a “tumor” that projects above a mucosal surface
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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)
© 2005 Elsevier
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Colonic Polyp: Tubular Adenoma
Stalk
Tumor
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Nomenclature – Malignant TumorsNomenclature – Malignant Tumors Sarcomas: mesenchymal tumorSarcomas: mesenchymal tumor
chrondrosarcoma: cartilaginous tumorchrondrosarcoma: cartilaginous tumor fibrosarcoma: fibrous tumorfibrosarcoma: fibrous tumor osteosarcoma: bone tumorosteosarcoma: bone tumor
Carcinomas: epithelial tumorsCarcinomas: epithelial tumors adenocarcinoma: gland forming tumoradenocarcinoma: gland forming tumor squamous cell carcinoma: squamous differentiationsquamous cell carcinoma: squamous differentiation undifferentiated carcinoma: no differentiationundifferentiated carcinoma: no differentiation note: carcinomas can arise from ectoderm, note: carcinomas can arise from ectoderm,
endoderm, or less likely, mesodermendoderm, or less likely, mesoderm
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Tumors with mixed differentiationTumors with mixed differentiation mixed tumors: e.g. pleomorphic adenoma of salivary glandmixed tumors: e.g. pleomorphic adenoma of salivary gland carcinosarcomacarcinosarcoma
TeratomaTeratoma tumor comprised of cells from more than one germ layertumor comprised of cells from more than one germ layer arise from totipotent cells (usually gonads)arise from totipotent cells (usually gonads) benign cystic teratoma of ovary is the most common teratomabenign cystic teratoma of ovary is the most common teratoma
Aberrant differentiation (not true neoplasms)Aberrant differentiation (not true neoplasms) Hamartoma: disorganized mass of tissue whose cell types are Hamartoma: disorganized mass of tissue whose cell types are
indiginous to the site of the lesion, e.g., lungindiginous to the site of the lesion, e.g., lung Choriostoma: ectopic focus of normal tissue (heterotopia), Choriostoma: ectopic focus of normal tissue (heterotopia),
e.g., pancreas, perhaps endometriosis tooe.g., pancreas, perhaps endometriosis too MisnomersMisnomers
hepatoma: malignant liver tumorhepatoma: malignant liver tumor melanoma: malignant skin tumormelanoma: malignant skin tumor seminoma: malignant testicular tumorseminoma: malignant testicular tumor lymphoma: malignant tumor of lymphocyteslymphoma: malignant tumor of lymphocytes
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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)
© 2005 Elsevier
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Natural History Of Malignant TumorsNatural History Of Malignant Tumors
1.1. Malignant change in the target Malignant change in the target cell, referred to as transformation cell, referred to as transformation
2.2. Growth of the transformed cells Growth of the transformed cells
3.3. Local invasionLocal invasion4.4. Distant metastases. Distant metastases.
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DifferentiationDifferentiation Well differentiated neoplasmWell differentiated neoplasm
Resembles mature cells of tissue of originResembles mature cells of tissue of origin Poorly differentiated neoplasmPoorly differentiated neoplasm
Composed of primitive cells with little Composed of primitive cells with little differentiationdifferentiation
Undifferentiated or “anaplastic” tumorUndifferentiated or “anaplastic” tumor Correlation with biologic behaviorCorrelation with biologic behavior
Benign tumors are well differentiatedBenign tumors are well differentiated Poorly differentiated malignant tumors usually Poorly differentiated malignant tumors usually
have worse prognosis than well differentiated have worse prognosis than well differentiated malignant tumors.malignant tumors.
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If cells LOOK BAD, they are probably going to BEHAVE BADLooking “bad” means NOT looking like the cells
they supposedly arose from!
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If cells LOOK GOOD, they are probably going to BEHAVE GOOD
Looking “good” means looking like the cells they supposedly arose from!
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***Pleomorphism***Pleomorphism SizeSize shapeshape
Abnormal nuclear morphologyAbnormal nuclear morphology
***Hyperchromasia***Hyperchromasia High nuclear cytoplasmic ratioHigh nuclear cytoplasmic ratio Chromatin clumpingChromatin clumping Prominent nucleoliProminent nucleoli
MitosesMitoses Mitotic rateMitotic rate Location of mitosesLocation of mitoses
Loss of polarity Loss of polarity
““ANAPLASIA” = CANCERANAPLASIA” = CANCER
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DysplasiaDysplasia Literally means abnormal growthLiterally means abnormal growth Malignant transformation is a multistep processMalignant transformation is a multistep process In dysplasia some but not all of the features of In dysplasia some but not all of the features of
malignancy are present, microscopicallymalignancy are present, microscopically
Dysplasia Dysplasia maymay develop into malignancy develop into malignancy Uterine cervixUterine cervix Colon polypsColon polyps
Graded as low-grade or high-grade, often prompting Graded as low-grade or high-grade, often prompting different clinical decisionsdifferent clinical decisions
Dysplasia may Dysplasia may NOTNOT develop into malignancy develop into malignancy HIGH grade dysplasia often classified with CISHIGH grade dysplasia often classified with CIS
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Tumor Growth RateTumor Growth Rate Doubling time of tumor cellsDoubling time of tumor cells
Lengthens as tumor growsLengthens as tumor grows 30 doublings (1030 doublings (1099 cells) = 1 g cells) = 1 g (months to years)(months to years) 10 more doublings (1 kg) = lethal burden 10 more doublings (1 kg) = lethal burden (“) (“)
Fraction of tumor cells in replicative poolFraction of tumor cells in replicative pool May be only 20% even in rapidly growing tumorsMay be only 20% even in rapidly growing tumors Tumor stem cellsTumor stem cells
Rate at which tumor cells are shed or lostRate at which tumor cells are shed or lost ApoptosisApoptosis MaturationMaturation
Implications for therapyImplications for therapy
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“clonal”
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Schematic Representation Of Tumor Growth
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Features of Malignant TumorsFeatures of Malignant Tumors
Cellular featuresCellular features
Local Local invasioninvasion CapsuleCapsule Basement membraneBasement membrane
MetastasisMetastasis Unequivocal sign of malignancyUnequivocal sign of malignancy Seeding of body cavitiesSeeding of body cavities LymphaticLymphatic HematogenousHematogenous
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Significance of Nodal MetsSignificance of Nodal Mets Example of breast cancerExample of breast cancer
Halsted radical mastectomyHalsted radical mastectomy Sentinel node biopsySentinel node biopsy
PrognosticPrognostic Number of involved nodes is an important Number of involved nodes is an important
component of TNM staging systemcomponent of TNM staging system TherapeuticTherapeutic
Overall risk of recurrenceOverall risk of recurrence Extent of nodal involvementExtent of nodal involvement Histologic grade and other considerationsHistologic grade and other considerations
““Adjuvant” chemotherapyAdjuvant” chemotherapy
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Benign vs Malignant FeaturesBenign vs Malignant Features
FeatureFeature BenignBenign MalignantMalignant
Rate of growthRate of growth Progressive but Progressive but slow. Mitoses few slow. Mitoses few and normaland normal
Variable. Mitoses Variable. Mitoses more frequent and more frequent and may be abnormalmay be abnormal
DifferentiationDifferentiation Well Well differentiateddifferentiated
Some degree of Some degree of anaplasiaanaplasia
LOCAL LOCAL INVASIOINVASIONN
Cohesive growth. Cohesive growth. Capsule & BM Capsule & BM not breachednot breached
Poorly cohesive Poorly cohesive and and
infiltrative!infiltrative!
MetastasisMetastasis AbsentAbsent May occurMay occur
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Geographic & Environmental Geographic & Environmental Sun exposureSun exposure
Melanomas 6x incidence New Zealand vs. IcelandMelanomas 6x incidence New Zealand vs. Iceland Blacks have low incidence of melanoma, so do normally Blacks have low incidence of melanoma, so do normally
pigmented areas like areolae on white peoplepigmented areas like areolae on white people Smoking and alcohol abuseSmoking and alcohol abuse Body massBody mass
Overweight = 50% increase in cancerOverweight = 50% increase in cancer Environmental vs. racial factorsEnvironmental vs. racial factors
Japanese immigrants to USAJapanese immigrants to USA Viral exposureViral exposure
Human papilloma virus (HPV) and cervical cancerHuman papilloma virus (HPV) and cervical cancer Hepatitis B virus (HBV) and liver cancer (Africa, Asia)Hepatitis B virus (HBV) and liver cancer (Africa, Asia) Epstein-Barr Virus (EBV) and lymphomaEpstein-Barr Virus (EBV) and lymphoma
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Change In Incidence Of Various Cancers With Migration From Japan To The United States
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Predisposing Factors for CancerPredisposing Factors for Cancer AgeAge
Most cancers occur in persons ≥ 55 yearsMost cancers occur in persons ≥ 55 years Childhood cancersChildhood cancers
Leukemias & CNS neoplasmsLeukemias & CNS neoplasms Bone tumorsBone tumors
Genetic predispostionGenetic predispostion Familial cancer syndromesFamilial cancer syndromes
Early age at onsetEarly age at onset Two or more primary relatives with the cancer (“soil” theory)Two or more primary relatives with the cancer (“soil” theory) Multiple or bilateral tumorsMultiple or bilateral tumors
Polymorphisms that metabolize procarcinogens, e.g., nitritesPolymorphisms that metabolize procarcinogens, e.g., nitrites Nonhereditary predisposing conditionsNonhereditary predisposing conditions
Chronic inflammation?Chronic inflammation? Precancerous conditionsPrecancerous conditions
Chronic ulcerative colitisChronic ulcerative colitis Atrophic gastritis of pernicious anemiaAtrophic gastritis of pernicious anemia Leukoplakia of mucous membranesLeukoplakia of mucous membranes Immune collapse?Immune collapse?
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Defnition of NeoplasiaDefnition 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
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MOLECULAR BASISMOLECULAR BASISof CANCERof CANCER
NON-lethal NON-lethal genetic damagegenetic damage A tumor is formed by the clonal expansion A tumor is formed by the clonal expansion
of a single precursor cell (of a single precursor cell (monoclonalmonoclonal)) Four classes Four classes of normal regulatory genesof normal regulatory genes
PROTO-oncogenesPROTO-oncogenes OncogenesOncogenes Oncoproteins Oncoproteins DNA repair genesDNA repair genes Apoptosis genesApoptosis genes
Carcinogenesis is a Carcinogenesis is a multistepmultistep process process
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TRANSFORMATION &TRANSFORMATION &PROGRESSIONPROGRESSION
Self-sufficiency in growth signalsSelf-sufficiency in growth signals Insensitivity to growth-inhibiting signalsInsensitivity to growth-inhibiting signals Evasion of apoptosisEvasion of apoptosis Defects in DNA repair: “Spell checker”Defects in DNA repair: “Spell checker” Limitless replicative potential: TelomeraseLimitless replicative potential: Telomerase AngiogenesisAngiogenesis Invasive abilityInvasive ability Metastatic abilityMetastatic ability
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Normal CELL CYCLE PhasesNormal CELL CYCLE Phases
INHIBITORS: Cip/Kip, INK4/ARFTumor (really growth) suppressor
genes: p53
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ONCOGENESONCOGENES Are MUTATIONS of NORMAL genes Are MUTATIONS of NORMAL genes
(PROTO-oncogenes)(PROTO-oncogenes) Growth FactorsGrowth Factors Growth Factor ReceptorsGrowth Factor Receptors Signal Transduction Proteins (RAS)Signal Transduction Proteins (RAS) Nuclear Regulatory ProteinsNuclear Regulatory Proteins Cell Cycle RegulatorsCell Cycle Regulators
Oncogenes code for Oncogenes code for Oncoproteins Oncoproteins
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CategoryPROTO- Oncogene
Mode of Activation
Associated Human Tumor
GFsPDGF-β chain SIS Overexpression Astrocytoma
OsteosarcomaFibroblast growth factors
HST-1 Overexpression Stomach cancer
INT-2 Amplification Bladder cancer
Breast cancerMelanoma
TGFα TGFα Overexpression Astrocytomas
Hepatocellular carcinomas
HGF HGF Overexpression Thyroid cancer
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CategoryPROTO- Oncogene
Mode of Activation
Associated Human Tumor
GF ReceptorsEGF-receptor family
ERB-B1 (ECFR)
Overexpression Squamous cell carcinomas of lung, gliomas
ERB-B2 Amplification Breast and ovarian cancers
CSF-1 receptor FMS Point mutation Leukemia
Receptor for neurotrophic factors
RET Point mutation Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas
PDGF receptor PDGF-R Overexpression Gliomas
Receptor for stem cell (steel) factor
KIT Point mutation Gastrointestinal stromal tumors and other soft tissue tumors
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CategoryPROTO- Oncogene
Mode of Activation
Associated Human Tumor
Signal TransductionProteinsGTP-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 tyrosine kinase
ABL Translocation Chronic myeloid leukemia
Acute lymphoblastic leukemia
RAS signal transduction
BRAF Point mutation Melanomas
WNT signal transduction
β-catenin Point mutation Hepatoblastomas, hepatocellular carcinoma
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CategoryPROTO- Oncogene
Mode of Activation Associated Human
Tumor
Nuclear Regulatory Proteins
Transcrip.activators
C-MYC Translocation Burkitt lymphoma
N-MYC Amplification Neuroblastoma, small cell carcinoma of lung
L-MYC Amplification Small cell carcinoma of lung
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MYCMYC Encodes for transcription factorsEncodes for transcription factors Also involved with apoptosisAlso involved with apoptosis
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P53 and RASP53 and RASp53p53
Activates DNA repair Activates DNA repair proteinsproteins
Sentinel of G1/S Sentinel of G1/S transitiontransition
Initiates apoptosisInitiates apoptosis Mutated in more than Mutated in more than
50% of all human 50% of all human cancerscancers
RASRAS H, N, K, etc., varietiesH, N, K, etc., varieties Single most common Single most common
abnormality of abnormality of dominant oncogenes in dominant oncogenes in human tumorshuman tumors
Present in about 1/3 of Present in about 1/3 of all human cancersall human cancers
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Tumor (really “GROWTH”) Tumor (really “GROWTH”) suppressor genessuppressor genes
TGF-TGF-ββ COLON COLON E-cadherinE-cadherin STOMACH STOMACH NF-1,2NF-1,2 NEURAL TUMORS NEURAL TUMORS APC/APC/ββ-cadherin -cadherin GI, MELANOMA GI, MELANOMA SMADsSMADs GI GI RBRB RETINOBLASTOMA RETINOBLASTOMA P53P53 EVERYTHING!! EVERYTHING!! WT-1WT-1 WILMS TUMOR WILMS TUMOR p16 (INK4a) p16 (INK4a) GI, BREAST (MM if inherited) GI, BREAST (MM if inherited) BRCA-1,2BRCA-1,2 BREAST BREAST KLF6KLF6 PROSTATE PROSTATE
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Evasion of APOPTOSISEvasion of APOPTOSIS
BCL-2BCL-2p53p53MYCMYC
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DNA REPAIR GENE DEFECTSDNA REPAIR GENE DEFECTS DNA repair is like a spell checkerDNA repair is like a spell checker
HNPCCHNPCC ( (HHereditary ereditary NNon-on-PPolyposis olyposis CColon olon CCancer [Lynch]): TGF-ancer [Lynch]): TGF-ββ, , ββ-catenin, BAX-catenin, BAX
Xeroderma Pigmentosum: UV fixing geneXeroderma Pigmentosum: UV fixing gene Ataxia Telangiectasia: ATM geneAtaxia Telangiectasia: ATM gene Bloom Syndrome: defective helicaseBloom Syndrome: defective helicase Fanconi anemiaFanconi anemia
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LIMITLESS REPLICATIVE LIMITLESS REPLICATIVE POTENTIALPOTENTIAL
TELOMERES determine the limited TELOMERES determine the limited number of duplications a cell will number of duplications a cell will have, like a cat with nine lives.have, like a cat with nine lives.
TELOMERASETELOMERASE, present in >90% of , present in >90% of human cancers, changes telomeres so human cancers, changes telomeres so they will have UNLIMITED they will have UNLIMITED replicative potentialreplicative potential
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TUMOR ANGIOGENESISTUMOR ANGIOGENESIS QQ: How close to a blood vessel must a cell be?: How close to a blood vessel must a cell be? A: 1-2 mmA: 1-2 mm
Activation of VEGF and FGF-bActivation of VEGF and FGF-b
Tumor size is regulated (allowed) by Tumor size is regulated (allowed) by angiogenesis/anti-angiogenesis balanceangiogenesis/anti-angiogenesis balance
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TRANSFORMATIONTRANSFORMATIONGROWTHGROWTH
BM INVASIONBM INVASIONANGIOGENESISANGIOGENESISINTRAVASATIONINTRAVASATIONEMBOLIZATIONEMBOLIZATION
ADHESIONADHESIONEXTRAVASATIONEXTRAVASATIONMETASTATIC GROWTHMETASTATIC GROWTH
etc.etc.
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Invasion FactorsInvasion Factors
DetachmentDetachment ("loosening up") of ("loosening up") of the tumor cells from each other the tumor cells from each other
AttachmentAttachment to matrix components to matrix components DegradationDegradation of ECM, e.g., of ECM, e.g.,
collagenase, etc. collagenase, etc. MigrationMigration of tumor cells of tumor cells
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METASTATIC GENES?METASTATIC GENES?
NM23NM23KAI-1KAI-1KiSSKiSS
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CHROMOSOME CHANGESin CANCER
TRANSLOCATIONS and INVERSIONS
Occur in MOST Lymphomas/Leukemias Occur in MANY (and growing numbers) of
NON-hematologic malignancies also
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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
EWS 22q12
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Carcinogenesis is “MULTISTEP” NO single oncogene causes cancer BOTH several oncogenes AND several
tumor suppressor genes must be involved Gatekeeper/Caretaker concept
Gatekeepers: ONCOGENES and TUMOR SUPPRESSOR GENES
Caretakers: DNA REPAIR GENES
Tumor “PROGRESSION” ANGIOGENESIS HETEROGENEITY from original single cell
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Carcinogenesis: The USUAL (3) Suspects
Initiation/Promotion concept: BOTH initiators AND promotors are needed NEITHER can cause cancer by itself
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
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Q: WHO are the usual suspects? Inflammation? Teratogenesis? Immune
Suppression? Neoplasia? Mutations?
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A: The SAME 3 that are ALWAYS blamed!
1) ChemicalsChemicals2) RadiationRadiation3) InfectiousInfectious PathogensPathogens
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CHEMICAL CARCINOGENS:INITIATORS
DIRECT β-Propiolactone Dimeth. sulfate Diepoxybutane Anticancer drugs
(cyclophosphamide, chlorambucil, nitrosoureas, and others)
Acylating Agents 1-Acetyl-imidazole Dimethylcarbamyl chloride
“PRO”CARCINOGENS Polycyclic and Heterocyclic
Aromatic Hydrocarbons Aromatic Amines, Amides,
Azo Dyes Natural Plant and Microbial
Products Aflatoxin B1 Hepatomas Griseofulvin Antifungal Cycasin from cycads Safrole from sassafras Betel nuts Oral SCC
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CHEMICAL CARCINOGENS:INITIATORS
OTHERS Nitrosamine and amides (tar, nitrites) Vinyl chloride angiosarcoma in Kentucky Nickel Chromium Insecticides Fungicides PolyChlorinated Biphenyls (PCBs)
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CHEMICAL CARCINOGENS:PROMOTORS
HORMONES PHORBOL ESTERS (TPA), activate kinase C PHENOLS DRUGS, many
“Initiated” cells respond and proliferate FASTER to promotors than normal cells
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RADIATION CARCINOGENS
UV:UV: BCC, SCC, MM (i.e., all 3)
IONIZING:IONIZING: photons and particulate Hematopoetic and Thyroid (90%/15yrs) tumors
in fallout victims Solid tumors either less susceptible or require a
longer latency period than LEUK/LYMPH BCCs in Therapeutic Radiation
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VIRAL CARCINOGENESIS
HPV SCC EBV Burkitt Lymphoma HBV HepatoCellular Carcinoma (Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma
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H. pylori CARCINOGENESIS
100% of gastric lymphomas (i.e., M.A.L.T.-omas)
Gastric CARCINOMAS also!
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HOST DEFENSES
IMMUNE SURVEILLENCE CONCEPT
CD8+ T-Cells NK cells MACROPHAGES ANTIBODIES
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CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells
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How do tumor cellsescape immune surveillance?
Mutation, like microbesMutation, like microbes
↓ ↓ MHC molecules on tumor cell surfaceMHC molecules on tumor cell surface Lack of CO-stimulation molecules, e.g., Lack of CO-stimulation molecules, e.g.,
(CD28, ICOS), not just Ag-Ab recognition(CD28, ICOS), not just Ag-Ab recognition Immunosuppressive agentsImmunosuppressive agents Antigen maskingAntigen masking Apoptosis of cytotoxic T-Cells (CD8), i.e., Apoptosis of cytotoxic T-Cells (CD8), i.e.,
the damn tumor cell KILLS the T-cell!the damn tumor cell KILLS the T-cell!
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Effects of TUMOR on the HOST
Location anatomic ENCROACHMENT HORMONE production Bleeding, Infection ACUTE symptoms, e.g., rupture, infarction METASTASES
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CACHEXIA Reduced diet: Fat loss>Muscle loss Cachexia: Fat loss AND Muscle loss TNF (α by default) IL-(6) PIF (Proteolysis Inducing Factor)
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PARA-Neoplastic SyndromesEndocrine (next) 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
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ENDOCRINECushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance
Pancreatic carcinoma
Neural tumors
Syndrome of inappropriate antidiuretic hormone secretion
Small cell carcinoma of lung; intracranial neoplasms
Antidiuretic hormone or atrial natriuretic hormones
Hypercalcemia Squamous cell carcinoma of lungParathyroid hormone-related protein
(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
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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?
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WELL?(pearls)
MODERATE?(intercellular bridges)
POOR?(WTF!?!)
GRADING for Squamous Cell Carcinoma
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ADENOCARCINOMA GRADINGLet’s have some FUN!
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LAB DIAGNOSISBIOPSYCYTOLOGY: (exfoliative)CYTOLOGY: (FNA, Fine
Needle Aspirate)
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IMMUNOHISTOCHEMISTRY
Categorization of undifferentiated tumors
Leukemias/LymphomasSite of originReceptors, e.g., ERA, PRA
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TUMOR MARKERS HORMONES: (Paraneoplastic Syndromes) “ONCO”FETAL: AFP, CEA ISOENZYMES: PAP, NSE PROTEINS: PSA, PSMA (“M” = “membrane”) GLYCOPROTEINS: CA-125, CA-195, CA-153 MOLECULAR: p53, RAS
NOTE: These SAME substances which can be measured in the blood, also can be stained by immunochemical methods in tissue
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MICRO-ARRAYSTHOUSANDS 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?