Primary Angiosarcomas of the Thyroid: New Insights Into the Genetic Background and Potentially Targetable Therapeutic Markers of an Ultrarare Disease

Thyroid angiosarcomas (TASs) are listed as a distinct entity in the World Health Organization classification of malignant tumors and represent highly aggressive neoplasms, with early metastasis and overall survival of few months. Owing to their rarity, data on tumorigenesis, molecular alterations, and potential therapeutic targets remain limited. We present a series of 16 primary TAS subjected to systematic molecular profiling and immunohistochemical assessment of clinically relevant, druggable biomarkers, such as fibroblast activation protein (FAP), SSTR2A, claudin 18.2, FOLR1, PD-L1, HER2, TROP2, and nectin-4. Next-generation sequencing was used to detect pathogenic DNA alterations, complemented by an RNA-based Archer fusion assay for gene fusion detection. MYC gene amplification was evaluated by fluorescence in situ hybridization. The cohort comprised 13 male and 3 female patients, with a median age of 71 years. PD-L1 expression was identified in 62.5% of tumors, whereas FAP and TROP2 were positive in 56% and 37.5%, respectively. Claudin 18.2 expression was observed in 1 case and weak SSTR2A staining in 2 cases. FOLR1, HER2, and nectin-4 were uniformly negative. Molecular analysis revealed pathogenic alterations in 56% of tumors, predominantly TP53 mutations, accompanied by additional variants affecting mitogen activated kinase- and PI3K-related pathways. No oncogenic gene fusions were detected. MYC gene amplification was present in 31% of cases. This study represents the largest cohort of primary TAS reported to date and provides an expanded characterization of their molecular and immunophenotypic features. The frequent expression of PD-L1 and FAP highlight potential avenues for targeted therapy. The broader-than-expected mutational landscape, including recurrent TP53 mutations, alterations in mitogen activated kinase and PI3K pathways, and notable MYC amplification, further refines current understanding of TAS biology. These findings offer a basis for the development of prospective therapeutic strategies in this rare and aggressive malignancy.