Challenges in lymphoma diagnosis in HIV positive patients in the South African setting

Abstract

An increase in high grade B-cell lymphomas has been noted in HIV infection. Sub-Saharan Africa is the epicentre of the epidemic and in Gauteng, South Africa >90% of patients with high grade lymphoma tested positive for HIV infection. The diagnosis of lymphoma may be challenging in HIV because of reactive conditions which mimic lymphomas, the atypical clinical presentation and the atypical histological findings. The WHO classification divides lymphomas into discrete categories. Despite this, tumours in HIV positive patients commonly show atypical morphological, immunophenotypic, molecular and cytogenetic features, making exact classification difficult. This has lead to an increase in the diagnosis of the highly aggressive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and BL. It appears likely that HIV-associated lymphomas represent a continuum of disease.

Introduction

The majority of people (∼68%) living with HIV are in sub-Saharan Africa [1], with South Africa having the highest number of cases world-wide [2]. Estimates suggest the prevalence of HIV infection in South African adults (ages 15–49 years, 2009/2010) is 17–18% and approximately 300,000–350,000 new infections occur annually [3]. Although substantial improvements have been made in access to highly active antiretroviral therapy (from 4% of those requiring therapy in 2004 to 40–60% in 2009 and 75% in 2011) [4], [5], [6], therapy is started late in the course of the disease once significant immunosuppression has already occurred [4], [7], [8]. For this reason, end-stage organ damage is prevalent. Duration of detectable viraemia and both nadir and a prolonged period with a low CD4 count both increase the risk of HIV-related malignancies [9], [10], [11].

Lymphoma has been recognized as an AIDS-defining malignancy since the first descriptions of the disease in 1984 [12]. International data suggest an increased risk of more than a hundred fold for lymphoma development in the setting of HIV infection prior to the initiation of highly active anti-retroviral therapy (HAART) [13]. Possible aetiologic factors in the development of lymphoma include reduced immunosurveillance and immune dysregulation, new and reactivated oncogenic viral infections, possible direct oncogenic effect of HIV related proteins and chronic antigenic stimulation [11], [14], [15], [16].

HIV-infection has been associated with specific types of lymphoma. These are predominantly high grade B-cell tumours and include Burkitt leukaemia/lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL), Plasmablastic lymphoma (PBL), Primary effusion lymphoma (PEL), Large cell lymphoma arising in HHV-8 associated multicentric Castleman’s disease and the recently added provisional category of B-Cell Lymphoma unclassifiable, with features intermediate between DLBCL and BL (BCLU) [17], [18].

In sub-Saharan Africa, accurate epidemiologic, aetiologic and clinical data is minimal. South African data, however, indicates that the incidence of lymphoma may be much lower in African settings than in the first world [19], [20], [21]. Preliminary studies conducted by our group suggest that HIV-related lymphomas in the Gauteng region of South Africa are increasing in number with increasing HIV prevalence and this is reflected by the high grade subtypes seen in state hospitals [22], [23]. In the 2007–2009 study periods, 62% of all patients diagnosed with lymphoma and greater than 90% of patients diagnosed with high grade B-cell lymphoma that were tested for HIV infection, were HIV infected [23].

In under-resourced environments, early diagnosis remains one of the best predictors of improved outcome. Accurate diagnosis remains a challenge, however, because of limited patient access to advanced diagnostic modalities, late patient presentation and atypical presentation [19]. In this review, we will discuss diagnostic predicaments which are common in our experience of the diagnosis of HIV-related lymphoma.