Immunoglobulin heavy-chain and/or light-chain rearrangement can be demonstrated in most cases of HIV+ lymphomas. Rearrangements for BCL6 and MYC are described in a minor fraction of DLBCL. In AIDS-associated Burkitt lymphoma, the structure of MYC rearrangements is similar to its non-HIV counterpart. In addition, TP53 mutations are relatively common (Ballerini et al. 1993). In contrast, PEL are negative for BCL2, BCL6, and MYC rearrangements, and no mutations in RAS or TP53 have been detected. Aberrant TCR rearrangements can be found in PEL (Raphael et al. 2008).

For the pathologist, the single most important information to be provided to is that the patient has HIV infection, because many morphological features in BL and DLBCL are shared by the tumor infiltrates in immunodeficient as well as in immunocompetent settings. BL in immunocompromised individuals may be more pleomorphic or demonstrate plasmacytoid differentiation. EBV infection in AIDS-associated DLBCL may be suspected by greater cellular pleomorphism, angioinvasive and angiodestructive growth, and – at times extensive – necrosis. In general, plasmablastic morphology in DLBCL should prompt examination of EBV examination, and DLBCL diagnosis in an effusion should prompt analysis for HHV8 LANA protein expression.

Patients should have a comprehensive medical history with attention paid to signs and symptoms of lymphoma and a detailed HIV history including prior opportunistic infections and history of HIV resistance, immune function, HIV viral control, and antiretroviral treatment. The physical examination should include a careful assessment of lymph node regions, the liver, and spleen. Relevant laboratory studies include a complete blood count, chemistry profile with lactate dehydrogenase (LDH) and uric acid levels, CD4 cell count, and HIV viral load. HIV and hepatitis B and C serologies should be assessed. A bone marrow aspirate and biopsy should be performed at initial diagnosis as involvement by lymphoma is found in up to 20 % of cases. Patients with aggressive B-cell lymphomas should have a lumbar puncture for analysis of cerebrospinal fluid by flow cytometry and cytology to check for leptomeningeal lymphoma (Hegde et al. 2005).

Imaging studies should include computed tomography (CT) scanning of the chest, abdomen, and pelvis. Radiographic evaluation of the head should also be performed preferably by magnetic resonance imaging (MRI). Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in HIV-negative aggressive lymphomas, but its role in HIV-associated lymphomas is very poorly studied at this point in time. One of the greatest limitations in using PET is that interpretation can be confounded by inflammation from HIV-associated nodal reactive hyperplasia, lipodystrophy, and infections (Dunleavy et al. 2010a, b). Prior experience evaluating FDG-PET in HIV-associated lymphoma is limited to small retrospective series where most scans were not predictive of remission.

The International Prognostic Index (IPI) is the standard prognostic assessment tool in HIV-negative DLBCL. Its applicability to HIV-associated DLBCL, however, is controversial. While in some studies using CHOP or R-CHOP, the IPI score has divided groups prognostically, this has not been the case with DA-EPOCH and in a recent study of short-course EPOCH-R (infusional etoposide, vincristine, and doxorubicin with prednisone, cyclophosphamide, and rituximab) in newly diagnosed HIV-associated DLBCL, the IPI did not predict PFS or OS (Dunleavy et al. 2010a; Ribera et al. 2008; Kaplan et al. 2005). The prognostic importance of CD4 cell count and immune function in HIV-associated DLBCL, neither of which are part of the IPI, are the most likely confounding variables. Patients with CD4 counts less than 100 cells/μL are at increased risk of serious opportunistic infections and death. Furthermore, as noted earlier, patients with severe immune suppression have a higher incidence of immunoblastic subtypes, most of which are of ABC derivation, and a poor outcome compared to patients with preserved immunity, where the GCB subtype is more common (Dunleavy et al. 2010a). Although a recently reported study from the AIDS Malignancy Consortium (AMC) did not find an association between the cell of origin and outcome in HIV-associated DLBCL, their analysis was retrospective and included patients treated with a variety of different regimens (Sparano et al. 2010; Chadburn et al. 2009; Dunleavy and Wilson 2010). Involvement of the CNS, which is increased in HIV-associated aggressive B-cell lymphomas, also confers an adverse prognosis.

The treatment of HIV-associated lymphoma has evolved over the last 30 years in line with improved control of HIV replication and preservation of immune function (Table 12.1).

In the pre-CART era, patients with HIV-associated lymphoma had poor outcomes with median survivals of 5–6 months. Because these outcomes were driven by both chemotherapy failure and infections, investigators have examined the effect of chemotherapy dose on survival. In one study, Kaplan and colleagues observed that higher doses of cyclophosphamide were associated with lower survival, suggesting that infections were a driving cause of death in these patients (Kaplan et al. 1989). In an attempt to reduce infectious deaths, the AIDS Malignancy Consortium (AMC) conducted a study of 192 untreated lymphoma patients randomly assigned to receive standard-dose m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) with granulocyte macrophage colony-stimulating factor (GM-CSF) support or low-dose m-BACOD without GM-CSF in an effort to reduce the toxicity of chemotherapy (Kaplan et al. 1997). Compared to full-dose therapy, reduced-dose treatment had a similar response rate (52 % versus 41 %, respectively) and median survival (6.8 versus 7.7 months, respectively) but lower hematological toxicity. This led the authors to conclude that lower dose chemotherapy was preferable in HIV-associated lymphoma. One shortcoming of the study was that although the authors controlled for the absolute CD4 cell count in the survival analysis, they did not include enough patients with high CD4 counts and, ultimately, could not support a definitive recommendation for this group where the benefit of full-dose chemotherapy on cure of the lymphoma may outweigh the infectious risks (Little et al. 2003). Importantly, before completion of this trial, a randomized multicenter study in HIV-negative aggressive lymphoma showed CHOP to be equally effective as m-BACOD and less toxic (Fisher et al. 1993). The better therapeutic index of CHOP led to its acceptance as a standard for HIV-associated lymphoma (Lim and Levine 2005).

The introduction of CART some 15 years ago has had a dramatic effect on the outcome of HIV-associated lymphomas with increases in median survival. While the reasons are multifactorial, they can be ultimately attributed to salutary effects of CART on immune function. Patients with preserved immune function have a lower risk of infectious complications, thereby enabling optimal chemotherapy administration, and as noted earlier, a more favorable tumor biology (Little et al. 2003; Fisher et al. 1993; Lim and Levine 2005; Carbone and Gloghini 2005). Interestingly, in one study that looked at risk-adapted intensive chemotherapy in 485 patients with AIDS-related lymphoma (ARL), CART was significantly associated with survival while the dose-intensity of CHOP-based therapy was not (Mounier et al. 2006).

Although the benefit of rituximab is well established in HIV-negative DLBCL, its role in HIV-associated DLBCL has been controversial (Coiffier et al. 2002). This debate stems from an AMC randomized phase III study of CHOP ± rituximab in HIV-associated aggressive lymphomas that found rituximab was associated with significantly more infectious deaths but only a trend in improved tumor control; based on this, the authors concluded that rituximab does not improve the clinical outcome of HIV-associated DLBCL (Kaplan et al. 2005). A retrospective analysis of 3 phase II trials from Italy, where patients received infusional cyclophosphamide, doxorubicin, and etoposide (CDE) with rituximab, also concluded that rituximab might increase infections (Spina et al. 2001, 2005). On closer evaluation of the AMC trial, however, the increased infectious deaths occurred primarily in patients with very low CD4 counts, and many patients received “maintenance” rituximab after chemotherapy, which has not been shown to be useful in HIV-negative DLBCL (Dunleavy et al. 2006).

Subsequent to the AMC study, a French group performed a phase II study of CHOP plus rituximab in HIV-associated NHL and the CR rate of 77 % and 2-year survival rate of 75 % suggested that rituximab was beneficial and could be given safely to this group of patients (Boue et al. 2006). To further address the controversy of rituximab, the AMC performed another randomized phase II study. At the time that this study was designed, the results of the EPOCH regimen in this population were very promising, and they randomized patients to receive concurrent versus sequential rituximab with EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and hydroxydaunorubicin) (Sparano et al. 2010; Chadburn et al. 2009; Dunleavy and Wilson 2010; Kaplan et al. 1989, 1997; Little et al. 2003). Importantly they found that concurrent rituximab was not associated with increased infectious deaths (Sparano et al. 2010; Chadburn et al. 2009; Dunleavy and Wilson 2010; Kaplan et al. 1989, 1997; Little et al. 2003). The study also examined if the CR rate with EPOCH-R was superior to CHOP ± rituximab, employing a predetermined retrospective analysis, and if concurrent versus sequential rituximab was more toxic and/or more effective. There was no difference in toxicity between the arms, and the authors rejected the null hypothesis of 50 % (associated with CHOP ± rituximab) in favor of 75 % CR for EPOCH with concurrent rituximab (p = 0.005; power 0.89) (Sparano et al. 2010). Based on this study, we consider it very unwise to omit rituximab from upfront therapy in HIV-associated lymphoma.

While one group demonstrated good efficacy with R-CHOP in a multicenter setting, it is concerning that 15 % of enrolled patients were not evaluable for response due to early events or lacking clinical and radiological evaluations (Boue et al. 2006). Though the AMC’s conclusions regarding EPOCH-R’s superiority over R-CHOP are based on a historical comparison, the dramatic differential outcome with these two regimens in a similar patient population suggests that EPOCH-R may be a superior regimen in this population. Whether or not there are subgroups of patients with HIV-associated DLBCL who may do as well with R-CHOP is unknown at this time and has not been studied prospectively.

Following on from the initial promising results with EPOCH, a second-generation EPOCH regimen termed short-course EPOCH-RR was developed (Dunleavy et al. 2010a). This approach is designed to address the dual challenge of achieving excellent tumor control while preserving immune integrity. While it was previously demonstrated that 6 cycles of DA-EPOCH is highly effective (PFS and OS of 73 and 60 % at 53 months) in HIV-associated lymphoma, with 5 years follow-up, the PFS and OS of SC-EPOCH-RR are 84 % and 68 %, respectively, and 79 % of patients only required 3 treatment cycles (Dunleavy et al. 2010a, b; Ribera et al. 2008; Sparano et al. 2010; Chadburn et al. 2009; Dunleavy and Wilson 2010; Kaplan et al. 1989, 1997, 2005; Little et al. 2003). Interestingly, with this approach, the clinical prognostic characteristics that make up the IPI and the IPI itself do not predict PFS or OS. Only tumor histogenesis is associated with lymphoma-specific outcome with 95 % of GCB versus 44 % of non-GCB DLBCL progression free at 5 years. Although, both EBV positivity of the tumor and low CD4 count at diagnosis are significantly associated with an inferior overall survival, they are not associated with lymphoma-specific outcome.

Though, following the advent of CART, there was a significant improvement in the outcome of HIV-associated DLBCL, this was not the case initially with HIV-associated Burkitt lymphoma, as reported in a retrospective series by Lim et al. (2005). This lack of improvement is likely explained by the widespread use of CHOP-based regimens, which have poor efficacy in BL (Dave et al. 2006; Bishop et al. 2000). While dose-intense regimens such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and CODOX-M-IVAC, with or without rituximab, have shown encouraging results in HIV-negative BL, they have not been studied too extensively in HIV-associated BL. One of the concerns with CODOX-M-IVAC is treatment-related toxicity in this population (Barnes et al. 2011; Cortes et al. 2002). In an attempt to reduce this, the AMC recently presented the results of a feasibility and toxicity study for HIV-associated BL and atypical BL and reported good overall survival rates with 65 % of patients completing treatment as per protocol (Noy et al. 2009).

Burkitt lymphoma highlights the necessity to balance treatment efficacy and toxicity by optimizing the therapeutic index, especially in patients who are immune suppressed and/or elderly. Based on its excellent activity in highly proliferative DLBCL and its favorable toxicity profile, EPOCH-R was studied in untreated BL and was highly effective (Dunleavy et al. 2011). The AMC also included several patients with BL or Burkitt-like lymphoma in their study of concurrent versus sequential EPOCH-R and reported high response rates in this group (Sparano et al. 2010).