Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMÈ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMÈs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumoractivated EMÈs (tEMÈ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMÈs, tEMÈs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMÈ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMÈs and PDA cells that orchestrates the formation of cancer nerve invasion. Cancer Res; 72(22); 5733-43. Ó2012 AACR.

Background The mainstay of treatment in adenoid cystic carcinoma (ACC) of the head and neck is surgical resection with negative margins. The purpose of this study was to define the margin status that associates with survival outcomes of ACC of the head and neck. Methods We conducted univariate and multivariate analyses of international data. Results Data of 507 patients with ACC of the head and neck were analyzed; negative margins defined as ≥5 mm were detected in 253 patients (50%). On multivariate analysis, the hazard ratios (HRs) of positive margin status were 2.68 (95% confidence interval [CI], 1.2–6.2; p = .04) and 2.63 (95% CI, 1.1–6.3; p = .03) for overall survival (OS) and disease-specific survival (DSS), respectively. Close margins had no significant impact on outcome, with HRs of 1.1 (95% CI, 0.4–3.0; p = .12) and 1.07 (95% CI, 0.3–3.4; p = .23) for OS and DSS, respectively, relative with negative margins. Conclusion In head and neck ACC, positive margins are associated with the worst outcome. Negative or close margins are associated with improved outcome, regardless of the distance from the tumor.

Although perineural invasion has no impact on survival, intraneural invasion is an independent predictor of poor prognosis. Recognition of intraneural invasion may help optimize treatment of patients with head and neck ACC.