GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers

Abstract

Background: Increased glycolytic activity is a hallmark of cancer, allowing staging and restaging with 18F-fluorodeoxyglucose-positron-emission-tomography (PET). Since interim-PET is an important prognostic tool in Hodgkin lymphoma (HL), the aim of this study was to investigate the expression of proteins involved in the regulation of glucose metabolism in the different HL subtypes and their impact on clinical outcome.

Methods: Lymph node biopsies from 54 HL cases and reactive lymphoid tissue were stained for glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and lactate exporter proteins MCT1 and MCT4. In a second series, samples from additional 153 HL cases with available clinical data were stained for GLUT1 and LDHA.

Results: Membrane bound GLUT1 expression was frequently observed in the tumor cells of HL (49% of all cases) but showed a broad variety between the different Hodgkin lymphoma subtypes: Nodular sclerosing HL subtype displayed a membrane bound GLUT1 expression in the Hodgkin-and Reed-Sternberg cells in 56% of the cases. However, membrane bound GLUT1 expression was more rarely observed in tumor cells of lymphocyte rich classical HL subtype (30%) or nodular lymphocyte predominant HL subtype (15%). Interestingly, in both of these lymphocyte rich HL subtypes as well as in progressively transformed germinal centers, reactive B cells displayed strong expression of GLUT1. LDHA, acting downstream of glycolysis, was also expressed in 44% of all cases. We evaluated the prognostic value of different GLUT1 and LDHA expression patterns; however, no significant differences in progression free or overall survival were found between patients exhibiting different GLUT1 or LDHA expression patterns. There was no correlation between GLUT1 expression in HRS cells and PET standard uptake values.

Conclusions: In a large number of cases, HRS cells in classical HL express high levels of GLUT1 and LDHA indicating glycolytic activity in the tumor cells. Although interim-PET is an important prognostic tool, a predictive value of GLUT1 or LDHA staining of the primary diagnostic biopsy could not be demonstrated. However, we observed GLUT1 expression in progressively transformed germinal centers and hyperplastic follicles, explaining false positive results in PET. Therefore, PET findings suggestive of HL relapse should always be confirmed by histology.

Figure 1

GLUT1 immunostaining.a, b. Reactive germinal centers showing membrane bound GLUT1 expression in follicular dendritic cells. c. GLUT1 expression in the enlarged mantle zone of a progressively transformed germinal center. d. NSCHL with membrane bound GLUT1 expression by the HRS cells. e. NSCHL with granular cytoplasmic expression of GLUT1 by the HRS cells. f. NLPHL with GLUT1 expression in the reactive B cells, but no GLUT1 expression in the LP cells.

Figure 2

LDHA, MCT4 and MCT1 immunostainings.a. NSCHL with strong cytoplasmic LDHA staining in the HRS cells. b. NLPHL with membrane bound expression of MCT4 in the LP cells. c. NSCHL with membrane bound expression of MCT1 in the HRS cells. d. LRCHL with nuclear staining for MCT1 in the HRS cells.