infectious etiologies of malignancy lalan s. wilfong, md texas oncology, pa february 4, 2004
TRANSCRIPT
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