Paugam A, Lebuisson A, Lortholary O, et al.
Peripheral blood and bone marrow cells cultivated in Novy-Mcneal-Nicolle medium for visceral leishmaniosis diagnosis revealed Rhodotorula fungemia in an AIDS patient with lymphoma.
Clin Lab. 2013; 59(1-2):215-6 [PubMed]

Rhodotorula is a ubiquitous yeast that can infect immunocompromised patients. Here, we present the case of a 45-year-old patient with AIDS who developed a Rhodotorula mucilaginosa fungemia. The patient had a past history of visceral leishmaniasis (VL) and was hospitalised to receive chemotherapy for a B-cell lymphoma of the sinonasal cavities. The patient had no fever and no signs of VL. A systematic research for Leishmania by blood and bone marrow cultures was made and he received liposomal amphtotericin B (3 mg/kg in a single dose) to prevent a VL relapse. Rhodotorula fungemia was accidentally detected after 17 days of blood culture using a specific medium for leishmaniasis diagnosis. This long culture incubation time was probably facilitated by amphotericin B treatment. Rhodotorula is an emerging pathogen that may escape detection due its slow growth in culture.

Zangari P, Santilli V, Cotugno N, et al.
Raising awareness of non-Hodgkin lymphoma in HIV-infected adolescents: report of 2 cases in the HAART era.
J Pediatr Hematol Oncol. 2013; 35(3):e134-7 [PubMed]

Human immunodeficiency virus (HIV) chronically infected patients are at increased risk of developing non-Hodgkin lymphoma compared with the general population. Highly active antiretroviral therapy has had a dramatic effect on the natural history of HIV infection, reducing the incidence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma and improving overall survival. However, problems related to adherence to treatment, frequently experienced during adolescence, may increase the risk of acquired immunodeficiency syndrome-related cancers. Optimizing highly active antiretroviral therapy and monitoring noncompliant patients with persisting HIV replication should be considered by physicians who take care of these patients. We herein report 2 cases of relapsed/progressive Burkitt lymphoma in HIV vertically infected adolescents.

Levine AM, Noy A, Lee JY, et al.
Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047.
J Clin Oncol. 2013; 31(1):58-64 [PubMed] Article available free on PMC after 01/01/2014

PURPOSE: Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers.
PATIENTS AND METHODS: We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy.
RESULTS: In 40 evaluable patients, median CD4 cells was 114/μL (range, 5 to 1,026/μL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/μL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection.
CONCLUSION: Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

Saggini A, Anemona L, Chimenti S, et al.
HIV-associated primary cutaneous anaplastic large cell lymphoma: a clinicopathological subset with more aggressive behavior? Case report and review of the literature.
J Cutan Pathol. 2012; 39(12):1100-9 [PubMed]

Human immunodeficiency virus (HIV)-infected patients carry an increased risk of lymphomagenesis. Although the majority of HIV-related lymphomas have a B-cell phenotype, the incidence of peripheral T-cell lymphomas (PTCL), including primary cutaneous subtypes, may be up to 15-fold higher than in the general population, with anaplastic large cell lymphomas (ALCL) accounting for 18-28% of HIV-associated PTCL. In contrast to systemic ALCL, the relation between HIV infection and primary cutaneous ALCL has been relatively neglected in the literature. We report the case of a primary cutaneous ALCL occurring in a 76-year-old patient with advanced HIV infection, and showing unusually aggressive course. Neither ALK1 immunohistochemical positivity nor evidence of EBV infection were detected; staging procedures at initial presentation ruled out systemic involvement. We provide a summary of the literature regarding primary cutaneous ALCL in HIV-infected patients. We draw attention to clinicopathological features, prognostic implications and therapeutic quandaries of HIV-related primary cutaneous ALCL. Further, we propose that a significant fraction of HIV-associated cases might represent a more aggressive subset of primary cutaneous ALCL.

Hentrich M, Berger M, Wyen C, et al.
Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study.
J Clin Oncol. 2012; 30(33):4117-23 [PubMed]

PURPOSE: Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL.
PATIENTS AND METHODS: Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD.
RESULTS: Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%).
CONCLUSION: In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.

Montoto S, Shaw K, Okosun J, et al.
HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era.
J Clin Oncol. 2012; 30(33):4111-6 [PubMed]

PURPOSE: The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL.
PATIENTS AND METHODS: From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS≥3: 68% v 26%, respectively; P<.001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy.
RESULTS: The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P=not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P=not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P=not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status.
CONCLUSION: This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS.

Tonolini M, Matacena G, Bianco R
Anorectal opportunistic diseases in human immunodeficiency virus/acquired immunodeficiency syndrome patients: spectrum of cross-sectional imaging findings.
Curr Probl Diagn Radiol. 2012 Nov-Dec; 41(6):220-32 [PubMed]

Patients infected with the human immunodeficiency virus, particularly male homosexuals, are prone to develop disorders involving the anorectal and perineal structures. Cross-sectional imaging techniques, such as multidetector computed tomography with multiplanar reformations and magnetic resonance imaging performed with phased-array coils, are increasingly adopted to detect and stage infectious and neoplastic diseases, and to assess posttreatment modifications. Pyogenic perianal sepsis may be usefully investigated with imaging, particularly to assess the presence and topography of abscess collections to allow a correct surgical choice. Rectal inflammatory involvement is frequently detected during intestinal opportunistic infections, such as cytomegalovirus, pseudomembranous, and amebic colitides, including primary and secondary imaging signs consistent with proctocolitis. Anal carcinoma and intestinal lymphoma are increasingly diagnosed; therefore, special attention should be paid to the identification of solid tissue consistent with tumor; furthermore, MRI provides optimal staging and posttreatment follow-up of neoplastic lesions. Knowledge of this varied spectrum of anorectal and perineal opportunistic abnormalities and their imaging appearances should help radiologists to propose appropriate differential diagnoses, suggest correlation with laboratory and microbiological assays or biopsy, and reliably assess therapeutic response.

Godot C, Patte C, Blanche S, et al.
Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era.
J Pediatr Hematol Oncol. 2012; 34(7):e282-8 [PubMed]

Chronic HIV infection leads to increased risk of non-Hodgkin B-cell lymphoma. However, only few recent data are available about their current management and prognosis in HIV-infected children since the advent highly active antiretroviral therapy (HAART). This multicenter retrospective study describes the 12 cases of B-cell non-Hodgkin lymphoma diagnosed in HIV-infected children in France between 1996 and 2009. All children had moderate to severe immunosuppression and high viral load at the time of diagnosis. Nine children had extracerebral primary sites and 3 had a primary central nervous system lymphoma. Eight patients had Burkitt lymphoma; 4 had diffuse large B-cell lymphoma. Concomitantly with HAART, all children with extracerebral lymphoma received intensive chemotherapy according to LMB protocol, those with primary central nervous system lymphoma received high-dose methotrexate. No toxicity-related deaths occurred. Ten patients entered complete remission (CR), 2 died of tumor progression despite a second line of therapy. No relapses occurred after CR (median follow-up, 72 mo). Thus, prognosis of patients unresponsive to first-line lymphoma treatment remains poor, but relapse seems to be rare when CR is achieved. Children without severe comorbidities can tolerate intensive chemotherapy with a mandatory HAART treatment, taking into account drug interactions.

Petoumenos K, van Leuwen MT, Vajdic CM, et al.
Cancer, immunodeficiency and antiretroviral treatment: results from the Australian HIV Observational Database (AHOD).
HIV Med. 2013; 14(2):77-84 [PubMed] Article available free on PMC after 01/02/2014

OBJECTIVES: The objective of the study was to conduct a within-cohort assessment of risk factors for incident AIDS-defining cancers (ADCs) and non-ADCs (NADCs) within the Australian HIV Observational Database (AHOD).
METHODS: A total of 2181 AHOD registrants were linked to the National AIDS Registry/National HIV Database (NAR/NHD) and the Australian Cancer Registry to identify those with a notified cancer diagnosis. Included in the current analyses were cancers diagnosed after HIV infection. Risk factors for cancers were also assessed using logistic regression methods.
RESULTS: One hundred and thirty-nine cancer cases were diagnosed after HIV infection among 129 patients. More than half the diagnoses (n = 68; 60%) were ADCs, of which 69% were Kaposi's sarcoma and 31% non-Hodgkin's lymphoma. Among the NADCs, the most common cancers were melanoma (n = 10), lung cancer (n = 6), Hodgkin's lymphoma (n = 5) and anal cancer (n = 5). Over a total of 21021 person-years (PY) of follow-up since HIV diagnosis, the overall crude cancer incidence rate for any cancer was 5.09/1000 PY. The overall rate of cancers decreased from 15.9/1000 PY [95% confidence interval (CI) 9.25-25.40/1000 PY] for CD4 counts < 100 cells/μL to 2.4/1000 PY (95% CI 1.62-3.39/1000 PY) for CD4 counts > 350 cells/μL. Lower CD4 cell count and prior AIDS diagnoses were significant predictors for both ADCs and NADCs.
CONCLUSIONS: ADCs remain the predominant cancers in this population, although NADC rates have increased in the more recent time period. Immune deficiency is a risk factor for both ADCs and NADCs.

Zhong DT, Shi CM, Chen Q, et al.
Study on effectiveness of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related non-Hodgkin's lymphoma.
Ann Hematol. 2012; 91(11):1757-63 [PubMed]

Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. Even though NHL is commonly chemosensitive to primary treatment, failure or relapse still occurs in a large number of patients. We conducted this retrospective study to evaluate the efficacy and safety of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related NHL (AIDS-NHL). Forty-eight patients with relapsed or refractory AIDS-NHL were treated with intravenous combination chemotherapy with GDP. The overall objective response rate was 54.1% (95% confidence interval, CI, 40.1-68.3%), with 10 complete responses and 16 partial responses. The 2-year overall survival rate (OS) was 70.8% (95% CI 58.0-83.7%), and the 5-year OS was 41.7% (95% CI 27.7-55.6%). The 2-year progression-free survival rate (PFS) was 37.5% (95% CI 23.8-51.2%), and the 5-year PFS was 25.0% (95% CI 12.8-37.3%). The median progression-free survival was 8.8 months (95% CI 0-20.3 months), and the median overall survival was 40.6 months (95% CI 22.6-58.6 months). Patients with B cell tumors who relapsed but had no B symptoms were clinical stage I/II, had infiltration fewer than two extranodal sites, had CD4⁺ counts >200 cells/μL, and had lactate dehydrogenase (LDH) less than the upper limit of normal benefited from GDP. The level of LDH had a significant impact on the response rate to chemotherapy with GDP (P = 0.015). Myelosuppression was the main side effect; the incidence of grade 3-4 anemia was 8.3%; leukopenia, 37.5%; and thrombocytopenia, 48.3%. Univariate and multivariate analyses were performed to determine variables for OS and PFS. This study confirms that GDP is an effective and safe salvage regimen in relapsed or refractory AIDS-NHL, was associated with modest declines in CD4⁺ lymphocyte counts, and did not promote HIV-1 viral replication.

Chao C, Silverberg MJ, Martínez-Maza O, et al.
Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell Lymphoma.
Clin Cancer Res. 2012; 18(17):4702-12 [PubMed]

PURPOSE: Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL) and examined the prognostic use of detecting EBV infection.
EXPERIMENTAL DESIGN: HIV-related DLBCL cases diagnosed between 1996 and 2007 within Kaiser Permanente California were identified. Immunohistochemical staining was used to analyze the expression of selected markers that are cell-cycle regulators, B-cell activators, and antiapoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman correlation coefficient. The prognostic use of EBV status was examined in multivariable Cox model adjusting for International Prognostic Index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination.
RESULTS: Seventy HIV-related DLBCL cases were included (31% EBV±). EBV+ tumor was associated with increased expression of BLIMP1 and CD30 and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [HR, 3.3; 95% confidence interval (CI), 1.6-6.6]. Area under the ROC curve showed improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)].
CONCLUSION: Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-κB pathway and that detecting tumor EBV status may have prognostic use in HIV-related DLBCLs.

Buxton J, Leen C, Goodlad JR
Polymorphic lymphoid proliferations occurring in HIV-positive patients: report of a case responding to HAART.
Virchows Arch. 2012; 461(1):93-8 [PubMed]

Epstein-Barr virus (EBV)-associated polymorphic lymphoid proliferations resembling polymorphic post-transplant lymphoproliferative disorders are a rare but recognised complication of the human immunodeficiency virus (HIV). These account for fewer than 5 % of HIV-associated lymphomas, and little information has been published regarding their treatment and outcome. Of the reported cases, many have presented with extranodal disease, not typical of lymphoma. We report the case of a patient presenting with lung infiltrates shown to be the result of an EBV-associated polymorphic lymphoproliferation resembling a polymorphic post-transplant lymphoproliferative disorder. The patient was simultaneously found to be HIV positive and commenced on highly active antiretroviral therapy. Without any specific anti-neoplastic treatment, the patient recovered completely and within 20 months had no symptoms or radiological evidence of a lymphoproliferative disorder. This illustrates the importance of recognising this uncommon condition in HIV-positive patients and avoiding potentially unnecessary chemotherapy.

Sasakawa A, Hirase C, Yamaguchi T, et al.
Interleukin-8 in the pathogenesis of primary central nervous system lymphoma in association with HIV infection.
Hematology. 2012; 17(3):144-50 [PubMed]

The pathogenesis of acquired immunodeficiency syndrome-associated primary central nervous system lymphoma (AIDS-associated PCNSL) remains unclear. However, cell adhesion molecules have been reported to be strongly associated with PCNSL. In this study, we established Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) from HIV-positive patients (LCL(HIV)) and normal individuals (LCL(N)). The expression of CD18 antigen by LCL(HIV) was stronger than that by LCL(N). We performed a cell adhesion assay using ISO-HAS, which is the human hemangiosarcoma cell line and expresses intercellular adhesion molecule 1 (CD54). The binding rates of LCL(HIV) and ISO-HAS without stimulation were higher than those of LCL(N). Further, we demonstrated that azidothymidine or simvastatin inhibited the binding rates of LCL(HIV) and ISO-HAS more significantly than those of LCL(N). Further, the levels of interleukin (IL)-8, a CD18 inducer, were higher in LCL(HIV) than in LCL(N). We conclude that interaction between IL-8 and CD18 may be critical to AIDS-related PCNSL.

Bayraktar UD, Ramos JC, Petrich A, et al.
Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium.
Leuk Lymphoma. 2012; 53(12):2383-9 [PubMed] Article available free on PMC after 01/02/2014

No comparative studies exist for relapsed/refractory (rel/rfr) acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL). To determine practices over the last decade and to assess the outcomes of salvage chemotherapy with curative intent and autologous stem cell transplant (ASCT), we retrospectively evaluated treatment outcomes in patients with rel/rfr ARL who were treated in 13 national AIDS Malignancy Consortium (AMC) sites between 1999 and 2008 (n = 88). The most commonly used second-line therapies were ICE (ifosfamide/carboplatin/etoposide, n = 34), dose adjusted EPOCH (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin, n = 17) and ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin, n = 11). The odds of achieving a response were lower for those with non-Hodgkin lymphoma (NHL) than for those with HL and for those with primary refractory disease than for those with relapse. Overall survival (OS) was significantly longer for those with relapsed disease compared to those with refractory disease and for those with non-Burkitt NHL compared to those with Burkitt. OS was longer in patients who underwent ASCT compared to those who did not (1-year OS: 63.2% vs. 37.2%). However, among 32 patients (36%) who achieved a complete or partial response (CR/PR) after second-line therapy, 1-year OS was not different between the two groups (87.5% for ASCT vs. 81.8% for non-ASCT). Long-term survival in some patients with rel/rfr ARL may be possible without transplant, although transplant remains the standard of care for chemotherapy sensitive disease.

Katusiime C, Kambugu A
A rare entity of primary extranodal diffuse large B cell lymphoma of the lower limb calf in an HIV-infected young adult on highly active antiretroviral therapy.
BMJ Case Rep. 2012; 2012 [PubMed]

Primary cutaneous and skeletal muscle lymphomas are particularly rare phenomena in HIV sero-positive patients. The authors report a case of primary extranodal malignant diffuse large B cell lymphoma of the left gastrocnemius in a 21-year-old young adult who presented to the Infectious Diseases Institute, Kampala, Uganda having been on antiretroviral therapy for 2 years. The patient is still undergoing chemotherapy.

Vivekanandarajah A, Bhatt VR, Krishnarasa B, et al.
Right upper quadrant pain and mass in a 41-year-old previously healthy man: a presenting feature of HIV-associated extranodal diffuse large B cell lymphoma with cardiac involvement.
BMJ Case Rep. 2012; 2012 [PubMed]

With an increasing pandemic of HIV/AIDS, the incidence of HIV-associated lymphoma is expected to rise. Here, the authors report a case of a 41-year-old man who presented with right upper quadrant pain and mass, and was subsequently diagnosed with HIV-associated diffuse large B cell lymphoma (DLBCL) with cardiac involvement. This case illustrates some of the uncommon and interesting aspects of DLBCL: primary extramedullary extranodal stage IV disease as the presenting feature; cardiac involvement at presentation; DLBCL as the only clue to the diagnosis of HIV; and management of HIV-associated DLBCL. This case is also a reminder of the importance of the routine HIV screening for all patients between the ages of 13-64 years, as advocated by centres of disease control and prevention.

Martis N, Mounier N
Hodgkin lymphoma in patients with HIV infection: a review.
Curr Hematol Malig Rep. 2012; 7(3):228-34 [PubMed]

Hodgkin lymphoma (HL) is one of the most common types of non-AIDS-defining tumors in the HIV-infected. Its incidence however seems to have increased under highly active anti-retroviral therapy (HAART). HIV-HL is a different entity from HL in HIV-negative subjects with a poorer prognosis that is associated with tumor-subtype, EBV-infection, and "B" symptoms. Despite the aggressive nature of the disease, clinical outcome has improved with combination therapies including appropriately timed antiretroviral strategies and the quality of supportive care-notably the use of hematopoietic growth factors. More intensive chemotherapy regimens with or without autologous stem cell transplantation appear to improve survival. Functional imaging such as positron emission tomography and computed tomography (FDG-PET) may help guide treatment strategy and minimize long-term toxicity.

Castillo JJ, Furman M, Beltrán BE, et al.
Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy.
Cancer. 2012; 118(21):5270-7 [PubMed]

BACKGROUND: Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi-institutional, retrospective study to describe characteristics and determine prognostic factors in HIV-associated PBL.
METHODS: For this study, the investigators included consecutive, HIV-positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)-negative, and expressed markers of plasmacytic differentiation.
RESULTS: Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T-helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm(3) . At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v-myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty-five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome.
CONCLUSIONS: The prognosis of PBL in HIV-infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV-associated PBL. Cancer 2012.

Capello D, Gloghini A, Baldanzi G, et al.
Alterations of negative regulators of cytokine signalling in immunodeficiency-related non-Hodgkin lymphoma.
Hematol Oncol. 2013; 31(1):22-8 [PubMed]

We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.

Thapa DR, Bhatia K, Bream JH, et al.
B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas.
AIDS. 2012; 26(9):1177-80 [PubMed] Article available free on PMC after 01/02/2014

We show that microRNA-21 is significantly elevated in peripheral B cells of HIV-infected individuals who go on to develop AIDS-related non-Hodgkin lymphoma (n=13, <3 years prior to diagnosis) when compared with HIV-negative (n=18) or HIV-positive controls (n=21) (P<0.01). Moreover, miR-21 is overexpressed in activated B cells and can be induced by interleukin 4 alone, or with CD40 or immunoglobulin M co-stimulation, and lipopolysaccharides, suggesting that miR-21 may help maintain B-cell hyperactivation, contributing to lymphomagenesis.

Leruez-Ville M, Seng R, Morand P, et al.
Blood Epstein-Barr virus DNA load and risk of progression to AIDS-related systemic B lymphoma.
HIV Med. 2012; 13(8):479-87 [PubMed]

BACKGROUND: AIDS-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the combined antiretroviral therapy (cART) era. Although most ARLs are associated with the Epstein-Barr virus (EBV), whether patients with high EBV burden are more at risk of developing ARL is unknown. This study investigated the relationship between high blood EBV DNA loads and subsequent progression to ARL.
METHODS: We identified 43 cases of ARL diagnosed between 1988 and 2007 within two cohorts (ANRS SEROCO/HEMOCO and PRIMO) and for which stored serum and peripheral blood mononuclear cell (PBMC) samples were available within 3 years before ARL diagnosis. For each case, two controls matched for the cohort and CD4 cell count in the year of ARL diagnosis were selected. EBV DNA was measured in PBMCs and serum samples with a commercial kit.
RESULTS: High levels of EBV DNA in PBMCs collected a median of 10 months before diagnosis were associated with an increased risk of developing systemic B lymphoma (adjusted odds ratio 2.47; 95% confidence interval 1.15; 5.32 for each 1 log copies/10(6) PBMC increase in EBV load) but not with primary brain lymphoma.
CONCLUSION: In this study, HIV-infected patients with undetectable EBV DNA in PBMCs did not develop ARL in the following 3 years, while high levels of EBV DNA in PBMCs predicted subsequent progression to systemic B lymphoma. Clinicians should be aware of the increased risk of developing systemic B lymphoma in HIV-infected patients with a high blood EBV DNA load.

Kaplan LD
HIV-associated lymphoma.
Best Pract Res Clin Haematol. 2012; 25(1):101-17 [PubMed]

The incidence of aggressive lymphoma in the setting of HIV infection is significantly increased relative to the general population. Combination antiretroviral therapy (cART) for HIV has reduced the incidence of these neoplasms and has significantly improved clinical outcome for those who do develop lymphoma and require chemotherapy. With the possible exception of those individuals with the most severe immunocompromise, patients with HIV-associated lymphoma can be treated with the same standard immuno-chemotherapy regimens used in the immunocompetent population with similar expectations for good clinical outcome. Infusional regimens like dose adjusted EPOCH-R appear to be highly effective first-line therapy and for relapsed patients high-dose chemotherapy with autologous stem cell support is well-tolerated and effective. However, it should be recognized that there are unique risks associated with management of lymphoma in this patient population. While opportunistic infections are no longer a significant cause of death, antiretroviral agents used for management of HIV infection may interact with chemotherapeutic agents and other adjunctive therapies making communication between the treating Oncologist and the patient's primary HIV treatment provider of prime importance.

Barreto L, Azambuja D, Morais JC
Expression of immunohistochemical markers in patients with AIDS-related lymphoma.
Braz J Infect Dis. 2012 Jan-Feb; 16(1):74-7 [PubMed]

AIDS-related lymphomas (ARL) present high biological heterogeneity. For better characterization of this type of lymphoma, the objectives of the present study were to evaluate the expression of immunohistochemical markers of cell differentiation (CD10, Bcl-6, MUM-1) and determine cell origin profile according to Hans' classification of diffuse large B-cell lymphoma in AIDS patients. This study included 72 consecutive patients with ARL diagnosed at the University Hospital, Universidade Federal do Rio de Janeiro (UFRJ) and at the Brazilian Instituto Nacional de Câncer (INCA) from 2000 to 2006. The morphologic distribution of the lymphomas was the following: 61% were diffuse large B-cell lymphomas (DLBCLs), 15% were Burkitt's lymphomas, 13% were plasmablastic lymphomas, 10% were high-grade lymphomas and 1% was follicular lymphoma. The positivity for each immunohistochemical marker in DLBCLs, Burkitt's lymphoma and plasmablastic lymphoma was respectively: CD20, 84%, 100%, and 0; CD10, 55%, 100%, and 0; Bcl-6, 45%, 80%, and 0; MUM-1, 41%, 20%, and 88%. A higher positivity of CD20 (84% x 56%, p = 0.01) was found in DLBCL compared to non-DLBCL; in Burkitt's lymphomas a higher positivity of CD10 (100% x 49%, p = 0.04) and Bcl-6 (80% x 39%, p = 0.035) were found compared to non-Burkitt's lymphomas. Germinal center (GC) profile was detected in 60% of DLBCLs. Our study suggests particular findings in ARL, as the most frequent phenotype was GC, different from HIV-negative patients.

Tsachouridou O, Christoforidou A, Metallidis S, et al.
Plasmablastic lymphoma of the oral cavity, a B cell-derived lymphoma associated with HIV infection: a case series.
Eur Arch Otorhinolaryngol. 2012; 269(6):1713-9 [PubMed]

OBJECTIVES: Plasmablastic lymphoma (PBL) of the oral cavity is a rare form of non-Hodgkin lymphoma that is most frequently met in human immunodeficiency (HIV) positive patients. Only a few cases have been reported worldwide since 1997. This clinical entity may escape detection due to its unusual immunophenotype and rare occurrence. Our aim is to present two cases with this rare condition that were diagnosed and treated in our department.
MATERIALS AND METHODS: We describe two cases of PBLs in HIV-infected patients, who presented with an expanding painless oral lesion and summarize the literature in order to elucidate the nature of this malignancy.
RESULTS: The first patient received chemotherapy with additional radiotherapy that led to complete remission of the disease, while the second experienced a relapse 6 months after treatment with chemotherapy, that caused his death after refusal of further treatment.
CONCLUSION: Because of the consistent epidemiological association of PBL with immunosuppression, any patient diagnosed with PBL should be tested for HIV. The clinical picture of PBL, including its affinity with HIV-infection, male sex, and its predilection for the oral cavity, may contribute to the differential diagnosis. Any oral mass occurring in an immunosuppressed patient should be referred for biopsy, since the early diagnosis of these tumors leads to better prognosis of the patients.

Lestuzzi C, Spina M, Martellotta F, Carbone A
Massive myocardial infiltration by HIV-related non-Hodgkin lymphoma: echocardiographic aspects at diagnosis and at follow-up.
J Cardiovasc Med (Hagerstown). 2012; 13(12):836-8 [PubMed]

A 23-year-old male presented with severe rest dyspnoea, engorged jugular veins, ankle oedema and heart rate 140 bpm. Computed tomography (CT) scan showed a large mediastinal mass with pericardial and atrial infiltration, pulmonary artery and superior vena cava compression. HIV infection was detected. Echocardiography showed 5 × 4 cm masses both in the right and the left atria, pericardial effusion, thickening of the right and left ventricular walls and hypokinesis; after intravenous contrast medium (SonoVue), the ventricular myocardium showed an increased, granular echogenicity, as did the mediastinal mass and pericardium. Nadroparin, bisoprolol, amiodarone and (suspecting non-Hodgkin lymphoma) steroids were started. After 3 days, at echocardiogram, the thickness of the ventricular walls was reduced and ejection fraction was improved. Mediastinal biopsy disclosed a large B-cell lymphoma. After starting systemic chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin) and highly active antiretroviral therapy (HAART), 11 days after admission the patient was in New York Heart Association (NYHA) class 1-2, with normal jugular veins and no oedema. The echocardiogram showed no more pericardial effusion, atrial masses reduced by 50%, normal interventricular septum thickness and ejection fraction. In August 2010, after six cycles of chemotherapy followed by radiotherapy, the patient was in complete remission. This case shows both the echocardiographic findings typical of neoplastic infiltration of the myocardium and the rapid improvement observed within a few days after chemotherapy. In the HAART era patients with HIV-related lymphoma and even massive involvement of the heart may receive aggressive treatment with curative intent. Echocardiography is useful in early assessment of the response to therapy.

Okosun J, Warbey V, Shaw K, et al.
Interim fluoro-2-deoxy-D-glucose-PET predicts response and progression-free survival in patients with Hodgkin lymphoma and HIV infection.
AIDS. 2012; 26(7):861-5 [PubMed]

BACKGROUND: Interim PET scans in HIV-negative patients with Hodgkin lymphoma has emerged as one of the most important prognostic tools. However, equivalent studies in HIV-positive patients are yet to be performed.
OBJECTIVE: We evaluated the prognostic value of interim [18F]-fluoro-2-deoxy-D-glucose-PET (18F-FDG PET) after two or three cycles of chemotherapy using adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) with concomitant HAART in HIV-positive patients with Hodgkin lymphoma.
METHODS: Patients with advanced HIV-Hodgkin lymphoma (HIV-HL) from six UK centres were included. Interim PET scans after two or three cycles of ABVD (PET-2 or PET-3) were carried out. Prognostic analysis correlated the 2-year progression-free survival (PFS) rate with the interim PET result.
RESULTS: Twenty-three evaluable patients were assessed, 21 achieved a negative interim PET and 22 achieved complete remission by computerized tomography scan criteria after ABVD therapy. After a median follow-up of 27 months (range 12-50), disease progression was seen in one patient. Treatment failure was seen in one of the two interim PET-positive patients and none of the interim PET-negative patients. The 2-year PFS for interim PET-positive patients was 50%, and 100% for interim PET-negative patients (P = 0.0012).
CONCLUSION: A negative interim 18F-FDG PET result is highly predictive of treatment success in HIV-HL patients.

Castillo JJ, Echenique IA
Rituximab in combination with chemotherapy versus chemotherapy alone in HIV-associated non-Hodgkin lymphoma: a pooled analysis of 15 prospective studies.
Am J Hematol. 2012; 87(3):330-3 [PubMed]

In HIV-positive patients with non-Hodgkin lymphoma (NHL), no benefit of adding rituximab to chemotherapy was seen in a randomized controlled trial (RCT). We performed a meta-analysis of prospective studies to ascertain outcomes in HIV-positive NHL patients treated with chemotherapy (chemo) versus rituximab and chemo (R-chemo). A literature search through September 2011 was performed using the key search "(HIV OR AIDS) AND lymphoma". The main outcomes were overall response rate (ORR), complete response rate (CRR) and 2-year overall survival (OS) and are reported as non-adjusted odds ratio (OR). We identified 15 prospective studies including 1,060 HIV-positive NHL patients, 675 treated with chemo and 385 with R-chemo. There was a higher proportion of HAART in R-chemo patients (82% vs. 68%; p < 0.01) but there were no differences in proportion of patients with advanced stage or high/high-intermediate age-adjusted International Prognostic Index (aaIPI) scores. Meta-analysis showed the OR for ORR, CRR and 2-year OS in patients treated with R-chemo was 1.39 (95% CI 0.79-2.47; p = 0.26), 1.66 (95% CI 0.98-2.82; p = 0.06) and 2.19 (95% CI 1.68-2.86; p < 0.001), respectively. HIV-positive lymphoma patients treated with R-chemo had higher odds for CR and 2-year OS when compared to chemo but also had a higher proportion of HAART usage.

Tedeschi R, Bortolin MT, Bidoli E, et al.
Assessment of immunovirological features in HIV related non-Hodgkin lymphoma patients and their impact on outcome.
J Clin Virol. 2012; 53(4):297-301 [PubMed]

BACKGROUND: Despite the era of highly active antiretroviral therapy, non-Hodgkin lymphoma (NHL) remains one of the main causes of death in HIV-infected patients, with a wide variation on the outcome.
OBJECTIVES: We investigated immunological status and EBV, HHV8, HIV viral load in a group of HIV-infected patients at diagnosis of NHL to evaluate their prognostic significance.
STUDY DESIGN: Eighty-one consecutive HIV+ NHL patients were studied. CD4 and CD8 cell counts, HHV8 DNA, EBV DNA, HIV RNA and HIV DNA were assessed at diagnosis and at 3 months after chemotherapy initiation. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of disease free survival (DFS) and overall survival (OS) were computed according to CD4 and CD8 cell counts, EBV DNA, HIV RNA and HIV DNA. HRs were, thereafter, computed also for continuous variation of CD4, CD8 cell counts and EBV DNA.
RESULTS: In the multivariate analysis, CD4<160 and CD8<590 cell/μl and EBV DNA≥300 c/ml were independently associated to DFS (HR=2.98; 95%CI: 1.26-7.03; HR=2.65, 95%CI: 1.13-6.19; HR=4.01; 95%CI: 1.81-8.91) and OS (HR=3.32; 95%CI: 1.41-7.83; HR=4.62, 95%CI: 1.91-11.19; HR=3.11, 95%CI: 1.42-6.80). HRs for DFS and OS decreased continuously with increasing CD4 and CD8 cell counts, while they increased continuously with increasing EBV DNA levels.
CONCLUSIONS: The association with survival of low CD4 and CD8 cell counts and detectable EBV viremia, measured at lymphoma's diagnosis, identified three independent prognostic biomarkers that might help in the management of NHL HIV+ patients, offering complementary information in the ascertainment of their outcome.

Barta SK, Lee JY, Kaplan LD, et al.
Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma.
Cancer. 2012; 118(16):3977-83 [PubMed] Article available free on PMC after 15/08/2013

BACKGROUND: Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)-associated, aggressive B-cell, non-Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.
METHODS: The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV-associated NHL who received either R-CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R-EPOCH (n = 51; AMC034). Age-adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R-CHOP vs R-EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event-free survival (EFS) and overall survival (OS).
RESULTS: Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R-EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment-associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).
CONCLUSIONS: The current analysis provided additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse large B-cell lymphoma (National Clinical Trial no. NCT00118209).

Corti M, Villafañe MF, Bistmans A, et al.
Oral cavity and extra-oral plasmablastic lymphomas in AIDS patients: report of five cases and review of the literature.
Int J STD AIDS. 2011; 22(12):759-63 [PubMed]

Plasmablastic lymphoma (PBL) is a distinct disease entity of the diffuse large B-cell lymphoma, which often occurs in HIV-positive patients. The immunophenotype of this lymphoid neoplasm is characterized by the presence of plasma cell-associated markers VS38c and CD138 antigens and the absence of B-cell markers such as CD20 and CD45. The most frequent site of involvement is the oral cavity and the jaw, while several reports describe the development of PBL in extra-oral sites including the lymph nodes, the anal canal, the soft tissue, the skin and the gastrointestinal tract as less frequent. Epstein-Barr virus is often associated with PBL pathogenesis and the neoplastic cells contain this virus genome. Here we review the epidemiological, clinical, immunological, histopathological and virological characteristics and their prognosis and outcome in a series of five patients with diagnoses of HIV/AIDS and PBL.