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AIDS-Related Lymphoma

Incidence of non-Hodgkin's lymphoma has increased in parallel with the AIDS epidemic. Lymphomas affecting HIV infected people are mostly of the aggressive B-cell types (diffuse large cell, B-immunoblastic, or small non-cleaved Burkitt's / Burkitt's like lymphoma) which are less common in non-HIV infected lymphoma patients. The HIV virus is not thought to a direct cause of lymphoma, rather it weakens the body's defences and may increase susceptibility to other infections such as the Epstein-Barr and HHV-8 viruses which are associated with these types of lymphomas.

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Chandra P, Agrawal A, Purandare N, et al.
Coincidental Observation of Global Hypometabolism in the Brain on PET/CT of an AIDS Patient With High-Grade Pulmonary Non-Hodgkin Lymphoma.
Clin Nucl Med. 2016; 41(8):646-7 [PubMed] Related Publications
AIDS-related dementia complex is the most severe form of cognitive dysfunction in a patient infected with human immunodeficiency virus. The use of FDG PET/CT to diagnose AIDS-related dementia complex has been studied previously and shows various specific metabolic patterns from striatal hypermetabolism in early asymptomatic stage to global hypometabolism in advanced stages. We present a case of a 49-year-old patient with long-standing human immunodeficiency virus infection, where global brain hypometabolism was noted coincidentally on FDG PET/CT done for initial staging of primary pulmonary non-Hodgkin lymphoma.

Banik T, Mondal K, Mandal R
Two cases of primary non-Hodgkin's lymphoma of female breast: Role of fine-needle aspiration cytology and cell-block immunohistochemistry.
Diagn Cytopathol. 2016; 44(3):235-40 [PubMed] Related Publications
Primary breast lymphoma (PBL) is an uncommon neoplastic condition. Though HIV-infection is a known risk factor for the development of extranodal lymphomas, mammary involvement is still a rarity. Radiologically, PBL appears as well circumscribed, heteroechoic, noncalcifying mass. Fine-needle aspiration cytology (FNAC) is commonly used to diagnose this neoplasm; however, subcategorization requires immunophenotypic characterization of the neoplastic cells. Herein, we report two cases of PBL, including a HIV-infected lady; in both the cases FNAC expressed features of non-Hodgkin's lymphoma. Finally, immunohistochemistry on cell-block with CD20 diagnosed both the cases as diffuse large B-cell lymphoma (DLBCL).

Guillet S, Gérard L, Meignin V, et al.
Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution.
Am J Hematol. 2016; 91(2):233-7 [PubMed] Related Publications
Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma with poor prognosis. Lymphoma cells are always infected with human herpesvirus-8 (HHV-8) and in most cases coinfected with Epstein-Barr virus. In classic presentation, PEL is characterized by body cavity effusions with or without mass lesions. A variant with only extracavitary localization has also been described. We report on a large single-center series of patients with PEL in the era of combined antiretroviral therapy (cART). The main objective was to compare the characteristics and the outcome of patients with classic (n = 34) and extracavitary (n = 17) variant PEL. At PEL diagnosis, no major difference was observed between the two groups in terms of demographic and HIV characteristics. Extracavitary localizations were exclusively nodal in six patients and involved various organs in 11 patients. Another HHV-8-associated disease was observed in 31 patients, Kaposi sarcoma in 25, and multicentric Castleman disease in 18 patients, without difference between the two groups. Thirty-two patients were treated with CHOP associated with high-dose methotrexate, 13 were treated with CHOP-derived regimen alone, and six patients received low-dose/no chemotherapy. Complete remission was achieved in 21 (62%) and seven (41%) patients of the classic and extracavitary groups, respectively. The median overall survival (OS) was 10.2 months. Despite a higher disease-free survival in the extracavitary group, there was no difference in OS between the two variants. Based on this series, characteristics of classic and extracavitary variants were very close. Although prognosis of PEL remains very severe in cART era, the median survival compares favorably with earlier series.

Dolcetti R, Gloghini A, Caruso A, Carbone A
A lymphomagenic role for HIV beyond immune suppression?
Blood. 2016; 127(11):1403-9 [PubMed] Free Access to Full Article Related Publications
Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.

Boons E, Vanstreels E, Jacquemyn M, et al.
Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.
EBioMedicine. 2015; 2(9):1102-13 [PubMed] Free Access to Full Article Related Publications
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

Lloyd IE, Clement PW, Salzman KL, et al.
An unusual and challenging case of HIV-associated primary CNS Lymphoma with Hodgkin-like morphology and HIV encephalitis.
Diagn Pathol. 2015; 10:152 [PubMed] Free Access to Full Article Related Publications
HIV-associated primary CNS lymphomas are well-recognized, almost exclusively EBV-driven neoplasms with poor clinical prognosis. We report a challenging, atypical case of an HIV-associated lymphoproliferative disorder with unusual morphologic features reminiscent of Hodgkin Lymphoma, accompanied by HIV encephalitis. A 52-year-old male presented with acute seizures after seven months of progressive neurocognitive decline that was clinically diagnosed as progressive supranuclear palsy. Clinical work-up revealed HIV infection along with two ring-enhancing lesions in the brain on MRI, and negative CSF EBV testing. Subsequent biopsy showed well-demarcated hypercellular regions in the brain comprised of scattered Reed-Sternberg-like cells in a background of small to medium-sized lymphocytes exhibiting focal angiocentricity and geographic necrosis. The atypical cells were positive for CD20, EBV, and CD79a, and negative for CD45, GFAP, CD15, CD30, and p24. These cells were admixed with numerous CD68-positive cells. The adjacent brain showed classic features of HIV encephalitis with perivascular, CD68 and p24-positive multinucleated giant cells. This case illustrates several diagnostic pitfalls in the work-up of HIV-associated brain lesions, as well as reporting a unique histomorphology for an HIV-related primary CNS lymphoproliferative disorder.

Grewal R, Cucuianu A, Swanepoel C, et al.
The role of microRNAs in the pathogenesis of HIV-related lymphomas.
Crit Rev Clin Lab Sci. 2015; 52(5):232-41 [PubMed] Related Publications
The incidence of HIV-related lymphomas (HRLs) is increased by 60-100 times in patients with HIV. When compared to the general population, patients with HRLs often present with extranodal lymphoid proliferation, most frequently of the gastrointestinal tract, central nervous system, liver and bone marrow. MicroRNAs (miRs) are non-coding double-stranded RNA molecules of 18-25 nucleotides that regulate post-translational gene expression by inhibiting translation or promoting degradation of messenger RNA complementary sequences. Before their discovery, tumorigenesis was thought to have been caused by the alteration of protein-coding oncogenes and tumor-suppressor genes, but once identified in B-cell chronic lymphocytic leukemia, miRs function as either oncogenes or tumor-suppressor genes was confirmed in different types of malignancies. Since miRs are clearly involved in tumorigenesis in many cancers, their role in HRLs is now receiving attention. A few studies have been conducted thus far in some HRLs on the involvement of miR in the pathogenesis of lymphoid malignancies. Since B-cell lymphomas arise from various stages of B-cell development in both HIV-infected and HIV-naïve patients, investigators have tried to determine the different miR signatures in B-cell development. As classic immunohistochemistry staining is sometimes not enough for the differential diagnosis of HRLs, in the present review, we have described the potential use of miRs in the prognosis and diagnosis of these diseases.

Carroll V, Garzino-Demo A
HIV-associated lymphoma in the era of combination antiretroviral therapy: shifting the immunological landscape.
Pathog Dis. 2015; 73(7) [PubMed] Free Access to Full Article Related Publications
HIV infection increases the risk of many types of cancer, including lymphoma. Combination antiretroviral therapy (cART) has reduced, but not eliminated, the risk of HIV-associated lymphoma. There has been a substantial shift in the subtypes of lymphoma observed in HIV-infected patients treated with cART. In this review, we will first outline these changes based on epidemiological studies and describe the impact of cART on lymphoma risk and mortality. Then, we will discuss some immunological factors that may contribute to the increased risk of lymphoma persisting after the administration of cART, including immunological non-response to therapy, chronic B-cell activation and dysfunction, T follicular helper cells, natural killer cells and altered lymphopoiesis. A better understanding of the pathophysiologic mechanisms of HIV-associated lymphoma under effective cART will inform future treatment strategies.

Pantanowitz L, Carbone A, Dolcetti R
Microenvironment and HIV-related lymphomagenesis.
Semin Cancer Biol. 2015; 34:52-7 [PubMed] Related Publications
Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment.

Taylor JG, Liapis K, Gribben JG
The role of the tumor microenvironment in HIV-associated lymphomas.
Biomark Med. 2015; 9(5):473-82 [PubMed] Free Access to Full Article Related Publications
There has been considerable interest in the role of the lymphoma microenvironment. Despite the use of highly active antiretroviral therapy (HAART), AIDS-related diffuse large-B-cell lymphoma remains common and HIV-relatedHIV-associated classical Hodgkin's lymphoma is increasing in incidence. Less is known about the impact HIV and HAART have on the lymphoma microenvironment. AIDS-related diffuse large B-cell lymphoma is highly angiogenic, demonstrates increased lymphoblastic histology, proliferation, increased activated cytotoxic T cells, reduced CD4(+) and FOXP3(+) T cells, but no differences in tumor-associated macrophages. Early initiation of HAART improves immunosurveillance, but cases without viral antigens appear able to avoid immunologic reaction. Increased T cell infiltrates seen with HAART treatment in HIV-related classical Hodgkin's lymphoma may contribute to malignant cell growth.

Basavaraj A, Shinde A, Kulkarni R, et al.
HIV associated Burkitt's lymphoma.
J Assoc Physicians India. 2014; 62(8):723-7 [PubMed] Related Publications
Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin Lymphoma (NHL) associated with chromosomal translocations resulting in upregulation of the proto-oncogene C-MYC, which drives progression through the cell cycle NHL accounts for approximately one third of AIDS-related malignancies and the frequency of BL is 2.4-20% of HIV-associated NHL. The outcome of HIV-associated non-Hodgkin lymphoma (NHL) has improved substantially in the highly active antiretroviral therapy (HAART) era. However, HIV-Burkitt lymphoma (BL), which accounts for up to 20% of HIV-NHL, still has poor outcome with standard chemotherapy. We present here a 26 years old female who presented with congestive cardiac failure and sudden onset paraparesis and was finally diagnosed to have right atrial mass and had extradural lesion extending from L2 to S1 which turned out to be High grade NHL-Burkitt's Lymphoma.

Arvey A, Ojesina AI, Pedamallu CS, et al.
The tumor virus landscape of AIDS-related lymphomas.
Blood. 2015; 125(20):e14-22 [PubMed] Free Access to Full Article Related Publications
Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.

Pratesi C, Zanussi S, Tedeschi R, et al.
γ-Herpesvirus load as surrogate marker of early death in HIV-1 lymphoma patients submitted to high dose chemotherapy and autologous peripheral blood stem cell transplantation.
PLoS One. 2015; 10(2):e0116887 [PubMed] Free Access to Full Article Related Publications
Autologous stem cell transplantation (ASCT) is a feasible procedure for human immunodeficiency virus-1 (HIV-1) lymphoma patients, whose underlying disease and intrinsic HIV-1- and ASCT-associated immunodeficiency might increase the risk for γ-herpesvirus load persistence and/or reactivation. We evaluated this hypothesis by investigating the levels of Epstein-Barr virus (EBV)- and Kaposi sarcoma-associated herpesvirus (KSHV)-DNA levels in the peripheral blood of 22 HIV-1-associated lymphoma patients during ASCT, highlighting their relationship with γ-herpesvirus lymphoma status, immunological parameters, and clinical events. EBV-DNA was detected in the pre-treatment plasma and peripheral blood mononuclear cells (PBMCs) of 12 (median 12,135 copies/mL) and 18 patients (median 417 copies/10(6) PBMCs), respectively; the values in the two compartments were correlated (r = 0.77, p = 0.0001). Only EBV-positive lymphomas showed detectable levels of plasma EBV-DNA. After debulking chemotherapy, plasma EBV-DNA was associated with lymphoma chemosensitivity (p = 0.03) and a significant higher mortality risk by multivariate Cox analysis adjusted for EBV-lymphoma status (HR, 10.46, 95% CI, 1.11-98.32, p = 0.04). After infusion, EBV-DNA was detectable in five EBV-positive lymphoma patients who died within six months. KSHV-DNA load was positive in only one patient, who died from primary effusion lymphoma. Fluctuations in levels of KSHV-DNA reflected the patient's therapy and evolution of his underlying lymphoma. Other γ-herpesvirus-associated malignancies, such as multicentric Castleman disease and Kaposi sarcoma, or end-organ complications after salvage treatment were not found. Overall, these findings suggest a prognostic and predictive value of EBV-DNA and KSHV-DNA, the monitoring of which could be a simple, complementary tool for the management of γ-herpesvirus-positive lymphomas in HIV-1 patients submitted to ASCT.

Barta SK, Samuel MS, Xue X, et al.
Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma.
Ann Oncol. 2015; 26(5):958-66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades.
PATIENTS AND METHODS: We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989-1995), early cART (1996-2000), recent cART (2001-2004), and contemporary cART era (2005-2010).
RESULTS: Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P < 0.001). While the age-adjusted IPI was a significant predictor of outcome in all time periods, the influence of other factors waxed and waned. Individual HIV-related factors such as low CD4 counts (<50/mm(3)) and prior history of AIDS were no longer associated with poor outcomes in the contemporary era.
CONCLUSIONS: Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

Zanussi S, Bortolin MT, Pratesi C, et al.
Autograft HIV-DNA load predicts HIV-1 peripheral reservoir after stem cell transplantation for AIDS-related lymphoma patients.
AIDS Res Hum Retroviruses. 2015; 31(1):150-9 [PubMed] Free Access to Full Article Related Publications
Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p = 0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R(2) = 0.84, p = 0.01) to month 12 follow-up (R(2) = 0.99, p = 0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure.

Schommers P, Hentrich M, Hoffmann C, et al.
Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort.
Br J Haematol. 2015; 168(6):806-10 [PubMed] Related Publications
Overall survival (OS) of patients with acquired immunodeficiency syndrome (AIDS)-related Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) was analysed in the German AIDS-related-Lymphoma-Cohort-Study. Of 291 patients prospectively included between January 2005 and December 2012, 154 had DLBCL, 103 BL and 34 PBL. Two-year OS rates were similar between BL (69%) and DLBCL patients (63%) but lower for PBL patients (43%). Intermediate (Hazard ratio [HR] 4·1 95% confidence interval [CI] 1·98-8·49) or high (HR 4·92 95% CI 2·1-11·61) International Prognostic Index, bone marrow involvement (HR 1·69 95% CI 1·00-2·84) and PBL histology (HR 2·24 95% CI 1·24-4·03) were independent predictors of mortality.

Crane GM, Xian RR, Burns KH, et al.
Primary effusion lymphoma presenting as a cutaneous intravascular lymphoma.
J Cutan Pathol. 2014; 41(12):928-35 [PubMed] Free Access to Full Article Related Publications
Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co-infection with Epstein-Barr virus (EBV) and human herpesvirus-8/Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here, we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53-year-old man with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) who presented with fevers, weight loss and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B- and T-cell antigens. The atypical cells expressed EBV and HHV-8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients.

Yamada M, Katano H, Yotsumoto M, et al.
Unique expression pattern of viral proteins in human herpesvirus 8-positive plasmablastic lymphoma: a case report.
Int J Clin Exp Pathol. 2014; 7(9):6415-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human herpesvirus 8 (HHV8)-positive plasmablastic lymphoma is a disease which correlates with acquired immunodeficiency syndrome (AIDS). Little is known about the pathogenesis of the disease due to its rarity. We report an autopsy case about AIDS related HHV-8-positive plasmablastic lymphoma and presents an examination about HHV8 related proteins for the disease by using immunohistochemical techniques.
CASE PRESENTATION: Two kinds of tumors complicated the male AIDS patient: one was HHV-8-positive plasmablastic lymphoma and the other was Kaposi's sarcoma (KS). Immunohistochemically, the lymphoma cells were positive for HHV8-associated lytic early proteins as well as HHV8 latency-associated nuclear antigen 1 (LANA-1), and, on the other hand, the lymphoma cells were negative for lytic immediately early proteins. KS was positive for only LANA-1.
CONCLUSION: These findings indicate that the lymphoma cells acquired an ability to proliferate without de novo HHV8 replication. Moreover, the onset mechanisms of HHV-8-positive plasmablastic lymphoma may be different from those of KS.

Pereira R, Carvalho J, Patrício C, Farinha P
Sustained complete remission of primary effusion lymphoma with adjunctive ganciclovir treatment in an HIV-positive patient.
BMJ Case Rep. 2014; 2014 [PubMed] Free Access to Full Article Related Publications
Primary effusion lymphoma (PEL) is one of the least common of the AIDS-related lymphomas, accounting for less than 1-4% of cases. Clinical manifestations depend on the extent and distribution of disease and, as in the majority of patients no detectable mass lesion is found, symptoms are related to fluid accumulation, dyspnoea (pleural or pericardial effusions), abdominal distension (ascites) or joint swelling. The median survival after diagnosis, even with aggressive chemotherapy, remains poor and remissions are often of short duration. We present the case of a 31-year-old man with AIDS and diagnosis of PEL, in whom sustained and complete remission of the tumour was achieved with adjunctive ganciclovir therapy. Since the disease is so uncommon, there is a paucity of data to guide the treatment of these patients; ganciclovir might be a potential antiviral therapeutic option, as demonstrated by the 2-year remission achieved in our patient.

Cobucci RN, Lima PH, de Souza PC, et al.
Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: a systematic review.
J Infect Public Health. 2015 Jan-Feb; 8(1):1-10 [PubMed] Related Publications
After highly active antiretroviral therapy (HAART) became widespread, several studies demonstrated changes in the incidence of defining and non-defining AIDS cancers among HIV/AIDS patients. We conducted a systematic review of observational studies evaluating the incidence of malignancies before and after the introduction of HAART in people with HIV/AIDS. Eligible studies were searched up to December 2012 in the following databases: Pubmed, Embase, Scielo, Cancerlit and Google Scholar. In this study, we determined the cancer risk ratio by comparing the pre- and post-HAART eras. Twenty-one relevant articles were found, involving more than 600,000 people with HIV/AIDS and 10,891 new cases of cancers. The risk for the development of an AIDS-defining cancer decreased after the introduction of HAART: Kaposi's sarcoma (RR=0.30, 95% CI: 0.28-0.33) and non-Hodgkin's lymphoma (RR=0.52, 95% CI: 0.48-0.56), in contrast to invasive cervical cancer (RR=1.46, 95% CI: 1.09-1.94). Among the non-AIDS-defining cancers, the overall risk increased after the introduction of HAART (RR=2.00, 95% CI: 1.79-2.23). The incidence of AIDS-defining cancers decreased and the incidence of non-AIDS-defining cancers increased after the early use of HAART, probably due to better control of viral replication, increased immunity and increased survival provided by new drugs.

Yang J, Wang P, Lv ZB, et al.
AIDS-related non-Hodgkin lymphoma: imaging feature analysis of 27 cases and correlation with pathologic findings.
Asian Pac J Cancer Prev. 2014; 15(18):7769-73 [PubMed] Related Publications
BACKGROUND: Some tumor types are related to HIV, including non-Hodgkin lymphoma (NHL). The morbidity and mortality of NHL has remained high, even after highly active antiretroviral therapy (HAART) was introduced. We collected cases of AIDS with NHL, and evaluated the imaging features and strategies for diagnosis.
MATERIALS AND METHODS: There were 27 patients with AIDS and tumors confirmed by pathology. There were 9 patients with Burkitt lymphoma, 16 with diffuse large B cell lymphomas (DLBCLs), and 2 with primary central nervous system (PCNS) lymphomas. All of the patients underwent a series of imaging studies. Three radiologists analyzed the images, and any disagreement was discussed until consensus was reached.
RESULTS: The radiologic manifestations of AIDS with NHL were mainly masses and lymphadenopathy, 3 patients having one mass and 12 two or more masses. 7 patients had lymphadenopathy in one site and 3patients had lymphadenopathy in two or more sites. Coarse mucosal folds, thickening of the gastrointestinal wall, and lumen narrowing were typical manifestations of NHL within the gastrointestinal tract. There were 4 patients with masses and 5 with lymphadenopathy inthe 9 with Burkitt lymphoma, and 11 patients with masses 5 with lymphadenopathy in the 16 with DLBCLs.
CONCLUSION: NHL is a malignancy that usually occurs in patients with AIDS. Imaging is an important method by which to evaluate lesions, masses, and lymphadenopathy. Fine needle aspiration biopsy and stereotaxis biopsy are useful methods by which to diagnose NHL.

Hoffmann C, Hentrich M, Gillor D, et al.
Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study.
HIV Med. 2015; 16(4):261-4 [PubMed] Related Publications
OBJECTIVES: The incidence of HIV-related non-Hodgkin lymphoma (NHL) but not that of Hodgkin lymphoma (HL) has been declining. The aim of the study was to compare HIV-infected patients with NHL and HL with respect to antiretroviral therapy (ART) exposure at the time of lymphoma diagnosis.
METHODS: HIV-infected patients with NHL and HL included in a prospective multicentre cohort study since January 2005 were compared with respect to ART exposure and viral load at the time of lymphoma diagnosis.
RESULTS: As of 31 December 2012, data for 329 patients with NHL and 86 patients with HL from 31 participating centres were available. Patients with HL were more likely to be on ART (73.5% vs. 39.1%, respectively; P < 0.001) and more frequently had a viral load below the detection limit (57.3% vs. 27.9%, respectively; P < 0.001) than patients with NHL. The proportion of patients with HL was 8.0% in ART-naïve patients, 34.8% in patients with current HIV RNA < 50 HIV-1 RNA copies/mL, and 50.0% in patients with both HIV RNA < 50 copies/mL for > 12 months and a CD4 cell count of > 200 cells/μL. Of note, 45.8% of all patients with NHL were not currently on ART and had a CD4 count of < 350 cells/μL.
CONCLUSIONS: This prospective cohort study shows that HL was as common as NHL in patients with sustained viral suppression and limited immune deficiency. In contrast to NHL, the majority of patients with HL were on effective ART, suggesting that ART provides insufficient protection from developing HL. The high proportion of untreated patients with NHL suggests missed opportunities for earlier initiation of ART.

Castillo JJ, Bower M, Brühlmann J, et al.
Prognostic factors for advanced-stage human immunodeficiency virus-associated classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine plus combined antiretroviral therapy: a multi-institutional retrospective study.
Cancer. 2015; 121(3):423-31 [PubMed] Related Publications
BACKGROUND: The treatment and outcomes of patients with human immunodeficiency virus (HIV)-associated Hodgkin lymphoma (HL) continue to evolve. The International Prognostic Score (IPS) is used to predict the survival of patients with advanced-stage HL, but it has not been validated in patients with HIV infection.
METHODS: This was a multi-institutional, retrospective study of 229 patients with HIV-associated, advanced-stage, classical HL who received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus combination antiretroviral therapy. Their clinical characteristics were presented descriptively, and multivariate analyses were performed to identify the factors that were predictive of response and prognostic of progression-free survival (PFS) and overall survival (OS).
RESULTS: The overall and complete response rates to ABVD in patients with HIV-associated HL were 91% and 83%, respectively. After a median follow-up of 5 years, the 5-year PFS and OS rates were 69% and 78%, respectively. In multivariate analyses, there was a trend toward an IPS score >3 as an adverse factor for PFS (hazard ratio [HR], 1.49; P=.15) and OS (HR, 1.84; P=.06). A cluster of differentiation 4 (CD4)-positive (T-helper) cell count <200 cells/μL was associated independently with both PFS (HR, 2.60; P=.002) and OS (HR, 2.04; P=.04). The CD4-positive cell count was associated with an increased incidence of death from other causes (HR, 2.64; P=.04) but not with death from HL-related causes (HR, 1.55; P=.32).
CONCLUSIONS: The current results indicate excellent response and survival rates in patients with HIV-associated, advanced-stage, classical HL who receive ABVD and combination antiretroviral therapy as well as the prognostic value of the CD4-positive cell count at the time of lymphoma diagnosis for PFS and OS.

Barta SK, Xue X, Wang D, et al.
A new prognostic score for AIDS-related lymphomas in the rituximab-era.
Haematologica. 2014; 99(11):1731-7 [PubMed] Free Access to Full Article Related Publications
While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).

Medel N, Hamao-Sakamoto A
A case of oral plasmablastic lymphoma and review of current trends in oral manifestations associated with human immunodeficiency virus infection.
J Oral Maxillofac Surg. 2014; 72(9):1729-35 [PubMed] Related Publications
Plasmablastic lymphoma (PBL) is a rare and aggressive type of non-Hodgkin lymphoma that in 2000 was classified as a distinct type of lymphoma related to acquired immune deficiency syndrome by the World Health Organization after the first reports of the disease surfaced in 1997. PBL is strongly associated with human immunodeficiency virus (HIV) infection and often occurs within the oral cavity. Despite intensive chemotherapy regimens and combinational antiretroviral therapy, the prognosis of PBL in HIV-infected patients remains poor. This article describes a case of oral PBL and a literature review of current trends in oral manifestations associated with HIV infection.

Sekar D, Hairul Islam VI, Thirugnanasambantham K, Saravanan S
Relevance of miR-21 in HIV and non-HIV-related lymphomas.
Tumour Biol. 2014; 35(9):8387-93 [PubMed] Related Publications
The critical role of microRNAs (miRNAs) in cell differentiation, homeostasis and cancer development has been extensively discussed in recent publications. The microRNAs with RISC enzyme complex allow it to find its complementary sequence, which is usually located in the 3'-untranslated region (UTR) of the target messenger RNA (mRNA). This is followed by inhibition of protein translation or promotion, resulting in degradation of the target gene. miR-21 has been mapped at chromosome 17q23.2, where it overlaps with the protein coding gene vacuole membrane protein 1 (VMP1), a human homologue of rat vacuole membrane protein. Recent evidence indicates that miR-21 plays a vital role in tumour cell proliferation, apoptosis and invasion. The inhibition of miR-21 may induce cell cycle arrest and increased chemosensitivity to anticancer agents, providing evidence that miR-21 functions as an oncogene in human cancer. Increased expression levels of miR-21 were observed in tumours arising from diverse tissue types. This also includes tumours of haematological origin, such as chronic lymphatic leukaemia, diffuse large B cell lymphomas (DLBCLs), acute myeloid leukaemia and Hodgkin lymphomas. Recently, it has been shown that high levels of B cell activation were induced by miR-21 in circulating B cells and are seen in HIV-infected individual. Notably, miR-21 is overexpressed in activated B cells, suggesting its assistance in maintaining B cell hyperactivation, which plays a pivotal role in HIV-infected cells. Therefore, miR-21 can be considered as a powerful biomarker in HIV-related lymphomas. The number of studies related to the role of miR-21 in HIV-related lymphomas is sparse; therefore, this mini review highlights the recent publications related to clinical impact and significance of miR-21, specifically in HIV- and non-HIV-related lymphomas.

Nolen BM, Breen EC, Bream JH, et al.
Circulating mediators of inflammation and immune activation in AIDS-related non-hodgkin lymphoma.
PLoS One. 2014; 9(6):e99144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation.
METHODS: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays.
RESULTS: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers.
CONCLUSIONS: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.

Prospero Ponce CM, Al Zubidi N, Beaver HA, et al.
HIV and cannot see.
Surv Ophthalmol. 2014 Jul-Aug; 59(4):468-73 [PubMed] Related Publications
A 55-year-old HIV-positive man presented with acute vision loss in the right eye and altered mental status. Ophthalmic evaluation revealed light perception vision OD with a right relative afferent pupillary defect, conjunctival chemosis, large mutton-fat keratitic precipitates, and diffuse cream-colored vitreous cells. Magnetic resonance imaging of the brain and orbit with and without contrast with fat saturation showed choroidal thickening OD, multifocal deep periventricular and deep ganglionic enhancing lesions, and a suprasellar mass. Brain biopsy showed diffuse large B-cell lymphoma. Intrathecal chemotherapy with methotrexate and cytarabine and whole brain radiation therapy failed. His mental status deteriorated. He developed pancytopenia, neutropenic fever, and septic shock and subsequently expired under palliative care.

Hentrich M, Hoffmann C, Mosthaf F, et al.
Therapy of HIV-associated lymphoma-recommendations of the oncology working group of the German Study Group of Physicians in Private Practice Treating HIV-Infected Patients (DAGNÄ), in cooperation with the German AIDS Society (DAIG).
Ann Hematol. 2014; 93(6):913-21 [PubMed] Related Publications
AIDS-related aggressive B cell lymphoma (HIV-NHL) is the second most common HIV-associated malignancy. In contrast, Hodgkin-lymphoma (HL) is one of the most common non-AIDS-defining malignancies. Current evidence-based recommendations for the treatment of HIV-associated lymphoma (HIV-lymphoma) are not available. A panel of experts in the field of HIV-related lymphoma performed literature searches of the PubMed, Medline, and Cochrane databases. The consensus process was carried out as an e-mail and meeting-based discussion group. Six cycles of R-CHOP or R-EPOCH are standard of care for patients (pts) with diffuse large B cell lymphoma (DLBCL). Pts with Burkitt lymphoma and good performance status should receive dose-intensive regimens such as the GMALL B-ALL/NHL protocol. Standard therapy has not been defined for pts with plasmablastic and primary effusion lymphoma. Pts with lymphoma in sensitive relapse should receive high-dose chemotherapy followed by autologous stem cell transplantation. Stage- and risk adapted treatment yields high remission and survival rates in pts with HIV-HL similar to those achieved in HIV-negative HL pts. Combination antiretroviral therapy (cART) should be applied concurrently to chemotherapy provided that pharmacokinetic interactions are being considered. Pts with HIV-lymphoma should usually be treated in an identical manner to HIV-negative patients.

Maso LD, Suligoi B, Franceschi S, et al.
Survival after cancer in Italian persons with AIDS, 1986-2005: a population-based estimation.
J Acquir Immune Defic Syndr. 2014; 66(4):428-35 [PubMed] Related Publications
BACKGROUND: Cancer survival in persons with AIDS (PWA) after introduction of antiretroviral therapies remains poorly characterized. The aim is to provide population-based estimates of cancer survival, overall and for the most important cancer types in PWA, and a comparison with persons without AIDS (non-PWA) affected by the same cancer.
METHODS: PWA with cancer at AIDS diagnosis or thereafter were individually matched with non-PWA by type of cancer, sex, age, year of diagnosis, area of living, and, for lymphomas, histological subtype. Five-year observed survival and hazard ratios (HRs) of death in PWA versus non-PWA with 95% confidence intervals (CIs) were estimated.
RESULTS: We included 2262 Italian PWA and 4602 non-PWA with cancer diagnosed during 1986-2005. Between 1986 and 1995, and 1996 and 2005, 5-year survival for all cancers in PWA improved from 12% to 41% and the corresponding HR versus non-PWA decreased from 5.1 (95% CI: 4.3 to 6.1) to 2.9 (95% CI: 2.6 to 3.3). During 1996-2005, HRs were 2.0 (95% CI: 1.4 to 2.9) for Kaposi sarcoma, 3.4 (95% CI: 2.9 to 4.1) for non-Hodgkin lymphoma, and 2.4 (95% CI: 1.4 to 4.0) for cervical cancer. HRs were 2.5 (95% CI: 2.1 to 3.1) for all non-AIDS-defining cancers, 5.9 (95% CI: 3.1 to 11.2) for Hodgkin lymphoma, and 7.3 (95% CI: 2.8 to 19.2) for nonmelanoma skin cancer. A ≤3-fold survival difference was found for cancers of the stomach, liver, anus, lung, brain, and the most aggressive lymphoma subtypes.
CONCLUSIONS: The persisting, although narrowing, gap in cancer survival between PWA and non-PWA indicates the necessity of enhancing therapeutic approaches, so that PWA can be provided the same chances of survival observed in the general population, and improving cancer prevention and screening.

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