Refined Prognostic Role of CD68-Positive Tumor Macrophages in the Context of the Cellular Micromilieu of Classical Hodgkin Lymphoma

Objective: Classical Hodgkin lymphoma (HL) consists of neoplastic Hodgkin and Reed-Sternberg cells (HRSC) and a nonneoplastic micromilieu that greatly outnumbers the HRSC. Studies on HRSC-related prognostic biomarkers have been unsuccessful, but the microenvironmental composition is of prognostic importance. Recently, the number of CD68-positive macrophages was correlated with adverse survival in HL, and there was a call to validate these results. Methods: We utilized immunohistochemistry to analyze the prognostic importance of the CD68-positive macrophage number compared to other cellular environmental components in an unselected series of 105 HLs in tissue microarrays. Results: Applying a cutoff score of <0.82% tumor macrophages, cases with increased numbers showed worse overall survival (mean 185 months, median 192) compared to cases with lower numbers (mean 285 months, median not reached). Eleven of 62 patients with 0.82% tumor macrophages died, compared to 19 of 43 with <0.82% (p > 0.001). The number of macrophages correlated with a low FOXP3-/high granzyme B-/high PD-1-positive micromilieu and patient age, but did not have independent prognostic significance. A combination background score taking into consideration all negative prognostic microenvironmental components (CD68-, PD-1- and granzyme B-positive cells) was of independent prognostic significance (p = 0.002). Conclusion: Increased numbers of CD68-positive tumor macrophages indicate an adverse overall outcome in HL.