CD20-negative CD138-positive leukemic large cell lymphoma with plasmablastic differentiation with an IgH/MYC translocation in an HIV-positive patient.

A 49-year-old HIV-positive Japanese man was referred to our hospital for multiple skin nodules. Many plasmablastic atypical lymphocytes were observed in the peripheral blood. He was diagnosed with diffuse large B cell lymphoma (DLBCL) by a biopsy of the inguinal lymph node. IgH/MYC translocation was detected by in situ hybridization of the lymph node and chromosomal analysis of bone marrow cells showed 46, XY, t(8 ; 14)(q24 ; q32)add(14)(q32), der(21)t(1 ; 21)(q12 ; p11). He showed a transient response to multi-agent chemotherapy, and during the course of salvage chemotherapy, he died of urinary infection. This case has unique clinical features compared with previously reported DLBCLs with plasmablastic differentiation.

Plasmablastic lymphoma of the oral cavity in an HIV-positive child.

A 7-year-old boy with a positive history of vertical HIV transmission presented with a painful swelling over the left upper jaw of 20 days' duration. A provisional diagnosis of non-Hodgkin's lymphoma or embryonal rhabdomyosarcoma was made. Fine-needle aspiration cytology findings were inconclusive, and incisional biopsy tissue on routine stains gave an impression of small round cell tumor with plasmacytoid features. A series of histochemical stains and immunohistochemical studies was carried out to differentiate and characterize this tumor. The salient immunostaining was negativity with all routine small round cell tumor markers and positivity with CD138 and lambda light chain restriction. The heterogeneous presentation of plasmablastic lymphoma as a variant of diffuse large B-cell lymphoma and its histogenesis is documented. Potential pitfalls and differential characterization of AIDS-plasmablastic lymphoma from other closely related tumors are addressed. The importance of excluding other common pediatric small round cell tumors by immunohistochemistry is highlighted. To the best of our knowledge, this is the first report of this entity in a vertically transmitted HIV-positive child.

Plasmablastic lymphoma in HIV+ patients: an expanding spectrum.

AIM: To describe an unusual human immunodeficiency virus (HIV)-associated lymphoma in uncommon sites. Plasmablastic lymphoma is a distinctive HIV-associated tumour that was first described in the jaws and oral cavity. Only two cases (stomach and lung) have been documented in extra-oral sites. MATERIALS AND METHODS: Four cases were encountered in HIV+ patients: three in the anorectal region and one which was nasal and paranasal. The cases were routinely processed and immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue. RESULTS: The cases showed the typical morphological appearances of a high-grade, blastic non-Hodgkin's lymphoma (brisk mitotic activity and tingible body macrophages). In addition, some cells had a plasmacytoid appearance and paranuclear clearing. Immunophenotypically, the tumour cells were negative for LCA, CD20 and CD45RA. However, a small proportion of cells (5%) were immunoreactive for CD79a and the majority were positive with VS38c, indicative of plasma cell differentiation. Kappa light chain and IgG heavy chain restriction was also detected. CONCLUSIONS: Plasmablastic lymphoma may occur in extra-oral sites and has a characteristic immunophenotype including focal expression of CD31 by the neoplastic cells. Awareness of the absence of expression of conventional B-cell markers and its presence in unusual sites should facilitate the diagnosis of plasmablastic lymphoma in HIV+ patients.

Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappa B.

The survival of viral mediated lymphomas depends upon constitutive nuclear factor kappa B (NF-kappaB) activity. AIDS-related human herpesvirus type 8-associated primary effusion lymphoma (PEL) responds poorly to chemotherapy and is almost invariably fatal. We have previously demonstrated that the antiviral combination of interferon alpha (IFN-alpha) and azidothymidine (AZT) induces apoptosis in PEL cell lines. We therefore used these agents as therapy for an AIDS patient with PEL. The patient had a dramatic response, with complete resolution of his malignant effusion in 5 days. In PEL cells, the death receptor ligand known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is markedly up-regulated by IFN-alpha; however, signals transduced by death receptors may also activate an antiapoptotic response mediated by NF-kappaB. In both the primary tumor cells from our patient and PEL cell lines, AZT selectively blocked nuclear entry of the NF-kappaB heterodimer p50 and p65, an effect not seen with other nonthymidine antiviral nucleosides. AZT monophosphate, the principal intracellular metabolite, inhibited phosphorylation and degradation of IkappaB by the IkappaB kinase complex. AZT- and IFN-alpha-mediated apoptosis was blocked by expression and nuclear localization of an IkappaB-resistant form of NF-kappaB (the p50 subunit linked to the transactivation domain of herpes simplex virus VP16). The proapoptotic effect of AZT and IFN-alpha in PEL occurs through the concomitant activation of TRAIL and blockade of NF-kappaB and represents a novel antiviral therapy for a virally mediated tumor.

Fine-needle aspiration cytology of a case of HIV-associated anaplastic myeloma.

Plasma cell neoplasia occurs much less frequently than high-grade B-cell non-Hodgkins lymphoma in HIV-infected patients, but is nevertheless an AIDS-associated malignancy. In this report, we describe the fine-needle aspiration (FNA) findings of a mass in the left parotid region with plasmablastic features that occurred in a 41-yr-old HIV-infected homosexual man whom we diagnosed as having anaplastic myeloma. The patient had normochromic, normocytic anemia with a hematocrit of 21%, a white blood count of 2.2 x 10(9)/l with 76% neutrophils, and a CD4 count of 31%. He also had elevated levels of calcium (13.2 mg/dl), alkaline phosphatase (25,400 IU/l), blood urea nitrogen (2,600 mg/dl), and creatinine (2.5 mg/dl). Serum protein electrophoresis showed polyclonal hypergammaglobulinemia without any monoclonal component. A bone survey revealed multiple punched-out lytic lesions. FNA smears showed large plasmacytoid cells with eccentrically placed nuclei, prominent nucleoli, and moderate amounts of basophilic cytoplasm. By immunocytochemical staining, tumor cells were negative for CD19, CD20, and leukocyte-common antigen (LCA), but strongly positive for CD38 and kappa light chain. Anaplastic myeloma and plasmablastic lymphoma were considered in the differential diagnosis. Although the cytomorphologic and immunophenotypic findings of our case overlapped with those of plasmablastic lymphoma, the pattern of bone involvement with punched-out lytic lesions and absence of localization of the tumor to the mucosa of the oral cavity led us to a diagnosis of anaplastic myeloma. The patient initially received antiretroviral therapy followed by thalidomide and pulse dexamethasome therapy, but his response was poor. His HIV load increased, and his malignancy rapidly progressed with the development of multiple vertebral lesions, extraosseous extension, and eventually cord compression. He died of the disease less than 2 mo after presentation.

Systemic non-Hodgkin's lymphoma with optic nerve infiltration in a patient with AIDS.

PURPOSE: To report the clinicopathologic features of a patient with AIDS and clinically regressed systemic non-Hodgkin's lymphoma who subsequently developed lymphomatous infiltration of the optic nerve and occlusion of the central retinal vein in both eyes. METHODS: The eyes of this patient were examined ophthalmologically and by fluorescein angiography. The eyes, brain, and body were obtained after death and studied by light microscopy. RESULTS: Ophthalmic examination and fluorescein angiography revealed optic nerve swelling and central retinal vein occlusion first in the left eye and shortly thereafter in the right eye. Postmortem histopathologic examination showed dense infiltration of both optic nerves by lymphoma as well as necrotizing vasculitis involving the retinal vessels near the left optic nerve head. Examination of the brain revealed lymphomatous involvement in the paraventricular region with associated necrosis and inflammation. No bone marrow recurrence or other residual systemic lymphoma was present. CONCLUSION: This case demonstrates that infiltrative optic neuropathy may occur as the sole ocular manifestation of disease recurrence in a patient with systemic non-Hodgkin's lymphoma otherwise thought to be in clinical remission.

Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders.

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma. To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied. To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells. Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions. (Blood. 2001;97:2130-2136)

Anaplastic large cell lymphoma (CD 30+), T-phenotype, in the heart of an HIV-positive man.

Non-Hodgkin's lymphomas described in patients with HIV-infection are most often high-grade B-cell lymphomas. Anaplastic large cell lymphoma (CD 30+) has been described in a minority of immunocompromised patients. Although sporadic reports of T-cell lymphomas associated with HIV infection are found in the literature, they have not been described to occur in the myocardium. We present a case of anaplastic large cell lymphoma (CD 30+), T-phenotype involving the heart in a 42-year-old HIV-positive patient.

Molecular profile of Epstein-Barr virus infection in HHV-8-positive primary effusion lymphoma.

Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants. A wild-type LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) individual PEL cases consistently harbor a single EBV strain; (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases; (3) no specific EBV genotype preferentially associates with PEL.

Human herpesvirus 8-associated solid lymphomas that occur in AIDS patients take anaplastic large cell morphology.

Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is a recently isolated human herpesvirus frequently identified in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Here we report three cases of HHV-8-bearing solid lymphomas that occurred in AIDS patients (Cases 1-3). All three patients were homosexual men presenting extranodal masses in the lungs (Case 1) or skin (Cases 2 and 3), together with the presence of Kaposi's sarcoma (Case 1), primary effusion lymphoma (Case 2), or multicentric Castleman's disease (Case 3). These solid lymphomas exhibited anaplastic large cell morphology and expressed CD30, corresponding to the recent diagnostic criteria of anaplastic large cell lymphoma (ALCL). The chromosomal translocation t(2;5)-associated chimeric protein p80NPM/ALK was not observed in any of these cases. HHV-8 was detected in all of these cases by polymerase chain reaction, immunohistochemistry of HHV-8-encoded ORF73 protein, and in situ hybridization of T1.1. Epstein-Barr virus was detected only in Cases 2 and 3 by in situ hybridization. It is interesting that inoculation of a cell line obtained from a primary effusion lymphoma cell in Case 2 to severe combined immunodeficiency mice produced HHV-8-positive and Epstein-Barr virus-negative tumors in inoculated sites. These tumor cells exhibited phenotypes of ALCL that were identical to the subcutaneous tumor cells of this particular patient. These findings clearly show that HHV-8 can associate with solid lymphomas and that it can take anaplastic large cell morphology. Those lymphomas should be distinguished from the classical ALCL as were defined by the revised European-American classification of lymphoid neoplasms even though morphology and a part of immunophenotype mimic that of classical ALCL.

True histiocytic lymphoma of the esophagus in an HIV-positive patient: an ultrastructural study.

A 56-year-old white woman, seropositive for human immunodeficiency virus for 18 months without signs of acquired immunodeficiency syndrome, presented with retrosternal pain and progressive dysphagia secondary to an exophytic esophageal mass. Biopsies of the tumor showed a malignant neoplasm composed of pleomorphic, noncohesive cells growing in a diffuse, sheet-like fashion. Immunohistochemically, tumor cells were nonreactive with epithelial, lymphoid, neural, and monocyte/macrophage markers. Despite the noncontributory immunohistochemical findings, ultrastructural study of the tumor cells revealed convincing histiocytic features. Individual cells possessed long, slender filopodial projections, prominent Golgi apparatus, residual bodies, rare lysosomes, and prelysosomes. Immunoglobulin heavy chain and T-cell receptor gamma gene rearrangement studies detected no evidence of a clonal gene rearrangement. The patient responded poorly to chemotherapy and died 5 months after her initial symptom of dysphagia.

Apoptosis-associated proteins in oral lymphomas from HIV-positive patients.

Extranodal oral lymphomas, seen with increasing frequency in HIV infection, may have dysfunctional apoptotic mechanisms that favor tumor progression. The purpose of this study was to evaluate extranodal lymphomas from HIV-positive patients for expression of apoptosis-associated proteins. Correlations were made with 10 histologically comparable extranodal lymphomas from HIV-negative patients and 6 hyperplastic lymph nodes from otherwise healthy young adults. Formalin-fixed tissue sections were immunohistochemically stained for apoptosis-associated proteins (Bcl-2, Bcl-x, Bax, Bak, p53, MDM2, BHRF). In situ hybridization was also done on deparaffinized sections for Epstein-Barr virus EBER mRNA. Eighteen consecutive oral lymphomas were studied in HIV/AIDS-positive patients. Four of 5 intermediate-grade lymphomas expressed Bcl-2 to a greater degree than did high-grade lymphomas (4 of 13). Most lymphomas were positive for Bcl-x and Bax, and few expressed Bak. The staining patterns for these proteins were similar to those seen in HIV-negative patients. Staining patterns were relatively consistent in the hyperplastic lymph nodes, whereas such patterns were irregular in lymphomas. Positive p53 staining was seen in 11 of 18 HIV-positive cases; 9 of these were also MDM2-positive. Double stains suggested that both p53 and MDM2 proteins were expressed in the same cells in these nine cases. Epstein-Barr virus-EBER mRNA was detected in 14 of 18 cases and in 3 of 10 cases from HIV-negative patients. BHRF staining was evident in only a few cells of three HIV-positive lymphomas. The irregular expression of Bcl-2, Bcl-x, Bax, and Bak in oral lymphomas indicates dysfunctional apoptotic mechanisms in these tumors. Bcl-2 staining differs with tumor grade. Positive staining for p53 and MDM2 proteins is a notable feature of lymphomas in HIV-positive patients and may relate to binding of MDM2 to wild-type p53. Epstein-Barr virus is more commonly associated with oral lymphomas in HIV-positive patients, although the Epstein-Barr virus-produced protein BHRF, which has Bcl-2-like activity, is minimally expressed.

Molecular and pathologic characterization of an AIDS-related body cavity-based lymphoma, including ultrastructural demonstration of human herpesvirus-8: a case report.

Body cavity-based lymphoma, also known as primary effusion lymphoma, is a newly recognized acquired immunodeficiency syndrome (AIDS)-related lymphoma that has been linked to the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). To date, direct visualization of the virus in a clinical sample has not been demonstrated. We have performed an extensive clinical, histologic, immunophenotypic, ultrastructural, and molecular genetic correlative study on multiple tissue samples obtained premortem and at autopsy from an patient with AIDS with Kaposi's sarcoma and body cavity-based lymphomas. We demonstrate the presence of human herpesvirus-8 in a primary clinical sample at the ultrastructural and molecular level, as well as document multiple lymphomatous tumor masses at autopsy.

Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.

This study was aimed at defining the histogenesis of the pathologic spectrum of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHL), including AIDS-related small noncleaved cell lymphoma (AIDS-SNCCL), AIDS-related large noncleaved cell lymphoma (AIDS-LNCCL), AIDS-related large cell immunoblastic lymphoma plasmacytoid (AIDS-IBLP), and AIDS-related primary effusion lymphoma (AIDS-PEL). Forty-six cases of AIDS-NHL were investigated for the expression pattern of BCL-6, a protein specifically expressed by germinal center (GC) B-cells, and CD138/syndecan-1 (syn-1), a marker of post-GC B-cell differentiation. Expression of BCL-6 and syn-1 segregated two major phenotypic patterns among AIDS-NHL: (1) the BCL-6+/syn-1- pattern associated with AIDS-SNCCL and AIDS-LNCCL; (2) the BCL-6-/syn-1+ pattern associated with AIDS-IBLP and AIDS-PEL. Among systemic AIDS-NHL infected by Epstein-Barr virus (EBV), expression of the EBV-encoded latent membrane protein-1 (LMP-1) preferentially associated with the BCL-6-/syn-1+ profile. Analysis of nonneoplastic lymph nodes showed that the two phenotypic patterns detected in AIDS-NHL correspond to physiologic stages of B-cell development, i.e., GC B-cells (BCL-6+/syn-1-) and preterminally differentiated post-GC B-cells (BCL-6-/syn-1+). Thus, BCL-6+/syn-1- AIDS-NHL reflects a GC stage of differentiation, whereas AIDS-NHL which are BCL-6-/syn-1+, and LMP-1+ when infected by EBV, derive from B cells that have entered post-GC plasmacell differentiation. These findings are relevant for the pathogenesis and differential diagnosis of AIDS-NHL.

Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection.

We report here a series of 16 highly malignant diffuse large B-cell lymphomas of the oral cavity with unique immunohistologic features. Fifteen of these developed in human immunodeficiency virus-positive patients. All cases displayed morphologic features of diffuse large-cell lymphomas but strikingly differed from them in that they showed a minimal or absent expression of the leukocyte common antigen as well as of the B-cell antigen CD20. Instead, the tumor cells showed a constant reaction with the plasma cell characteristic antibody VS38c and a frequent reaction with the CD79a antibody. This, in conjunction with a variable expression of cytoplasmic Ig and a monoclonal rearrangement of the Ig heavy chain gene in all of the three tested cases confirmed the B-cell nature, the clonal origin, and the plasmacellular differentiation of these neoplasms. The majority of these tumors were negative for the BCL-6 protein, with the remaining cases showing only a partial and weak expression of this antigen. An association with the Epstein-Barr virus (EBV) was found in 9 of 15 tested cases showing abundant EBV-encoded nuclear RNA transcripts in the absence of EBNA-2. Five of the EBV-positive cases variably expressed LMP-1. We propose to name these tumors plasmablastic lymphomas, in accordance with their morphologic and immunohistologic features. Knowledge of this lymphoma entity is important to avoid confusion with nonlymphoid malignancies due to the lack of commonly used lymphoid markers.

In situ detection of PCR-amplified HIV-1 and EBV nucleic acids in hyperplastic lymph nodes and in AIDS-related lymphoma.

The purpose of this study was to determine the in situ distribution of PCR-amplified HIV-1 and EBV DNA in hyperplastic lymph nodes and in AIDS-related lymphomas. PCR amplified HIV-1 DNA was detected, on average, in about 30% and 20% of the CD4 and CD21 dendritic cells, respectively, in and around the expanded germinal centers of hyperplastic lymph nodes in seropositive, asymptomatic people. PCR-amplified EBV DNA was noted, on average, in about 20% of L26 B-cells. The amplified HIV-1 DNA was noted in rare non-neoplastic cells in five AIDS-related lymphomas; the other three cases were negative for the viral DNA. Amplified EBV DNA was detected in five of eight lymphomas but in only three of these tissues did the viral DNA localize to the malignant cells. We conclude that although many cells in hyperplastic lymph nodes from people with early HIV-1 infection contain HIV-1 and EBV DNA, these viruses are of ten absent in the malignant cells of AIDS-related lymphoma. This suggests that although infection by these viruses and the concomitant lymphoid hyperplasia may predispose to lymphoma, the viruses are not required for maintenance of the malignant phenotype.