1. Infectious etiologies of Malignancy Lalan S. Wilfong, MD Texas Oncology, PA February 4, 2004

2. Cancer Pathogenesis

3. Etiology of Malignancy Chemical exposures Chemical exposures  cigarette smoke  benzene Physical factors Physical factors  radiation exposure  UV light Genetics Genetics  Li-Fraumeni  HNPCC Infections Infections

4. Infections Viruses, bacteria, and parasites Viruses, bacteria, and parasites  All implicated in etiology of different malignancies  Major health issue  15% of cancers worldwide  higher in developing countries Prevention could eliminate certain cancers Prevention could eliminate certain cancers Treatment of infection can cure the cancer Treatment of infection can cure the cancer

5. Oncogenic Infectious Agents

6. Characteristics Ability to establish chronic infection Ability to establish chronic infection Established infection in individuals destined to develop malignancy Established infection in individuals destined to develop malignancy Interval of years between initial infection and malignancy Interval of years between initial infection and malignancy Benign outcome for most infected individuals Benign outcome for most infected individuals

7. Mechanisms Induces changes within the cell Induces changes within the cell  HPV Induces chronic inflammation in target tissue Induces chronic inflammation in target tissue  H pylori Increased tumor risk due to immunosuppression of host Increased tumor risk due to immunosuppression of host  HIV

8. Human Papillomavirus More than 80 different HPV types exist More than 80 different HPV types exist Highly species specific Highly species specific Induce squamous epithelial and fibroepithelial tumors in their natural hosts Induce squamous epithelial and fibroepithelial tumors in their natural hosts  Benign warts  Cancer – high risk subtypes 16, 18, 31, 33 Full productive cycle is supported only in squamous epithelial cells Full productive cycle is supported only in squamous epithelial cells

9. HPV Genome Circular ds-Dna 8000 base pairs Circular ds-Dna 8000 base pairs Genome divided into two parts Genome divided into two parts  Early region – encodes viral proteins involved in viral DNA replication and cellular transformation  Late region – encodes viral capsid proteins Devita

10. Mechanism E6 Interacts with E6 associated protein Interacts with E6 associated protein  Ubiquitin protein ligase  Ubiquitinates p53  Proteolyis of p53 p53 mediates cell cycle arrest in response to DNA damage p53 mediates cell cycle arrest in response to DNA damage E7 Interacts with retinoblastoma tumor suppressor gene Disrupts complex between pRB and E2F-1 transcription factor Activates expression of genes in cell-cycle progression

11. Cervical Cancer Link between HPV and cervical cancer noted in 1970 Link between HPV and cervical cancer noted in 1970 Risks for cervical cancer Risks for cervical cancer  Sexual promiscuity  Early age of onset of sexual activity  Poor sexual hygiene EBV DNA found in CIN EBV DNA found in CIN Etiology of 85-90% of cervical cancers Etiology of 85-90% of cervical cancers

12. Prevention Sex Education Sex Education Early detection with serotype testing in pap smears Early detection with serotype testing in pap smears Vaccination Vaccination  NEJM, Koutsky, et al 347:21  HPV-16 vaccine  3.8 women / 100 woman years in placebo vs 0 in vaccine arm had infection with HPV  All 9 cases of CIN occurred in placebo arm

13. Helicobacter Pylori Suspected as one possible etiology of gastric cancer Suspected as one possible etiology of gastric cancer  Causes atrophic gastritis  Intestinal metaplasia Also implicated in development of gastric maltoma Also implicated in development of gastric maltoma  90% of cases are H pylori positive

14. Pathogenesis Infection by H Pylori Increase in MALT tissue Additional genetic mutations Malt lymphoma

15. Treatment Multiple trials confirm efficacy of antibiotics Multiple trials confirm efficacy of antibiotics  Triple drug therapy to eradicate H pylori  More effective in early stage lesions  Reported complete remission rates of 70-80%  Lower rates in lesions that infiltrate the muscularis or have lymph node involvement Strict endoscopic and hematologic follow up Strict endoscopic and hematologic follow up Chemotherapy reserved for those cases who progress despite antibiotic therapy Chemotherapy reserved for those cases who progress despite antibiotic therapy

16. Campylobacter jejuni Implicated in development of immunoproliferative small intestinal disease Implicated in development of immunoproliferative small intestinal disease  AKA alpha chain disease  MALT lymphoma characterized by  Infiltration of the bowel wall with a plasma- cell population  Secretes a monotypic, truncated immunoglobulin  heavy chain Lecuit, et al. NEJM 2004; 350:239-48 Lecuit, et al. NEJM 2004; 350:239-48

17. Immunoproliferative Small Intestinal Disease Spectrum of histologic changes Spectrum of histologic changes  Seemingly benign lymphoid infiltration  Malignant diffuse large-B-cell lymphoma Occurs mainly in Mediterranean basin, Africa, and Middle East Occurs mainly in Mediterranean basin, Africa, and Middle East Accounts for 1/3 of all GI lymphomas in the Middle East Accounts for 1/3 of all GI lymphomas in the Middle East Clinical presentation varied  Chronic diarrhea  Wasting  heavy chain in serum and urine Can have BM involvement Treat with antibiotics

18. Lecuit, M. et. al. N Engl J Med 2004;350:239-248 Histologic and Immunohistologic Studies of Endoscopic-Biopsy Specimens from the Index Patient

19. Identification of Causative Agent Used PCR to identify Campylobacter DNA in 6 patients with archival tissue and index patient Used PCR to identify Campylobacter DNA in 6 patients with archival tissue and index patient FISH analysis confirmed result in all but one patient FISH analysis confirmed result in all but one patient IHC also confirmed result IHC also confirmed result

20. Lecuit, M. et. al. N Engl J Med 2004;350:239-248 Fluorescence in Situ Hybridization (FISH) and Immunohistochemical Analysis of Tissue Specimens

21. Conclusion Infections can cause malignancies Infections can cause malignancies New associations being discovered New associations being discovered Prevention of infection could eliminate certain malignancies Prevention of infection could eliminate certain malignancies Treatment of the infection can cure other malignancies Treatment of the infection can cure other malignancies