Macrophage Density Predicts Facial Nerve Outcome and Tumor Growth after Subtotal Resection of Vestibular Schwannoma

Introduction: Vestibular schwannoma (VS) behavior following subtotal resection (STR) is highly variable. Overall progression rates have been reported as high as 44%, and optimal management strategies are controversial with respect to both modality and timing, with various authors advocating for initial observation, stereotactic radiosurgery (SRS) either up-front or at time of progression, or repeat microsurgery at time of confirmed remnant growth. Correspondingly, identification of a reliable clinical or pathologic marker associated with progression after STR would inform essential clinical decision making.

Methods: Fifty-two consecutive patients with sporadic VS who underwent STR by a single neurosurgery-neurotology team at our institution were included. A prospectively-maintained institutional VS registry was retrospectively reviewed for primary endpoints including tumor progression and postoperative facial nerve function. Pathologic specimens were stained for Ki67, CD68, and S100, for proliferating cells, macrophages, and macrophages or Schwannian tumor cells, respectively—each of which was then quantitated by digital imaging analysis. Pathologic review was blinded to clinical outcome. Macrophage density was defined as the ratio of CD68+ macrophages to S100+ macrophages and Schwannian tumor cells. Clinical outcomes were correlated with pathologic markers using Chi-square test, Student’s t-test, and linear regression.

Results: Thirteen individuals (25%) progressed during a mean 53 months of follow-up (range 17–135). Favorable postoperative facial nerve function (House-Brackmann I-II) was achieved in 42 (81%). Higher macrophage density was significantly associated with both tumor progression (p = 0.02) and unfavorable facial nerve function (p = 0.02). Ki67 percent positivity was not significantly associated with either clinical outcome (p = 0.7; p = 0.5). Macrocystic changes were observed in 14 (27%), and were significantly associated with lower macrophage density (p = 0.01).

Conclusion: Macrophage density may provide an important marker for individuals at highest risk for progression in VS after STR, potentially prompting closer surveillance or consideration for upfront SRS following surgery. This finding supports preceding conclusions that an intra-tumoral macrophage-predominant inflammatory response may induce tumor growth, highlighting a potential target for immunotherapy. The finding that elevated macrophage density correlates with adverse facial nerve outcomes suggests that increased preoperative inflammation may worsen adhesion at the facial nerve-tumor interface and predispose to a more difficult dissection.