Background: NMC is a rare subtype of squamous cancer defined by rearrangement of the NUT gene. NMC is typically found in the thorax, although ~20% of cases arise in the HN. NMC is almost uniformly fatal. We report on a cohort of patients (pts) with HN NMC to identify disease characteristics, treatment and outcomes. Methods: A clinical database was established using demographic and outcomes data available on all known cases of HN NMC obtained from the International NMC Registry (www.NMCRegistry.org). Clinicopathologic variables were assessed for 40 pts, the largest cohort of HN NMC studied to date. Outcome data from 31 patients treated from 1990-2013 were available for survival analyses. Results: HN NMC incidence has increased annually since 2010. Median age was 21.9 years (range 0.1-81.7), male: female (%) was 45:55, sinonasal origin was 50%, and the BRD4-NUT fusion was found in 82%. At diagnosis, 36% had regional node metastases and 15% had distant metastases. Initial treatment was upfront surgery (S) +/- adjuvant chemoradiation (CRT) or adjuvant radiation (RT) (48%), upfront RT +/- chemotherapy (C) (21%), or upfront C +/- S or RT (31%). Median progression-free survival (PFS) was 7.2 months (range 6.3-8.7). Median overall survival (OS) was 9.8 months (range 6.6-15.6). The 2-year PFS was 27% (95% CI, 9-44). The 2-year OS was 31% (95% CI, 13-50). Upfront S +/- post-operative CRT or RT, and S with negative margins were significant predictors of improved PFS and OS. Initial RT or C, type of C regimen, and NUT translocation type were not significantly associated with improved outcome. Conclusions: HN NMC portends a poor prognosis. Aggressive initial surgical resection with or without post-operative CRT or RT may be associated with enhanced survival. C or RT alone is inadequate, and the development of targeted therapies is now underway.

* 12/14 had S then CRT, 1/14 had S then RT.