Case Report Hepatosplenic gd T-cell lymphoma following seven malaria infections Rocío Hassan, 1 Sergio A. L. Franco, 2 Claudio Gustavo Stefanoff, 1,3 Sergio O. Romano, 4 Hilda R. Diamond, 1 Luiz G. P. Franco, 2 Héctor N. Seuánez 5,6 and Ilana R. Zalcberg 1 1 Bone Marrow Transplantation Center, 4 Pathology Department and 5 Genetics Division, National Institute of Cancer, 2 Hematology Department, DAHO Clinic and 3 Postgraduate Program in Clinical Medicine, 6 Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Hepatosplenic gd T-cell lymphoma (HSTL) is a clinico- pathological entity associated with an immunocompro- mised status in approximately 25% of patients. Herein is described a case of HSTL in a 53-year-old Brazilian man with seven previous malaria infections, initially misdiag- nosed as a hyperreactive splenomegaly due to chronic malaria. A characteristic lymphoid infiltrate was observed in spleen, liver and bone marrow sinusoids/sinuses. Neo- plastic cells had a CD45RO+, CD2+, CD7+, CD3+, CD5–, CD8+, CD56+, perforin+, FasL-negative, T-cell receptor (TCR)ab-negative, TCRgd+ profile. Analyses of g and d TCR rearrangements confirmed diagnosis of gd T-cell lym- phoma by detecting Vg I/Vd1-Jd1 clonal rearrangements. Sensitive polymerase chain reaction (PCR) for Plasmo- dium falciparum, Epstein–Barr virus and herpesvirus-8 failed to demonstrate infection. The disease progressed to a fatal outcome following cutaneous infiltration and leuke- mic proliferation. The authors also comment on the asso- ciation of lymphoma and infection, focusing on PCR diagnosis of TCRg and d clonal rearrangements and the presumed pathogenic events leading to HSTL in the context of chronic malaria infection. Initial lymphomagenic stages might not be direct consequences of antigenic stimulation of Vd1 T-cells, but might depend on interac- tions between gd T and B cells during cooperative or regu- latory responses to Plasmodium sp. Key words: Hepatosplenic gd lymphoma, malaria, TCR gene rearrangements The proposed association between cancer and infection relies on the observation that infectious agents, by inducing cell proliferation due to strong antigenic stimuli, increase the risk of acquiring mutations while progressively draining and impairing T-cell-mediated antitumor surveillance. 1 This is coincident with cancer prevalence in immunocompromised hosts 2 or in situations of excessive immune stimulation. 3 Malaria provokes a suite of vigorous serological and cel- lular responses 4 to which the endemic type of Burkitt’s lym- phoma, in Epstein–Barr virus (EBV)-infected individuals, is associated. 5,6 In this process, and consequently to a translo- cation of MYC to the Ig loci, a small, EBV+, B-cell clone with disregulated MYC expression acquires a transformed phe- notype and continuously expands in response to malaria- induced antigenic super-stimulation and scarcity of cytotoxic T lymphocytes (CTL). 6,7 Recently, a novel splenic B-cell lym- phoma, ethiopathogenically related to a malaria-induced massive splenomegaly, was described in Africa, in which chronic antigenic stimulation and immune impairment were postulated as pathogenic factors. 8,9 Hepatosplenic gd T-cell lymphoma (HSTL) is a rare, aggressive entity associated with an immunocompromised status in approximately 25% of patients. 10–13 It is predominant in young adult male patients and is characterized by hepatosplenomegaly, peripheral blood cytopenias, sinusal/ sinusoidal localization of malignant cells in spleen and liver and an aggressive course. 10 Diagnosis of HSTL is difficult as in other peripheral lymphomas with splenic commitment. Moreover, in tropical regions, hepatosplenomegaly with sinu- soidal lymphocytosis is associated with several other condi- tions 14 imposing additional difficulties for diagnosing B- and T-cell lymphomas. Here we report a case of HSTL in a patient who suffered at least seven previous malaria infections. Methodological aspects involved in diagnosis and the presumed relationship between HSTL and malaria are discussed. Correspondence: Rocío Hassan, PhD, Instituto Nacional de Câncer (INCA) Bone Marrow Transplantation Center (CEMO), Praça da Cruz Vermelha 23, 6° Andar, 20230-130, Rio de Janeiro, RJ, Brazil. Email: biomol@inca.gov.br Received 13 October 2005. Accepted for publication 2 July 2006. © 2006 The Authors Journal compilation © 2006 Japanese Society of Pathology Pathology International 2006; 56: 668–673 doi:10.1111/j.1440-1827.2006.02027.x