[Research progress in clinical pathology and molecular mechanisms of pancreatic adenosquamous carcinoma].

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Abstract

Pancreatic adenosquamous carcinoma (PASC) is a rare exocrine malignancy of the pancreas with an increasing incidence, histologically defined by the coexistence of adenocarcinoma and squamous carcinoma components. Current pathological diagnosis typically requires the squamous component to comprise at least 30% of the tumor. However, this threshold remains controversial given the unconfirmed independent prognostic value of the extent of squamous differentiation. Compared with pancreatic ductal adenocarcinoma (PDAC), PASC exhibits greater aggressiveness and heterogeneity, contributing to a poorer prognosis with a median survival of approximately 9 months. Despite its distinct biological behavior, specific preoperative diagnostic methods and targeted therapeutic strategies remain elusive. Diagnostically, while PASC lacks specific molecular markers, the ring-enhancement sign observed in the arterial phase of contrast-enhanced CT may aid distinction from PDAC. Owing to the lack of standardized therapeutic strategies, treatment largely follows guidelines established for PDAC, offering limited survival benefits, though platinum-based chemotherapy and radiotherapy show potential efficacy. Notably, the rationale for immunotherapy lies in the high programmed death-ligand 1 (PD-L1) expression in the squamous component and an immunosuppressive microenvironment characterized by specific checkpoint interactions, such as the TIGIT-CD155 axis. Furthermore, the cellular origin and evolutionary trajectory of PASC remain debated. While monoclonal origin is the prevailing theory, it remains unclear whether the squamous component arises from adenocarcinoma transdifferentiation or from pancreatic pluripotent stem cells. At the molecular level, PASC shares genomic and transcriptomic features with PDAC yet maintains a distinct identity. Concurrently, its tumor microenvironment (TME) displays unique landscapes, differing significantly from PDAC in immune and stromal components like T cells, macrophages, and fibroblasts. Moreover, marked intratumoral heterogeneity is observed between the adenocarcinoma and squamous carcinoma regions within the same tumor. Future efforts should prioritize multi-omics and laser microdissection technologies to establish a refined molecular classification system, alongside the integration of liquid biopsy and artificial intelligence (AI)-assisted radiomics for accurate preoperative diagnosis. This comprehensive strategy is essential to shift clinical practice from empirical treatment to personalized precision medicine, ultimately improving outcomes for this refractory disease. This article systematically reviews the epidemiology and clinicopathological features of PASC, and specifically explores the therapeutic potential of platinum-based chemotherapy, radiotherapy, and immunotherapy. Furthermore, special attention is given to recent advances in monoclonal origin patterns, unique genomic and transcriptomic alterations, and TME heterogeneity.

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