AIDS-related lymphoma

What every physician needs to know about AIDS-related lymphoma:

HIV is associated with malignancy, as it is estimated that approximately 30 to 40% of HIV+ patients develop cancer. The incidence of both AIDS-defining and non-AIDS-defining malignancies is significantly increased in HIV+ patients. The AIDS defining malignancies include non-Hodgkin lymphoma (NHL, also known as AIDS-related lymphoma or ARL), Kaposi’s sarcoma, and cervical cancer. The non-AIDS defining malignancies include Hodgkin lymphoma (HL), anal cancer, liver cancer, skin cancer, head and neck cancer, testicular cancer, multiple myeloma, and colorectal cancer. Since the widespread use of highly active combination antiretroviral therapy (HAART, cART), the overall incidence of ARL has declined but remains significantly increased compared to the non-HIV population.

The ARLs are comprised of aggressive and highly aggressive B-cell NHL subtypes. Systemic NHL accounts for greater than 80% of ARLs, of which 75 to 80% are diffuse large B-cell lymphoma (DLBCL), with centroblastic or immunoblastic histology, and 20 to 25% are Burkitt’s lymphoma (BL). Primary central nervous system lymphoma (PCNSL) accounts for 10 to 15% of ARLs. Primary effusion lymphoma (PEL), formerly called “body cavity lymphoma”, and plasmablastic lymphoma, each account for less than 5% of ARL. Importantly, ARLs comprise a substantial proportion of NHL in the United States of America (6% of all DLBCL, 20% of BL, 27% of PCNSL).

Are you sure your patient has AIDS-related lymphoma? What should you expect to find?

What are the major clinical and pathologic characteristics of AIDS-related lymphoma?

Patients with ARL or HIV+ HL commonly present with B symptoms (fever, drenching night sweats, weight loss), lymphadenopathy, advanced stage disease (Stage IIB to IV), and extranodal disease including an increased risk of central nervous system (CNS) involvement.

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Systemic ARL and HIV+ HL have more aggressive clinical, laboratory, and pathologic features than their HIV-negative counterparts, with a greater incidence of advanced stage disease, B symptoms, and extranodal involvement. In general, the median age is 36 to 40. Median CD4 is less than 200/mcL for most subtypes, except for BL, where the median CD4 count is usually 200/mcL or greater. Most patients have peripheral lymphadenopathy. B symptoms occur in 65 to 85% of cases. Extranodal disease occurs in 70%, with 20% showing involvement of the bone marrow and 15 to 25% involvement of the gastrointestinal (GI) tract. Central nervous system (CNS) infiltration, particularly leptomeningeal disease, is common and may occur in 1 to 20% of cases.

The majority of patients (60 to 80%) have advanced stage disease (stage IIB-IV). Thirty percent of patients have a pre-existing diagnosis of AIDS, before they are diagnosed with ARL.

Non-Hodgkin lymphoma

ARLs are comprised of aggressive and highly aggressive B-cell NHL subtypes, and in many cases a unique association with Epstein-Barr virus (EBV) or human herpesvirus 8 (HHV-8, also known as Kaposki’s sarcoma-associated herpesvirus [KSHV]) may be found.


– DLBCL represents the most common subtype of ARL. The median CD4 count at the time of diagnosis is less than 200/mcL. Clinically, patients may present with B symptoms, lymphadenopathy, splenomegaly, cytopenias, and/or evidence of local end-organ compromise due to lymphomatous infiltration.

– Histology shows large, irregularly shaped cells containing multiple nucleoli, with a Ki67 index (a measure of mitotic activity) that is usually in the range of 40 to 70%, rarely exceeding 90%. HIV+ DLBCL may be further categorized into immunoblastic or centroblastic histology. Approximately 70% of all HIV+ DLBCL are positive for EBV (100% of immunoblastic DLBCL and 40% of centroblastic DLBCL). The typical immunophenotype is sIg+ (surface immunoglobulin) CD20+ CD5-negative; there is an anaplastic variant that is positive for CD30. A subset of patients may be positive for the c-myc translocation that is seen in BL (see below); such cases may represent c-myc+ DLBCL, which carries a poorer prognosis than most cases of DLBCL, or “double hit lymphoma” if there is a concurrent translocation in the bcl-2 gene, which carries an especially poor prognosis (see below).

  • BL (small non-cleaved cell lymphoma)

– BL is the second most common subtype of ARL. Median CD4 count is 200/mcL or greater. Clinically, patients often present with profound B symptoms, lymphadenopathy, cytopenias, and/or neurologic symptoms due to CNS involvement.

– Histology shows medium-sized cells containing multiple nucleoli, with basophilic cytoplasm and cytoplasmic vacuoles; overall morphology shows areas of cellular apoptosis and necrosis with scattered macrophages, giving rise to a “starry sky” appearance. The Ki67 index BL is 90 to 100%. Translocations involving the c-myc gene on chromosome 8 are the defining molecular feature of BL, with t(8;14) seen in 95% of cases; cases that carry both a c-myc translocation and a translocation involving the bcl-2 gene on chromosome 18 (t(14;18)) are defined as “double hit lymphoma” and have a very aggressive clinical course with a poor prognosis. About 30% of HIV+ BL cases are positive for EBV. The typical immunophenotype is sIgM+ CD20+ CD10+ CD5-negative.


– PCNSL involves the CNS and is associated with advanced HIV and profound immunosuppression, with a median CD4 count of less than 30/mcL at initial presentation. Median age is 37. About 50% of patients present with neurologic symptoms such as lethargy, confusion, memory loss, personality changes, focal neurologic deficits, or seizures. The risk of developing PCNSL increases with increasing time after initial diagnosis of HIV, as 80% of HIV+ PCNSL arises in patients who have a pre-existing diagnosis of AIDS. Histologically, the lymphoma cells have immunoblastic morphology. There is a 100% association with EBV.

  • PEL

– PEL is a rare and aggressive lymphoma involving some type of malignant effusion (ascites, pleural effusion, or pericardial effusion). Median age at presentation is in the late 30s, with a median CD4 count of 80 to 130/mcL.

– Clinically, patients have symptoms related to the underlying effusion; extracavitary involvement is uncommon, although a solid tumor variant with or without effusions has been reported and is associated with idiopathic thrombocytopenic purpura and Coombs positive autoimmune hemolysis. Pathologically, the lymphoma cells are large, heterogeneous in appearance, and demonstrate plasmacytoid differentiation (that is, eccentric nuclei, abundant basophilic cytoplasm, and perinuclear Golgi complex). There is a 100% association with HHV-8; 90 to 100% of cases are positive for EBV. Unlike DLBCL, BL, and PCNSL, PEL is CD20-negative; additional immunophenotype is negative for sIg and positive for plasma cell markers CD38+, CD138+, and VS38c+.

  • Plasmablastic lymphoma

– Plasmablastic lymphoma is a rare subtype of ARL, with a median age of 39 at presentation and a median CD4 count of 120/mcL. The most common form is plasmablastic lymphoma of the oral cavity, which typically presents with a toothache or oral abscess, accompanied by expanding gingival or palatal lesion, with or without B symptoms. Extra-oral involvement, especially involving the GI tract or skin, may be seen in 30% of cases. Histology shows large cells with plasmacytoid differentiation and a high proliferation rate. More than 80% of cases are positive for EBV but negative for expression of latent membrane protein 1 (LMP1). Like PEL, plasmablastic lymphoma of the oral cavity is CD20-negative and positive for plasma cell markers CD38, CD138+, and VS38c+.

Hodgkin lymphoma

– HIV+ HL is not considered one of the ARLs, although HIV infection is associated with HL and the incidence of HL in HIV+ patients is higher than in the general population. Median age at presentation is 29, with a median CD4 count of 275/mcL; like BL, HL is therefore not associated with profound immunosuppression.

– Eighty-one percent of patients have stage III-IV disease. Seventy-seven percent have B symptoms. Extranodal disease is seen in 63% of cases; unlike HIV-negative HL, up to 40 to 50% of patients with HIV+ HL may have bone marrow involvement, and involvement of the liver and CNS has also been reported. Mediastinal disease occurs in a minority of patients. Histologically, there are four basic histologic subtypes of classical HL (nodular sclerosis, lymphocyte depletion, mixed cellularity, and lymphocyte rich); while in HIV-negative HL, the most common histologic subtype is nodular sclerosis, which carries a more favorable prognosis than the other subtypes, in HIV+ HL 25 to 30% of cases are nodular sclerosis while 40 to 50% of cases are mixed cellularity, which carries a less favorable prognosis. More than 75% of cases are positive for EBV.

Beware of other conditions that can mimic AIDS-related lymphoma:

Other conditions that can mimic AIDS-related lymphoma

The usual presentation of ARL is an HIV+ patient with lymphadenopathy and B symptoms. In evaluating such patients, the differential diagnosis for lymphadenopathy in HIV+ patients should be kept in mind. The key procedure that establishes a diagnosis of ARL is biopsy, so it is essential that clinicians understand when a lymph node biopsy is or is not indicated in an HIV+ patient.

The following is a broad list of conditions that cause lymphadenopathy, especially in HIV+ patients.

  • Infections

– Advanced or progressive HIV, tuberculosis, toxoplasmosis, viral infections (especially EBV or Cytomegalovirus), fungal infections (especially histoplasmosis, coccidiomycosis, or Cryptococcus), bacterial infections (including Bartonella or syphilis).

  • Other malignancies

– Leukemia, solid tumor metastases (for example, Virchow’s left supraclavicular node in gastric or abdominal malignancies, Sister Mary Joseph umbilical nodule in GI or gynecologic cancers), Kaposi’s sarcoma, multicentric Castleman’s disease.

  • Inflammatory diseases

– A number of inflammatory diseases can cause lymphadenopathy in HIV+ or HIV-negative patients. This includes lupus, rheumatoid arthritis, Still’s disease, Churg-Strauss syndrome, Kawasaki’s disease, Kikuchi disease, sarcoidosis, amyloidosis.

  • Rare causes of lymphadenopathy

– A complete differential diagnosis of lymphadenopathy in HIV+ or HIV-negative patients also includes rare conditions such as lysosomal storage diseases, chronic granulomatous disease, or serum sickness. In addition, certain medications may be associated with lymphadenopathy, including phenytoin, allopurinol, sulfa antibiotics, penicillin, and hydralazine.

What individuals are most at risk for developing AIDS-related lymphoma?

What are risk factors for HIV+ lymphoma?
  • ARL

– Low CD4 count (less than 200/mcL in all subtypes except for BL, which usually shows a CD4 count of 200/mcL or more), high HIV viral load, and lack of HAART (cART) use.

  • HL

– Data are conflicting with regards to CD4 count and risk of HL; of note, an increased risk of HL may be seen in the first few months after initiation of HAART (cART), concomitant with a rise in CD4, suggesting that HL may be a component of immune reconstitution inflammatory syndrome.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

What are the components of an evaluation for AIDS-related lymphoma?
  • Evaluate for B symptoms:

– Fever greater than 100.4F

– Drenching night sweats, requiring change of clothes

– Weight loss of greater than 10 pounds or 5% body weight over 6 to 12 months

  • Evaluate for symptoms of common extranodal sites of disease (GI, CNS, pulmonary)

  • Calculate ECOG (Eastern Cooperative Oncology Group) performance status (PS)

  • Review prior AIDS-defining illnesses (for example, Pneumocystis jiroveci infection, CNS toxoplasmosis, pulmonary tuberculosis, recurrent pneumonia, thrush)

Physical examination
  • Peripheral lymph nodes. Features suspicious for lymphoma include:

– Size greater than 1 cm, or a progressive increase in size

– Persistent enlargement for more than 4 weeks

– Firm or rubbery consistency

– Fixed or immobile lymph nodes

– Non-tender to palpation

– Diffuse lymphadenopathy

– Posterior cervical, supraclavicular, or epitrochlear nodes

  • Liver/spleen (evaluate for hepatosplenomegaly)

  • Waldeyer’s ring (lymphoid tissue in posterior oropharynx/tonsils, which may rarely demonstrate enlargement due to lymphomatous infiltration)


In particular, history of HAART (cART) and immunosuppression should be obtained.

Laboratory tests
  • CD4 count

  • HIV viral load

  • Complete blood count (CBC) with peripheral blood smear

  • Peripheral blood flow cytometry

  • Lactate dehyrogenase (LDH)

  • Laboratory markers for tumor lysis syndrome (TLS):


– Uric acid

– Potassium

– Calcium (both for TLS, and because hypercalcemia of malignancy can be seen with lymphoma)

– Phosphate

– Creatinine

– Anion gap

  • Serologies for HBV (hepatitis B virus) and HCV (hepatitis C virus)

– Case reports of fatal HBV reactivation in NHL after rituximab in the absence of anti-HBV therapy exist, so serologic testing for hepatitis viruses must be performed prior to initiation of rituximab therapy.

  • Anti-nuclear antibody, serum protein electrophoresis (SPEP) with immunofixation, urine protein electrophoresis (UPEP) with immunofixation, beta-2 microglobulin

  • Consider testing for EBV or HHV-8 viral load

  • For aggressive or highly aggressive NHL or for HL

– Whole-body combination PET/CT (positron emission tomography/computed tomography) scan; for indolent NHL, CT scan is usually adequate.

  • Brain or spine MRI if suspect PCNSL or secondary CNS involvement by systemic lymphoma

  • Echocardiogram or radionuclide ventriculography to assess cardiac function, prior to administration of anthracycline-containing chemotherapy

  • Excisional lymph node biopsy, or core biopsy of extranodal site (fine-needle aspiration is generally inadequate for definitive diagnosis and classification of lymphoma)

  • Bone marrow biopsy

  • Cerebrospinal fluid analysis

– To include cell count/differential, cytology, flow cytometry, EBV viral load (which is predictive of either PCNSL or secondary CNS infiltration by systemic ARL), and molecular analysis of immunoglobulin heavy chain gene rearrangements.

  • Cerebrospinal fluid analysis

– Should be performed in ARL patients with risk factors for CNS involvement, including BL, DLBCL with greater than one extranodal site and a high LDH, or bone marrow, sinus, epidural, testicular, or ovarian infiltration.

Risk assessment
  • ARL:

– International Prognostic Index (IPI) score. This is the most widely-used prognostic index to estimate survival in patients with aggressive or highly-aggressive NHL. The IPI retains prognostic utility in ARL, although survival for patients with ARL may be lower than for HIV-negative NHL. Components of the IPI are: age greater than 60, ECOG PS greater than 1, high LDH, greater than 1 extranodal site of disease, and stage III to IV disease (acronym: “APLES”).

– HIV score (French GELA [Groupe d’Etude des Lymphomes de l’Adulte] study group). Components are: ECOG performance status of 2 or more, prior AIDS, and CD4 less than 100/mcL.

  • HL:

– International Prognostic Score (IPS). This is used to assess prognosis in stage IIB to IV HL and retains utility in HIV+ HL. Components of the IPS score are: white blood cells (WBC) greater than 15,000/mcL, age greater than 45, lymphopenia (lymphocytes less than 600/mcL, or less than 8% of total WBC count), male gender, albumin less than 4g/dL, stage IV disease, and hemoglobin less than 10.5 g/dL (acronym: “WALMASH”).

What imaging studies (if any) will be helpful in making or excluding the diagnosis of AIDS-related lymphoma?

Whole-body PET/CT is the single most useful diagnostic imaging study in evaluation of aggressive or highly aggressive HIV+ NHL and HL.

Brain MRI is indicated for PCNSL, or for evaluation of secondary CNS involvement by systemic NHL.

If you decide the patient has AIDS-related lymphoma, what therapies should you initiate immediately?

Once a diagnosis of ARL has been confirmed, treatment for lymphoma should be initiated promptly (see “More definitive therapies?” below).

Diagnostic evaluation

For all suspected cases of ARL, diagnostic evaluation must be expedited. Appropriate procedural specialties should be consulted immediately to obtain necessary tissue for diagnosis. Pathology should be notified for accelerated review of tissue specimens.

Highly active combination antiretroviral therapy

Infectious Disease should be consulted regarding administration of HAART (cART). Initiation and optimization of HAART are essential components of ARL treatment, although certain HAART regimens may interfere with chemotherapy metabolism.

Steroids and radiotherapy

If PCNSL is suspected, Neuro-oncology should be consulted regarding initiation of steroids and further evaluation for either systemic chemotherapy or whole-brain radiotherapy (WBRT); Radiation Oncology should be consulted if WBRT is recommended, and high-dose methotrexate should not be given after WBRT due to the risk of leukoencephalopathy. For other ARL subtypes, Radiation Oncology should be consulted if there is evidence of impending neurologic compromise due to a spinal compressive mass, as radiotherapy and steroids may be indicated.

Tumor lysis syndrome

Patients with TLS based on laboratory tests (see “What laboratory studies should you order to help make the diagnosis and how should you interpret the results?” above), or who are at high risk of developing TLS (for example, patients with BL, a high Ki67 index, or a high uric acid) should undergo prophylactic measures to prevent TLS. These should include the initiation of aggressive intravenous (IV) hydration (without sodium bicarbonate, as urinary alkalinzation worsens calcium-phosphate precipitation and according to some references, may also lead to reduced solubility of hypoxanthine/xanthine) and allopurinol (at a dose of 200mg three times per day, adjusted for creatinine clearance). If uric acid is greater than 7.5g/dL, rasburicase 0.15 to 0.2mg/kd IV may be considered. For patients with renal dysfunction, oliguria, or severe abnormalities in TLS laboratory tests (for example, hyperkalemia, or hyperphosphatemia with oliguria), Nephrology should be consulted for evaluation for dialysis. TLS laboratory tests should be monitored every 6 to 12 hours until LDH, uric acid, and phosphate normalize.

More definitive therapies?

What are the definitive therapies for ARL?
Basic principles of treatment of ARL
  • Clinical outcomes of patients with ARL in the HAART (cART) era approach those of HIV-negative NHL

  • HAART (cART) is an essential component of treatment of ARL

– HAART improves complete response rates and overall survival and decreases opportunistic infections in patients with ARL undergoing chemotherapy. Some practitioners administer HAART concomitantly with chemotherapy, while others temporarily hold HAART during chemotherapy, as there is some debate as to whether the biology of HIV+ lymphoma may change in response to concurrent HAART. As discussed above (see “If you decide the patient has AIDS-related lymphoma, what therapies should you initiate immediately?”), certain types of HAART may interfere with chemotherapy metabolism, so Infectious Disease consultation is always recommended regarding optimization of HAART in ARL patients. Zidovudine should be avoided, due to its myelosuppressive effects.

  • ARL patients undergoing chemotherapy have an increased risk of infection

– Patients with ARL undergoing treatment for lymphoma are at increased risk of infection. Granulocyte colony stimulating factor (GCSF) is administered prophylactically to all patients with ARL who are being treated with cytotoxic chemotherapy. Since chemotherapy will decrease CD4 count, all patients should receive Pneumocystisprophylaxis. Many centers also call for routine enteric antibiotic, antiherpetic, and/or antifungal prophylaxis.

  • Rituximab may be associated with increased infectious toxicity

– Some studies suggest that while rituximab improves remission rates in CD20+ DLBCL, it may be associated with an increased risk of infectious deaths in patients with severe lymphopenia (CD4 less than 50/mcL). Some practitioners avoid its use in this particular setting, while others administer it regardless. This is less of an issue with BL as opposed to other ARL subtypes, as the median CD4 count in BL is usually 200/mcL or greater.

  • Prophylactic CNS chemotherapy may be considered

– Because of the increased incidence of CNS disease in ARL patients, at some institutions prophylactic CNS chemotherapy is routinely administered to all patients with ARL, while at other centers, CNS prophylaxis is given only if there are additional risk factors (see “What laboratory studies should you order to help make the diagnosis and how should you interpret the results?” above). Standard CNS prophylaxis includes intrathecal methotrexate or intrathecal cytarabine.

Chemotherapy regimens and role of radiotherapy

As with HIV-negative lymphomas, the choice of chemotherapy regimen, need for CNS prophylaxis, and role of radiotherapy are dictated by pathologic subtype, stage, and institutional preference.


  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) +/- rituximab

– Multiple studies have demonstrated the tolerability and efficacy of full dose CHOP with concurrent HAART in HIV+ DLBCL, with greater than 60% of patients achieving complete response (CR), and greater than 50% achieving long-term survival. Incorporation of rituximab is appropriate if CD4 is greater than 50/mcL.

  • Dose-adjusted (DA) EPOCH (infusional etoposide, vincristine, doxorubicin with prednisone and dose-escalated cyclophosphamide titrated according to nadir neutropenia) +/- rituximab

– DA-EPOCH with concurrent or sequential HAART is highly effective and well-tolerated in HIV+ DLBCL, with greater than 70% of patients achieving CR and greater than 50% surviving long-term. DA-EPOCH is preferred over CHOP in DLBCL with high proliferation rates (Ki67 greater than 80% and/or presence of c-myc translocation) and in BL. If rituximab is used, DA-EPOCH with concurrent rituximab is associated with higher CR compared to DA-EPOCH followed by rituximab. Following completion of DA-EPOCH, CD4 counts typically recover by 12 months on HAART.


  • DA-EPOCH + rituximab

– The most widely used regimen for HIV+ BL is DA-EPOCH + rituximab, based on a seminal randomized trial in HIV+ BL and DLBCL, in which patients were treated with DA-EPOCH with either concurrent or sequential rituximab; outcomes in this study favored DA-EPOCH with concurrent rituximab. HAART may be administered concurrently with or sequentially following chemotherapy.

  • Modified Magrath regimen + rituximab (RCODOX-M/IVAC) (rituximab, cyclophosphamide, vincristine, and doxorubicin, alternating with high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine

– A retrospective study reported favorable outcomes with RCODOX-M/IVAC in HIV+ and HIV-negative BL patients, although a small number of HIV+ patients who received rituximab developed septic complications.

  • Other intensive chemotherapy regimens

– Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and high-dose cytarabine) + rituximab.

– LMB86 (three-phase regimen incorporating cyclophosphamide, vincristine, prednisone, doxorubicin, high-dose methotrexate, etoposide, and high-dose AraC) if CD4 greater than 200/mcL.

– PETHEMA regimen (cyclophosphamide, prednisone, vincristine, high-dose methotrexate, ifosfamide, teniposide, cytarabine, doxorubicin, and intrathecal methotrexate/cytarabine/hydrocortisone).


Outcomes for PCNSL are generally poor due to advanced HIV infection, although prognosis has improved in the HAART era, with median survival greater than 18 months in some series. The optimal treatment of HIV+ PCNSL remains uncertain; WBRT with corticosteroids and HAART is an accepted standard of care and effective palliative therapy. Some studies support the use of chemotherapy alone (for example, high-dose methotrexate) or combined modality therapy with chemotherapy (for example, procarbazine, lomustine, vincristine, or high-dose methotrexate) plus WBRT. As mentioned above, the risk of delayed neurotoxicity/leukoencephalopathy is increased with combined modality regimens, particularly if high-dose methotrexate is given after WBRT.


Outcomes with PEL are generally poor, with short response durations. The optimal treatment of PEL remains uncertain. Some case reports describe attainment of CR with HAART alone. CHOP or CHOP-like chemotherapy is associated with a median survival of approximately 6 months. Other chemotherapy options include DA-EPOCH or CDE (cyclophosphamide, doxorubicin, etoposide). Case reports have described anti-tumor activity with interferon-alpha in combination with zidovudine, intracavitary cidofovir (to inhibit HHV-8 replication), bortezomib, or liposomal anthracycline. There is no role for rituximab, as PEL is CD20-negative.

Plasmablastic lymphoma

Outcomes for treatment of plasmablastic lymphoma are generally poor. Cytotoxic chemotherapy (CHOP, ACVBP [doroxubicin, cyclophosphamide, vindesine, bleomycin, prednisone], hyper-CVAD, or EPOCH) may be used, with survivals that are usually on the order of months, although some patients who receive chemotherapy + HAART have survived for years. There are case reports of transient tumor regression after HAART alone. As with PEL, there is no role for rituximab, as plasmablastic lymphoma of the oral cavity is CD20-negative.


Treatment of HIV+ HL is similar to that for HIV-negative HL, with the addition of HAART + GCSF. Outcomes are generally favorable. As with HIV-negative HL, HIV+ HL patients with limited stage disease (stage I-IIA) are often treated with abbreviated chemotherapy followed by radiation, while those with advanced stage disease (stage IIB-IV) are treated with extended chemotherapy alone, although it should be noted that most patients with HIV+ HL present with advanced stage disease.

Standard chemotherapy regimens for HIV+ HL include ABVD (doxorubicin, bleomycin, vincristine, and dacarbazine) and Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone, with radiotherapy). BEACOPP, an aggressive multiagent chemotherapy regimen that is standard-of-care for HIV-negative HL in Europe, is likely too toxic for patients with HIV infection and is not recommended for treatment of HIV+ HL. Phase II trials report that greater than 80% of HIV+ HL patients achieve CR with standard therapy.

What other therapies are helpful for reducing complications?

HIV+ patients who receive chemotherapy carry a significant risk of severe infections due to chemotherapy-induced neutropenia and underlying immunodeficiency. GCSF should be started approximately 1 day after completion of chemotherapy. All HIV+ patients undergoing cytotoxic chemotherapy should receive Pneumocystis prophylaxis; at many institutions, routine enteric antibiotic, anti-herpetic, and/or anti-fungal prophylaxis may also be given. Patients undergoing chemotherapy should receive routine oral care to prevent thrush and mucositis (for example, fluconazole or nystatin oral rinses, or Biotene mouthwash).

All patients should be counseled regarding complications of chemotherapy, including nausea, vomiting, alopecia, mucositis, cytopenias, and infections. Social work and Infectious Disease consultations are indicated for all HIV+ patients with cancer.

What should you tell the patient and the family about prognosis?

What are the prognostic factors for ARL
The most important prognostic factors for ARL are IPI score, CD4 count, and response to HAART (cART)

Outcomes for ARLs have historically been worse than for HIV-negative NHL, although in the HAART era and with modern chemotherapy regimens, outcomes are becoming similar. DLBCL and BL have favorable prognoses overall when treated with the therapeutic approaches outlined above (see “More definitive therapies?”), with 50 to 80% of patients achieving long-term remission, and median survivals on the order of a few to several years.

Outcomes for DLBCL are better than for BL, although patients with BL who tolerate intensive chemotherapy may also have excellent long-term outcomes. PCNSL, PEL, and plasmablastic lymphoma of the oral cavity have poor prognoses, with median survivals typically on the order of a few to several months. Outcomes for HIV-associated HL are worse than for HIV-negative HL but still generally favorable, with a median survival on the order of several years.

Poor prognostic factors for ARL include:

  • Low CD4 count at the time of diagnosis

  • No HAART use, or no suppression of HIV viral load or improvement in CD4 count after initiation of HAART

  • Advanced stage disease

  • ECOG PS of 2 or greater

  • Prior AIDS or AIDS-defining illness

  • Age greater than 35

  • History of IV drug use

  • Bone marrow involvement

  • Lack of CR after chemotherapy

  • High HIV score (French GELA group)

  • High IPI score

  • Molecular determinants: absence of CD10, absence of CD20, non-germinal center phenotype, EBV+

"What if" scenarios.

Severe infections in the setting of chemotherapy-induced neutropenia, and increased risk of cancer recurrence

The major complications in HIV+ cancer patients undergoing chemotherapy are severe infections in the setting of chemotherapy-induced neutropenia, and increased risk of cancer recurrence due to the natural history of HIV+ malignancies, coupled with the necessary chemotherapy dose-reductions and treatment delays that occur because of cytopenias and other comorbidities.

What if a patient with ARL develops chemotherapy-induced neutropenia, with or without fever?
  • GCSF

– Ensure that GCSF is being administered appropriately (for example, daily Neupogen, or a single dose of Neulasta).

  • Pneumocystis prophylaxis

– Prophylactic therapy against Pneumocystis is indicated in all ARL and HIV+ HL patients undergoing cytotoxic chemotherapy. However, medications such as trimethoprim/sulfamethoxazole (TMP/SMX) may worsen cytopenias, and other anti-Pneumocystis medications may be indicated (for example, inhaled pentamidine, atovaquone, or dapsone if glucose-6-phosphate dehydrogenase deficiency has been ruled out), although the ability of these other medications to prevent Pneumocystis pneumonia is inferior to TMP/SMX.

  • Fluoroquinolones

– Prophylactic fluoroquinolones may be considered in order to prevent enteric bacterial infections during period of neutropenia.

  • Febrile neutropenia

– If fever is greater than 100.4 F, treatment must ensue emergently for febrile neutropenia. Patients must be brought to the hospital for evaluation; CBC, blood and urine cultures, chest X-ray, and assessment of indwelling central venous catheters are standard. Empiric anti-pseudomonal antibiotics +/- vancomycin should be started immediately. For patients with prolonged neutropenia, long-term steroid use, or persistent fevers despite several days of appropriate anti-pseudomonal antibiotics, antifungal therapy may be indicated. If febrile neutropenia persists despite appropriate empiric antibacterial and antifungal therapy, medications (including HAART) should be reviewed, and further infectious work-up for other opportunistic infections (for example, Cytomegalovirus, tuberculosis, mycobacterium avium-intracellulare infection, histoplasmosis) should be pursued.

  • Dose-reduction or dose-delay for subsequent chemotherapy

– For ARL patients who develop neutropenia with or without fever or other infectious complications, dose-reduction or dose-delay for subsequent chemotherapy may be indicated. Of note, while in HIV-negative HL chemotherapy is administered at full-dose and on-time regardless of cytopenias, in HIV+ HL, the concern for neutropenic infections may warrant delay of chemotherapy.

What if mucositis develops?

– Viscous lidocaine or “magic mouthwash” (Maalox, Benadryl, and viscous lidocaine in a 1:1:1 ratio) may be used for pain relief of mucositis. In severe cases, oral or intravenous narcotics may be required; rarely, total parenteral nutrition may be necessary.

What if the lymphoma does not respond to chemotherapy or relapses?

If ECOG PS is favorable, salvage chemotherapy (for example, ICE (ifosfamide, cyclophosphamide, etoposide), RICE (rituximab + ICE), DHAP (dexamethasone, cytarabine, cisplatin), or ESHAP (etoposide, Solu-Medrol, high-dose cytarabine, cisplatin)) may be indicated. If chemosensitivity to salvage chemotherapy is documented, high-dose chemotherapy and autologous stem cell transplant is an effective treatment option in selected patients. Rarely, allogeneic stem cell transplantation has been performed in HIV+ patients. If ECOG PS is unfavorable, palliative chemotherapy or hospice may be considered.


HIV does not infect the malignant B-cells of ARL and is not directly oncogenic. ARL arises from uncontrolled B cell proliferation in the setting of HIV-mediated immune dysregulation, involving the complex interplay of multiple biologic factors. The human herpes viruses EBV and HHV-8 may play a direct oncogenic role, given the association of specific sub-types of ARL with EBV and HHV-8. Other factors include T cell dysfunction, dendritic cell dysfunction, and aberrant cytokine production driven by HIV infection.

What other clinical manifestations may help me to diagnose AIDS-related lymphoma?

The clinical manifestations of ARL are protean

The presentation of different ARLs and of HIV+ HL is discussed above (“Are you sure your patient has AIDS-related lymphoma?”). Less commonly, patients may present with abnormal laboratory tests alone, including abnormal liver function tests, elevated LDH, unexplained cytopenias, tumor lysis syndrome, or hypercalcemia.

Although patients with advanced HIV infection (defined as CD4 less than 100/mL, high viral load, and a prior or existing diagnosis of AIDS diagnosis) are at greater risk of developing HIV+ lymphoma than those with less advanced HIV, in the HAART (cART) era, patients with CD4 greater than 200/mcL comprise an increasing proportion of HIV+ lymphoma cases, particularly for BL and HL. Clinicians should therefore maintain a high index of suspicion for lymphoma in all HIV+ patients with unexplained systemic symptoms, lymphadenopathy, and/or localized organ-specific manifestations.

What other additional laboratory studies may be ordered?

  • Hepatitis serologies

  • LDH

  • Calcium

  • TLS laboratory tests

  • Peripheral blood flow cytometry

What's the evidence?

Carbone, A. “AIDS-related non-Hodgkin's lymphomas: from pathology and molecular pathogenesis to treatment”. Hum Pathol. vol. 33. 2002. pp. 392-404. [This is a comprehensive review of molecular genetic and virologic pathogenesis of ARL and clinicopathologic correlations.]

Carbone, A, Cesarman, E, Spina, M, Gloghini, A, Schulz, TF. “HIV-associated lymphomas and gamma-herpes viruses”. Blood. vol. 113. 2009. pp. 1213-24. [This review discusses the spectrum of B cell differentiation in ARL associated with EBV of HHV-8. Those associated with EBV or HHV-8 commonly exhibit plasmacytoid/plasmablastic features. EBV infection occurs at different rates in different lymphoma types, whereas HHV-8 is specifically associated with PEL, which usually occurs in the setting of profound immunosuppression.]

Dunleavy, K, Wilson, WH. “How I treat HIV-associated lymphoma”. Blood.. vol. 119. 2012. pp. 3245-55. [This comprehensive review touches upon the pathobiology, diagnosis, evaluation, and treatment of HIV-associated lymphomas in the era of highly active combination anti-retroviral therapy. Practical management and therapeutic controversies are discussed in detail, including chemotherapy dose intensity, role of rituximab, and timing of initiation of combination anti-retroviral therapy.]

[This paper reviews the diagnosis, risk stratification, and therapy of HIV-associated HL in the era of combination anti-retroviral therapy.]

Kaplan, LD, Lee, JY, Ambinder, RF. “Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010”. Blood. vol. 106. 2005. pp. 1538-43. [In this large randomized phase III trial conducted in the HAART era, the addition of rituximab to CHOP in patients with ARL was associated with improved tumor responses compared to CHOP alone (CR [complete response] 57.6% versus 47%). However, these benefits were offset by an increase in infectious deaths (14% versus 2%), particularly in those individuals with CD4 counts less than 50, and there was no significant difference in time to progression, progression-free survival, or overall survival for patients treated with or without rituximab.]

Sparano, JA, Lee, JY, Kaplan, LD. “AIDS Malignancy Consortium. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma”. Blood. vol. 115. 2010. pp. 3008-16. [This is a seminal paper from the HAART era comparing efficacy and safety of daEPOCH with concurrent versus sequential rituximab in a randomized trial of 106 patients with systemic ARL, including 27 patients with BL. Seventy-five patients received HAART during therapy. Concurrent rituximab was associated with higher response compared to sequential rituximab (73% versus 55%), with comparable toxicity, suggesting that concurrent rituximab plus daEPOCH is an effective regimen for HIV-associated lymphoma, including BL. Infectious death rate was high in patients with CD4 less than 50.]

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