Arachidonic Acid Metabolism-Related Molecules as Candidate Markers in Subclassification of Lymphoma

Abstract

Arachidonic acid metabolites, like prostaglandins and leukotrienes, have been suggested to play an important role not only in inflammation but also in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1), a sister enzyme to 5-LO (which is essential for leukotriene synthesis), are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma (HL) and certain HL-derived cell lines, and that these cells convert arachidonic acid to the novel pro-inflammatory eoxins (Int J Cancer, 2008; FEBS J, 2008; PNAS, 2008). Given the pleiotropic effects of the CysLT1 receptor and 15-LO-1 and the fact that their expression is strictly regulated in a cell-type and tissue-specific manner, it was of interest to elucidate whether these proteins are exclusively expressed by the tumor cells of the classical HL entities. Therefore, the expression of these molecules was investigated by immunohistochemistry in a broad range of lymphomas (lymphocyte predominance (LP) HL, MALT lymphoma, T cell-derived anaplastic large cell lymphomas (ALCL), immunocytoma, mantle cell lymphoma, B-CLL, Burkitt lymphoma, follicular lymphoma, DLBCL, PTCL, primary mediastinal B cell lymphoma (PMBCL), T cell-rich B cell lymphoma; n=58). The tumor cells in one of four T cell-derived ALCLs, in contrast to all other studied non-Hodgkin lymphomas (NHLs) and LP HL tumors, strongly expressed 15-LO-1. PMBCL was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. These findings further corroborate the pathologic overlap between PMBCL and classical HL. Although most cases of PMBCL are identified by routine diagnostics, the distinction between PMBCL and DLBCL may be challenging. After future careful validation in extended patient series, the CysLT1 receptor may be a potential additional marker to phenotypically distinguish these two lymphoma entities.