Objective  To investigate the clinicopathological features, immunophenotype, and prognosis of head and neck spindle cell squamous cell carcinoma (SCSCC) to improve the understanding and diagnosis of this tumor.

  Methods  Clinicopathological data collected from January 2012 to December 2022 at the First Affiliated Hospital, Air Force Military Medical University from 20 patients with head and neck SCSCC were retrospectively reviewed for histological morphology and immunophenotype. In situ and fluorescence in situ hybridization were performed to detect EBV-encoded ribonucleic acid (EBER) status and MDM2 gene amplification, respectively.

  Results  The median age among the 20 SCSCC cases was 67 years with a male-to-female ratio of 4:1. Tumor locations were laryngeal (35.0%) and sinonasal (30.0%). SCSCC presented as polypoid or exogenous growths (61.5%), often with surface ulceration (90.0%). Histologically, sarcomatoid growth patterns were exhibited in 75.0% of the patients (n=15), while the remainder showed granular tissue-like or angiosarcomatoid patterns. Most tumors (65.0%) displayed components of conventional squamous cell carcinomas, with a predominant occurrence of high to moderate differentiation (91.7%). In terms of immunohistochemistry, AE1/AE3 was expressed in 83.3% (15/18) of cases, while p63 and p40 expression rates were 62.5% and 66.7%, respectively. All cases were negative for EBER. The Ki-67 proliferation index ranged 10%–70%. Overall, 33.3% (1/3) of the cases showed MDM2 gene amplification. Among these, the median follow-up time for 18 patients was 18.3 months (range: 1–92 months), with 6 survivors and 12 deaths.

  Conclusions  Head and neck SCSCC is more prevalent among elderly male smokers, predominantly exhibits a polypoid growth pattern, and does not display human papillomavirus or Epstein–Barr virus infection. Diagnosis requires a comprehensive evaluation of clinical and pathological features and immunophenotype. Surgical resection is the primary treatment method.