Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 5: Disease-Specific Treatment

Non-Hodgkin Lymphoma

Background

Non-Hodgkin lymphoma (NHL) is a diverse group of more than 20 malignant diseases originating in the cells of the immune system. The incidence of NHL is up to 60 times higher in HIV-infected patients than in HIV-noninfected persons, and the risk of NHL increases with declining immune function. In the United States, rates of NHL among HIV-infected persons increased dramatically in the early years of the HIV epidemic, but the rate has stabilized since the advent of antiretroviral therapy (ART).

Ninety percent of HIV-related NHL cases are of B-cell origin and they are frequently high-grade in nature. Although B-cell lymphomas may occur at any stage of HIV disease, they are seen more frequently in patients with lower CD4 cell counts (particularly CD4 counts of <100 cells/µL). Central nervous system (CNS) lymphoma typically is seen only in patients with advanced AIDS (the CD4 count usually is <50 cells/µL). NHL is an AIDS-defining condition. A viral factor, the Epstein-Barr virus (EBV), is linked to CNS and some types of systemic NHL in people with AIDS.

The majority of patients with NHL present with unexplained fever, sweats, or weight loss ("B symptoms"), and lymphadenopathy. Extranodal disease often is present at the time of diagnosis. Common sites of extranodal disease include the CNS, gastrointestinal (GI) tract, lungs, and bone marrow.

S: Subjective

Patients may complain of enlarged lymph nodes and often report B symptoms such as fever, weight loss, and night sweats. B symptoms are present in 80% of patients with systemic AIDS-related NHL. In patients with these complaints, it is important to exclude opportunistic infections (OIs) when evaluating for lymphoma.

Headaches, seizures, and altered mental status often are present in patients with CNS lymphoma.

Other symptoms may include changes in bowel habits, GI bleeding, abdominal pain, and early satiety, shortness of breath, and cough.

Take a careful history, asking about the symptoms described above, their duration, severity, progression, and any associated symptoms.

Inquire about current or recent CD4 cell counts and the CD4 nadir. Ask whether the patient is taking ART or OI prophylaxis.

O: Objective

Measure vital signs and weight; compare with previous values.

Perform a complete physical examination with special attention to:

• General appearance and nutritional status (appearance of illness, cachexia)
• Skin (pallor, jaundice)
• Lungs (effusion, abnormal sounds)
• Abdomen (hepatosplenomegaly)
• Lymph nodes (note size, consistency, mobility, and degree of tenderness)
• Nervous system, including mental status

A: Assessment

The differential diagnosis is broad and is determined in part by the patient's CD4 count. It includes both infectious and noninfectious etiologies, such as:

• Other malignancies, including Hodgkin disease
• HIV infection; persistent generalized lymphadenopathy
• Immune reconstitution syndrome
• Mononucleosis; Epstein-Barr virus infection
• Mycobacterium avium complex (MAC)
• Tuberculosis
• Histoplasmosis, other fungal diseases
• Toxoplasmosis (for CNS disease)
• Progressive multifocal leukoencephalopathy (PML) (for CNS disease)
• Bartonella
• Lymphogranuloma venereum
• Castleman disease

P: Plan

Diagnostic Evaluation

Definitive diagnosis of lymphoma requires identification of lymphomatous cells, usually obtained by excisional biopsy.

Biopsy of lymph node or other site

Rapidly expanding or otherwise abnormal lymph nodes or masses should be biopsied. Fine needle aspiration (FNA) biopsy may determine the diagnosis, but excisional biopsy should be obtained if the FNA is unrevealing. (Also, FNA may not yield enough cells for definitive diagnosis). See chapter Lymphadenopathy for more information.

Other that studies help to determine the extent of involvement, rule out other diseases, and determine the patient's clinical status include complete blood count (CBC) with differential, liver function tests, electrolyte and lactate dehydrogenase (LDH) measurements, and peripheral blood smear. (Otherwise-unexplained cytopenias and peripheral blood smear abnormalities may suggest bone marrow involvement. Elevated LDH is nonspecific but may be seen in patients with lymphoma.)

Perform blood cultures, MAC culture, tuberculosis studies, serum cryptococcal antigen, or other laboratory work as indicated by the patient's symptoms.

Radiographic studies

Patients with unexplained CNS symptoms or signs should receive brain imaging by computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI); MRI is the more sensitive study. See chapter Neurologic Symptoms for more information.

Perform chest x-ray and CT scans of other areas as indicated by the patient's presentation. Positron emission tomography or gallium scanning also may be used to assess the extent of the disease.

Cerebrospinal fluid studies

Lumbar puncture (LP) should be performed in all persons diagnosed with NHL and in those suspected of having CNS lymphoma (brain imaging should be obtained first to rule out the presence of mass lesions that might cause herniation upon LP). Studies should include cytology, cell count, protein and glucose measurements, and any studies needed to rule out infections or other causes of the patient's symptoms (eg, bacterial, mycobacterial, and fungal cultures).

Bone marrow biopsy

This procedure may yield the diagnosis if other studies are negative. It also should be performed for patients with known NHL to assess for bone marrow involvement.

Treatment

If possible, patients should be evaluated and treated by an oncologist experienced in the treatment of HIV-related malignancies. Systemic chemotherapy is the only curative treatment, but the optimal treatment for AIDS-related NHL has not been defined. The standard regimen for advanced disease is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), though the specific treatment will depend on the specific type of lymphoma and on patient characteristics. In patients with very low CD4 cell counts, rituximab may be withheld because of the risks of further immunosuppression. Patients with meningeal involvement should receive concomitant intrathecal chemotherapy (medication given directly into the CNS via a lumbar puncture or Ommaya reservoir) using methotrexate and cytarabine.

Patients treated with ART in addition to chemotherapy appear to have better survival rates than do those treated with chemotherapy alone. Therefore, all patients should receive ART, if possible, in addition to chemotherapy.

Prognosis is dependent on the type and stage of the lymphoma and on the stage of HIV disease. A CD4 count of <200 cells/µL, extranodal disease including bone marrow, and a poor performance status are indicative of a poor prognosis. Patients with Stage IV NHL and very low CD4 counts usually have a life expectancy of <6 months. However, 50% of those patients may die from an OI rather than from the lymphoma. Patients who achieve a complete response with chemotherapy have a survival benefit that may range from 6 to 20 months or longer. In general, outcomes are better in patients taking ART for their HIV infection.

Patient Education

• Successful treatment of NHL requires meticulous adherence to the treatment plan. Patients who sporadically receive treatment put themselves at risk for the adverse effects of treatment but may receive little of the benefit. Advise patients to take all of their medications exactly as prescribed and to attend all of their scheduled chemotherapy and follow-up clinic appointments.
• Different chemotherapy regimens have different side effect profiles. Not all patients who receive chemotherapy will be nauseous or lose their hair. Educate patients about the possible side effects of chemotherapy and other medications and advise them to call their health care providers if they develop these.
• Encourage patients who are not taking ART to agree to start; emphasize the importance of close adherence.
• Emphasize to patients the importance of medications in preventing OIs, if these are indicated.

References

• Biggar R, Engels E, Ly S, et al. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr. 2005 Jul 1;39(3):293-9.
• Bonnet F, Jouvencel AC, Parrents M, et al. A longitudinal and prospective study of Epstein-Barr virus load in AIDS-related non-Hodgkin lymphoma. J Clin Virol. 2006 Aug;36(4):258-63. Epub 2006 Jun 9.
• Cassidy J, Bissett D, Spence RAJ, eds. Oxford Handbook of Oncology. Oxford Press: New York. 2002:551-570.
• Diamond C, Taylor TH, Im T, et al. Highly active antiretroviral therapy is associated with improved survival among patients with AIDS-related primary central nervous system non-Hodgkin's lymphoma. Curr HIV Res. 2006 Jul;4(3):375-8.
• Pazdur R, Coia L, Hoskins W, et al, eds. AIDS-Related Malignancies. In: Cancer Management: A Multidisciplinary Approach. 9th ed. CMP Healthcare Media: Manhasset, NY. 2005;639-663.
• Pazdur R, Coia L, Hoskins W, et al, eds. Non-Hodgkin's Lymphoma. In: Cancer Management: A Multidisciplinary Approach. 9th ed. CMP Healthcare Media: Manhasset, NY. 2005;697-747.