The inflammatory microenvironment in patients with advanced and relapsing hypopharyngeal squamous cell carcinoma

Abstract

Hypopharyngeal squamous cell carcinoma (HPSCC) is frequently diagnosed at an advanced stage and is associated with limited therapeutic options and poor prognosis. Increasing evidence highlights the relevance of the tumour microenvironment (TME), particularly inflammatory cell populations, for tumour progression and treatment response. Tumour-associated macrophages (TAMs), especially CD68-positive subsets, have emerged as potential diagnostic and prognostic markers. Factor X (FX), a key component of the coagulation cascade with additional immunomodulatory functions, may contribute to macrophage recruitment and influence TME composition. This study aimed to characterise the inflammatory landscape of advanced HPSCC with a focus on FX_CD68-positive TAMs and to explore associations with clinical outcome. Histopathological and immunohistochemical analyses were performed on tumour samples from 31 patients with advanced HPSCC. Acute inflammation was graded based on neutrophil infiltration, while chronic inflammation was assessed through lymphoid aggregates and overall inflammatory cell density. FX_CD68-positive macrophages were quantified and correlated with clinical data including stage, treatment modality, and relapse. All tumours demonstrated pronounced acute and chronic inflammation. Most patients (n = 29) presented with UICC stage II–IV disease. Eleven patients (35%) developed a relapse, typically showing stronger chronic inflammation in the primary tumour. Recurrent tumours displayed heterogeneous densities of FX_CD68-positive TAMs, whereas specimens obtained after radio(chemo)therapy exhibited reduced inflammatory infiltration. These findings indicate that HPSCC is a highly immunogenic tumour entity. Components of the TME, particularly FX_CD68-positive TAMs, may represent promising biomarkers for risk stratification and could support the development of personalised therapeutic strategies.