In this large series of Ugandan children with epidemic KS, LN involvement was observed in the majority of cases. Lymphadenopathic KS appeared to be a discrete clinical presentation, which tended to occur in younger children and at higher CD4 T-cell counts. Of those KS cases with a documented outcome, a large proportion responded to treatment with chemotherapy and/or ART.
In adults with endemic KS, disease is typically limited to the skin, while HIV-associated KS tends to be more aggressive, and oral cavity and visceral lesions are common. Although lymphatic obstruction and lymphedema are frequent features of KS in HIV-infected adults, prominent LN involvement has been reported less often [15
]. In contrast, we observed LN involvement in the majority of children, which tended to occur more often at younger ages. This association between younger age and KS lymphadenopathy has been reported previously among children both with and without HIV infection [6
Lymphadenopathy has been associated with HHV-8 seroconversion in adults [20
], suggesting that a mononucleosis-like syndrome might occur in some persons with primary HHV-8 infection. An analogous pattern of disease may occur after infection with Epstein-Barr virus (EBV) infection, the most similar human herpesvirus to HHV-8, and the development of EBV-associated Hodgkin lymphoma. Hjalgram et al. [22
] found patients with infectious mononucleosis to have a relative risk of EBV-associated Hodgkin disease that peaked in less than 3 years after acquiring EBV infection. Perhaps lymphadenopathic KS in susceptible individuals results from a rapid progression from the onset of HHV-8 infection to the development of malignancy.
Susceptibility to rapid progression to KS would appear to be mediated by factors other than advanced HIV disease, as lymphadenopathic KS was associated with higher CD4 T-cell levels. Furthermore, after adjustment for CD4 T-cell count, age no longer predicted LN involvement of KS. This suggests that, although lymphadenopathic KS is observed more often in children, younger age may not be causal. Rather, the preponderance of lymphadenopathic KS among children may be a function of the early age at which HHV-8 infection is acquired in endemic areas [23
]. There is evidence that HIV-infected adults who become infected with HHV-8 are more likely to develop KS than those who are infected with HHV-8 prior to HIV [26
]. Unlike most adults with KS in Uganda, HIV infection in the majority of these children was likely acquired before HHV-8 infection at birth or through breastfeeding. This temporal difference may contribute to the apparent differences in KS presentation in children compared to those in adults.
Several limitations of this study should be noted. Histopathology reports were documented for only 26 patients. Although biopsy is routinely performed for confirmation of KS diagnosis among patients at the UCI, records were unavailable for some patients. Therefore, some lymphadenopathy may have been due to causes other than KS, including HIV itself [14
]. The treatment response rate observed was almost certainly biased by the large number of children lost to follow-up, among whom we expect disproportionately poor outcomes. Furthermore, interpretation of these outcome data is complicated by the lack of information about co-morbidities, length of treatment, and duration of response.
The number of favorable outcomes recorded for children in this series is encouraging. However, prospective studies in children, including controlled trials of antiretroviral and cancer chemotherapy drugs are needed. Children with KS may respond differently to chemotherapy than adults, requiring alternate regimens. Current state of the art regimens used for adult KS patients in resource-rich countries, such as liposomal doxorubicin, have not been evaluated in children and may not be appropriate for use in resource-poor settings [27
]. Future studies to elucidate the viral and host factors that lead to KS may result in additional treatment options. Ideally, such knowledge would also inform rational interventions to prevent HHV-8 infection and/or its progression to malignancy.