A lymphomagenic role for HIV beyond immune suppression?

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.

Classification of AIDS-related lymphoma cases between 1987 and 2012 in Japan based on the WHO classification of lymphomas, fourth edition.

The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein-Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.

Expression of immunohistochemical markers in patients with AIDS-related lymphoma.

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.

Expression of immunohistochemical markers in patients with AIDS-related lymphoma

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 percent were diffuse large B-cell lymphomas (DLBCLs), 15 percent were Burkitt's lymphomas, 13 percent were plasmablastic lymphomas, 10 percent were high-grade lymphomas and 1 percent was follicular lymphoma. The positivity for each immunohistochemical marker in DLBCLs, Burkitt's lymphoma and plasmablastic lymphoma was respectively: CD20, 84 percent, 100 percent, and 0; CD10, 55 percent, 100 percent, and 0; Bcl-6, 45 percent, 80 percent, and 0; MUM-1, 41 percent, 20 percent, and 88 percent. A higher positivity of CD20 (84 percent x 56 percent, p = 0.01) was found in DLBCL compared to non-DLBCL; in Burkitt's lymphomas a higher positivity of CD10 (100 percent x 49 percent, p = 0.04) and Bcl-6 (80 percent x 39 percent, p = 0.035) were found compared to non-Burkitt's lymphomas. Germinal center (GC) profile was detected in 60 percent of DLBCLs. Our study suggests particular findings in ARL, as the most frequent phenotype was GC, different from HIV-negative patients.

Changing pattern of lymphoma subgroups at a tertiary academic complex in a high-prevalence HIV setting: a South African perspective.

BACKGROUND: HIV infection has been associated with an increased risk of non-Hodgkin lymphoma, particularly in the first world. Despite the high burden of HIV infection in sub-Saharan regions, published data on HIV and malignancies are sparse from these areas. MATERIALS AND METHODS: We recently published data on lymphomas diagnosed from January 2004 to December 2006, at a single center in Johannesburg, to serve as a baseline for long-term comparison during the period of highly active antiretroviral therapy rollout. We report a retrospective analysis of the follow-up data collected from January 2007 to December 2009 at the Johannesburg academic hospital complex (Gauteng, South Africa). RESULTS: There were 2225 new diagnoses of lymphoproliferative disorders made during 2007-2009 as compared with 1897 cases diagnosed during 2004-2006. A significant increase in both high-grade B-cell lymphomas and Hodgkin lymphoma was documented during 2007-2009. This was associated with a statistically significant increase in HIV prevalence in those tested (from 44.3% in 2004-2006 to 62.0% in 2007-2009). HIV-positive patients presented at a statistically significantly younger median age and showed a relative overrepresentation of females when compared with HIV-negative patients. HIV-positive patients were diagnosed at later stages of HIV infection when compared with patients in the first world. CONCLUSIONS: The pattern of lymphoma subtypes and the demographics of the patients diagnosed have altered in association with significantly increased HIV prevalence. These changes have important public health implications. In particular, scale-up and earlier access to highly active antiretroviral therapy is essential with continued monitoring as access to therapy improves.

Plasmablastic lymphomas with light chain restriction - plasmablastic extramedullary plasmacytomas?

BACKGROUND: It is diagnostically difficult to differentiate plasmablastic lymphomas (PBLs) from plasma cell neoplasms with plasmablastic differentiation. Plasmablastic lymphomas are currently classified as 'PBL of the oral mucosa' and 'PBL with plasmacytic differentiation'. METHODS: Forty-five cases of PBL were retrieved from the Departments of Oral Pathology of the Universities of Pretoria and Limpopo, South Africa. Clinical features and HIV status were recorded and each case was classified as 'PBL of the oral mucosa type' or as 'PBL with plasmacytic differentiation'. Immunohistochemistry included: CD45, CD3, CD20, CD79a, CD38, CD138, MUM1, Ki-67 and kappa and lambda light chains. Positivity was recorded based on the percentage of positive staining cells as focal (5-20%); intermediate (20-70%) or diffuse (>70%). In situ hybridization was performed for Epstein-Barr virus (EBV) and HHV-8. Results were recorded as positive or negative. RESULTS: All cases showed some degree of plasmacytic differentiation. All were negative for CD20 with reactive T cells detected with CD3. Diffuse and strong positive staining was found with Ki-67 and MUM1, but variable immunoreactivity was found with CD79a, CD45, CD38 and CD138. Twenty cases (47%) showed light chain restriction. Epstein-Barr virus was detected in 44/45 cases and HHV-8 in none. CONCLUSIONS: The morphological classification of PBLs is not valid as all cases showed some degree of plasmacytic differentiation. We propose that PBLs with light chain restriction be reclassified as 'plasmablastic extramedullary plasmacytomas' and managed accordingly. The rest represents true PBLs. The true nature of these neoplasms as an entity should be further investigated with molecular and genetic studies.

[AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8]. / Linfomas asociados con la infección por el virus de la inmunodeficiencia humana: subtipos histológicos y asociación con los virus de Epstein Barr y Herpes-8.

Non-Hodgkin lymphomas (NHL) of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV) infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL) diagnosed at the Histopathological Division of the Instituto de Investigaciones Hematológicas of the National Academy of Medicine. Five were females and 43 were males with a median of age of 37 years at the time of the diagnosis. Micrometer sections were prepared and stained with hematoxilin-eosin; immunohistochemical examination for the presence of Epstein-Barr virus (EBV) was carried out in 48/48 cases. Additionally, biotinilated oligonucleotides were used to determine the presence of DNA of the Human Herpes virus type-8 (HHV-8) in 14/14 biopsy smears corresponding to plasmablastic lymphomas (PL). All were fenotype B cell lymphomas with an aggressive course and advanced neoplasm disease at the time of diagnosis. Virological findings showed the strong association between EBV and AIDS-related NHL. According to the histopathological subtype, the EBV genome was detected in 16/21 (76%) diffuse large B cell lymphomas, 1/3 Burkitt lymphoma and 3/4 (75%) of primary central nervous system lymphomas. Globally, EBV genome was detected in 20/28 NHL of this series. Detection of HHV-8 was negative in all cases of PL. Hodgkin lymphoma were more frequent in males 18/20 (90%), with an aggressive clinical course and a significant predominance of the subtypes associated with worse prognosis (90% of cases). We detected a significant association between EBV and HL (90% of cases). We consider that all cases of AIDS related lymphomas should be assessed for the presence of EBV because its presence may play a role in the prognosis.

Linfomas asociados con la infección por el virus de la inmunodeficiencia humana: subtipos histológicos y asociación con los virus de Epstein Barr y Herpes-8 / AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8

Los linfomas no Hodgkin (LNH) constituyen la segunda neoplasia definitoria de Sida más frecuente. En el presente trabajo se evaluaron 48 casos de linfomas asociados con la enfermedad debida al virus de la inmunodeficiencia humana (HIV) diagnosticados en la División Histopatología del Instituto de Investigaciones Hematológicas de la Academia Nacional de Medicina. Se incluyeron en la investigación 5 mujeres y 43 hombres con una mediana de edad al momento del diagnóstico de la neoplasia de 37 años. La evaluación morfológica se realizó en cortes coloreados con hematoxilina-eosina, estudio inmunohistoquímico para la detección del virus de Epstein Barr (VEB) en 48/48 casos, y mediante sonda oligonucleotídica biotinilada para la detección del ADN del Herpes virus humano tipo-8 (HHV-8) en 14/14 linfomas plasmoblásticos (LP). Todos fueron linfomas de fenotipo B, con un curso clínico agresivo y enfermedad neoplásica avanzada al momento del diagnóstico. Se pudo demostrar la fuerte asociación del VEB con los linfomas asociados al sida, con frecuencias que variaron según el subtipo histológico: 16/21 (76%) para los linfomas difusos de grandes células; 1/3 casos (33%) de linfomas de Burkitt y 3/4 (75%) en los linfomas primarios del sistema nervioso central. Globalmente, el genoma del VEB se detectó en 20/28 (71%) de las muestras de biopsias de LNH de esta serie. La detección del HHV-8 resultó negativa en los 14 LP. Los linfomas de Hodgkin fueron más frecuentes en varones,18/20 (90%), con un curso clínico agresivo y franco predominio de los subtipos histológicos de peor pronóstico (90% de casos). En estas neoplasias también se comprobó una frecuente asociación patogénica con el VEB (90% de casos).

Non-Hodgkin lymphomas (NHL) of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV) infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL) diagnosed at the Histopathological Division of the Instituto de Investigaciones Hematológicas of the National Academy of Medicine. Five were females and 43 were males with a median of age of 37 years at the time of the diagnosis. Micrometer sections were prepared and stained with hematoxilin-eosin; immunohistochemical examination for the presence of Epstein-Barr virus (EBV) was carried out in 48/48 cases. Additionally, biotinilated oligonucleotides were used to determine the presence of DNA of the Human Herpes virus type-8 (HHV-8) in 14/14 biopsy smears corresponding to plasmablastic lymphomas (PL). All were fenotype B cell lymphomas with an aggressive course and advanced neoplasm disease at the time of diagnosis. Virological findings showed the strong association between EBV and AIDS-related NHL. According to the histopathological subtype, the EBV genome was detected in 16/21 (76%) diffuse large B cell lymphomas, 1/3 Burkitt lymphoma and 3/4 (75%) of primary central nervous system lymphomas. Globally, EBV genome was detected in 20/28 NHL of this series. Detection of HHV-8 was negative in all cases of PL. Hodgkin lymphoma were more frequent in males 18/20 (90%), with an aggressive clinical course and a significant predominance of the subtypes associated with worse prognosis (90% of cases). We detected a significant association between EBV and HL (90% of cases). We consider that all cases of AIDS related lymphomas should be assessed for the presence of EBV because its presence may play a role in the prognosis.

AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy.

We aimed to compare AIDS risk-adapted intensive chemotherapy in AIDS-related lymphoma (ARL) patients before and after the advent of highly active antiretroviral therapy (HAART). A total of 485 patients aged from 18 to 67 years were randomly assigned to chemotherapy after stratification according to an HIV score based on performance status, prior AIDS, and CD4(+) cell counts below 0.10 x 10(9)/L (100/mm(3)). A total of 218 good-risk patients (HIV score 0) received ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone) or CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisolone); 177 intermediate-risk patients (HIV score 1), CHOP or low-dose CHOP (Ld-CHOP); and 90 poor-risk patients (HIV score 2-3), Ld-CHOP or VS (vincristine and steroid). The 5-year overall survival (OS) in the good-risk group was 51% for ACVBP versus 47% for CHOP (P = .85); in the intermediate-risk group, 28% for CHOP versus 24% for Ld-CHOP (P = .19); and in the poor-risk group, 11% for Ld-CHOP versus 3% for VS (P = .14). The time-dependent Cox model demonstrated that the only significant factors for OS were HAART (relative risk [RR] 1.6, P < .001), HIV score (RR 1.7, P < .001), and the International Prognostic Index (IPI) score (RR 1.5, P < .001) but not chemotherapy regimen. Our findings indicate that in ARL patients, HIV score, IPI score, and HAART affect survival but not the intensity of the CHOP-based chemotherapy.

Analysis of 1983 cases of malignant lymphoma in Thailand according to the World Health Organization classification.

Studying a large series of malignant lymphoma is important to increasing our understanding of this disease. Based on the World Health Organization classification system, 1983 cases of lymphoma at Siriraj Hospital were classified as either non-Hodgkin lymphoma (NHL) (92.1%) or Hodgkin lymphoma (HL) (7.9%). The NHL cases were 75% B cell type and 25% T cell type. Diffuse large B-cell lymphoma, unspecified peripheral T-cell lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma, precursor T lymphoblastic lymphoma, and Burkitt lymphoma accounted for 84.3% of all NHL cases found. Mixed cellularity and nodular sclerosis types constituted 77.7% of the HL cases found. An overall male preponderance was observed, but sex distribution differed among various types of lymphoma, and a female preponderance was observed in the elderly subjects. Changes in the frequency of B-cell NHL by age were characteristic: <50% in the first decade of life, a further decrease in the second decade, >60% in the third decade, and increases thereafter, reaching 90% after the seventh decade. High frequency of follicular lymphoma in Bangkok but low frequency in the Northeastern region and high frequency of HL in the Southern region were significant (P <0.05). Extranodal involvement was observed in 58.7% of NHLs, commonly affecting the upper aerodigestive tract and gastrointestinal tract, with some differences in geographical distribution. Higher frequencies of T-cell NHLs involving extranodal sites and of B-cell NHLs involving lymph nodes were significant (P <0.05). The distribution of various types of lymphoma and comparison with other large series of lymphoma further demonstrates the heterogeneity of this disease.

Epidemiology of AIDS-related malignancies an international perspective.

Patients with HIV infection are at increased risk for developing Kaposi's sarcoma, non-Hodgkin's lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population--lung, breast, colon/rectum, stomach, liver, and prostate--are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkin's lymphoma, cervical carcinoma in situ (CIS), other anogenital neoplasms (invasive cancer and CIS), leiomyosarcoma, and conjunctival squamous cell carcinoma. There is inconclusive evidence, however, with regard to HIV infection being associated with invasive cervical cancer, testicular seminoma, or hepatocellular carcinoma. Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk.

Biology and management of AIDS-associated non-Hodgkin's lymphoma.

The treatment of HIV-related lymphomas is evolving in the era of HAART. Standard-dose chemotherapy and dose-intensive therapies appear to be feasible. Whether outcomes are improved with combination chemotherapy and HAART remains unclear. Efforts aimed at developing pathogenic-based therapies will continue as the mechanisms of HIV lymphomagenesis are elucidated.

[Lymphoma genesis in the context of HIV infection]. / Lymphomagenèse au cours de l'infection par le VIH.

The incidence of lymphomas is high among HIV infected patients. These lymphomas are non-Hodgkin's lymphoma (NHL) in 70% of cases and Hodgkin's disease (HD) in 30% of cases. Their localization is often extra-nodal with early dissemination. B-cell high grade NHL predominates. The most frequent histological types are diffuse large B-cell lymphoma (30 to 40%) and Burkitt's lymphoma (40 to 50%). Other histological types are low-grade B-cell lymphoma, polymorphic B cell lymphoma and primary effusion lymphoma. Three main factors are predominant in HIV-related lymphomagenesis: cellular immunodeficiency, oncogene viruses (Epstein-Barr and HHV8) and molecular lesions. HIV-related cellular immunodeficiency leads to the increase of EBV infected B-cells and to the diminution of antitumor immunity. Clonal EBV genome is found in lymphoma cells in 30 to 70% of cases of HIV-related NHL. It expresses oncogenic proteins including LMP-1 which behaves like an activated CD40. It induces the expression of intra-cellular genes which stimulate cell growth and inhibit apoptosis. Cytogenetic and molecular lesions are not specific to HIV-related NHL or to histological subtypes. A better knowledge of these mechanisms should lead to the development of specific targeted treatments (antiviral, cytotoxic anti-EBV lymphocytes, cell cycle regulators).