Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort

Abstract

Most patients with vestibular schwannomas can be cured with microsurgical resection, or tumor growth can be stabilized by radiotherapy in certain cases. Recurrence is rare but usually difficult to treat. Treatment alternatives to local therapies are not established. There is growing evidence of the role of inflammatory processes in schwannomas, which may be exploitable by targeted innovative therapies. To further define the impact of inflammation with tumor growth in vestibular schwannoma, we performed immunohistochemical analyses of CD3, CD8, CD68 and CD163 to assess lymphocyte and macrophage infiltration in 923 tumor tissue samples of surgically resected vestibular schwannomas. An inflammatory score was compared with tumor size and volumetric growth. We observed a significantly larger preoperative tumor size with increased expression rates of CD3, CD8, CD68 and CD163 (p < 0.0001, p < 0.0001, p = 0.0015 and p < 0.0001, respectively), but no differences in percentual volumetric tumor growth. When all four markers were combined as an inflammatory score, tumors with high inflammatory infiltration showed slower percentual growth in a multivariate analysis, including MIB1 expression (p = 0.0249). We conclude that inflammatory cell infiltration increases with larger tumor size but is associated with slower percentual volumetric tumor growth.

Tumor‐Associated Macrophages in Vestibular Schwannoma and Relationship to Hearing

“…Although the composition varies with each tumor, immune cells can infiltrate the TME and take on several roles that promote and/or resist inflammation and tumor proliferation. 24 Although the mechanisms have not been fully elucidated, several studies have found associations between TAMs, tumor growth, and HL in VS. 5 , 22 , 25 - 28 …”

“… 21 , 28 , 29 Because of differences in how tumor growth was measured across studies, it remains unclear from these investigations whether macrophage infiltration is actually protective and slows the dynamic volumetric tumor growth rate. 28 …”

“…Furthermore, we did not find significant correlations between preoperative tumor volume and CD80 or CD163 levels, which is contradictory to other investigations that have found links between macrophages and tumor size and/or progression. 21 , 27 - 29 This discrepancy may reflect several factors, including differences in patient selection for surgery and proportions of small to large tumors. While we analyzed 30 consecutive patients, some researchers analyzed fast- and slow-growing tumors, excluding tumors where growth rate was not assessed.…”

“…While we analyzed 30 consecutive patients, some researchers analyzed fast- and slow-growing tumors, excluding tumors where growth rate was not assessed. 21 , 27 - 29 We did not assess tumor growth rates because only a third of patients underwent initial observation. The discrepancy may also reflect methodologic differences in tissue processing, macrophage subtypes evaluated, antibodies used, staining protocols, and target quantification.…”

“…Although the composition varies with each tumor, immune cells can infiltrate the TME and take on several roles that promote and/or resist inflammation and tumor proliferation. 24 Although the mechanisms have not been fully elucidated, several studies have found associations between TAMs, tumor growth, and HL in VS. 5,22,[25][26][27][28] In a retrospective investigation of 46 patients with VS with subtotal resections, Graffeo et al 25 found that higher macrophage density (defined as the ratio of CD68 1 macrophages to S100 1 cells) was significantly associated with tumor progression postoperatively. However, it was unknown whether M1 and/or M2 macrophages were implicated, as CD68 is a nonspecific pan-macrophage marker.…”