HIV Associated Malignancies Amanda Peppercorn M D Assistant

HIV Associated Malignancies Amanda Peppercorn, M. D. Assistant Professor of Medicine Division of Infectious Diseases University of North Carolina 3/17/2018

Overview § HIV associated malignancies • Indicator condition in AIDS • Interplay with oncogenic viruses • Epidemiology § Diagnosis § Therapy University of North Carolina 3/17/2018

Case #1 § HPI: 73 yo CM, Yale professor, no significant pmhx • Jan 2003 - complained of fatigue to PCP, routine labs showed new anemia with Hct 32% and platelets 110 K • Extensive evaluation by Heme/onc over next several months including bone marrow bx unrevealing except for abd u/s showed splenomegaly and he was diagnosed after extensive GI eval with “cryptogenic cirrhosis” even though no evidence of liver pathology, portal HTN or liver synthetic dysfunction • November 2003 - episode of left thoracic zoster, self resolves University of North Carolina 3/17/2018

§ May 2004 - develops new left facial palsy, treated for HSV and Lyme cranial neuritis (despite negative Lyme antibody) with steroids, valtrex and doxycycline with improvement in sx § July 2004 - facial palsy returns and over 1 -2 weeks is noted by son to be confused § August 2004 - develops lethargy obtundation and is admitted to OSH where Brain MRI shows new periventricular rim enhancing lesion with mass effect • HIV antibody finally sent and is positive • LP done after administration of steroids v+EBV PCR, +atypical lymphocytes c/w Primary CNS Lymphoma v. CD 4 70, Viral load 75 K University of North Carolina 3/17/2018

§ Patient treated with Combivir and Sustiva with good virologic response – Required neupogen and erythropoitin throughout cancer treatment course § Lymphoma treated with IT methotrexate, steroids and whole brain XRT with regression – Complicated by febrile neutropenia – Complicated by severe perianal HSV outbreak – Patient’s neurologic status completely improved University of North Carolina 3/17/2018

Historical Time-line § § § § March 1981: First report of 8 cases of Kaposi’s sarcoma among MSM in SF and NY June 1981: MMWR reports 5 cases PCP in previously healthy young MSM in LA, 2 died 1982: phrase “AIDS” coined, first 4 cases NHL reported 1983: Primary CNS lymphoma (PCNSL) described 1984: viruses “LAV” (lymphadenopathy associated virus) and HTLV-III isolated 1985: Non-Hodgkins Lymphoma added to KS and PCNSL by CDC as AIDS-defining condition 1986: LAV/HTLV-III HIV 1993: Cervical carcinoma added as ADC University of North Carolina 3/17/2018

AIDS Defining Malignancies (ADMs) § § § KS Lymphoma: PCNSL, Immunoblastic, Burkitt’s, Primary Effusion Cervical carcinoma Up to 40% of HIV+ pts had an ADM in the pre. HAART era After PCP, malignancy was most frequent OI University of North Carolina 3/17/2018

HAART Era § Decline in KS, NHL, proportional to CD 4 count § Non-ADMs > ADMs in overall morbidity/mortality § Cancer accounts for approx 30% deaths in HIV+ currently § Traditional RFs: smoking, etoh, viral co-infections University of North Carolina § Non-ADMs with greater frequency in HIV+(SIR=standardized incidence ratio): • • • Anal (HPV), SIR 19. 6 Lung (tobacco), SIR 2. 6 Hodgkin’s disease (EBV), SIR 13. 6 Liver (HBV, HCV, etoh), SIR 3. 3 Head/neck (tobacco, etoh, HPV), 2. 2 Melanoma, other skin cancers (SCC, merkel cell, BCC) • MM, SIR 2. 2 • Leukemia, SIR 2. 2 • Brain CA, gastric, renal, testicular (seminoma) 3/17/2018

Oncogenic Virus Association Virus Malignancy Hepatitis B Hepatocellular carcinoma Hepatitis C Hepatocellular carcinoma EBV NHL, Hodgkins disease, Primary CNS lymphoma, nasopharyngeal carcinoma HPV Cervical, Anal, Head and Neck HHV-8 (KSHV) Kaposi’s sarcoma, Primary Effusion Lymphoma (Body Cavity Lymphoma) University of North Carolina 3/17/2018

Pathogenesis § § § Similar risk as seen in transplant recipients who experience 100 -fold increased risk of cancer (renal, SCC, NLH, KS, uterine, cervic, vulva, sarcoma) Loss of immune surveillance of tumor cells ? Role of HIV genes in oncogenesis (esp as growth factors) University of North Carolina 3/17/2018

KS § § § § Low grade soft tissue sarcoma, vascular Low CD 4 HHV-8 (KSHV) Skin (predominant) Visceral: bronchus/lung, GI tract, liver, oral Treatment: HAART, XRT, anthracyclines, paclitaxel, pegylated interferon, laser or cryotherapy IRIS University of North Carolina 3/17/2018

KS on heel of immunocompromised patient Images courtesy of Dr. Stephen Tabet. University of North et al. HEPP News (Brown Medical School), August/September 2001. 3/17/2018 Nicodemus M Carolina

TIS Staging Classification Good Risk Poor risk Tumor, T T 0: confined to skin and/or LNs or minimal oral dx T 1: tumor associated edema or ulceration, extensive oral KS, GI KS, other non-nodal viscera Immune System, I I 0: CD 4>200 CD 4< 200 Systemic illness, S S 0: no hx OI or thrush, no S 1: hx OI or thrush, “B” B sx, Karnofsky score>70 sx, karnofscky performance score<70, other HIV related illness (ex lymphoma, neurologic) University of North Carolina 3/17/2018

NHL § § § 70 -90% High grade B cell lymphomas (large B cell, immunoblastic, Burktt’s—cmyc translocation) PCNSL— 15% Primary Effusion Lymphoma (“Body Cavity Lymphoma”)—rare University of North Carolina 3/17/2018

NHL § § § Present at more advanced stage, extranodal disease (GI tract common), bone marrow, liver and lung, CNS, 80% Stage 4 disease at presentation • More often with “B” sx—night sweats, fever, weight loss Incidence inversely related to CD 4 count but can occur at any CD 4 Diagnosis same as in non-HIV pt but higher rate of asymptomatic CNS involvement • FNA usually not adequate, need excisional BX University of North Carolina 3/17/2018

NHL Treatment § Optimal therapy not defined: • Standard first line therapies (CHOP) not as effective or durable in HIV population (increased expression of MDR-1 gene) • IT methotrexate or ara-C • HAART definitely improves survival • 50 -60% response rate • High rate of OI complications • Alternative regimens: EPOCH, M-BACOD • No good second line regimens, BMT not an option currently University of North Carolina 3/17/2018

HAART with Chemotherapy § Burkitt’s Retrospective study of Hyper-CVAD +/HAART [Cortes, Cancer 2002] • 6/7 on HAART CR, 4/4 no HAART died § Large B cell Lymphoma Retrospective study of CHOP-HAART (24 pts) versus CHOP (+/- AZT mono, 80 pts)[Vaccher, Cancer 2001] • OI: 18 v 52% • Survival: long term survival versus medium 7 months University of North Carolina 3/17/2018

HAART and Chemotherapy § § § PI v NNRTI based regimen equivalent Some anti-neoplastic effect of AZT and PIs Need to implement OI prophylaxis with low CD 4 counts in setting of bone marrow suppression Mucositis, chemo related n/v can inhibit oral intake of ARVs IL-6 inhibitors under investigation Role of rituximab unclear; marked increased death rate due to infection [Kaplan, Blood 2005] University of North Carolina 3/17/2018

Primary Effusion Lymphoma § § § Rare HHV-8 Serous effusions (pleural, peritoneal, pericardial, joint effusions) with malignant lymphocytes No mass lesions CHOP + HAART Very poor prognosis University of North Carolina 3/17/2018

PCNSL § § § EBV 100 -1000 x higher than general population CD 4<100, usually <50 Dx: LP +EBV, MRI with homogeneous, sometimes ring enhancing lesions, often periventricular, often +mass effect, Thallium SPECT with early uptake Tx: whole brain XRT + steroids +/- IT methotrexate Prognosis: poor in pre-HAART era, overall still very poor University of North Carolina 3/17/2018

Hodgkin’s Lymphoma and HIV § § § Usually advanced stage at time of diagnosis (stage 3, 4) More extra-nodal involvement—bone marrow, liver Worse prognostic cell type—mixed cellularity histologic subtype (nodular schlerosis most common in non-HIV) Worse overall prognosis Better outcomes in era of HAART University of North Carolina 3/17/2018

Cervical Cancer § § § Co-infection with HPV Earlier age with advanced disease Paps recommended twice a year at time of HIV dx; if normal, can screen every year Dx, Management same as in non-HIV population No relation to CD 4 count University of North Carolina 3/17/2018

Global HIV epidemic, 1990‒ 2005 Number of people living with HIV (millions) % HIV prevalence, adult (15‒ 49) 50 5. 0 • 38. 6 million living with HIV [33 to 46 million] 40 4. 0 30 3. 0 20 2. 0 10 1. 0 0 0. 0 1995 2000 2005 • 24. 5 million in SS Africa [21. 6 to 27. 4 million] • 4. 1 million new infections [3. 4 to 6. 2 million] • 2. 8 million deaths Number of people living with HIV [2. 4 to 3. 3 million] % HIV prevalence, adult (15 -49) Bar indicates the range around the estimate University of North Carolina Source: UNAIDS 2006 3/17/2018

Children § § § Leiomyosarcoma (? EBV) NHL Cervical, thyroid/ lung KS Burkitt’s University of North Carolina 3/17/2018

ADMs in Developing Nations § § KS in Africa (men and women) NHL (less than developed nations) Cervical cancer (unclear how HIV has impacted) SCC of the conjunctiva (? HPV) • Related to sun exposure • Risen over past 30 years in Ss Africa • 10 fold higher in HIV+ University of North Carolina 3/17/2018

Case #2 § § § 60 yo woman w longstanding HIV c/b: HIVAN on HD, remote PCP, remote GB HAART regimen: abacavir, efavirenz, atazanavir, ritonavir with excellent CD 4 and virologic suppression Routine mammogram: 8 cm left breast mass with enlarged left axillary mass University of North Carolina 3/17/2018

§ § § Work up: T 2 N 2 M 0 disease “locally advanced” due to +LN Well differentiated, ER+, PR-, Her-2 Treated with “dose-reduced” neoadjuvant Taxol alone due to “co-morbidities” Taxol tolerated well except for diarrhea and alopecia Followed by radical modified mastectomy which showed poor response to chemo with 3 cm residual disease CD 4 drop from 800 to 150, dapsone initiated University of North Carolina 3/17/2018

§ Oncologist starts pt on Tamoxifen § Seen in HIV clinic • Tamoxifen metabolism made completely unpredictable by ritonavir • Recommendation made to oncology to use Arimidex instead of Tamoxifen for more reliable anti-tumor effect • Seen recently in clinic for CA-MRSA gluteal abscess and bacteremia University of North Carolina 3/17/2018

Lessons § § § Screen: PSA, mammogram, cervical (anal) pap, colonoscopy, yearly CXR in smokers, AFP/liver imaging in HBV and ESLD/cirrhosis/HCV ADVOCATE! Check HAART drug interactions with chemotherapy and make necessary modifications • Try to maintain full chemo and full HAART • Monitor carefully for infectious complications, need to implement OI prophylaxis • Emerging data that HAART + high CD 4 count renders pt outcomes to general cancer treatment equivalent to non-HIV+ population University of North Carolina 3/17/2018

University of North Carolina 3/17/2018

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