Tumor-Associated Macrophages in Pediatric Classical Hodgkin Lymphoma: Association with Epstein-Barr Virus, Lymphocyte Subsets, and Prognostic Impact

Abstract

Purpose: Tumor-infiltrating macrophages are associated with adverse outcome in adult classical Hodgkin lymphoma (cHL). We have previously shown age-related changes in the lymphocyte composition of pediatric cHL. We therefore hypothesized that the number, function, and prognostic impact of macrophages in pediatric cHL would be different from adult cases.Experimental Design: We analyzed the number of macrophages and dendritic cells (DC) in the tumor microenvironment of pediatric cHL by immunohistochemistry. Results were analyzed in context of age, histologic characteristics, Epstein-Barr virus (EBV) status, clinical follow-up, and our previous study of T-cell populations in these cases.Results: One hundred cHL cases were studied, including 69% nodular sclerosis and 23% mixed cellularity cases. A total of 44.8% of cases were EBV-positive. Patients 10 years displayed more CD14 þ cells (P ¼ 0.025). In comparison with nodular sclerosis, mixed cellularity was characterized by higher numbers of CD14 þ , (P ¼ 0.003) and CD163 þ cells (P ¼ 0.027). EBV þ cases exhibited higher numbers of 02). CD68-positive cells did not displayan effect on outcome. Worse overall survival was observed in cases with CD163/CD8 ratio !2 (P ¼ 0.007). High numbers of CD163 þ cells were associated with worse progression-free survival (PFS; P ¼ 0.015).Furthermore, high numbers of CD163 þ and granzyme B þ cells were associated with worse PFS in EBVnegative (P ¼ 0.005) but not in EBV-positive cases. Conclusion: Our results suggest that macrophage composition in pediatric cHL is distinct from adults. Functional status of macrophages and their value as prognostic indicators in pediatric cHL may depend on EBV status.

Serum CD163 and TARC as Disease Response Biomarkers in Classical Hodgkin Lymphoma

“…Tissue-associated macrophages (TAM) are potentially one of the most powerful independent markers for clinical prediction in cHL, (12)(13)(14)(15)(16)(17)(18) as well as potentially representing a novel therapeutic target (34). The best markers of TAMs are still a matter of debate (35).…”

“…The best markers of TAMs are still a matter of debate (35). Results from studies are conflicting, with some, but not all, finding that high protein expression (by immunohistochemistry) of the monocyte/macrophage markers CD68 and CD163 correlated with adverse outcomes (12)(13)(14)(15). Although our study was not designed to test the prognostic ability of tissue CD163, we did find (in line with some but not all prior reports), that values were associated with both Hasenclever score and the presence or absence of early-stage disease.…”

“…CD163 is an M2 macrophage marker that is also expressed in a subset of monocytes, and is highly expressed within tumor-infiltrating cells of the malignant node. Tissue levels of CD163 within the cHL node may be associated with survival, but results are conflicting (12)(13)(14)(15)(16)(17)(18). A study of serum CD163 (sCD163) in patients with stage I/ II melanoma found that pretherapy sCD163 was an independent predictor of survival (19).…”

High tumour-associated macrophages infiltration is correlated with poor survival outcome in classical Hodgkin’s lymphoma

“…[5,41] In the third study, there was no association of CD68 with clinical outcome, probably due to small number of cases. [50] There was no substantial difference between manual visual method and computer assisted method regarding the relation of CD68+ TAM infiltration with outcome. Challenges in using computer assisted methods include lack of availability in the routine diagnostic work, its labour intensiveness, and dependence on the overall visual volume.…”

“…Few studies used a computer assisted methods to quantify immunohistochemical staining of CD68+ TAM infiltration. [5,41,50] In two of them there was association between CD68+TAM infiltration and poor DFS and OS. [5,41] In the third study, there was no association of CD68 with clinical outcome, probably due to small number of cases.…”