Hypoxia‐related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma.

Aims: The present study evaluates the impact of hypoxia‐related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma (cHL). Methods and results: Eighty‐one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia‐related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin–Reed–Sternberg (HRS) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX+ positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX/Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX+ positive compared to CAIX− negative HRS cells (P < 0.001). Seventy‐two months' progression‐free survival (PFS) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) (P < 0.001), while the overall survival (OS) did not differ (P = 0.097). Conclusion: Hypoxic stress‐related adaptation – highlighted by CAIX expression – results in cellular quiescence in HRS cells, potentially contributing to the short‐term failure of the standard chemotherapy in cHL. [ABSTRACT FROM AUTHOR]