The World Health Organization classification of hematopoietic malignancies recognizes AIDS-associated lymphomas as a specific category to acknowledge the significant impact of HIV on the pathophysiology and prognosis of lymphomas [2
]. The pathogenetic mechanisms contributing to lymphoma genesis are complex and include chronic antigen stimulation, genetic abnormalities, cytokine dysregulation, and the role of herpes viruses: Epstein–Barr virus (EBV) and Kaposi Sarcoma Human Virus (KSHV, HHV8) [5
]. The overall survival of patients with HIV-related NHLs is inferior compared to HIV-negative patients, and in HIV, the majority of patients present with widespread disease and with higher risk for central nervous system involvement. The introduction of HAART extended the lifespan of AIDS patients and some studies indicated a decrease of the incidence of lymphomas in AIDS since widespread availability of HAART [6
]. The combination of HAART with aggressive chemotherapy, such as CHOP, not only is tolerable and effective treatment in patients with HIV and NHL but the initial good response to HAART is also associated with higher complete response rates to the chemotherapy (77% response to CHOP versus 50% in nonresponders) [7
]. The association between HIV and classical Hodgkin lymphoma is less clear, and, unexpectedly, the incidence of Hodgkin lymphoma in AIDS has increased since HAART was introduced [8
]. Of note, HIV-related Hodgkin lymphoma is associated with EBV in nearly all cases [9
], and it has been postulated that the EBV-encoded latent membrane protein (LMP1; which is functionally homologous to activated CD40), is essential to the antiapoptotic phenotype of the Reed–Sternberg cells, replacing the CD40/CD40 ligand interaction by CD4+ T cells, which are decreased in AIDS [10
Though diffuse large B cell lymphoma is one of the most common NHL associated with AIDS, there are virtually no data available about the association of HIV and PMLBCL. So far, only one case of PMLBCL has been described in the literature in the setting of AIDS [4
]. This patient, a 29-year-old woman with 12 years of history of HIV infection without prior AIDS-defining illness, presented with fever, night sweats, cough, and a CD4 count of 316/μL. HAART therapy was initiated but had to be discontinued within a few days due to development of Stevens–Johnson syndrome. Biopsies via mediastinotomy established the diagnosis of PMLBCL, with no evidence of extrathoracic disease upon staging. Chemotherapy with CHOP and granulocyte colony-stimulating factor was started; however, 6 days after the first cycle of treatment, the patient died from neutropenic sepsis.
In our current report, the clinical presentation in Case 1 is classical in terms that the patient is a young woman who presents with a mediastinal mass and her disease is localized to the mediastinum (Table summarizes the clinical findings of Cases 1 and 2 in comparison to the case reported by Milling et al.). This patient was known to have HIV but because she was pregnant, she only received AZT monotherapy and had very low CD4 T-cell count (152/μL) at diagnosis. In contrast, the clinical presentation of Case 2 is unusual in several aspects. The patient is a male and in addition to a large mediastinal mass, he has widespread disease at presentation. Similarly to Case 1, he did not receive HAART therapy prior to his presentation and his CD4 T-cell count was low (140/μL). Neither of the two patients had evidence of bone marrow or central nervous system involvement. The immunophenotype of the lymphoma cells of both cases is consistent with previously described phenotype of PMLBCL: CD45+, CD20+, CD23+, and partially CD30+. In Case 2, but not in Case 1, the lymphoma cells also express Bcl-6, a finding unusual but not excluding the diagnosis of PMLBCL. An important finding in Case 1 is the EBV positivity in approximately 30% of the lymphoma cells by EBER in situ hybridization. The role of EBV in the pathogenesis of PMLBCL in the immunocompetent host was previously dismissed. In one study, only two cases were positive for EBV of 41 PMLBCL cases [11
]; others reported complete absence of EBV [12
]. The previously reported case of PMLBCL in HIV-infected patient also was negative for EBV with EBER in situ hybridization [4
]. In our case, it is not clear as to what extent the EBV positivity contributes to lymphoma pathogenesis or represents EBV infection acquired during the course of disease. Yet, the finding of 30% EBER-positive lymphoma cells is likely to be clinically significant, since Park et al. recently reported that EBER positivity of 20% or more in lymphoma cells in DLBCL is associated with significantly poorer overall survival and progression-free survival compared to EBV-negative DLBCLs [13
]. In the immunocompromised, such as AIDS or post-transplant state, EBV infection even in a minority of lymphoma cells might have significant impact on disease pathogenesis and outcome. Since the molecular signature of PMLBCL resembles that of classical Hodgkin lymphoma [14
], EBV infection might contribute to an anti-apoptotic phenotype of the lymphoma cells with a similar mechanism as observed in HIV-associated Hodgkin lymphoma. In our patient with EBV-associated PMLBCL, despite the localized nature of the lymphoma, the tumor continued to progress during chemotherapy resulting in death of the patient after 5 months of diagnosis. Unlike Case 1, Case 2 responded well to a combination of HAART and chemotherapy and improved rapidly, despite widespread disease at diagnosis.
Comparison of the clinical features of Case 1, Case 2, and the case reported by Milling et al. 2004
In summary, though increased incidence of PMLBCL has not been established in AIDS due to the rarity of these cases, PMLBCL occurs in HIV and appears to present in the setting of low CD4 T-cell count as a rapidly growing mediastinal mass. A good response to a combination of HAART and chemotherapy can be obtained even in cases with widespread disease. More cases are necessary to characterize the relationship between PMLBCL and HIV and to determine the impact of EBV infection on disease pathogenesis and prognosis in the immunocompromised.