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Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)

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Presentation on theme: "Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)"— Presentation transcript:

1 Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC) Cancers in HIV: A Growing Problem Cancers in HIV: A Growing Problem

2 AIDS Defining Cancers Kaposi’s sarcomaKaposi’s sarcoma B-cell non-Hodgkin’s lymphomaB-cell non-Hodgkin’s lymphoma Primary CNS lymphomaPrimary CNS lymphoma Cervical cancerCervical cancer

3 Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005. Shiels M S et al. J Natl Cancer Inst 2011;103: Cancer Incidences in HIV in USA

4 Categorizing Cancers in PWHA AIDS Defining CancerAIDS Defining Cancer(decreasing) –KS –NHL (BL, CNS, DLCBL) –Cervical Cancer ( added in 1993) Non AIDS defining Cancers (increasing)Non AIDS defining Cancers (increasing) –Anal Cancer –Lung Cancer –Hodgkin Lymphoma –Liver Cancer Elevated risk but rareElevated risk but rare –Merkel Carcinoma –Leiomyosarcoma –Salivary gland LEC Unchanged riskUnchanged risk –Breast –Colorectal –Prostate –Follicular lymphoma

5 Cancer is the One of the Most Frequent Causes of Death in HIV-Infected Patients Cause of Death Cancer (all) 29%34% Cancer - AIDS defining Cancer - AIDS defining16%13% Cancer - Non-AIDS defining Cancer - Non-AIDS defining13%21% Hepatitis (non cancer) 14%12% Other infections 7%4% Mortalité 2000 and 2005 studies: Bonnet et al., Cancer 101; 317:2004 and CID 48;633: 2009.

6 7 Notable Cancers in HIV Cancer Relative Risk in U.S. people with AIDS vs. general pop (SIR ) Estimated cases/yr in US based on HIV/Cancer Match Registry data Etiologic agents Relationship with immune suppression (CD4 or AIDS) Kaposi sarcoma 22,100735KSHV+++ Non-Hodgkin lymphoma EBV+++ Cervical cancer 4.285HPV+ Lung cancer Tobacco+ Hodgkin lymphoma EBV++ Anal cancer HPV++ Liver cancer HCV, HBV, alcohol + Refs: Engels AIDS 2006, Biggar JNCI 2007, Engels Int J Cancer 2008, Chaturvedi JNCI 2009, Guiguet Lancet Oncol 2009

7 Cancers in HIV Disease AIDS-DefiningVirus Kaposi’s SarcomaHHV-8Kaposi’s SarcomaHHV-8 Non-Hodgkin’s Lymphoma EBV, HHV-8Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical CarcinomaHPVInvasive Cervical CarcinomaHPV Non-AIDS Defining Anal CancerHPVAnal CancerHPV Hodgkin’s DiseaseEBVHodgkin’s DiseaseEBV Leiomyosarcoma (pediatric)EBVLeiomyosarcoma (pediatric)EBV Squamous Carcinoma(oral)HPVSquamous Carcinoma(oral)HPV Merkel cell CarcinomaMCVMerkel cell CarcinomaMCV HepatomaHBV, HCVHepatomaHBV, HCV

8 HIV-Cancers: Overview Non-AIDS defining malignanciesNon-AIDS defining malignancies Anogenital neoplasiaAnogenital neoplasia LymphomasLymphomas Kaposi’s SarcomaKaposi’s Sarcoma Cancer PreventionCancer Prevention

9 Non-AIDS Defining Cancers NADC

10 Non AIDS-defining Cancers Emerging Epidemiologic Features Proportion of Cancers in HIV NADC31%58% Standardized Incidence Ratio Lung Hodgkin lymphoma Larynx Pancreas Liver03.7 Engels EA, Int J Cancer. 2008;123:

11 Factors Contributing to the Increase in Cancer cases in HIV 4-fold increase in HIV/AIDS Population4-fold increase in HIV/AIDS Population Patients living longer and not dying of OIPatients living longer and not dying of OI Rising proportion of HIV pts > 50 yoRising proportion of HIV pts > 50 yo Cancer incidence increases with ageCancer incidence increases with age Greater and earlier start to smoking in HIVGreater and earlier start to smoking in HIV Increase in some CA incidence rate among HIVIncrease in some CA incidence rate among HIV –Lung (3X), anal (29X), liver (3X), HL (13X) –Suggests may be additional risk from HIV

12 Pathogenesis of Cancer in HIV Many are virally-induced cancers, but not allMany are virally-induced cancers, but not all Immune activation, immune dysregulation, inflammation and decreased immune surveillanceImmune activation, immune dysregulation, inflammation and decreased immune surveillance HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genesHIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV) 1HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV) 1 Increase susceptibility to effects of carcinogensIncrease susceptibility to effects of carcinogens Endothelial/epithelial cell abnormalities induced or facilitated by HIV may allow for cancer developmentEndothelial/epithelial cell abnormalities induced or facilitated by HIV may allow for cancer development Population differences based on genetics and exposure to carcinogensPopulation differences based on genetics and exposure to carcinogens Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26

13 Outcomes of cancer in HIV With prolonged survival of HIV population and aging, more people will develop cancer, especially NADCs.With prolonged survival of HIV population and aging, more people will develop cancer, especially NADCs. HIV-infected cancer patients may have worse outcomes in some cancersHIV-infected cancer patients may have worse outcomes in some cancers –Late presentation, advanced stage –Poor access to care –Medical comorbidity, treatment toxicity Unclear if HIV has adverse impact on cancer behavior, immune control, cancer-free survivalUnclear if HIV has adverse impact on cancer behavior, immune control, cancer-free survival Limited data for guiding cancer treatment in HIV-infected peopleLimited data for guiding cancer treatment in HIV-infected people Biggar JAIDS 2005, Little J Clin Oncol 2008, Rengan Lancet Oncol 2012, Suneja AIDS 2013

14 Anogenital Cancers

15 Invasive cervical carcinomaInvasive cervical carcinoma –Considered an AIDS-defining condition –Leading cause of cancer death in women worldwide Anal cancer 1Anal cancer 1 –Not AIDS defining but very common and growing incidence Oral and Head/Neck cancer also HPV relatedOral and Head/Neck cancer also HPV related HPV involvement 1-2HPV involvement 1-2 –Both derive from precancerous lesions due to HPV –Most cancer causing strains: 16, 18, 31, 33, 35, 45 –Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia –Cancer can be prevented with early diagnosis and vaccines 1 Phelps RM, et al. Int J Cancer. 2001;94: Martin F, et al. Sex Transm Infect. 2001;77:

16 Spectrum of HPV disease Morphologic Continuum Low-grade diseaseHigh-grade disease

17 Rectal mucosa Columns of Morgagni Dentate (pectinate) line Squamous mucosa Skin Levator ani muscle Subcutaneous Deep External sphincter ani muscles Superficial Anal anatomy Ryan DP et al. New Engl J Med. 2000;342:

18 Anal and Cervical Cancer Incidence  Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000  Cervical cancer currently: 8-10/100,000  Anal cancer among HIV+ MSM in USA: up to 137/100,000 American Cancer Society. Cervical cancer facts Daling JR et al. N Engl J Med. 1987;317: Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.

19 19 Prevalence of anal HPV detection among MSM Population-based data Chin-Hong et al. Ann Int Med. 2008;149; Prevalence, % HIV-seropositive participants HIV-negative participants All participants

20 Redfield IRC 2100

21 Lymphomas

22 Pathology of AIDS-Related Non-Hodgkin’s Lymphoma Small noncleaved-cell lymphomaSmall noncleaved-cell lymphoma –Burkitt’s lymphoma and Burkitt-like lymphoma Immunoblastic lymphoma (primary CNS)Immunoblastic lymphoma (primary CNS) Diffuse large-cell lymphoma (90% CD20+)Diffuse large-cell lymphoma (90% CD20+) –Large noncleaved-cell lymphoma –CD30+ anaplastic large B-cell lymphoma Plasmablastic lymphomaPlasmablastic lymphoma Advanced stage (>75% III or IV)Advanced stage (>75% III or IV) Extranodal involvementExtranodal involvement –Central nervous system, liver, bone marrow, gastrointestinal Tirelli U, et al. AIDS. 2000;14:

23 EBV-positive tumors Burkitt’s lymphoma Nasopharyngeal carcinoma

24 AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General Population Besson et al. Blood. 2001; 98: Little et al Blood. 2003; 101:

25 Hodgkin’s Disease Association with HIV-infectionAssociation with HIV-infection –Hodgkin’s disease: RR: 5 to 30 –Non-Hodgkin’s disease: RR: 24 to 165 –Incidence increasing rapidly in post HAART era –>95% are EBV+ Patients with HIV present with:Patients with HIV present with: –B symptoms (70% to 96%), worse histology, higher-stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia Good response to MOPP/ABVGood response to MOPP/ABV –Complete response: 74.5% –2-year disease-free survival: 62% but more relapses in HIV –Early good results with Stanford V, BEACOPP and brentuximab vendotin Gerard L, et al. AIDS. 2003;17:81-87.

26 Kaposi’s Sarcoma

27 One of the first recognized AIDS-defining illnessesOne of the first recognized AIDS-defining illnesses Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sitesVascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sites –Human herpesvirus-8 (HHV8) or KSHV HHV8HHV8 –DNA virus found in both HIV+ and HIV- KS. –Tropism for B cells and endothelial cells, high titers in saliva –Also associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIV –Genome codes for viral homologs of human proteins involved in cell cycle regulation and signaling HIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growthHIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growth

28 AIDS-associated Kaposi’s Sarcoma TransmissionTransmission Mostly MSM in USMostly MSM in US IVDU and Heterosexual as wellIVDU and Heterosexual as well Resource limited setting – Africa and S. AmericaResource limited setting – Africa and S. America KS still most common cancer in HIVKS still most common cancer in HIV PrevalencePrevalence 1300 cases/100,000 persons/yr cases/100,000 persons/yr cases/100,000 persons/yr cases/100,000 persons/yr 2006 Decline of 10% / yearDecline of 10% / year Cause of considerable morbidity and mortality in Africa and Latin AmericaCause of considerable morbidity and mortality in Africa and Latin America

29 Clinical Manifestations Mucocutaneous, macular or nodular, dark colorMucocutaneous, macular or nodular, dark color LymphadenopathyLymphadenopathy VisceralVisceral Often asymptomaticOften asymptomatic Mouth, esophagus, stomach, bowel, liver, spleenMouth, esophagus, stomach, bowel, liver, spleen Pulmonary KSPulmonary KS Rapidly fatalRapidly fatal Dyspnea without fever, hemoptysisDyspnea without fever, hemoptysis Diffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusionsDiffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusions Edema, can be extensive and symptomaticEdema, can be extensive and symptomatic

30 Kaposi’s Sarcoma

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33 Oral Kaposi’s Sarcoma

34 KS in Africa – A “Different” Disease?

35 Pulmonary KS on CXR & CT Scan

36 Treatments for Kaposi’s Sarcoma Radiation therapyRadiation therapy Photodynamic (laser) therapyPhotodynamic (laser) therapy CryotherapyCryotherapy Alitretinoin gel – 9-cis retinoic acid (topical)Alitretinoin gel – 9-cis retinoic acid (topical) Antiretroviral therapyAntiretroviral therapy Liposomal anthracyclinesLiposomal anthracyclines PaclitaxelPaclitaxel BleomycinBleomycin Vinca alkaloidsVinca alkaloids GemcitabineGemcitabine Alpha InterferonAlpha Interferon Local 1 Systemic 1,2 1 Levine AM, et al. Eur J Cancer. 2001;37: Mitsuyasu RT, et al. Cancer Management. 2008:

37 Cancer Prevention Smoking Cessation – Highest prioritySmoking Cessation – Highest priority Hepatitis and HPV vaccinationHepatitis and HPV vaccination Yearly cervical and anal Pap tests – Gyn and HRAYearly cervical and anal Pap tests – Gyn and HRA Maintain high index of suspicion for cancerMaintain high index of suspicion for cancer Yearly breast, prostate (incl. PSA) examYearly breast, prostate (incl. PSA) exam Advise sun screen and avoid overexposureAdvise sun screen and avoid overexposure Complete family history for malignanciesComplete family history for malignancies If Hepatitis B or C positive, follow LFTs andIf Hepatitis B or C positive, follow LFTs and perhaps AFP periodically (?)

38 Summary As patients live longer with HIV, morbidity and mortality from cancers are increasingAs patients live longer with HIV, morbidity and mortality from cancers are increasing The types of cancers in HIV may vary in different populations around the worldThe types of cancers in HIV may vary in different populations around the world Treatment of malignancies in HIV should be vigorous and appropriate to the situationTreatment of malignancies in HIV should be vigorous and appropriate to the situation Side effects of therapy should be treated/preventedSide effects of therapy should be treated/prevented Prevention strategies for virally-associated malignancies in HIV need to be investigatedPrevention strategies for virally-associated malignancies in HIV need to be investigated Through prospective clinical trials research can treatment and prevention strategies be effectively evaluatedThrough prospective clinical trials research can treatment and prevention strategies be effectively evaluated

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41 Thank You For information on AMC clinical trials see: information on AMC clinical trials see: For information on NCI programs in HIV cancer see:For information on NCI programs in HIV cancer see:http://www.cancer.gov/cancertopics/types/AIDS To refer for AMC clinical trials in LA, call UCLA CARE Center ask for Maricela Gonzalez or page/ Dr. Mitsuyasu, refer for AMC clinical trials in LA, call UCLA CARE Center ask for Maricela Gonzalez or page/ Dr. Mitsuyasu,


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