6.2 MANAGEMENT OF HIV-ASSOCIATED LYMPHOMA
The immunodeficiency state in HIV infection predisposes one to the development of both opportunistic infections and neoplasms. In the latter case, lymphoma is usually a late manifestation. The incidence of different types of lymphoma including Hodgkin's disease, non-Hodgkin lymphoma (NHL) and T-cell lymphoma is increased in HIV infected individuals, though only immunoblastic and primary central nervous system (CNS) lymphoma are increased significantly. Three kinds of HIV-associated lymphoma are included as an AIDS-defining illness under the Centres for Disease Control (CDC) classification system - Burkitt's, immunoblastic and primary CNS lymphoma.1 In Hong Kong, NHL has accounted for 2.2% (up to end of 2000) of all AIDS defining illnesses reported over the years.
Epidemiologically, all exposure categories appear to be at equal risk to the development of lymphoma. With the widespread use of highly active antiretroviral therapy (HAART), the incidence of primary CNS lymphoma is apparently declining due to improved immunity. However, the absolute number of reported NHL may paradoxically rise as life expectancy increases.
There are two main clinical types of HIV-associated lymphoma - systemic lymphoma arising in the periphery, and CNS lymphoma limited to the central nervous system. Large overseas studies suggested that systemic lymphoma was the commoner of the two.2 The average CD4 cell count at which HIV-associated systemic lymphoma occurs is around 100 cells/mm3, compared to less than 50 in CNS lymphoma. The latter carries a worse prognosis. Between 12% to 16% of HIV infected individuals eventually die of lymphoma. Other unusual types of HIV-associated lymphoma are primary effusion lymphoma, Hodgkin's Disease and T-cell lymphoma.3
Pathologically, AIDS related lymphoma arises as a consequence of long-term stimulation4 and proliferation of lymphocytes due to HIV itself as well as to reactivation of prior EBV infection secondary to immunosuppression.5 Activation of c-myc and bcl oncogene is probably involved in the pathogenesis.6 Two-thirds of AIDS associated lymphoproliferative disorders are of high grade aggressive types including either B-immunoblastic or small cell non-cleaved lymphoma (either Burkitt or non-Burkitt subtype). The remaining third are intermediate grade diffuse large cell lymphoma.7
The algorithms for managing HIV-associated lymphoma are provided at the end of this chapter.
I. Diagnosis of lymphoma in HIV/AIDS
The main differential diagnoses of HIV-associated lymphoma are other causes of lymphadenopathy, notably Persistent Generalised Lymphadenopathy (PGL) and other infections. The characteristic features which might suggest lymphoma as opposed to reactive lymphadenopathy include rapidity of growth, asymmetry, extranodal involvement, and a relatively low CD4 cell count. Fluctuation of lymph node size over time is quite characteristic of PGL. Early diagnosis of lymphoma in patients with HIV infection can be difficult since reactive lymph node enlargement is quite common while extranodal involvement is not uncommon in the setting of HIV infection. For systemic lymphoma, extranodal diseases could occur in such sites as the liver, gastrointestinal tract, bone marrow, and rarely subcutaneous and soft tissues, presenting with corresponding symptomatology in the organ system. On the other hand, opportunistic infections like toxoplasmosis may mimic primary CNS lymphoma. It is important to note that tuberculosis (TB) can present as lymph node enlargement.
It is of prime importance not only to ascertain the diagnosis of lymphoma, but the histological typing and staging before initiation of treatment. A high index of clinical suspicion is crucial in making a diagnosis of HIV-related lymphoma promptly. Other investigations may be indicated to differentiate lymphoma from other lesions. Some examples are:
Investigations should then be followed by measures to obtain histological diagnosis. Though fine needle aspiration biopsy of lymph node may be helpful in the diagnosis of certain infections, it has not replaced conventional excisional biopsy. The latter is still preferred in the evaluation of lymphadenopathy if the suspicion of lymphoma is imminent.
II. Assessment of a case of lymphoma
Assessment of a case of lymphoma determines the prognosis and the plan of treatment. Several factors are associated with shortened survival in patients with AIDS related lymphoma. These include CD4 < 100 cells/mm3, history of AIDS prior to the diagnosis of lymphoma, advanced stage, older age (greater than 35 years), poor performance status, primary CNS lymphoma, injecting drug use and elevated LDH level.
The histology and extent of disease provide guidance to treatment. Histologically, HIV-associated NHL is often aggressive and is of high or intermediate grade. Clonality measurement may be another factor for assessing prognosis, with a better survival for monoclonal versus polyclonal lymphoma.8 A staging work-up is suggested in Box 6.2, although it has small impact on treatment in patients with NHL. The Ann-Arbor staging system, originally derived for use in Hodgkin's disease, is commonly adopted (Box 6.3).
III. Treatment of HIV-associated lymphoma
In principle, high-grade lymphoma should be treated aggressively with curative intent. However, initial studies with aggressive regimens yielded dismal results with only a fraction of patients achieving complete remission and a high frequency of relapse and fatal opportunistic infections. The quality of life was severely undermined. Hence the planning of treatment needs to be guided by the clinical, virological and immune status of the patient, the histology and staging of the lymphoma, as well as the potential treatment complications. Oncologic consultation is recommended.
III.A Treatment of systemic lymphoma
At the outset of the AIDS epidemic in the early 1980s, the use of dose intensive therapy was considered for HIV-associated systemic lymphoma. The results were generally poor, which could be related to the toxicity of chemotherapy, and/or the poor immune status of patients treated. A modified form of chemotherapy using a lower dose has since replaced standard chemotherapy as the recommended form of therapy. Outcome is generally poor in those who fail the initial regimen. In practice the following regimens can be considered:
As CNS relapse is common, routine lumbar puncture with CSF cytological analysis and prophylaxis is recommended as long as it is not contraindicated on the results of CT or MRI scan.15 As systemic lymphoma occurs rarely in conjunction with primary CNS lymphoma, extensive routine evaluation is unnecessary in most patients unless there is CSF seedling. In such instance, local treatment with radiotherapy is warranted. The benefit of combination chemotherapy followed by whole brain irradiation is not ascertained.
III.B Treatment of primary CNS lymphoma
Whole brain irradiation is the treatment of choice for primary CNS lymphomas although the outlook is generally gloomy. Other alternatives are intrathecal ara-C or methotrexate, or combined chemotherapy and radiotherapy. A therapeutic trial of anti-toxoplasma treatment can be considered if histological diagnosis is not available.
III.C Other treatment issues
The prognosis of HIV-associated lymphoma is linked partly with the patients' immune status. The advent of highly active antiretroviral treatment (HAART) can probably be used safely but with caution in conjunction with multiple chemotherapy for lymphoma. The success of HAART in improving the immunological status as well as general well being of a patient is likely to make standard therapies more tolerable. This would favour approaches that involve dose-escalation rather than reduction in future.
One potentially fatal complication of chemotherapy is the development of neutropaenia. G-CSF can be used in HIV patients in conjunction with chemotherapy.
References