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Objectives: To analyze characteristics, treatment outcomes, and prognostic factors of sarcomatoid squamous cell carcinoma of the head and neck. Study Design: Retrospective chart review. Setting: Tertiary care center. Subjects and Methods: Fifty-five patients were treated for sarcomatoid squamous cell carcinoma of the head and neck between 1996 and 2018. Data collection included clinical history, tumor characteristics, pathology, treatment modality, and outcomes. Mean follow up was 17.1 months. Cox univariate analysis was used to evaluate for associations with locoregional recurrence, distant metastasis, and overall survival. Results: Most patients were white males with a smoking history and median age 66 years (range 41-92) at diagnosis. Twenty-two percent had prior head and neck radiation. Tumor site was most frequently oral cavity (41.8%), followed by larynx (29.1%), and oropharynx (16.4%). Half presented with early T stage disease (15.5% T0, 12.7% T1, 30.9% T2) and the remainder with late stage disease (16.4% T3, 34.5% T4). Locoregional recurrence rate was 60.0%, metastatic recurrence was rate 21.8%, with median time to recurrence of 4 months and mean overall survival of 20 months. Presence of lymphovascular space invasion was statistically associated with locoregional recurrence (P =.018, HR 3.55 [95% CI 1.24, 10.14]) and poorer overall survival (P =.015, HR 2.92 [95% CI 1.23, 4.80]). Treatment with multimodality therapy was associated with decreased locoregional recurrence (P =.039, HR 0.39 [95% CI 0.16, 0.95]) but did not impact overall survival. Conclusion: Sarcomatoid squamous cell carcinoma remains a rare and aggressive disease variant with high recurrence rates and high mortality. High risk features such as lymphovascular space may indicate the need for more aggressive therapy. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinomas (HNSCC) induced by human papillomavirus (HPV) have increased recently in the US. However, the distinct alterations of molecules involved in the death pathways and drug effects targeting inhibitor of apoptosis proteins (IAPs) have not been extensively characterized in HPV(+) HNSCC cells. In this study, we observed the distinct genomic and expression alterations of nine genes involved in cell death in 55% HNSCC tissues, which were associated with HPV status, tumor staging, and anatomic locations. Expression of four genes was statistically correlated with copy number variation. A panel of HPV(+) HNSCC lines showed abundant TRAILR2 and IAP1 protein expression, but were not sensitive to IAP inhibitor birinapant alone, while combinatory treatment with TNFα or especially TRAIL enhanced this drug sensitivity. The death agonistic TRAILR2 antibody alone showed no cell inhibitory effects, whereas its combination with birinapant and/or TRAIL protein demonstrated additive or synergistic effects. We observed predominantly late apoptosis mode of cell death after combinatorial treatments, and pan-caspase (ZVAD) and caspase-8 (ZIETD) inhibitors attenuated treatment-induced cell death. Our genomic and expression data-driven study provides a framework for identifying relevant combinatorial therapies targeting death pathways in HPV(+) HNSCC and other squamous cancer types. [ABSTRACT FROM AUTHOR]