MAL Is Expressed in a Subset of Hodgkin Lymphomas and Identifies a Population of Patients with Poor Prognosis.

Recent evidence suggests that classical Hodgkin lymphoma (cHL) and primary mediastinal diffuse large B-cell lymphoma (PMLBL) have similarities that span clinical, histopathologic, and molecular genetic features. MAL is a gene that encodes a protein associated with lipid rafts in T-cells and epithelial cells. In T-cells, it is involved in the reorganization of lipid rafts during T-cell receptor activation and signaling. MAL is overexpressed in PMLBL and in a minority of cHL cases; however, data on its expression in a large series of cHL with clinical follow-up is lacking. In order to determine whether there might be some clinical significance associated with MAL expression, we evaluated MAL expression in a series of cHL by immunohistochemistry. Clinical information including age, sex, stage, bulky tumors (≥ 1/3 of the thoracic diameter or mass ≥ 10cm), hemoglobin, WBC, lymphocyte count, albumin, and outcome were collected for the cHL patients. Tissue microarrays containing diffuse large B-cell lymphoma (n=33), PMLBL (n=41), and cHL (n=87) were stained for MAL. 54% of PBLBL, 17% of cHL, and 3% of non-mediastinal diffuse large B-cell lymphomas were found to express MAL. Focussing on cHL, MAL expression correlated with the nodular sclerosis histologic subtype (P=0.03, Fisher exact). Overall, 22 HL patients have failed (relapse or death) and 15 patients have died. Median follow-up of patients alive and free of disease is 6.7 years (range 1.0–16.9 years). The 5-year failure-free and overall survival are 75 +/− 5% and 85 +/−4%, respectively. Using P<0.1 as significant, univariable analysis (Wilcoxon rank sum) showed that the following factors were associated with shorter failure free survival and overall survival: age ≥ 45 (P=0.01 and P<0.001, respectively), stage III/IV (P=0.09 and P=0.03, respectively), and MAL expression (P=0.05 and P=0.01, respectively). Cox proportional hazards modeling showed that the following were independent predictors of both time to treatment failure and overall survival: age (P=0.03 and 0.01, respectively), stage (P=0.06 and 0.04, respectively), and MAL expression (P=0.06 and 0.02, respectively). These data suggest that MAL expression in cHL identifies a biologically different subset of cHL compared to those cases that lack MAL and that MAL expression is a predictor of adverse outcome.