minarcik robbins 2013_ch7-neoplasm

NeoplasiaNeoplasia

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

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

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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© 2005 Elsevier

Colonic Polyp: Tubular Adenoma

Stalk

Tumor

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

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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© 2005 Elsevier

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.

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.

If cells LOOK BAD, they are probably going to BEHAVE BADLooking “bad” means NOT looking like the cells

they supposedly arose from!

If cells LOOK GOOD, they are probably going to BEHAVE GOOD

Looking “good” means looking like the cells they supposedly arose from!

***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

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

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

“clonal”

Schematic Representation Of Tumor Growth

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

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

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

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

Change In Incidence Of Various Cancers With Migration From Japan To The United States

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?

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

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

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

Normal CELL CYCLE PhasesNormal CELL CYCLE Phases

INHIBITORS: Cip/Kip, INK4/ARFTumor (really growth) suppressor

genes: p53

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

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

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

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

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

MYCMYC Encodes for transcription factorsEncodes for transcription factors Also involved with apoptosisAlso involved with apoptosis

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

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

Evasion of APOPTOSISEvasion of APOPTOSIS

BCL-2BCL-2p53p53MYCMYC

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

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

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

TRANSFORMATIONTRANSFORMATIONGROWTHGROWTH

BM INVASIONBM INVASIONANGIOGENESISANGIOGENESISINTRAVASATIONINTRAVASATIONEMBOLIZATIONEMBOLIZATION

ADHESIONADHESIONEXTRAVASATIONEXTRAVASATIONMETASTATIC GROWTHMETASTATIC GROWTH

etc.etc.

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

METASTATIC GENES?METASTATIC GENES?

NM23NM23KAI-1KAI-1KiSSKiSS

CHROMOSOME CHANGESin 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

    EWS 22q12

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

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

Q: WHO are the usual suspects? Inflammation? Teratogenesis? Immune

Suppression? Neoplasia? Mutations?

A: The SAME 3 that are ALWAYS blamed!

1) ChemicalsChemicals2) RadiationRadiation3) InfectiousInfectious PathogensPathogens

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

CHEMICAL CARCINOGENS:INITIATORS

OTHERS Nitrosamine and amides (tar, nitrites) Vinyl chloride angiosarcoma in Kentucky Nickel Chromium Insecticides Fungicides PolyChlorinated Biphenyls (PCBs)

CHEMICAL CARCINOGENS:PROMOTORS

HORMONES PHORBOL ESTERS (TPA), activate kinase C PHENOLS DRUGS, many

“Initiated” cells respond and proliferate FASTER to promotors than normal cells

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

VIRAL CARCINOGENESIS

HPV SCC EBV Burkitt Lymphoma HBV HepatoCellular Carcinoma (Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma

H. pylori CARCINOGENESIS

100% of gastric lymphomas (i.e., M.A.L.T.-omas)

Gastric CARCINOMAS also!

HOST DEFENSES

IMMUNE SURVEILLENCE CONCEPT

CD8+ T-Cells NK cells MACROPHAGES ANTIBODIES

CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells

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!

Effects of TUMOR on the HOST

Location anatomic ENCROACHMENT HORMONE production Bleeding, Infection ACUTE symptoms, e.g., rupture, infarction METASTASES

CACHEXIA Reduced diet: Fat loss>Muscle loss Cachexia: Fat loss AND Muscle loss TNF (α by default) IL-(6) PIF (Proteolysis Inducing Factor)

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

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  

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 GRADINGLet’s have some FUN!

LAB DIAGNOSISBIOPSYCYTOLOGY: (exfoliative)CYTOLOGY: (FNA, Fine

Needle Aspirate)

IMMUNOHISTOCHEMISTRY

Categorization of undifferentiated tumors

Leukemias/LymphomasSite of originReceptors, e.g., ERA, PRA

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

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?