Implication of HTLV-I Infection, Strongyloidiasis, and P53 Overexpression in the Development, Response to Treatment, and Evolution of Non-Hodgkin's Lymphomas in an Endemic Area (Martinique, French West Indies)

Abstract

A clinicopathologic study was conducted to assess the implication of HTLV-I infection, Strongyloides stercoralis (Ss) infection, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphoma (NHL) in Martinique, French West Indies. Two groups of patients, with 22 and 41 participants with B-cell and T-cell lymphoma, respectively, were analyzed. HTLV-I antibodies were detected in 24 (59%) patients with T-cell lymphoma of whom 19 (46%) fulfilled diagnostic criteria of adult T-cell leukemia/lymphoma (ATLL). By comparison with other T-cell lymphomas, patients with ATLL were significantly younger (52 versus 63 years; p = .03), had a significantly higher incidence of hypercalcemia (60% versus 0%; p = .0001), a trend for higher incidence of digestive tract localization (21% versus 4%; p = .1) and significantly shorter median survival (6 versus 17 months; p = .03). Similar results were observed when all 24 HTLV-I-infected patients with T-cell lymphoma were compared with the 17 seronegative patients. Strongyloidiasis was diagnosed in 11 of 34 patients tested for Ss infection. All 4 Ss-infected (Ss-positive) ATLL patients treated with combination chemotherapy achieved complete remission (CR) versus only 2 of 7 Ss-negative ATLL patients (p = .04). In addition, survival of Ss-positive patients with ATLL was better than that of the uninfected patients: 27 versus 5 months, p = .04, respectively). P53 expression was assessed by immunohistochemistry on lymph node biopsies from 37 patients including 18 B-cell lymphomas, 14 ATLL, and 5 other T-cell lymphomas. P53 overexpression (P53-positive) was observed in 6 samples that corresponded in all 6 patients with ATLL. All P53-positive ATLL patients had stage IV disease with elevated lactate dehydrogenase (LDH) levels. By comparison with other ATLL patients studied for p53 expression, P53-positive ATLL were characterized by a lower response rate to combination chemotherapy (CR: 0 of 6 versus 4 of 6; p = .04) and a shorter survival (2 versus 9 months, p = .04). Our results suggest that ATLL represents almost 50% of T-cell lymphomas in Martinique; Ss infection during ATLL seems to be linked with a high response rate to chemotherapy and prolonged survival; and P53 overexpression is observed in almost 50% of aggressive ATLL from Martinique and, even in advanced clinical subtypes, is associated with resistance to chemotherapy and short-term survival.

Current views in HTLV-I-associated adult T-cell leukemia/lymphoma

“…Several cycles of transient active proliferation combined with chromosomal instability may be required for a clonal selection and the development of adult T-cell leukemia. In support of such a model, a high frequency of T-cell clonal expansion has been associated with chronic antigenic stimulation in carriers of S. stercoralis [122,123], and a higher frequency of leukemia has been reported in individuals carrying this parasite [124][125][126].…”

Effect of treatment of Strongyloides infection on HTLV‐1 expression in a patient with adult T‐cell leukemia

“…Alternatively, Strongyloides may have caused general immunosuppression that permitted HTLV-1 replication and spread, which reversed after ivermectin treatment with associated weight gain and decreased intestinal inflammation. Expansion of infected T-cells may enhance genetic instability resulting in inactivation of DNA repair mechanisms, predisposing to cancer [3,21,22]. Thus, Strongyloides and HTLV-1 coinfection may lead to ATLL in a manner parallel to coinfection with malaria and Epstein-Barr virus which has been linked to Burkitt's lymphoma [23].…”

“…This is based on epidemiologic association of Strongyloides and HTLV-1 infections in Brazil, the Caribbean Islands, and Southern Japan, and from small clinical series reporting more severe disease manifestations in the presence of both infections than with either one alone [2][3][4]. The mechanism for the synergism between these two infectious agents is unclear.…”

High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis

“…In Martinique, the French West Indies, the prevalence of Ss infection in the general population is about 2% whereas 20% of Ss-infected individuals are coinfected by HTLV-1 (Patey et al, 1992). In the same area, the prevalence of Ss infection in ATLL is 42 versus 23% in other T-cell lymphomas (Agape et al, 1999). Pathogenically, EBV-associated lymphomagenesis is assumed to result from the malaria-associated chronic stimulation of germinal center cell proliferation together with a possible acquired EBV-speci®c T-cell immune de®ciency.…”