NEOPLASIA Abdulmalik Alsheikh,M.D,FRCPC. CARCINOGENESIS Carcinogenesis is a multistep process at both the phenotypic and the genetic levels. Carcinogenesis

NEOPLASIANEOPLASIA

Abdulmalik Abdulmalik Alsheikh,M.D,FRCPCAlsheikh,M.D,FRCPC

CARCINOGENESISCARCINOGENESIS

Carcinogenesis is a multistep Carcinogenesis is a multistep process at both the phenotypic and process at both the phenotypic and the genetic levels.the genetic levels.

It starts with a genetic damage:It starts with a genetic damage: EnvironmentalEnvironmental

ChemicalChemical RadiationRadiation ViralViral

InheretedInhereted

CarcinogenesisCarcinogenesis

Genetic damage lead to “ mutation”Genetic damage lead to “ mutation” single cell which has the genetic single cell which has the genetic

damage undergoes neoplastic damage undergoes neoplastic prliferation ( clonal expansion) prliferation ( clonal expansion) forming the tumor massforming the tumor mass


Where are the targets of the genetic Where are the targets of the genetic damage??damage??

Four regulatory genes are the main Four regulatory genes are the main targets:targets: Growth promoting protooncogenesGrowth promoting protooncogenes

Protooncogene > mutation > oncogeneProtooncogene > mutation > oncogene Growth inhibiting (supressors) genesGrowth inhibiting (supressors) genes Genes regulating apoptosisGenes regulating apoptosis DNA repair genesDNA repair genes


Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype: Self-sufficiency in growth signalsSelf-sufficiency in growth signals Insensitivity to growth-inhibitory signalsInsensitivity to growth-inhibitory signals Evasion of apoptosisEvasion of apoptosis Limitless replicative potentialLimitless replicative potential Sustained angiogenesisSustained angiogenesis Ability to invade and metastsizeAbility to invade and metastsize


A - Self-sufficiency in Growth signals:A - Self-sufficiency in Growth signals: Oncogene: Gene that promote Oncogene: Gene that promote

autonomous cell growth in cancer cellsautonomous cell growth in cancer cells They are derived by mutations in They are derived by mutations in

protooncogenesprotooncogenes They are characterized by the ability to They are characterized by the ability to

promote cell growth in the absence of promote cell growth in the absence of normal growth-promoting signalsnormal growth-promoting signals

Oncoproteins : are the products Oncoproteins : are the products


Remember the cell cycle !!Remember the cell cycle !! Binding of a growth factor to its receptor Binding of a growth factor to its receptor

on the cell membraneon the cell membrane Activation of the growth factor receptor Activation of the growth factor receptor

leading to activation of signal-leading to activation of signal-transducing proteins transducing proteins

Transmission of the signal to the nucleusTransmission of the signal to the nucleus Induction of the DNA transcriptionInduction of the DNA transcription Entry in the cell cycle and cell divisionEntry in the cell cycle and cell division


HOW CANCER CELLS ACQUIRE HOW CANCER CELLS ACQUIRE SELF-SUFFICIENCY IN GROWTH SELF-SUFFICIENCY IN GROWTH SIGNALS??SIGNALS??


1- Growth factors:1- Growth factors: Cancer cells are capable to synthesize Cancer cells are capable to synthesize

the same growth factors to which they the same growth factors to which they are responsive are responsive

E.g. Sarcomas ---- > TGF-E.g. Sarcomas ---- > TGF- Glioblastoma-----> PDGFGlioblastoma-----> PDGF


2-Growth factors receptors:2-Growth factors receptors: Receptors --- mutation ----continous Receptors --- mutation ----continous

signals to cells and uncontroled signals to cells and uncontroled growthgrowth

Receptors --- overexpression ---cells Receptors --- overexpression ---cells become very sensitive ----become very sensitive ----hyperresponsive to normal levels of hyperresponsive to normal levels of growth factorsgrowth factors


Example : Example : Epidermal Growth Factor ( EGF ) Epidermal Growth Factor ( EGF )

Receptor familyReceptor family HER2 HER2

Amplified in breast cancers and other tumorsAmplified in breast cancers and other tumors High levels of HER2 in breast cancer indicate High levels of HER2 in breast cancer indicate

poor prognosispoor prognosis Anti- HER2 antibodies are used in treatmentAnti- HER2 antibodies are used in treatment


3- Signal-transducing proteins :3- Signal-transducing proteins : They receive signals from activated They receive signals from activated

growth factors receptors and growth factors receptors and transmitte them to the nucleus. transmitte them to the nucleus. Examples :Examples : RASRAS ABLABL


RAS :RAS : 30% of all human tumors contain 30% of all human tumors contain

mutated RAS gene . E.g : colon . mutated RAS gene . E.g : colon . Pancreas cancersPancreas cancers

Mutations of the RAS gene is the most Mutations of the RAS gene is the most common oncogene abnormality in common oncogene abnormality in human tumorshuman tumors

Mutations in RAS --- cells continue to Mutations in RAS --- cells continue to proliferateproliferate

CarcinogenesisCarcinogenesis ABL gene ABL gene

ABL protooncogene has a tyrosine kinase ABL protooncogene has a tyrosine kinase activityactivity

Its activity is controlled by negative Its activity is controlled by negative regulatory mechanismregulatory mechanism

E.g. : chronic myeloid leukemia ( CML ) :E.g. : chronic myeloid leukemia ( CML ) : t( 9,22) ---ABL gene transferred from ch. 9 to ch. 22t( 9,22) ---ABL gene transferred from ch. 9 to ch. 22 Fusion with BCR ---> BCR-ABL Fusion with BCR ---> BCR-ABL BCR-ABL has tyrosine kinase acttivity ---BCR-ABL has tyrosine kinase acttivity ---

( oncogenec)( oncogenec)


CML patients are treated with CML patients are treated with ( Gleevec) which is inhibitor of ABL ( Gleevec) which is inhibitor of ABL kinase kinase


4- Nuclear transcription factors :4- Nuclear transcription factors : Mutations may affect genes that Mutations may affect genes that

regulate transcription of DNA regulate transcription of DNA growth growth autonomyautonomy

E.g. MYCE.g. MYC MYC protooncogene produce MYC protein MYC protooncogene produce MYC protein

when cell receives growth signalswhen cell receives growth signals MYC protein binds to DNA leading to MYC protein binds to DNA leading to

activation of growth-related genesactivation of growth-related genes


Normally … MYC decrease when cell Normally … MYC decrease when cell cycle begins …but ..in tumors there cycle begins …but ..in tumors there is sustained expression of MYC is sustained expression of MYC continuous proliferation continuous proliferation

E.g. Burkitt Lymphoma ; MYC is E.g. Burkitt Lymphoma ; MYC is dysregulated due to t( 8,14)dysregulated due to t( 8,14)


5- Cyclins and cyclins- dependent kinases5- Cyclins and cyclins- dependent kinases Progression of cells through cell cycles is Progression of cells through cell cycles is

regulated by CDKs after they are activated regulated by CDKs after they are activated by binding with cyclinsby binding with cyclins

Mutations that dysregulate cyclins and Mutations that dysregulate cyclins and CDKs will lead to cell proliferation …e.g.CDKs will lead to cell proliferation …e.g. Cyclin D genes are overexpressed in breast, Cyclin D genes are overexpressed in breast,

esophagus and liver cancers.esophagus and liver cancers. CDK4 is amplified in melanoma and sarcomasCDK4 is amplified in melanoma and sarcomas


Main changes in the cell physiology that Main changes in the cell physiology that lead to formation of the malignant lead to formation of the malignant phenotype:phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals

B- Insensitivity to growth-inhibitory B- Insensitivity to growth-inhibitory signalssignals

C- Evasion of apoptosisC- Evasion of apoptosis

D- Limitless replicative potentialD- Limitless replicative potential

E- Sustained angiogenesisE- Sustained angiogenesis

F- Ability to invade and metastsizeF- Ability to invade and metastsize


2. Insensitivity to growth-inhibitory 2. Insensitivity to growth-inhibitory signalssignals

Tumor supressor genes control ( apply Tumor supressor genes control ( apply brakes) cells proliferationbrakes) cells proliferation

If mutation caused disruption to them If mutation caused disruption to them cell becomes insensitive to growth cell becomes insensitive to growth inhibitioninhibition uncontrolled proliferation uncontrolled proliferation

Examples: RB, TGF-Examples: RB, TGF-, APC, TP53, APC, TP53


RB ( retinoblastoma ) gene :RB ( retinoblastoma ) gene : First tumor supressor gene discoveredFirst tumor supressor gene discovered It was discovered initially in It was discovered initially in

retinoblastomasretinoblastomas Found in other tumors, e.g. breast caFound in other tumors, e.g. breast ca RB gene is a DNA-binding protein RB gene is a DNA-binding protein RB is located on chromosome 13RB is located on chromosome 13


RB gene exists in “ active “ and “ RB gene exists in “ active “ and “ inactive” formsinactive” forms

If activeIf active will stop the advancing will stop the advancing from G1 to S phase in cell cyclefrom G1 to S phase in cell cycle

If cell is stimulated by growth If cell is stimulated by growth factors factors inactivation of RB gene inactivation of RB gene brake is releasedbrake is released cells start cell cells start cell cycle …G1 cycle …G1 SSM …then RB gene is M …then RB gene is activated againactivated again


Retinoblastoma is an uncommon Retinoblastoma is an uncommon childhood tumorchildhood tumor

Retinoblastoma is either sporadic (60%) Retinoblastoma is either sporadic (60%) or familial ( 40% )or familial ( 40% )

Two mutations required to produce Two mutations required to produce retinoblastomaretinoblastoma

Both normal copies of the gene should Both normal copies of the gene should be lost to produce retinoblastomabe lost to produce retinoblastoma


Transforming Growth Factor- Transforming Growth Factor- pathway:pathway: TGF-TGF-is an inhibitor of proliferationis an inhibitor of proliferation It regulate RB pathwayIt regulate RB pathway Inactivation of TGF-Inactivation of TGF-lead to cell lead to cell

proliferationproliferation Mutations in TGF-Mutations in TGF-pathway are present pathway are present

in :in : of pancreatic cancersof pancreatic cancers of colon cancersof colon cancers


Adenomatous Polyposis Coli – Adenomatous Polyposis Coli – Catenin pathway:Catenin pathway: APC is tumor supressor geneAPC is tumor supressor gene APC gene loss is very common in colon APC gene loss is very common in colon

cancerscancers It has anti-proliferative action through It has anti-proliferative action through

inhibition of inhibition of Catenin which activate cell Catenin which activate cell proliferationproliferation

Individuals with mutant APC develop Individuals with mutant APC develop thousands of colonic polypsthousands of colonic polyps


One or more of the polyps will One or more of the polyps will progress to colonic carcinomaprogress to colonic carcinoma

APC mutations are seen in 70% to APC mutations are seen in 70% to 80% of sporadic colon cancers80% of sporadic colon cancers


TP53 ( P53 )TP53 ( P53 ) It has multiple functionsIt has multiple functions Mainly : Mainly :

Tumor suppressor gene ( anti-proliferative )Tumor suppressor gene ( anti-proliferative ) Regulates apoptosisRegulates apoptosis


TP53 senses DNA damageTP53 senses DNA damage Causes G1 arrest to give chance for Causes G1 arrest to give chance for

DNA repairDNA repair Induce DNA repair genes Induce DNA repair genes If a cell with damaged DNA cannot If a cell with damaged DNA cannot

be repaired, it will be directed by be repaired, it will be directed by TP53 to undergo apoptosisTP53 to undergo apoptosis


With loss of TP53, DNA damage goes With loss of TP53, DNA damage goes unrepairedunrepaired

Mutations will be fixed in the Mutations will be fixed in the dividing cells, leading to malignant dividing cells, leading to malignant transformationtransformation

TP53 is called the “ guardian of the TP53 is called the “ guardian of the genome”genome”

70% of human cancers have a defect in 70% of human cancers have a defect in TP53TP53

It has been reported with almost all types It has been reported with almost all types of cancers : e.g. lung, colon, breastof cancers : e.g. lung, colon, breast

In most cases, mutations are acquired, In most cases, mutations are acquired, but can be inhereted, e.g : Li-Fraumeni but can be inhereted, e.g : Li-Fraumeni syndromesyndrome



Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals

B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals






Evasion of apoptosis:Evasion of apoptosis: Mutations in the genes regulating Mutations in the genes regulating

apoptosis are factors in malignant apoptosis are factors in malignant transformationtransformation

Cell survival is controlled by genes that Cell survival is controlled by genes that promote and inhibit apoptosis promote and inhibit apoptosis


Reduced CD95 level inactivate death –Reduced CD95 level inactivate death –induced signaling cascade that cleaves induced signaling cascade that cleaves DNA to cause deathDNA to cause death tumor cells less tumor cells less susceptible to apoptosissusceptible to apoptosis

DNA damage induced apoptosis (with the DNA damage induced apoptosis (with the action of TP53 ) can be blocked in tumorsaction of TP53 ) can be blocked in tumors See figure 6-24 , page 189See figure 6-24 , page 189

loss of TP53 and up-regulation of BCL2 loss of TP53 and up-regulation of BCL2 prevent apoptosisprevent apoptosis









Limitless replicative potential :Limitless replicative potential : Normally there is progressive Normally there is progressive

shortening of telomeres at the ends of shortening of telomeres at the ends of chromosomeschromosomes

Telomerase is active in normal stem Telomerase is active in normal stem cells but absent in somatic cellscells but absent in somatic cells

In tumor cells : activation of the enzyme In tumor cells : activation of the enzyme telomerase, which can maintain normal telomerase, which can maintain normal telomere lengthtelomere length









Sustained angiogenesisSustained angiogenesis Neovascularization has two main Neovascularization has two main

effects: effects: Perfusion supplies oxygen and nutrientsPerfusion supplies oxygen and nutrients Newly formed endothelial cells stimulate Newly formed endothelial cells stimulate

the growth of adjacent tumor cells by the growth of adjacent tumor cells by secreting growth factors, e.g : PDGF, IL-1secreting growth factors, e.g : PDGF, IL-1

Angiogenesis is required for metastasisAngiogenesis is required for metastasis


How do tumors develop a blood How do tumors develop a blood supply?supply? Tumor-associated angiogenic factors Tumor-associated angiogenic factors These factors may be produced by These factors may be produced by

tumor cells or by inflammatory cells tumor cells or by inflammatory cells infiltrating the tumor e.g. macrophagesinfiltrating the tumor e.g. macrophages

Important factors : Important factors : Vascular endothelial growth factor( VEGF ) Vascular endothelial growth factor( VEGF ) Fibroblast growth factorFibroblast growth factor









Ability to invade and metastsize:Ability to invade and metastsize: Two phases : Two phases :

Invasion of extracellular matrixInvasion of extracellular matrix Vascular dissimenation and homing of Vascular dissimenation and homing of

tumor cellstumor cells


Invasion of ECM:Invasion of ECM: Malignant cells first breach the Malignant cells first breach the

underlying basement membraneunderlying basement membrane Traverse the interstitial tissueTraverse the interstitial tissue Penetrate the vascular basement Penetrate the vascular basement

membrane membrane Gain access to the circulationGain access to the circulation


Invasion of the ECM has four steps:Invasion of the ECM has four steps: Detachment of tumor cells from each Detachment of tumor cells from each

otherother Attachments of tumor cells to matrix Attachments of tumor cells to matrix

componentscomponents Degradation of ECMDegradation of ECM Migration of tumor cells Migration of tumor cells


Vascular dissemination and homing Vascular dissemination and homing of tumor cells:of tumor cells: May form emboli May form emboli Most travel as single cellsMost travel as single cells Adhesion to vascular endotheliumAdhesion to vascular endothelium extravasationextravasation








Genomic InstabilityGenomic Instability

Enabler of malignancyEnabler of malignancy Due to defect in DNA repair genesDue to defect in DNA repair genes Examples:Examples:

Hereditary Nonpolyposis colon Hereditary Nonpolyposis colon carcinoma(HNPCC)carcinoma(HNPCC)

Xeroderma pigmentosumXeroderma pigmentosum Familial breast cancerFamilial breast cancer

Genomic InstabilityGenomic Instability

Familial breast cancer:Familial breast cancer: Due to mutations in BRCA1 and BRCA2 Due to mutations in BRCA1 and BRCA2

genesgenes These genes regulate DNA repairThese genes regulate DNA repair Account for 80% of familial breast Account for 80% of familial breast

cancercancer They are also involved in other They are also involved in other

malignanciesmalignancies

Molecular Basis of Molecular Basis of multistep Carcinogenesismultistep Carcinogenesis

Cancer results from accumulation of Cancer results from accumulation of multiple mutationsmultiple mutations

All cancers have multiple genetic All cancers have multiple genetic alterations, involving activation of alterations, involving activation of several oncogenes and loss of two or several oncogenes and loss of two or more tumor suppressor genesmore tumor suppressor genes

Molecular Basis of Molecular Basis of multistep Carcinogenesismultistep Carcinogenesis

Tumor progressionTumor progression

Many tumors become more Many tumors become more aggressive and acquire greater aggressive and acquire greater malignant potential…this is called “ malignant potential…this is called “ tumor progression” …not increase in tumor progression” …not increase in size!!size!!

By the time, the tumor become By the time, the tumor become clinically evident, their constituent clinically evident, their constituent cells are extremely heterogeneouscells are extremely heterogeneous

Karyotypic Changes in Karyotypic Changes in TumorsTumors

Translocations: Translocations: In CML : t(9,22) …” Philadelphia In CML : t(9,22) …” Philadelphia

chromosome”chromosome” In Burkitt Lymphoma : t(8,14)In Burkitt Lymphoma : t(8,14) In Follicular Lymphoma : t(14,18)In Follicular Lymphoma : t(14,18)

DeletionsDeletions Gene amplification:Gene amplification:

Breast cancer : HER-2Breast cancer : HER-2

Carcinogenic AgentsCarcinogenic Agents

ChemicalsChemicals RadiationRadiation Microbial agentsMicrobial agents


Chemicals:Chemicals: Natural or syntheticNatural or synthetic Direct reacting or indirectDirect reacting or indirect Indirect Indirect need metabolic conversion need metabolic conversion

to be active and carcinogenicto be active and carcinogenic Indirect chemicals are called “ Indirect chemicals are called “

procarcinogens “ and their active end procarcinogens “ and their active end products are called “ ultimate products are called “ ultimate carcinogens”carcinogens”


All direct reacting and ultimate All direct reacting and ultimate chemical carcinogens are highly chemical carcinogens are highly reactive as they have electron-reactive as they have electron-deficient atomsdeficient atoms

They react with the electron rich They react with the electron rich atoms in RNA,DNA and other atoms in RNA,DNA and other cellular proteinscellular proteins


Examples:Examples: Alkylating agentsAlkylating agents Polycyclic hydrocarbons:Polycyclic hydrocarbons:

Cigarette smokingCigarette smoking Animal fats during broiling meatsAnimal fats during broiling meats Smoked meats and fishSmoked meats and fish


Aromatic amines and azo dyes:Aromatic amines and azo dyes: -naphthylamine cause bladder cancer in -naphthylamine cause bladder cancer in

rubber industries and aniline dyerubber industries and aniline dye Some azo dyes are used to color foodSome azo dyes are used to color food Nitrosamines and nitrosamides are used Nitrosamines and nitrosamides are used

as preservatives. They cause gastric as preservatives. They cause gastric cancer.cancer.

Aflatoxin B: produced by aspirigillus Aflatoxin B: produced by aspirigillus growing on improperly stored grains. It growing on improperly stored grains. It cause hepatocellular carcinomacause hepatocellular carcinoma


Mechanism of action of chemical Mechanism of action of chemical carcinogens:carcinogens: Most of them are mutagenic. i.e. cause Most of them are mutagenic. i.e. cause

mutationsmutations RAS and TP53 are common targetsRAS and TP53 are common targets


Radiation carcinogenesisRadiation carcinogenesis UV rays of sunlightUV rays of sunlight X-raysX-rays Nuclear radiationNuclear radiation Therapeutic irradiationsTherapeutic irradiations

Radiation has mutagenic effects: Radiation has mutagenic effects: chromosomes breakage, chromosomes breakage, translocations, and point mutationstranslocations, and point mutations


UV rays of sunlight :UV rays of sunlight : Can cause skin cancers: melanoma, Can cause skin cancers: melanoma,

squamous cell carcinoma, and basal cell squamous cell carcinoma, and basal cell carcinomacarcinoma

It is capable to damage DNA It is capable to damage DNA With extensive exposure to sunlight, the With extensive exposure to sunlight, the

repair system is overwhelmedrepair system is overwhelmed skin skin cancer cancer

They cause mutations in TP53 geneThey cause mutations in TP53 gene


Viral and Microbial oncogenesisViral and Microbial oncogenesis

DNA virusesDNA viruses

RNA virusesRNA viruses

other organismsother organisms

Carcinogenic AgentsCarcinogenic Agents Viral oncogenes:Viral oncogenes:

carry genes that induce cell replication as part of the viral life cycle

host cell has endogenous genes that maintain the normal cell-cycle

Viral infection mimics or blocks these normal cellular signals necessary for growth regulation


RNA Oncogenic virusesRNA Oncogenic virusesHuman T-Cell Leukemia Virus type 1 Human T-Cell Leukemia Virus type 1

(HTLV-1)(HTLV-1)• RNA retrovirus targets / transforms T-cellsRNA retrovirus targets / transforms T-cells

• causes T-Cell leukemia/Lymphoma causes T-Cell leukemia/Lymphoma

• Endemic in Japan and CaribbeanEndemic in Japan and Caribbean

• Transmitted like HIV but only 1% of infected Transmitted like HIV but only 1% of infected

develop T-Cell leukemia/Lymphoma develop T-Cell leukemia/Lymphoma

• 20-30 year latent period20-30 year latent period


No cure or vaccine No cure or vaccine Treatment : chemotherapy with Treatment : chemotherapy with

common relapsecommon relapse


DNA Oncogenic VirusesDNA Oncogenic Viruses virus DNA forms stable association with virus DNA forms stable association with

host’s DNAhost’s DNA transcribed viral DNA transforms host celltranscribed viral DNA transforms host cell

Examples: Examples: papilloma virusespapilloma viruses

Epstein-Barr (EBV)Epstein-Barr (EBV)

Hepatitis B (HBV)Hepatitis B (HBV)

Kaposi sarcoma herpes virusKaposi sarcoma herpes virus


Human Papillomavirus (HPV)Human Papillomavirus (HPV)• 70 types70 types• squamous cell carcinoma of squamous cell carcinoma of

cervixcervix anogenital regionanogenital region mouth mouth larynxlarynx


sexually transmittedsexually transmitted Cervical cancer Cervical cancer

85% have types 16 and 1885% have types 16 and 18

Genital wartsGenital warts types 6 and 11types 6 and 11


HPV causing benign tumors:HPV causing benign tumors:

types 6, 11types 6, 11

HPV causing malignant tumors :HPV causing malignant tumors : types 16, 18, 31types 16, 18, 31

vDNA integrates w/ hostvDNA integrates w/ host


HPV (types 16 and 18)HPV (types 16 and 18) over-expression of Exon 6 and 7over-expression of Exon 6 and 7

E6 protein binds to Rb tumor E6 protein binds to Rb tumor suppressor suppressor

replaces normal transcription replaces normal transcription factorsfactors

decreases Rb synthesisdecreases Rb synthesis E7 protein binds to TP53E7 protein binds to TP53

facilitates degradation of TP53facilitates degradation of TP53


HPV infection alone is not sufficient -HPV infection alone is not sufficient - other risk factors:other risk factors:

cigarette smokingcigarette smoking

coexisting infectionscoexisting infections

hormonal changeshormonal changes


Epstein-Barr VirusEpstein-Barr Virus• common virus worldwidecommon virus worldwide• Infects B lymphocytes and epithelial cells Infects B lymphocytes and epithelial cells

of oropharynxof oropharynx

• causes infectious mononucleosiscauses infectious mononucleosis• EBV infection may cause malignancy EBV infection may cause malignancy

Burkitt’s LymphomaBurkitt’s Lymphoma B cell lymphoma in immunosuppressedB cell lymphoma in immunosuppressed Nasopharyngeal carcinomaNasopharyngeal carcinoma


Nasopharyngeal carcinoma Nasopharyngeal carcinoma Cancer of nasopharygeal epitheliumCancer of nasopharygeal epithelium

Endemic in South China, parts of AfricaEndemic in South China, parts of Africa 100% of tumors contain EBV genome in 100% of tumors contain EBV genome in

endemic areasendemic areas


Burkitt LymphomaBurkitt Lymphoma

highly malignant

B cell tumor

sporadic rare

occurrence worldwide

most common

childhood tumor in

Africa

all cases have

t(8:14))


causes B lymphocyte cell proliferationcauses B lymphocyte cell proliferation loss of growth regulationloss of growth regulation predisposes to mutation, esp. t(8:14)predisposes to mutation, esp. t(8:14)


Hepatitis B virus (HBV) Strong association with Liver Cancer

world-wide, but HBV infection is most common in Far East and Africa

HBV infection incurs up to 200-fold risk


Helicobacter Pylori• bacteria infecting stomach• implicated in:

peptic ulcers gastric lymphoma

Mucosal Associated Lymphoid Tumor (MALT)

gastric carcinoma

Host defenseHost defense

Tumor Antigens:Tumor Antigens: Tumor-specific antigens: present only Tumor-specific antigens: present only

on tumor cellson tumor cells Tumor-associated antigens: present on Tumor-associated antigens: present on

tumor cells and some normal cellstumor cells and some normal cells


Tumor antigens may:Tumor antigens may: Result from gene mutations: TP53, RASResult from gene mutations: TP53, RAS Be products of amplified genes: HER-2Be products of amplified genes: HER-2 Viral antigens: from oncogenic virusesViral antigens: from oncogenic viruses Be differentiation specific: PSA in prostate Be differentiation specific: PSA in prostate Oncofetal antigens: CEA, Alpha fetoprotein Oncofetal antigens: CEA, Alpha fetoprotein

normal embryonic antigen but absent in normal embryonic antigen but absent in adults….in some tumors it will be re-expressed, adults….in some tumors it will be re-expressed, e.g: colon ca, liver cancer e.g: colon ca, liver cancer


Antitumor mechanisms involve:Antitumor mechanisms involve: Cytotoxic T lymphocytesCytotoxic T lymphocytes Natural killer cells Natural killer cells MacrophagesMacrophages Humoral mechanisms : Humoral mechanisms :

Complement systemComplement system Antibodies Antibodies

Clinical featuresClinical features

Tumours cause problems because :Tumours cause problems because : Location and effects on adjacent structures:

(1cm pituitary adenoma can compress and destroy the surrounding tissue and cause hypopituitarism).

(0.5 cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension).

Tumors may cause bleeding and secondary infections

lesion ulcerates adjacent tissue and structures

Clinical featuresClinical features Effects on functional activity

hormone synthesis occurs in neoplasms arising in endocrine glands:

adenomas and carcinomas of β cells of the islets of the pancreas produce hyperinsulinism.

Some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids.

aldosterone induces sodium retention, hypertension and hypokalemia

Usually such activity is associated with well differentiated benign tumors more than carcinomas.


Cancer cachexia Usually accompanied by weakness, anorexia and

anemia Severity of cachexia, generally, is correlated with

the size and extend of spread of the cancer. The origins of cancer cachexia are multifactorial:

anorexia (reduced calorie intake) increased basal metabolic rate and calorie expenditure

remains high. general metabolic disturbance


Paraneoplastic syndromes

They are symptoms that occur in cancer patients and cannot be explained.

They are diverse and are associated with many different tumors.

They appear in 10% to 15% of pateints. They may represent the earliest manifestation of

an occult neoplasm. They may represent significant clinical problems

and may be lethal. They may mimic metastatic disease.


The most common paraneoplastic syndrome are: Hypercalcemia Cushing syndrome Nonbacterial thrombotic endocarditis

The most often neoplasms associated with these syndromes: Lung and breast cancers and

hematologic malignancies

Clinical FeaturesClinical Features

Grading :Grading : Grade I, II, III, IVGrade I, II, III, IV Well, moderately, poorly differentiated, Well, moderately, poorly differentiated,

anaplasticanaplastic Staging :Staging :

SizeSize Regional lymph nodes involvementRegional lymph nodes involvement Presence or absence of distant metastasisPresence or absence of distant metastasis

TNM systemTNM system


T (primary tumor): T1, T2, T3, T4T (primary tumor): T1, T2, T3, T4 N (regional lymph nodes): N0, N1, N (regional lymph nodes): N0, N1,

N2, N3N2, N3 M (metastasis): M0, M1M (metastasis): M0, M1


American Joint committee system American Joint committee system ( AJC )( AJC ) Stages 0 to IVStages 0 to IV Using TNM features Using TNM features

Laboratory DiagnosisLaboratory Diagnosis

Morphologic methodes Biochemical assays Molecular diagnosis


Microscopic Tissue DiagnosisMicroscopic Tissue Diagnosis the gold standard of cancer diagnosis.. Several sampling approaches are available:

Excision or biopsy Frozen section

fine-needle aspiration Cytologic smears


Biochemical assaysBiochemical assays:: Useful for measuring the levels of tumor

associated enzymes, hormones, and tumor markers in serum.

Useful in determining the effectiveness of therapy and detection of recurrences after excision

Elevated levels may not be diagnostic of cancer (PSA).

Only few tumor markers are proved to be clinically useful, example CEA and α- fetoprotein.


Molecular diagnosisMolecular diagnosis Polymerase chain reaction (PCR) example: detection of BCR-ABL transcripts

in chronic myeloid leukemia. Fluorescent in situ hybridization (fish) it is useful for detecting chromosomes

translocation characteristic of many tumorsBoth PCR and Fish can show amplification of

oncogenes (HER2 and N-MYC)

Documents

NEOPLASIA Abdulmalik Alsheikh,M.D,FRCPC. CARCINOGENESIS Carcinogenesis is a multistep process at both the phenotypic and the genetic levels. Carcinogenesis