Non-Hodgkin Lymphoma
The incidence of NHL is 60 times higher in individuals with HIV infection than in the general population. The overall occurrence of lymphoma as a manifestation of AIDS has declined somewhat as treatment of HIV has improved.
Although NHL currently accounts for less than 5% of all initial AIDS-defining conditions, it accounts for as many as 28% of all AIDS-related deaths. The majority of patients present with advanced-stage, high- or intermediate-grade, B-cell lymphoma and have a high frequency of extranodal involvement. Primary CNS lymphoma occurs in approximately 0.5% of patients with AIDS.
The majority of patients with AIDS-related lymphoma have advanced HIV disease. Median CD4 cell counts in patients with systemic lymphoma range from 100/μL to 200/μL, although NHL can occur at any CD4 cell count.
Epidemiology
At-risk groups
NHL occurs with approximately equal frequency in all population groups infected by HIV, including intravenous drug users, homosexual-bisexual men, transfusion recipients, and patients with hemophilia.
Gender and race
AIDS-related NHL is seen more frequently in men than in women and occurs more often in whites than in blacks.
Age
The age distribution of AIDS-related NHL follows the distribution of HIV infection. Primary CNS lymphoma occurs with the same frequency in all age groups.
Geography
Current data do not indicate any geographic differences in the incidence of AIDS-related NHL.
Etiology and Risk Factors
AIDS-related NHL is believed to arise as a consequence of continued stimulation of B-cell proliferation as a result of HIV, Epstein-Barr virus (EBV), and other infections, all of which occur in the setting of profound T-cell immunodeficiency. An association between the polyomavirus, simian virus 40, and diffuse large B-cell and follicle-type lymphoma has been detected. HIV also induces the expression of a number of cytokines (eg, interleukin [IL]-6 and IL-10) that can further increase B-cell activation.
Small noncleaved lymphomas
Genetic errors are increased in the setting of chronic B-cell proliferation, and a variety of chromosomal translocations resulting in oncogene activation can lead to polyclonal and monoclonal B-cell expression. Other molecular biological abnormalities associated with small noncleaved lymphomas include expression of an abnormal TP53 (alias p53) tumor-suppressor gene and the c-myc or ras oncogene.
Immunoblastic lymphoma
The pathogenesis of AIDS-related immunoblastic lymphoma appears to be distinct from that of small noncleaved lymphoma and is more likely related to EBV infection without c-myc dysregulation. Clonal integration of EBV within tumor cells, with expression of various latent EBV proteins, has been demonstrated in essentially all cases of AIDS-related primary CNS lymphoma and in as many as two-thirds of systemic lymphomas.
Diffuse large cell lymphoma
The specific molecular aberrations described in patients with AIDS-related diffuse large cell lymphoma appear distinct as well, with recent descriptions of abnormal BCL6 expression in approximately 40% of cases.
Body cavity–based lymphoma/primary effusion lymphoma
This appears to be highly associated with HHV-8 and EBV. The tumor cells stain positive for CD45. The disease appears to occur predominantly in males and may coexist with KS in patients with AIDS.
Signs and Symptoms
B symptoms
These events (ie, fever, weight loss, and night sweats) are seen in approximately 80% of patients with systemic AIDS-related NHL. In these patients, it is mandatory to exclude the presence of occult opportunistic infections before ascribing B symptoms to the lymphoma itself.
Extranodal involvement
Advanced-stage disease is expected in the majority of patients, with extranodal involvement reported in 60% to 90% of patients in most series. Common sites of extranodal involvement include the CNS (occurring in approximately 30% of patients), GI tract (25%), and bone marrow (25%). Essentially any other site in the body can also be involved, including the rectum, soft tissue, oral cavity, lungs, and heart.
CNS lymphoma. Patients with primary CNS lymphoma often present with focal neurologic deficits, seizures, and/or altered mental status. Any site in the brain may be involved, and one to four space-occupying lesions are usually seen on magnetic resonance imaging (MRI) or computed tomography (CT) scan.
Other sites. Changes in bowel habits, GI bleeding, weight loss, pain, and hepatomegaly are common presenting symptoms in patients with GI involvement. Pancytopenia may indicate bone marrow involvement.
Primary effusion lymphoma. Patients usually present with pleural or pericardial effusion without an identifiable mass. Pain, shortness of breath, and B symptoms are the main initial complaints.
Screening and Diagnosis
Diagnosis of NHL in patients with AIDS requires histologic confirmation by biopsy with immunophenotypic and/or molecular gene-rearrangement studies.
Evaluation
A complete staging evaluation should be done. This should include:
• CT or MRI of the head
• Positron emission tomography/CT scan of whole body
• Bone marrow aspiration and biopsy
• Liver function studies
• Spinal fluid analysis
Assessing spinal fluid for EBV
The presence of EBV DNA in cerebrospinal fluid, as determined by polymerase chain reaction, appears to have a high specificity and sensitivity for the diagnosis of primary CNS lymphoma.
Pathology
Common tumor types
More than 95% of AIDS-related NHL cases are of B-lymphocyte origin. Most AIDS-related NHL tumors are high-grade types, including the immunoblastic and small noncleaved lymphomas. Diffuse large cell lymphoma constitutes up to 30% of AIDS lymphomas.
Less common tumor types
Although not considered part of the AIDS epidemic, several cases of T-cell lymphoma occurring in HIV-infected patients have been described. In addition, cases of Ki-1–positive, large cell anaplastic lymphoma and plasmablastic lymphoma have been reported in HIV-infected patients. The clinical and pathologic characteristics of these forms of lymphoma are similar to those seen in non–HIV-infected individuals.
CNS lymphomas
These are typically of the immunoblastic or large cell type.
GI and oral cavity lymphomas
Large cell or immunoblastic lymphomas are also more likely to involve the GI tract and oral cavity than are small noncleaved lymphomas.
Primary effusion lymphomas
The cells are large and pleomorphic with prominent nucleoli and immunoblastic morphology. Clonal immunoglobulin DNA rearrangement demonstrates clonality of the tumor cells but not surface immunoglobulin expression.
Staging and Prognosis
Staging system
Staging of AIDS-related NHL is the same as that for non–AIDS-related NHL. The Ann Arbor classification system for staging of NHL is used (see "Non-Hodgkin Lymphoma" chapter), and the staging workup includes imaging studies, as well as bone marrow and CNS evaluation for lymphomas.
Prognostic factors
Five factors have been shown to correlate most closely with a shorter survival in patients with systemic AIDS-related NHL:
• A history of opportunistic infection before the lymphoma
• CD4 cell count less than 100/μL
• International Prognostic Index score
• Karnofsky Performance Status (KPS) score less than 70
• Stage IV disease, especially if due to bone marrow or meningeal involvement
Chemotherapy for AIDS-related NHLIn patients without these findings, the median survival is typically 11 to 12 months, compared with a median survival of approximately 4 to 5 months in those with one or more of these adverse prognostic features.
Three factors correlate with better survival in patients with primary CNS lymphoma:
• KPS score greater than 70
• Age less than 35 years
• Adequate dose of radiation therapy
Type of lymphoma
To date, no major differences have been seen in response or survival among the various pathologic types of systemic AIDS-related NHL. Patients with polyclonal lymphomas appear to have better tumor responses to chemotherapy and better survival. Patients with primary CNS lymphoma have an extremely poor prognosis, with a median survival of only 2 to 3 months despite therapy; treatment with potent antiretroviral therapy does seem to improve survival. The prognosis for patients with primary effusion lymphoma is also poor, with a median survival of only 5 months.
Treatment
Systemic NHL
Chemotherapy. The mainstay of treatment for patients with systemic AIDS-related NHL is chemotherapy. Because the likelihood of tumor dissemination is great, AIDS patients who develop NHL must be assumed to have widespread disease at presentation and should be treated with systemic chemotherapy, even if tumor dissemination is not confirmed on routine staging evaluation.
Some of the commonly used regimens designed for AIDS-related NHL are listed in Table 3. No regimen appears to be superior to any other, although recent findings show that the EPOCH regimen (etoposide, prednisone(Drug information on prednisone), vincristine [Oncovin], cyclophosphamide(Drug information on cyclophosphamide), doxorubicin(Drug information on doxorubicin)) gives the best results to date.
CNS prophylaxis with either intrathecal cytarabine (50 mg) or intrathecal methotrexate(Drug information on methotrexate) (10 to 12 mg) every week for four treatments has been shown to be effective in reducing the incidence of CNS relapse.
The role of rituximab(Drug information on rituximab) in AIDS-related lymphoma is not clearly defined, given that it induces greater remissions but can cause more cellular and humoral immunodeficiency and may predispose to life-threatening infections. Prospective trials evaluating the use of rituximab in AIDS lymphoma have had mixed results. Given these data, clinicians should consider using rituximab in patients with CD20-positive NHL who have CD4 cell counts greater than 50/μL or using it in combination with multiple prophylactic antibiotics.
Dose intensity. Standard-dose chemotherapy (eg, cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) is generally recommended for most patients with AIDS-related NHL. Results from trials using continuous infusion therapy (eg, EPOCH or CDE [cyclophosphamide, doxorubicin, etoposide(Drug information on etoposide)]) have shown better CR rates and long disease progression-free and overall survival.
Certain subsets of patients with high CD4 cell counts (> 100/μL), no B symptoms, lower disease stage at presentation (stage I or II), and good performance status (0 or 1) may enjoy prolonged survival (> 2 years) when treated with either a standard-dose or intensive, high-dose regimen.
Growth factor and other support. The major dose-limiting toxic effect of multiagent chemotherapy regimens is myelosuppression. Studies of methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone(Drug information on dexamethasone) (m-BACOD) or CHOP chemotherapy demonstrated that coadministration of myeloid hematopoietic growth factors enhanced patient tolerance of these regimens. In addition, prophylaxis with trimethoprim(Drug information on trimethoprim)/sulfamethoxazole, azithromycin, fluconazole(Drug information on fluconazole), valganciclovir (Valcyte), and ciprofloxacin(Drug information on ciprofloxacin) can also reduce the risk of infection during intensive chemotherapy and rituximab.
Salvage chemotherapy. Patients in whom initial treatment fails or relapse occurs after initial remission rarely achieve a prolonged second remission. Studies of various salvage regimens with or without autologous stem cell support have demonstrated some early promising results.
Second-line chemotherapy (eg, etoposide, methylprednisolone(Drug information on methylprednisolone), high-dose cytarabine(Drug information on cytarabine), cisplatin(Drug information on cisplatin) [ESHAP]) has been shown to produce a CR of up to 31% and a PR of 23%, with a median survival of 7.1 months, in patients with refractory or relapsed AIDS-related NHL.
Sidebar: A pooled analysis of AIDS Malignancy Consortium trials evaluating rituximab plus CHOP versus rituximab plus EPOCH provided additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 cell count grreater than 50/μL (Barta SK et al: Cancer 118:3977-3983, 2012).
Radiation therapy. The role of radiotherapy in systemic lymphoma is limited to consolidation of the effects of chemotherapy. Treatment principles are similar to those used for aggressive NHL in the non-HIV setting and typically involve the use of involved or extended fields only.
• Lymphomatous meningitis—For patients with lymphomatous meningitis and/or radiographically detectable cerebral deposits, "step-brain" irradiation (including the covering meninges) is administered along with intrathecal chemotherapy to control microscopic spinal disease. Focal radiation therapy may be required for known tumor deposits in the spine. Unfortunately, many such patients develop multiple deposits anywhere along the spinal axis, either synchronously or metachronously.
Fractionated doses of 3,000 to 4,500 cGy may be used to control local lymphoma deposits in nodal areas. Patients who have lymphomatous meningitis typically have a poor prognosis and are best treated with regimens that do not unduly occupy their time (eg, 3,000 cGy in 10 fractions over 2 weeks).
Treatment of primary CNS lymphoma
An effective therapy for patients with AIDS-related CNS lymphoma has not yet been found, although many AIDS oncologists find high-dose methotrexate with leucovorin rescue more effective than radiation therapy.
