This document provides an overview of neoplasia (tumors), including definitions, nomenclature used to classify tumors, the biology of tumor growth, epidemiology, and the molecular basis of cancer and carcinogenesis. It discusses the natural history of malignant tumors, differentiation in tumors, tumor growth rates, features that distinguish benign from malignant tumors, predisposing factors for cancer development, and the molecular basis of cancer formation through genetic changes that result in oncogene activation and tumor suppressor gene inactivation during the multistep process of carcinogenesis.

1. NeoplasiaNeoplasia

2. 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

3. 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

4. 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 formingpapillary 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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7. Colonic Polyp: Tubular Adenoma
Stalk
Tumor

8. 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

14.  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 areHamartoma: 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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18. Natural History Of Malignant TumorsNatural History Of Malignant Tumors
1.1. Malignant change in the targetMalignant change in the target
cell, referred to ascell, referred to as
transformationtransformation
2.2. Growth of the transformed cellsGrowth of the transformed cells
3.3. Local invasionLocal invasion
4.4. Distant metastases.Distant metastases.

19. 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 littleComposed 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 usuallyPoorly differentiated malignant tumors usually
have worse prognosis than well differentiatedhave worse prognosis than well differentiated
malignant tumors.malignant tumors.

20. If cells LOOK BAD, they are probably going to BEHAVE BAD
Looking “bad” means NOT looking like the cells they supposedly
arose from!

21. If cells LOOK GOOD, they are probably going to BEHAVE GOOD
Looking “good” means looking like the cells they supposedly arose from!

23. ***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 polarityLoss of polarity
““ANAPLASIA” = CANCERANAPLASIA” = CANCER

25. 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 ofIn dysplasia some but not all of the features of
malignancy are present, microscopicallymalignancy are present, microscopically

DysplasiaDysplasia maymay develop into malignancydevelop into malignancy
 Uterine cervixUterine cervix
 Colon polypsColon polyps
 Graded as low-grade or high-grade, often promptingGraded as low-grade or high-grade, often prompting
different clinical decisionsdifferent clinical decisions
 Dysplasia mayDysplasia may NOTNOT develop into malignancydevelop into malignancy
 HIGH grade dysplasia often classified with CISHIGH grade dysplasia often classified with CIS

28. 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 gcells) = 1 g (months to years)(months to years)
 10 more doublings (1 kg) = lethal burden10 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

29. “clonal”

30. Schematic Representation Of Tumor
Growth

31. Features of Malignant TumorsFeatures of Malignant Tumors
 Cellular featuresCellular features

LocalLocal invasioninvasion
 CapsuleCapsule
 Basement membraneBasement membrane
 MetastasisMetastasis
 Unequivocal sign of malignancyUnequivocal sign of malignancy
 Seeding of body cavitiesSeeding of body cavities
 LymphaticLymphatic
 HematogenousHematogenous

39. 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 importantNumber 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

40. Benign vs Malignant FeaturesBenign vs Malignant Features
FeatureFeature BenignBenign MalignantMalignant
Rate of growthRate of growth Progressive butProgressive but
slow. Mitoses fewslow. Mitoses few
and normaland normal
Variable. MitosesVariable. Mitoses
more frequent andmore frequent and
may be abnormalmay be abnormal
DifferentiationDifferentiation WellWell
differentiateddifferentiated
Some degree ofSome degree of
anaplasiaanaplasia
LOCALLOCAL
INVASIOINVASIO
NN
Cohesive growth.Cohesive growth.
Capsule & BMCapsule & BM
not breachednot breached
Poorly cohesivePoorly cohesive
andand
infiltrative!infiltrative!
MetastasisMetastasis AbsentAbsent May occurMay occur

46. Geographic & EnvironmentalGeographic & 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 normallyBlacks 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

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

48. 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?

49. 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

50. MOLECULAR BASISMOLECULAR BASIS
of CANCERof CANCER
 NON-lethalNON-lethal genetic damagegenetic damage
 A tumor is formed by the clonal expansionA tumor is formed by the clonal expansion
of a single precursor cell (of a single precursor cell (monoclonalmonoclonal))
 Four classesFour classes of normal regulatory genesof normal regulatory genes
 PROTO-oncogenesPROTO-oncogenes
 OncogenesOncogenes OncoproteinsOncoproteins
 DNA repair genesDNA repair genes
 Apoptosis genesApoptosis genes
 Carcinogenesis is aCarcinogenesis is a multistepmultistep processprocess

51. 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

53. Normal CELL CYCLE PhasesNormal CELL CYCLE Phases
INHIBITORS: Cip/Kip, INK4/ARF
Tumor (really growth) suppressor genes: p53

54. ONCOGENESONCOGENES
 Are MUTATIONS of NORMAL genesAre 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 forOncogenes code for  OncoproteinsOncoproteins

55. Category
PROTO-
Oncogene
Mode of
Activation
Associated Human
Tumor
GFs
PDGF-β chain SIS Overexpression Astrocytoma
Osteosarcoma
Fibroblast
growth factors
HST-1 Overexpression Stomach cancer
INT-2 Amplification Bladder cancer
Breast cancer
Melanoma
TGFα TGFα Overexpression Astrocytomas
Hepatocellular
carcinomas
HGF HGF Overexpression Thyroid cancer

56. Category
PROTO-
Oncogene
Mode of
Activation
Associated Human
Tumor
GF
Receptors
EGF-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

57. Category
PROTO-
Oncogene
Mode of
Activation
Associated Human
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
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

58. Category
PROTO-
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

59. MYCMYC
 Encodes for transcription factorsEncodes for transcription factors
 Also involved with apoptosisAlso involved with apoptosis

60. P53 and RASP53 and RAS
p53p53
 Activates DNA repairActivates DNA repair
proteinsproteins
 Sentinel of G1/SSentinel of G1/S
transitiontransition
 Initiates apoptosisInitiates apoptosis
 Mutated in more thanMutated in more than
50% of all human50% of all human
cancerscancers
RASRAS
 H, N, K, etc., varietiesH, N, K, etc., varieties
 Single most commonSingle most common
abnormality ofabnormality of
dominant oncogenes indominant oncogenes in
human tumorshuman tumors
 Present in about 1/3 ofPresent in about 1/3 of
all human cancersall human cancers

62. Tumor (really “GROWTH”)Tumor (really “GROWTH”)
suppressor genessuppressor genes
 TGF-TGF-ββ  COLONCOLON
 E-cadherinE-cadherin  STOMACHSTOMACH
 NF-1,2NF-1,2  NEURAL TUMORSNEURAL TUMORS
 APC/APC/ββ-cadherin-cadherin  GI, MELANOMAGI, MELANOMA
 SMADsSMADs  GIGI
 RBRB  RETINOBLASTOMARETINOBLASTOMA
 P53P53  EVERYTHING!!EVERYTHING!!
 WT-1WT-1  WILMS TUMORWILMS TUMOR
 p16 (INK4a)p16 (INK4a)  GI, BREAST (MM if inherited)GI, BREAST (MM if inherited)
 BRCA-1,2BRCA-1,2  BREASTBREAST
 KLF6KLF6  PROSTATEPROSTATE

63. Evasion of APOPTOSISEvasion of APOPTOSIS
BCL-2BCL-2
p53p53
MYCMYC

64. DNA REPAIR GENE DEFECTSDNA REPAIR GENE DEFECTS
 DNA repair is like a spell checkerDNA repair is like a spell checker
 HNPCCHNPCC ((HHereditaryereditary NNon-on-PPolyposisolyposis CColonolon
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

65. LIMITLESS REPLICATIVELIMITLESS REPLICATIVE
POTENTIALPOTENTIAL
 TELOMERES determine the limitedTELOMERES determine the limited
number of duplications a cell willnumber 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 sohuman cancers, changes telomeres so
they will have UNLIMITEDthey will have UNLIMITED
replicative potentialreplicative potential

66. 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) byTumor size is regulated (allowed) by
angiogenesis/anti-angiogenesis balanceangiogenesis/anti-angiogenesis balance

67. TRANSFORMATIONTRANSFORMATION
GROWTHGROWTH
BM INVASIONBM INVASION
ANGIOGENESISANGIOGENESIS
INTRAVASATIONINTRAVASATION
EMBOLIZATIONEMBOLIZATION
ADHESIONADHESION
EXTRAVASATIONEXTRAVASATION
METASTATIC GROWTHMETASTATIC GROWTH
etc.etc.

68. Invasion FactorsInvasion Factors
 DetachmentDetachment ("loosening up") of("loosening up") of
the tumor cells from each otherthe tumor cells from each other
 AttachmentAttachment to matrix componentsto matrix components
 DegradationDegradation of ECM, e.g.,of ECM, e.g.,
collagenase, etc.collagenase, etc.
 MigrationMigration of tumor cellsof tumor cells

70. METASTATIC GENES?METASTATIC GENES?
 NM23NM23
 KAI-1KAI-1
 KiSSKiSS

71. CHROMOSOME CHANGES
in CANCER
 TRANSLOCATIONS and INVERSIONS
 Occur in MOST Lymphomas/Leukemias
 Occur in MANY (and growing numbers) of
NON-hematologic malignancies also

72. 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

73. 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

74. 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

76. Q: WHO are the usual suspects?
 Inflammation?
 Teratogenesis?
 Immune
Suppression?
 Neoplasia?
 Mutations?

77. A: The SAME 3 that are
ALWAYS blamed!
1) ChemicalsChemicals
2) RadiationRadiation
3) InfectiousInfectious PathogensPathogens

78. 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

79. CHEMICAL CARCINOGENS:
INITIATORS
OTHERS
 Nitrosamine and amides (tar, nitrites)
 Vinyl chloride angiosarcoma in Kentucky
 Nickel
 Chromium
 Insecticides
 Fungicides
 PolyChlorinated Biphenyls (PCBs)

80. CHEMICAL CARCINOGENS:
PROMOTORS
 HORMONES
 PHORBOL ESTERS (TPA), activate kinase C
 PHENOLS
 DRUGS, many
“Initiated” cells respond and proliferate
FASTER to promotors than normal cells

81. 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

82. VIRAL CARCINOGENESIS
 HPV SCC
 EBV Burkitt Lymphoma
 HBV HepatoCellular Carcinoma (Hepatoma)
 HTLV1 T-Cell Malignancies
 KSHV Kaposi Sarcoma

83. H. pylori CARCINOGENESIS
 100% of gastric lymphomas (i.e., M.A.L.T.-
omas)
 Gastric CARCINOMAS also!

84. HOST DEFENSES
 IMMUNE SURVEILLENCE CONCEPT
 CD8+ T-Cells
 NK cells
 MACROPHAGES
 ANTIBODIES

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

86. How do tumor cells
escape 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!

87. Effects of TUMOR on the HOST
 Location anatomic ENCROACHMENT
 HORMONE production
 Bleeding, Infection
 ACUTE symptoms, e.g., rupture, infarction
 METASTASES

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

89. PARA-Neoplastic Syndromes
Endocrine (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


90. 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 lung
Parathyroid 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

91. 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?

92. WELL?
(pearls)
MODERATE?
(intercellular bridges)
POOR?
(WTF!?!)
GRADING for Squamous Cell Carcinoma

93. ADENOCARCINOMA GRADING
Let’s have some FUN!

94. LAB DIAGNOSIS
BIOPSY
CYTOLOGY: (exfoliative)
CYTOLOGY: (FNA, Fine
Needle Aspirate)

95. IMMUNOHISTOCHEMISTRY
Categorization of
undifferentiated tumors
Leukemias/Lymphomas
Site of origin
Receptors, e.g., ERA, PRA

96. 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

97. 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?