A 30-year-old female with a body

Figure 1. Gingival lesion identified at the initial diagnosis of HIV infection.

Laboratory examinations revealed pancytopenia (white blood cell count 1.60 × 103/ìL, neutrophils 59.4%, lymphocytes 29.1%, monocytes 11.5%, red blood cell count 2.9 × 106/ìL, hemoglobin 8.4 g/dL, hematocrit 26.2%, and platelet 63 × 103/ìL), elevated lactic dehydrogenase 593 IU/L (normal range 225-450) and elevated gamma globulins 32.7% (normal range 11-22%). Electrolytes, liver function tests, creatinine, and urea were within normal limits. Her CD4 were 102 cells/ìl and HIV viral load 30,764 copies/ml. The patient was further investigated with CT scans of the chest, abdomen, and pelvis that did not show any abnormal findings. Highly active antiretroviral therapy (HAART) with zidovudine, lamivudine, and effavirenz as well as primary prophylaxis for opportunistic infections with atovaquone (she was allergic to cotrimoxazole) and azithromycin was initiated.

The histological and immunochemistry findings of the biopsy of the oral cavity mass showed plasmablastic lymphoma. The neoplastic infiltrate was diffuse with notable fibrosis. Focally, there were findings of ulceration and infiltration of the mucosa. The cell population consisted of large cells of the type of immunoblasts and plasmablasts while a small number of plasma cells were also present. An especially high proportion of cells undergoing mitosis was found. The immunochemistry testing showed that neoplastic cells were CD138+ (100%), EMA+ (40%), LCA+ (isolated cells), 4KB5+ (isolated cells), UCHL-1+ (isolated cells), L26-, CD79-, and CD10-. The proportion of cellular multiplication (staining with MIB-1 antibody) was especially high (~95% of the tumor cells).

The patient started to receive antineoplastic therapy 10 weeks after the initiation of antiretroviral therapy. She received two cycles of CHOP (cyclophosphamide, doxorubicin, vincristin, and prednizolone). Although a third cycle was planned to be administered, the continuing pancytopenia and a viral infection of the upper respiratory tract with fever (<38.7C) led to its postponement. Hematopoietic factors (granulocyte colony stimulating factor and erythropoietin) were administered to manage the pancytopenia although several transfusions were required over time. Virological examinations showed positive serology for adenovirus IgM (+), EBV-VCA IgG (+), EBNA (+), and parvovirus B19 IgG antibodies. Adenovirus IgM (+) antibodies and pancytopenia persisted and three 5-day cycles of intravenous gamma globulin were administered over an 8-week period when adenovirus IgM/IgG (+) antibodies were detected while zidovudine, which may cause anemia, was substituted to stavudine. By this time the pancytopenia showed signs of remission.

A gradual decrease in size of the oral lesion was noted after the second cycle of chemotherapy with CHOP, which led to the disappearance of the lesion 7 months after the initiation of the antineoplastic treatment. The patient was at this point concomitantly reporting to be in very good health condition and compliantly adhering to HAART and primary prophylaxis for opportunistic infections (OIs).

The initial viral load measurement at presentation was reduced from 30,764 to 9,800 and then to <50 copies/ml at consecutive three-monthly intervals which then remained, with the exception of a small bleep of 72 copies/ml at 33 months on HAART, to below detection levels at measurements over corresponding periods to date. The CD4 cells increased over this period to 438 cells/ìl, 61 months following the diagnosis and initiation of HAART [(Figure 2. Immunological (CD4 count/mm3) and virological (HIV viral load expressed in viral copies/ml, "0" value on the Y axis represents <50 viral copies/mL) parameters as well as main therapeutic regimens administered to the patient (EFV = efavirenz, 3-TC = lamivudine, AZT = zidovudine, D4T = stavudine, CHOP = cyclophoshamide, doxorubicin, vincristin, prednizolone)]. Primary prophylaxis for OIs was discontinued at six months after reaching and sustaining >200 CD4 cells/ìl.

The patient has achieved to date survival of 59 months and full remission of plasmablastic lymphoma while at the same time her clinical, virological and immunological parameters, display a picture fully compatible with an effective and sustained suppression of her HIV infection.

Teaching points

• Although 40% of all NHLs, in the general population, arise at extranodal sites, in only 3% of them the primary presentation is in the oral cavity [1-3]. However, among patients with lymphoma, those infected with HIV had lymphoma in the oral cavity five times more often than immunocompetent patients [4]. One third of these HIV patients with lymphoma in the oral cavity had the lymphoma type called plasmablastic lymphoma [4].
• Plasmablastic lymphoma derives from B-cells and is categorised as a subtype of diffuse large B-cell lymphoma (DLBCL). It is generally limited to the oral cavity at the time of diagnosis, although extension to distant sites frequently occurs at a later stage. Plasmablastic lymphoma is known to be rapidly progressive with the overall prognosis being significantly poor among HIV infected patients. The median survival of patients with the disease, that received combination chemotherapy and/or radiation therapy, is reported to be about 6 months. [5-9]. After the initiation of treating HIV infected patients with the highly active antiretroviral therapy (HAART) (year 1997), an increase of the median survival time has been noticed, in all HIV infected patients with DLBCL, from 8.3 to 43.2 months [10].
• In this report, we present the case of an HIV infected patient with plasmablastic lymphoma with prolonged survival (alive 60 months after the initial diagnosis and remains in complete remission) and review the available data regarding the diagnosis, clinical course, management, and outcome of patients with this type of lymphoma.
• The most noteworthy point of our case report is that our HIV infected patient has had a remarkably prolonged survival after the diagnosis of plasmablastic lymphoma of the oral cavity. Our patient attained a full clinical remission (CR) following a combination of HAART and two cycles of chemotherapy with CHOP, which started shortly after the initiation of HAART, and remains in continuous remission 61 months after the diagnosis of lymphoma.
• In 1984, a multicenter study described the clinical spectrum of NHLs in HIV infected patients [11]. Since 1985, the term "AIDS-related lymphomas" has been used in literature to describe specifically those NHLs that are presented in HIV infected patients. Although some cases of HIV-related Hodgkin's lymphoma have been reported [12,13], its increased incidence in conjunction with HIV is not yet considered to be clearly demonstrated [14]. Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types, consisting almost exclusively of B-cell tumors of aggressive type. These include: a) Diffuse large B-cell lymphoma (DLBCL), b) B-cell immunoblastic lymphoma and c) Small noncleaved lymphoma, either Burkitt or Burkitt-like [15].
• Plasmablastic lymphoma is considered as an HIV-related entity, representing a subtype of DLBCL. Histologically, AIDS-related plasmablastic lymphoma is composed of a monomorphic and cohesive pattern of plasmablasts with basophilic cytoplasm. Immunophenotypically, it fails to express the most common B-cell-associated surface antigens, whereas it consistently expresses high levels of plasmacell-associated markers, including VS38c and CD138/syndecan-1 [5].
• There is a reported in the literature predilection of plasmablastic lymphoma for the oral cavity [6], although few reports suggest contiguous gastrointestinal tract site localisation either as a primary site involvement or as a site for involvement in relapse episodes of PBL in a minority of cases [16,17]. All HIVAIDS plasmablastic lymphomas referred to in the bibliography seem to be clinically very aggressive and the prognosis appears to be poor with a median survival of 6 months [5-9].
• The outcome of lymphoma in HIV infected patients has been reported to be correlated with immunologic and virologic response to HAART [18,19]; our patient, in agreement with this observation, has had a prompt response to HAART and has sustained maximum virological suppression and continuous CD4 cell number restoration throughout her management and follow-up. It is suggested, that immune deficiency may confer an intrinsic resistance of lymphoma towards therapeutic agents. This is related to the higher tendency to lymphoma relapse in HIV-infection patients and thus to poor overall prognosis [4, 9].
• It is not yet known which is the most appropriate chemotherapy treatment regimen for patients with AIDS-related lymphoma. Delays in therapy and dose reductions are often necessary, and some investigators have suggested the use of lower-dose chemotherapeutic regimens. Since myelosuppression and opportunistic infections are the predominant toxic effects, effort has focused on combination chemotherapy with colony stimulating factors support and antiretroviral therapy. Less myelosuppression was seen when a 96-hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE) was combined with filgrastim (G-CSF) and didanosine (ddI) or highly active antiretroviral therapy (HAART) [20]. Both, modified-dose or full-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) can be safely given in combination with HAART [21-25]. We administered cyclophosphamide, vincristin, doxorubicin, and prednizolone (CHOP) in full dose, in two cycles, and have achieved full remission of the lymphoma. This chemotherapeutic regimen remains the treatment of choice in the management of plasmablastic lymphomas while the combination with HAART seems to confer an efficacy enhancement.
• The persistent adenovirus infection with IgM (+) serology and pancytopenia in our patient, which were established following the 2nd cycle of chemotherapy, were managed with the administration of iv gamma globulin and, granulocyte colony stimulating factor and erythropoietin respectively; it is not clear whether the adenovirus infection per se or the administration of iv gamma globulin for its management, played a role in the positive treatment outcome of this patient.
• According to recently conducted analysis of clinical data [9], we can advocate that sufficient immunologic and virologic control in HIV-patients with plasmablastic lymphoma, achieved by HAART, correlates with better response to chemotherapy and improved clinical outcomes, along with prolonged complete remission.
• Infection with the human immunodeficiency virus (HIV) dramatically increases the risk of development of lymphoma. According to the statistics provided by the Lymphoma Research Foundation of America (LRFA) approximately 25-30% of all patients with acquired immunodeficiency syndrome (AIDS) develop lymphoma, with the non-Hodgkin lymphoma (NHL) being more frequent than Hodgkin's lymphoma (HL) in a 4:1 rate.

Acknowledgement
This case was prepared for our website by Drs George Panos, Efthymia A. Karveli, and Ourania Nikolatou. We thank Dr. Theodora Papadaki, Department of Hemo-Pathology, Evangelismos Hospital, Athens, Greece, for reviewing the pathology slides and Dr. Anna Kouramba, Department of Hemophilia and Transfusion Medicine, Laiko General Hospital, Athens, Greece for her contribution in the care of the patient.

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