Grey Zone Lymphoma, Unclassifiable With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma: Better Results With CHOP-Like Regimens
Authors: Nadeem Omar , Treaba Diana O , Castillo Jorge J , Butera James N 
Published: October 2019

Abstract

Background
Grey Zone Lymphoma (GZL), with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (CHL), is a relatively new entity per the latest WHO classification. Limited clinical data exists on this rare lymphoma and the ideal management remains uncertain. We performed a comprehensive literature review of reported cases to better define its clinical characteristics and the natural history of this rare entity.

Methods
A comprehensive MEDLINE search was performed using key words “gray zone or grey zone or unclassifiable or indeterminate and lymphoma” through July of 2013. Cases were included in the analysis if they met the pathological definition of GZL as defined by the WHO criteria, based on the typical morphological and immunophenotypic pattern. Cases without primary patient data were excluded. Of the 554 abstracts reviewed from the primary MEDLINE search, 45 articles met study criteria for review. Of those, 8 articles involving 39 cases met criteria for inclusion in our analysis. Two additional cases were identified at our local institution. Comparison of complete response (CR) rates between ABVD-like and CHOP-like regimens was calculated using Fisher’s exact test. P-values <0.05 were considered statistically significant.

Results
Of the 41 cases included in this analysis, the median age of presentation was 33.5 (range 13-85) with a slight male predominance (59%). B symptoms were present in 77% of cases and 75% presented with early stage (I or II). Mediastinal lymphadenopathy was the most common site of disease (89%). Pathological data were available for analysis in all 41 patients. Sixty-eight percent of cases had a morphological appearance of CHL with Reed-Sternberg cells. Immunophenotype revealed positivity for CD20 (90%), CD30 (95%), CD15 (63%), CD45 (73%), CD79a (100%), BOB1 (72%), OCT2 (89%) and PAX5 (100%). Forty-one percent were positive for EBV based on EBER and/or LMP1 expression. Clinical outcome data were available for review for 20 of the 41 patients Treatment was variable and included either initial CHL regimens (ABVD, BEACOPP) or DLBCL regimens (CHOP, EPOCH, with or without rituximab). Seven patients received initial treatment with ABVD-like regimens, of which 4 did not show a response, 3 achieved a partial response (PR) and there were no reported complete responses. Of the seven patients treated with CHOP-like regimens, 5 had clinical outcome data available. Four patients achieved a CR, 1 patient achieved a PR (Fisher’s for CR rate P=0.01). All patients that achieved CR after CHOP-like regimens received consolidation radiation therapy. Seven patients underwent an autologous stem cell transplantation, of which there were two reported relapses within the first 6 months. The median follow up for the entire cohort was 15 months and the 2-yr overall survival (OS) was 87% with a median OS that was not reached.

Conclusions
GZL, with features intermediate between CHL and DLBCL, is a rare entity with variable prognosis. This lymphoma subtype commonly presents at an early stage with B symptoms and mediastinal involvement. A high proportion were EBV positive. None of the patients that received initial ABVD-like regimens achieved a CR. The response rates were higher in patients that received initial CHOP-like regimens, although the sample size was small. Additional studies are warranted to better understand the optimal treatment regimens in these patients.

Disclosures:
No relevant conflicts of interest to declare.