Burkitt lymphoma is a high-grade B-cell lymphoma classified as a non-Hodgkin lymphoma (NHL). Compared to diffuse large B-cell lymphoma, it is a tumor with the highest of mitotic indices and a proliferative index of approximately 100%.1,2 Commonly, it presents in children or young adults, and is considered one of the most clinically aggressive form of NHL.3 One of the most important risk factors for developing intermediate or high-grade NHL is a prolonged state of immunosuppression.3,4 This risk factor was identified during the early years of the Acquired Immunodeficiency Syndrome (AIDS) epidemic when a significant increase in the incidence of non-Hodgkin B-cell lymphomas was identified among men who had sex with men.5,6 In 1985, the Centers for Disease Control and Prevention in Atlanta, Georgia, expanded the list of AIDS-defining illnesses to include the high-grade B-cell NHLs.4,5
In the past decade, there have been several advancements in the utility of highly active antiretroviral therapy (HAART), which has led to a decreasing incidence of many opportunistic infections including Pneumocystis jiroveci and other AIDS-defining illnesses. However, epidemiologic studies comparing the pre-HAART era to the HAART era have demonstrated mixed results in the incidence of NHL among human immunodeficiency virus (HIV)-infected individuals, including Burkitt lymphoma.4,7-9
We report the case of a Burkitt lymphoma occurring in an HIV seropositive male, and review the relationship between HIV disease and Burkitt lymphoma as well as the presentation and management of this disease.
A 41-year-old Caucasian male presented to our clinic with a 2- to 3-week history of ptosis of the left eyelid and right testicular swelling. He first noticed these symptoms after initiating antiretroviral therapy during a prior hospitalization. He also experienced severe headaches in the left orbital region, worsening weakness, and weight loss of approximately 50 to 60 pounds in the previous 5 to 6 months. Upon presentation, he was wheelchair bound because he was too weak to walk. He denied vision changes, paresthesias, numbness, syncope, fever, chills, or night sweats. His medical history was otherwise significant only for a recent diagnosis of HIV 2 months before this presentation.
Before initiating HAART, his CD4+ count was 58 cells/μL with a viral load of 500,000 copies/mL. He was prescribed lamivudine 150 mg/zidovudine 300 mg (Combivir) 1 tablet twice daily, lopinavir 133.3 mg/ritonavir 33.3 mg (Kaletra) 3 capsules twice daily, and sulfamethoxazole 800 mg/trimethoprim 160 mg daily.
On physical examination, the patient was afebrile and cachetic appearing. He had marked left eyelid ptosis and the ipsilateral pupil was dilated to 8 mm. Left oculomotor palsy was present. He had decreased sensation over his chin bilaterally. Pinprick sensation was intact in all 4 extremities. Muscle strength was normal in the upper extremities and decreased in the lower extremities. There was diminished vibratory sense over both lower limbs. Deep tendon reflexes were absent in both the upper and lower limbs. Heel to shin ataxia was present. His right testicle was enlarged, without erythema, and was nontender to palpation. No lymphadenopathy was appreciated in the inguinal, cervical, supraclavicular, or axillary areas.
After evaluation in the clinic, the patient was directly admitted to the hospital for further workup. Relevant laboratory studies included white blood cell count 3.2 × 103 cells/μL (4.0-10.5) with 7% atypical lymphocytes, hemoglobin 9.1 g/dL (11.7-14.9), and hematocrit 28% (34-46). After 2½ weeks of HAART, his CD4+ count improved to 166 cells/μL and his viral load was 5600 copies/mL. Tests for hepatitis, a serum cryptococcal antigen, a toxoplasmosis panel, a serum human chorionic gonadotropin level, and a serum alpha fetoprotein level were unremarkable.
A testicular ultrasound revealed enlarged, hyperemic testicles with a diffuse heterogenous echo texture suggestive of a metastatic neoplasm versus an infectious or inflammatory process. A neurology consultation was obtained and a magnetic resonance imaging scan of the brain was performed. Magnetic resonance imaging revealed a heterogeneous opacity in the left posterior ethmoid and bilateral sphenoid sinuses with extension into the petrous portion of the temporal bone (Fig. 1). A biopsy of the mass and temporal bone was performed by ear, nose, and throat surgeons.
Two days after his discharge, the pathology of the biopsy revealed a single sheet of neoplastic-appearing cells in which the tingeable body macrophages had a "starry-sky" appearance, which was consistent with Burkitt lymphoma. The patient was informed to come to the medicine clinic for a lumbar puncture and bone marrow biopsy by the primary care physicians. The results of the lumbar puncture were: clear, white blood cell count 3 cells/μL, glucose 60 mg/dL (30-70), protein 373 mg/dL (13-40), Gram stain was negative, and there were no malignant cells. The bone marrow specimen showed atypical, blastlike cells also consistent with Burkitt lymphoma. The patient was referred to oncology for further treatment and was continued on his antiretroviral regimen. After initial discussion with the oncologist, the patient refused the chemotherapy regimen recommended for personal reasons and died 4 months after this hospital stay.
Acquired Immunodeficiency Syndrome-related lymphomas can be categorized primarily into 4 subsets: Hodgkin, NHL including Burkitt, diffuse large cell lymphomas, and primary effusion lymphomas. Burkitt lymphoma continues to surface in the adult HIV-infected population and it constitutes 24% to 35% of HIV-associated NHLs.3,10 Typically, endemic Burkitt lymphoma is rarely seen in adults above the age of 35 and comprises less than 1% of adult NHLs.11,12 In the pre-HAART era, the incidence of all NHL cases was 60 to 200 times higher in HIV-infected patients than in non-HIV-infected patients.5 With the advent of HAART, the risk of acquiring Burkitt lymphoma did not seem to change appreciably in 1997-1999 when compared with 1992-1996.13 In contrast, HAART seemed to significantly reduce primary central nervous system (CNS) lymphoma, systemic diffuse large cell lymphoma, and Kaposi sarcoma.13
Burkitt lymphoma is a B-cell lymphoma, CD19+/CD20+, that has a characteristic starry-sky appearance when examined microscopically.3 Patients with AIDS-related Burkitt lymphoma typically express the c-myc oncogene.3 The c-myc gene on the long arm of chromosome 8 can translocate with regions on chromosomes 2, 12, and 22, causing a dysregulation of expression of c-myc expression.3,12 This c-myc gene regulates the transcription of a large number of genes involved in the cell cycle and apoptosis.3Endemic Burkitt lymphoma seems to have a strong association (>90% of cases) with Epstein-Barr virus, but only 30% of HIV-associated Burkitt lymphoma biopsy specimens test positive for Epstein-Barr virus by immunohistochemistry.4,10
Prolonged immunosuppression, such as that which occurs with HIV infection, is a risk factor for Burkitt lymphoma. The risk seems to increase with the duration of HIV infection. Patients who have been HIV seropositive for 8 years or more have a 3.6 greater risk for NHL than those patients who have been seropositive for less than 4 years, after adjusting for CD4+ T-helper cell counts.14 Commonly, HIV seropositive patients at the time of diagnosis of Burkitt lymphoma tend to have higher CD4+ counts (>150 cells/μL) as compared with diffuse large cell (~60 cells/μL) or primary CNS lymphoma (~24 cells/μL).13
The most common presenting symptoms of AIDS-related NHL are B-cell symptoms of fever, night sweats, and weight loss that occur in 60% to 70% of patients.4,15 Patients commonly present with advanced disease, such as Ann Arbor classification stage III or IV.15 Extranodal involvement is also common, particularly in the gastrointestinal tract, liver, and bone marrow.5 Central nervous system involvement occurs in 20% to 40% of patients and can present a diagnostic challenge.15 The CNS lesions may show ring enhancement similar to some opportunistic infections observed with HIV.15 Therefore, toxoplasmosis needs to be included in the differential and ruled out when an HIV patient presents with a focal neurologic deficit. Typically, toxoplasmosis will have many ring-enhancing lesions, whereas NHL will only have a few enhancing lesions.15
The treatment of AIDS-related lymphoma is evolving. Standard regimens for the treatment of AIDS-related Burkitt lymphoma are m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).15,16 Many trials have compared the use of standard dose versus low-dose chemotherapy in the HIV population.17 Human immunodeficiency virus disease is myelosuppressive, and patients infected with HIV have decreased hematopoietic reserve in the face of chemotherapy.15 The low-dose chemotherapy has been used to help limit the exacerbation of immunosuppression caused by treatment.15-19 Rituximab therapy is controversial in HIV-associated NHL. In a recent study, the addition of rituximab to CHOP therapy seemed to improve tumor response, but that benefit was offset by the increased number of infectious deaths observed in the rituximab and CHOP therapy group versus CHOP therapy alone.20 Central nervous system spread is a common complication with lymphoma, and prophylaxis with intrathecal methotrexate and cytarabine has been used in the treatment regimens.3,5,15
The advances in HAART have allowed the use of more aggressive, standard dose, chemotherapy regimens.4,5,15 Treatment with HAART helps minimize the CD4+ cell count decline that normally occurs during chemotherapy and helps protect against opportunistic infections.3,4,21 The CD4+ count may recuperate more rapidly in patients treated with HAART while on chemotherapy.4,5,21 Administration of granulocyte colony-stimulating factor has been used to help attenuate the degree of myelotoxicity and immunosuppression during chemotherapy.15 There is no evidence at this time that granulocyte colony-stimulating factor stimulates HIV replication.5,15 A complication encountered in the treatment of Burkitt lymphoma is tumor lysis syndrome. Prophylactic measures of adequate hydration, use of allopurinol, and monitoring of electrolytes are recommended in the overall treatment scheme.
In patients with HIV-related lymphoma, the prognosis is poor and the survival rates are variable.15 The prognosis of Burkitt lymphoma can be evaluated by a number of different factors, including CD4+ count, performance status, older age, extranodal involvement, and constitutional symptoms.15 Among all AIDS-defining NHLs, 4 factors that emerge as poor prognostic indicators are the following: CD4+ T-helper count <100 cells/μL, age older than 35 years, intravenous drug use, and stage III/IV disease.17,22
Complete remission rates in patients with AIDS-related NHL utilizing HAART and chemotherapy range from 48% to 92%.5 The median survival of patients with systemic HIV-associated NHL has increased from 2 to 13 months to greater than 24 months in patients treated with HAART while undergoing chemotherapy.23 Recent data utilizing chemotherapy followed by HAART in AIDS-related lymphoma reported a 74% complete response rate and a 73% progression free survival rate at 53 months.24 In HIV-associated Burkitt lymphoma, complete response rates and 2-year event-free survival rates of 64% and 59%, respectively, were comparable to HIV-negative patients (63% and 62%) utilizing a CODOX-M/IVAC chemotherapy regimen.16
Burkitt lymphoma continues to pose challenges in the HIV-infected population. Burkitt may present at more advance stages with multiple areas of extranodal involvement. The longer a person is infected with HIV, the higher the risk of developing Burkitt lymphoma. The treatment of Burkitt lymphoma in the HIV population poses some unique challenges. Concomitant treatment with HAART has helped reduce the decline in CD4+ count and immunosuppression caused by chemotherapy treatment, and survival rates are improving.
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