Expression of the Human Germinal Center Associated Lymphoma (HGAL) Protein Identifies a Subset of Classical Hodgkin Lymphoma of Germinal Center Derivation and Improved Outcome.

Classical Hodgkin lymphoma (CHL) exhibit crippled somatic mutations in rearranged Ig genes and an immunophenotype unlike any other hematolymphoid malignancy. Expression profiles of CHL cell lines show that CHL is most closely related to EBV-transformed peripheral blood B-cells with marked loss of B lineage-specific gene expression. The Human Germinal center-Associated Lymphoma (HGAL) gene was identified as a candidate molecule that predicted improved outcome in diffuse large B-cell lymphoma. Previously, we showed that HGAL mRNA and protein are expressed specifically in germinal centers (GC), GC-derived lymphomas and a substantial proportion of CHL. Here, we sought to investigate whether HGAL protein expression could serve to distinguish biologically distinct subgroups of CHL. Ninety informative cases of CHL on a tissue microarray of 1.0 mm representative cores of paraffin embedded tissue were used. Staining was performed and the percent of stained Hodgkin cells was scored on a 3-tiered scale as negative (0%), weak (<30%), and strong (>30%), as previously described (Natkunam et al. Blood 2005, 105:3979–86). These cutoffs were chosen before results were correlated with clinical endpoints. Twenty-five patients (28%) showed no staining for HGAL and 25 patients (28%) had weak staining; HGAL was strongly expressed in 40 patients (44%). Thirteen of the 90 patients had died and 19 had failed (i.e. relapsed or died). The overall 5-year survival (OS) and failure-free survival (FFS) rates were 87% + 4% and 79% + 4%, respectively. HGAL expression was associated with improved OS in univariate analysis (p=0.04, no vs weak/strong staining), as were age < 45 years (p<0.001), stage I or II (p=0.02), and possibly histology (nodular sclerosing vs other, p=0.09). However, in multivariate analysis with age, stage and histology, HGAL expression no longer had an impact (p=0.93). HGAL did not impact FFS in either univariate (p=0.13) or multivariate analysis (p=0.87). The expression of the GC-specific marker HGAL in a subset of CHL suggests that a substantial proportion of CHL retain characteristics of lymphomas of GC derivation. The association with improved OS in univariate but not multivariate analysis suggests HGAL may be a biologic marker related to known clinical parameters of improved OS and FFS. Comparative studies with well-characterized GC markers, BCL6 and CD10, and with BCL2, MUM1 and Blimp-1 are underway to further define biologically distinct subsets of CHL. Analysis of additional cases of CHL is also on-going to substantiate these findings in multivariate analysis.