In this study, we sought to validate the recent finding that the expression of HGAL at the time of diagnosis is related to outcome in patients with cHL. It is absolutely necessary to validate the prognostic power of each newly identified biomarker in an independent cohort of patients. In addition, we aimed to determine if HGAL can be combined with clinical factors to identify subgroups with particularly good or poor prognosis.
The selected cohort of patients had features similar to the general cHL population at presentation. Furthermore, the response to the ABVD therapy in this cohort is similar to previously reported results achieved with this therapeutic approach [1
], thus indicating that the studied cohort is representative of the general patient population with cHL. Our findings demonstrate that HGAL expression is correlated with FFS, but not with overall survival in patients with cHL. The association of a positive HGAL stain with improved FFS remained significant in the multivariate analysis, along with stage, over-riding the effect of B symptoms and performance status. Since the prognosis of patients with HL is excellent with reported cure rates approaching 80–90%, defining HL subgroups with 15% difference in FFS is clinically relevant. These findings are concordant with our previous observations that HGAL expression predicts improved failure-free survival of patients with cHL, but failed to confirm HGAL’s predictive power for overall survival. This discrepancy may be related to the different salvage approaches used in this study and previously reported cohorts of patients, since the overall survival accounts for the effects of different salvage regimens given to patients with primary resistance to treatment, and to those who relapsed after a complete remission. In contrast, FFS is a better indicator of response to initial therapy and its correlation with HGAL expression confirms that this biomarker can be useful for the identification of cHL subgroups with distinct response to the standard initial therapy.
The confirmation that HGAL, a protein highly specific to GC-derived lymphomas, is expressed in 70–80% of patients with cHL sheds light on the pathogenesis and derivation of this disease. Although HRS cells were found to be of B cell origin due to the presence of rearranged and somatically mutated Ig V genes, they show an immunophenotype that is different from any other cell in the hematopoietic system, with co-expression of markers unrelated or not specific to the B lineage since the B-lineage-specific gene expression program was shown to be lost in HRS cells [11
]. Although IL-4- and IL-13-induced signaling may contribute to HGAL expression and regulation [8
], its expression in cHL cells most likely represents its derivation from GC B-cells. Although the function of HGAL is largely unknown, recent studies revealed that it affects the motility of normal GC lymphocytes as well as lymphoma cells [12
]. Whether HGAL may affect additional characteristics of malignant lymphocytes that could contribute to the improved response to therapy and better clinical outcome is currently under intense investigation.
In conclusion, this study validates the recent finding of a correlation between HGAL protein expression and patient outcome in a large, clinically well-characterized and uniformly treated representative cohort of patients with classical HL. HGAL retained its independent predictive power for FFS in the multivariate analysis, when individual components of the IPS were incorporated, but it was not an independent predictor when the IPS itself, composed of multiple clinical variables, was introduced in the analysis. While this finding indicates that HGAL expression may not have additional prognostic value over the IPS alone, the results of this study suggest that there may be underlying differences in the biology of cHL tumors. Consequently, identification of prognostic markers such as HGAL, along with other similarly validated markers, may not only improve our prognostic ability in cHL but may also elucidate the complex biology of these tumors.