Infectious etiologies of Malignancy

Lalan S. Wilfong, MDLalan S. Wilfong, MD

Texas Oncology, PATexas Oncology, PA

February 4, 2004February 4, 2004

Cancer Pathogenesis

Etiology of Malignancy Chemical exposuresChemical exposures

cigarette smokecigarette smoke benzenebenzene

Physical factorsPhysical factors radiation exposureradiation exposure UV lightUV light

GeneticsGenetics Li-FraumeniLi-Fraumeni HNPCCHNPCC

InfectionsInfections

Infections

Viruses, bacteria, and parasitesViruses, bacteria, and parasites All implicated in etiology of different All implicated in etiology of different

malignanciesmalignancies Major health issueMajor health issue

15% of cancers worldwide15% of cancers worldwidehigher in developing countrieshigher in developing countries

Prevention could eliminate certain cancersPrevention could eliminate certain cancers Treatment of infection can cure the cancerTreatment of infection can cure the cancer

Oncogenic Infectious AgentsAgent Tumor Type Annual Cases WorldwideBacteriaHelicobacter pylori Stomach cancer, gastric lymphoma 505,000Campylobacter jejuni Alpha chain disease rareVirusesHuman papillomavirus Cervical, anal, vaginal, and other 447,000Hepatitis B virus Liver cancer 285,000Hepatitis C virus Liver cancer 113,000Human immunodeficiency virus Kaposis, NHL 52,000Human herpes type 8 Kaposis’s 44,000Epstein-Barr virus Lymphomas 30,000Human T-cell lymphotropic virus Adult T-cell leukemia 3000ParasitesSchistosomes Bladder cancer 10,000Liver flukes Cholangiocarcinoma 800

Characteristics

Ability to establish chronic infectionAbility to establish chronic infection Established infection in individuals destined Established infection in individuals destined

to develop malignancyto develop malignancy Interval of years between initial infection Interval of years between initial infection

and malignancyand malignancy Benign outcome for most infected Benign outcome for most infected

individualsindividuals

Mechanisms

Induces changes within the cellInduces changes within the cell HPVHPV

Induces chronic inflammation in target Induces chronic inflammation in target tissue tissue H pyloriH pylori

Increased tumor risk due to Increased tumor risk due to immunosuppression of hostimmunosuppression of host HIVHIV

Human Papillomavirus

More than 80 different HPV types existMore than 80 different HPV types exist Highly species specificHighly species specific Induce squamous epithelial and fibroepithelial Induce squamous epithelial and fibroepithelial

tumors in their natural hoststumors in their natural hosts Benign wartsBenign warts Cancer – high risk subtypes 16, 18, 31, 33Cancer – high risk subtypes 16, 18, 31, 33

Full productive cycle is supported only in Full productive cycle is supported only in squamous epithelial cellssquamous epithelial cells

HPV Genome

Circular ds-Dna 8000 base Circular ds-Dna 8000 base pairspairs

Genome divided into two Genome divided into two partsparts Early region – encodes Early region – encodes

viral proteins involved viral proteins involved in viral DNA in viral DNA replication and cellular replication and cellular transformationtransformation

Late region – encodes Late region – encodes viral capsid proteinsviral capsid proteins

Devita

Mechanism

E6E6 Interacts with E6 Interacts with E6

associated proteinassociated protein Ubiquitin protein Ubiquitin protein

ligaseligase Ubiquitinates p53Ubiquitinates p53 Proteolyis of p53Proteolyis of p53

p53 mediates cell cycle p53 mediates cell cycle arrest in response to DNA arrest in response to DNA damagedamage

E7E7 Interacts with Interacts with

retinoblastoma tumor retinoblastoma tumor suppressor genesuppressor gene

Disrupts complex between Disrupts complex between pRB and E2F-1 pRB and E2F-1 transcription factortranscription factor

Activates expression of Activates expression of genes in cell-cycle genes in cell-cycle progressionprogression

Cervical Cancer

Link between HPV and cervical cancer noted in Link between HPV and cervical cancer noted in 19701970

Risks for cervical cancerRisks for cervical cancer Sexual promiscuitySexual promiscuity Early age of onset of sexual activityEarly age of onset of sexual activity Poor sexual hygienePoor sexual hygiene

EBV DNA found in CINEBV DNA found in CIN Etiology of 85-90% of cervical cancersEtiology of 85-90% of cervical cancers

Prevention

Sex EducationSex Education Early detection with serotype testing in pap Early detection with serotype testing in pap

smearssmears VaccinationVaccination

NEJM, Koutsky, et al 347:21NEJM, Koutsky, et al 347:21 HPV-16 vaccineHPV-16 vaccine 3.8 women / 100 woman years in placebo vs 0 3.8 women / 100 woman years in placebo vs 0

in vaccine arm had infection with HPVin vaccine arm had infection with HPV All 9 cases of CIN occurred in placebo armAll 9 cases of CIN occurred in placebo arm

Helicobacter Pylori

Suspected as one possible etiology of Suspected as one possible etiology of gastric cancergastric cancer Causes atrophic gastritisCauses atrophic gastritis Intestinal metaplasiaIntestinal metaplasia

Also implicated in development of gastric Also implicated in development of gastric maltomamaltoma 90% of cases are H pylori positive90% of cases are H pylori positive

Pathogenesis

Infection by H Pylori

Increase in MALT tissue

Additional genetic mutations

Malt lymphoma

Treatment

Multiple trials confirm efficacy of antibioticsMultiple trials confirm efficacy of antibiotics Triple drug therapy to eradicate H pyloriTriple drug therapy to eradicate H pylori More effective in early stage lesionsMore effective in early stage lesions Reported complete remission rates of 70-80%Reported complete remission rates of 70-80% Lower rates in lesions that infiltrate the Lower rates in lesions that infiltrate the

muscularis or have lymph node involvementmuscularis or have lymph node involvement Strict endoscopic and hematologic follow upStrict endoscopic and hematologic follow up Chemotherapy reserved for those cases who Chemotherapy reserved for those cases who

progress despite antibiotic therapyprogress despite antibiotic therapy

Campylobacter jejuni

Implicated in development of immunoproliferative Implicated in development of immunoproliferative small intestinal diseasesmall intestinal disease AKA alpha chain diseaseAKA alpha chain disease MALT lymphoma characterized byMALT lymphoma characterized by

Infiltration of the bowel wall with a plasma-Infiltration of the bowel wall with a plasma-cell populationcell population

Secretes a monotypic, truncated Secretes a monotypic, truncated immunoglobulin immunoglobulin heavy chain heavy chain

Lecuit, et al. NEJM 2004; 350:239-48Lecuit, et al. NEJM 2004; 350:239-48

Immunoproliferative Small Intestinal Disease Spectrum of histologic Spectrum of histologic

changeschanges Seemingly benign Seemingly benign

lymphoid infiltrationlymphoid infiltration Malignant diffuse large-Malignant diffuse large-

B-cell lymphomaB-cell lymphoma Occurs mainly in Occurs mainly in

Mediterranean basin, Mediterranean basin, Africa, and Middle EastAfrica, and Middle East

Accounts for 1/3 of all GI Accounts for 1/3 of all GI lymphomas in the Middle lymphomas in the Middle EastEast

Clinical presentation Clinical presentation variedvaried Chronic diarrheaChronic diarrhea WastingWasting

heavy chain in heavy chain in serum and urineserum and urine

Can have BM Can have BM involvementinvolvement

Treat with antibioticsTreat with antibiotics

Lecuit, M. et. al. N Engl J Med 2004;350:239-248

Histologic and Immunohistologic Studies of Endoscopic-Biopsy Specimens from the Index Patient

Identification of Causative Agent

Used PCR to identify Campylobacter DNA Used PCR to identify Campylobacter DNA in 6 patients with archival tissue and index in 6 patients with archival tissue and index patientpatient

FISH analysis confirmed result in all but FISH analysis confirmed result in all but one patientone patient

IHC also confirmed resultIHC also confirmed result

Lecuit, M. et. al. N Engl J Med 2004;350:239-248

Fluorescence in Situ Hybridization (FISH) and Immunohistochemical Analysis of Tissue Specimens

Conclusion

Infections can cause malignanciesInfections can cause malignancies New associations being discoveredNew associations being discovered Prevention of infection could eliminate Prevention of infection could eliminate

certain malignanciescertain malignancies Treatment of the infection can cure other Treatment of the infection can cure other

malignanciesmalignancies