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WCRJ 2014; 1 (3): e291

LYMPHOMAS AND OTHER IN HIV-INFECTED PATIENTS

A. CARBONE 1, A. GLOGHINI 2, E. VACCHER 3, P. DE PAOLI 4

1Department of , 3Department of Medical , 4Molecular Virology and Scientific Di - rectorate, Centro di Riferimento Oncologico Aviano, Istituto Nazionale Tumori, IRCCS, Aviano (PN), Italy, 2Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy

Absract: Individuals infected by HIV might develop several types of more frequently than uninfected people. represent the most frequent malignancy among patients with HIV/AIDS (PWHA). Other cancer types that have increased in PWHA include Kaposi sarcoma (KS), cancer of the cervix, anus, lung and . Multicentric (MCD), a lymphoprolifera - tive disorder presenting with heterogeneous pathological and clinical features, comprises disease en - tities with a complex aetiology and overlapping pathogenesis. MCD can be found in association with HIV infection, KS, primary effusion and its solid variant, and . This paper focuses on the different type of lymphomas that are generally occurring in PWHA. A com - prehensive understanding of the intricacies of viral coinfection will probably lead to additional ad - vances in managements for these disorders.

KEY WORDS: Lymphomas, HIV, AIDS, Kaposi sarcoma .

INTRODUCTION LYMPHOMAS

Despite the introduction of highly active antiretro - Lymphomas occurring specifically in HIV-positive viral therapy or combination antiretroviral therapy patients which are listed in Table 2 display a phe - (HAART or cART, respectively) patients infected notype related to . BL with plasmacytoid with HIV might develop certain types of cancer differentiation have expression of CD20, CD10, more frequently than uninfected people. BCL6, absence of BCL2, and a proliferation rate Lymphomas represent the most frequent malig - close to 100%. In other HIV-associated lymphomas nancy among patients with HIV/AIDS (PWHA), dis - tumor cells display a plasma cell differentiation-re - playing a 60-200 fold and 8 -10 fold higher relative lated phenotype. Specifically, plasma cell surface risk of developing non-Hodgkin lymphoma (NHL) markers, such as CD138, are upregulated, whereas and Hodgkin lymphomas (HL), respectively, com - markers of mature B cells, such as CD20 and CD45, pared to HIV uninfected people 1-3 . Diffuse large B- are usually downregulated 4. Similarly, transcription cell lymphoma (DLBCL), in particular, remains the factors associated with B cells in general (such as main type of cancer that develops in HIV-positive pa - PAX5 and BCL6) are downregulated, whereas the tients. The incidence of other lymphomas such as fact that the transcriptional program has transitioned (BL), HL, primary effusion lym - to that of plasma cells can be demonstrated by the phomas (PEL) and (PBL) expression of BLIMP1, XBP1, and IRF4/MUM1 of the oral cavity type still remain high (Table 1) 1,2 . proteins (Figure 1) 4-7 .

Corresponding Author : Antonino Carbone, MD; e-mail: [email protected] 1 Table 1. Table 2. Categories of lymphomas commonly occurring in Lymphomas occurring specifically in HIV-infected HIV-infected patients 8. patients.

The same aggressive lymphomas that develop sporadi - • BL plasmacytoid cally in the absence of HIV infection • Systemic IBL plasmacytoid • Burkitt lymphoma • PCNSL (IBL plasmacytoid) – Classical; Plasmacytoid diff.; Atypical • Hodgkin lymphoma • Diffuse large B-cell lymphoma • PEL and its solid variant – Centroblastic; Immunoblastic • PBL of the oral cavity • MALT lymphoma (rare) • MCD- associated PBL • Peripheral T-cell lymphoma (rare) • Classical Hodgkin’s lymphoma Unusual lymphomas occurring specifically in PWHA • Primary effusion lymphoma chemical staining for ORF73/LANA is the stan - • Plasmablastic lymphoma of the oral cavity dard assay to detect evidence of KSHV. • Lymphoma associated with KSHV-associated multi - centric PBL of the oral cavity type. PBL consists of a Castleman Disease relatively uniform tumor cell population displaying Lymphomas also occurring in other immunodeficient a cohesive pattern and a plasma cell related mor - states phology. The so called plasmablasts display abun - • Polymorphic B-cell lymphoma (PTLD-like) dant basophilic cytoplasm and eccentric nuclei that are either plasma cell-like or immunoblastic cell- like. PBL are characterized by strong immunos - Furthermore, lymphomas occurring in patients taining with the plasma cell markers MUM1/IRF4 with HIV are closely linked to other viral infections. and by high proliferative index. GL, DLBCL, plasmablastic lymphoma and HL are associated with Epstein-Barr (EBV) infection 4,8- Other cancers (Table 3), although this association is not uniform 11 . By contrast, PEL and its solid variants are con - sistently linked to Kaposi sarcoma-associated The risk of Kaposi sarcoma remains substantially herpesvirus (KSHV) infection 4,8 . Nonetheless, 70 - increased in HIV-infected patients on effective 80% of PEL are associated with EBV infection 4. cART. Other cancers that have a strong association HIV-associated DLBCL of the immunoblastic with PWHA include anal, cervical, hepatocellular type comprises predominantly large lymphoma and lung cancers 12 . cells with prominent central nucleoli. Importantly, recent studies have reported a three - Classic PEL morphologically shows features fold decrease in the incidence of Kaposi sarcoma bridging immunoblastic and anaplastic large-cell and NHL (but not in ) after the im - lymphomas, and frequently displays a certain de - pact of cART and a substantial increase of the num - gree of plasma cell differentiation. Immunocyto - ber of non-AIDS-defining cancer (notably cancer of

Fig. 1. Lymphomas occurring specifically in HIV-infected patients, their relationship with viral infection and stage of B-cell differentiation. Adapted from ref. 7.

2 LYMPHOMAS AND OTHER CANCERS IN HIV-INFECTED PATIENTS

Table 3. Table 4. The spectrum of HIV-associated NHL and their re - Other cancer types occurring in patients with lationship with gamma herpesvirus infection. HIV/AIDS and relationship with infectious agents Lymphoma EBV EBV KSHV Cancer type Infectious agent type (%) latency (%) Kaposi sarcoma KSHV Burkitt lymphoma + (60%) I– Cervical cancer, HPV HPV with plasmacytoid Lower female genital tract HPV differentiation (vulva and vagina) Diffuse large B-cell lymphoma Anal carcinoma HPV • Immunoblastic + (90%) II/III – HBV/HCV plasmacytoid Merkel cell carcinoma Merkel cell variant polyomavirus Primary effusion + (90%) I + (100%) Lung carcinoma ? lymphoma Colorectal carcinoma ? and solid variants Plasmablastic lymphoma + (80%) 0/I – of the oral cavity type Large B-cell lymphoma ––+ (100%) The coexistence of KS and MCD has been re - arising in HHV8- ported in 54%-72% of HIV-infected patients at di - associated multicentric 21,22 Castleman disease agnosis , whereas the occurrence of B-cell Polymorphic B-cell lymphomas has been identified in HIV-infected pa - lymphoma + (>90%) I/II/III – tients with MCD with incidence 15-fold higher than (PTLD-like) that in the HIV-infected population without MCD 23 . Recently, a new clinical entity that describes a severe systemic infection/reactivation with KSHV the liver, anus, lung, non-melanocytic skin, and has been proposed within the spectrum of KSHV- HL) 13-17 . However, statistical analyses showed that associated MCD: KSHV inflammatory syndrome the increase in non AIDS-defining cancer was (KICS) 24-26 . mainly driven by the presence of an ageing popula - The complex interplay between KSHV and tion with HIV in more-developed countries 14 . HIV have dramatically elevated risk for develop - As a consequence of effective cART, an increas - ment of KSHV-induced malignancies, i.e. KS, ing number of elderly people with HIV/AIDS reaches PEL, and MCD (Figure 2) 27 . an age in which epithelial cancer become frequent. Although MCD, KS and PEL are disease enti - These cancers are mostly infection-related ties displaying distinct clinical and pathological (Table 4), and exhibit histopathological and im - features (see above), KSHV-associated MCD is munophenotypical features similar to those ob - usually a tangle of these different entities which served in HIV-negative patients. are also commonly associated with HIV and Coinfection of HIV with different rep - KSHV infection (Figure 2). resents a common issue in malignancies of im - Interactions among coinfecting viruses may in - mune compromised hosts crease cellular transformation and oncogenesis. A role of viral cooperation in lymphomagenesis is Multicentric Castleman disease (MCD) suggested by the simultaneous detection of coin - fecting viruses within the same neoplastic cells. This occurs in HIV-associated PEL tumor cells MCD is lymphoid disorder, presenting with het - harbouring EBV and KSHV infection. In other erogeneous features. CD was first described as a cases, non specific mechanisms inducing cellular solitary lesion 18 , occurring most often in the medi - proliferation and genetic abnormalities are prefer - astinum or pulmonary hilus, although its presence entially involved 28 . in other anatomic sites was subsequently estab - lished. Sporadic reports of a “multicentric” variant Concluding remarks of CD (MCD) subsequently appeared in the liter - ature 19,20 . Updated definition of Multicentric Castleman Understanding the involvement of viral infection disease (after AIDS epidemic). MCD has become in specific lymphomas and other malignancies, and increasingly relevant in recent years given its as - defining the molecular mechanisms of viral car - sociation with HIV and KSHV infections. KSHV- cinogenesis are important steps towards better pre - associated MCD is characterized by the presence vention, diagnosis and treatment strategies for of plasmablasts harbouring KSHV HIV-associated cancers.

3 2. SHIELS MS, E NGELS EA, L INET MS, C LARKE CA, L I J, H ALL HI, H ARTGE P, M ORTON LM. The epidemic of non- hodgkin lymphoma in the united states: Disentangling the effect of HIV, 1992-2009. Cancer Epidemiol Bio - markers Prev 2013; 22: 1069-1078. 3. POLESEL J, C LIFFORD GM, R ICKENBACH M, D AL MASO L, BATTEGAY M, B OUCHARDY C, F URRER H, H ASSE B, L EVI F, PROBST -H ENSCH NM, S CHMID P, F RANCESCHI S; S WISS HIV COHORT STUDY . Non-hodgkin lymphoma incidence in the swiss HIV cohort study before and after highly active an - tiretroviral therapy. AIDS 2008; 22: 301-306. 4. CARBONE A, C ESARMAN E, S PINA M, G LOGHINI A, S CHULZ TF. HIV-associated lymphomas and gamma-her - pesviruses. Blood 2009; 113: 1213-1224. 5. CESARMAN E. Pathology of lymphoma in HIV. Curr Opin Oncol 2013; 25: 487-494. 6. CHADBURN A, A BDUL -N ABI AM, T ERUYA BS, L O AA. Lym - phoid proliferations associated with human immunode - ficiency virus infection. Arch Pathol Lab Med 2013; 137: 360-370. Fig. 2. KSHV-associated multicentric Castleman disease. A tan - 7. GLOGHINI A, D OLCETTI R, C ARBONE A. Lymphomas occur - gle of different entities requiring multitarget treatment strategies. ring specifically in HIV-infected patients: From patho - Adpated from an illustration created in Adobe Illustrator for The genesis to pathology. Semin Cancer Biol 2013; 23: Consumer Associations annual report cover (http://www.graph - 457-467. icnet.co.uk/wp/tangle-3/). 8. RAPHAEL M, S AID J, B ORISH B, C ESARMAN E, H ARRIS NL. Lymphomas associated with HIV infection. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, In their interesting paper entitled “Moving For - Thiele J, Vardiman JW, editors. WHO Classification of Tu - ward in HIV-Associated Cancer”, published in mours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC, 2008; pp. 340-342. Journal of Clinical Oncology, Gopal and col - 29 9. KAPLAN LD. HIV-associated lymphoma. Best Pract Res leagues affirm that 1) grouping HIV-associated Clin Haematol 2012; 25: 101-117. cancers as infection-related or infection-unrelated 10. ROSCHEWSKI M, W ILSON WH. EBV-associated lymphomas is a good strategy in cancer diagnosis and research; in adults. Best Pract Res Clin Haematol 2012; 25: 75-89. 2) characterizing tumors with respect to genomic 11. CARBONE A, D OLCETTI R, G LOGHINI A, M AESTRO R, V AC - CHER E, DI LUCA D, T IRELLI U, B OIOCCHI M. Immunophe - features is really important to optimize treatment. notypic and molecular analyses of acquired immune Besides the relationship of HIV-associated cancers deficiency syndrome-related and epstein-barr virus-as - with epidemiological research and diagnosis and sociated lymphomas: a comparative study. Hum Pathol patients treatment, the Agenda by Gopal and Col - 1996; 27: 133-146. leagues draws the reader’s attention on interesting, 12. GRULICH AE, V AN LEEUWEN MT, F ALSTER MO, V AJDIC CM. Incidence of cancers in people with HIV/AIDS compared but still little known key points, such as 1) viral co - with immunosuppressed transplant recipients: a meta- operation and tumor pathogenesis, and 2) the inter - analysis. Lancet 2007; 370: 59-67. actions between tumor development, cART use, 13. SHIELS MS, P FEIFFER RM, G AIL MH, H ALL HI, L I J, HIV replication and immunosuppression. CHATURVEDI AK, B HATIA K, U LDRICK TS, Y ARCHOAN R, In conclusion, we propose that the agenda of GOEDERT JJ, E NGELS EA. Cancer burden in the HIV-in - fected population in the united states. J Natl Cancer Inst HIV-associated cancers should move forward also 2011; 103: 753-762. by defining strict criteria to establish the patho - 14. FRANCESCHI S, L ISE M, C LIFFORD GM, R ICKENBACH M, L EVI genetic association between infectious agents and F, M ASPOLI M, B OUCHARDY C, D EHLER S, J UNDT G, E SS S, cancer and by designing unique prospective clini - BORDONI A, K ONZELMANN I, F RICK H, D AL MASO L, E LZI L, cal trials on the management of cancer in patients FURRER H, C ALMY A, C AVASSINI M, L EDERGERBER B, K EISER O; S WISS HIV C OHORT STUDY . Changing patterns of can - at high comorbidity rate, including drug-drug in - cer incidence in the early- and late-HAART periods: The teraction studies. Prevention/surveillance of can - swiss HIV cohort study. Br J Cancer 2010; 103: 416-422. cer in the context of immunosuppression remains 15. 1993 revised classification system for HIV infection and a challenge. The agenda should include integrated expanded surveillance case definition for AIDS among care practices to proactively monitor patients with adolescents and adults. MMWR Recomm Rep 1992; 41: 1-19. long-term viral-immune monitoring and risk-ad - 30 16. ANCELLE -P ARK RA, A LIX J, D OWNS AM, B RUNET JB. Impact justed cancer surveillance programs . of 1993 revision of adult/adolescent AIDS surveillance case-definition for europe. national coordinators for References AIDS surveillance in 38 european countries. Lancet 1995; 345: 789-790. 1. SIMARD EP, P FEIFFER RM, E NGELS EA. Cumulative inci - 17. SAHASRABUDDHE VV, S HIELS MS, M CGLYNN KA, E NGELS dence of cancer among individuals with acquired im - EA. The risk of hepatocellular carcinoma among indi - munodeficiency syndrome in the united states. Cancer viduals with acquired syndrome in 2011; 117: 1089-1096. the united states. Cancer 2012; 118: 6226-6233.

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18. CASTLEMAN B, I VERSON L, M ENENDEZ VP. Localized medi - leukin-6-related systemic inflammatory syndrome in pa - astinal lymphnode hyperplasia resembling thymoma. tients co-infected with kaposi sarcoma-associated her - Cancer 1956; 9: 822-830. pesvirus and HIV but without multicentric castleman 19. GABA AR, S TEIN RS, S WEET DL, V ARIAKOJIS D. Multicentric disease. Clin Infect Dis 2010; 51: 350-358. giant hyperplasia. Am J Clin Pathol 1978; 25. TAMBURRO KM, Y ANG D, P OISSON J, F EDORIW Y, R OY D, 69: 86-90. LUCAS A, S IN SH, M ALOUF N, M OYLAN V, D AMANIA B, 20. FRIZZERA G, M ORAN EM, R APPAPORT H. Angio-im - MOLL S, VAN DER HORST C, D ITTMER DP. Vironome of ka - munoblastic . diagnosis and clinical posi sarcoma associated herpesvirus-inflammatory cy - course. Am J Med 1975; 59: 803-818. tokine syndrome in an AIDS patient reveals co-infection 21. BOWER M, N EWSOM -D AVIS T, N ARESH K, M ERCHANT S, L EE of human herpesvirus 8 and human herpesvirus 6A. Vi - B, G AZZARD B, S TEBBING J, N ELSON M. Clinical features rology 2012; 433: 220-205. and outcome in HIV-associated multicentric castleman's 26. POLIZZOTTO MN, U LDRICK TS, W ANG V, A LEMAN K, W YVILL disease. J Clin Oncol 2011; 29: 2481-2486. KM, M ARSHALL V, P ITTALUGA S, O'M AHONY D, W HITBY D, 22. MYLONA EE, B ARABOUTIS IG, L EKAKIS LJ, G EORGIOU O, P A- TOSATO G, S TEINBERG SM, L ITTLE RF, Y ARCHOAN R. Human PASTAMOPOULOS V, S KOUTELIS A. Multicentric castleman's and viral interleukin-6 and other cytokines in kaposi sar - disease in HIV infection: A systematic review of the lit - coma herpesvirus-associated multicentric castleman dis - erature. AIDS Rev 2008; 10: 25-35. ease. Blood 2013; 122: 4189-4198. 23. OKSENHENDLER E, B OULANGER E, G ALICIER L, D U MQ, 27. DA SILVA SR, DE OLIVEIRA DE. HIV, EBV and KSHV: Viral DUPIN N, D ISS TC, H AMOUDI R, D ANIEL MT, A GBALIKA F, cooperation in the pathogenesis of human malignan - BOSHOFF C, C LAUVEL JP, I SAACSON PG, M EIGNIN V. High in - cies. Cancer Lett 2011; 305: 175-185. cidence of kaposi sarcoma-associated herpesvirus-re - 28. DE PAOLI P. Novel virally targeted therapies of EBV-associ - lated non-hodgkin lymphoma in patients with HIV ated tumors. Curr Cancer Drug Targets 2008; 8: 591-596. infection and multicentric castleman disease. Blood 29. GOPAL S, A CHENBACH CJ, Y ANIK EL, D ITTMER DP, E RON JJ, 2002; 99: 2331-2336. ENGELS EA. Moving forward in HIV-associated cancer. J 24. ULDRICK TS, W ANG V, O'M AHONY D, A LEMAN K, W YVILL Clin Oncol 2014; 32: 876-880. KM, M ARSHALL V, S TEINBERG SM, P ITTALUGA S, M ARIC I, 30. DE PAOLI P, C ARBONE A. Pathogenesis of HIV-Associated WHITBY D, T OSATO G, L ITTLE RF, Y ARCHOAN R. An inter - Cancer. J Clin Oncol 2014 Jul 7 [Epub ahead of print]

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