Pseudoendocrine sarcoma is a recently described rare, epithelioid neuroendocrine-like soft tissue neoplasm with a distinctive phenotype. Predominantly affecting older adults in paraspinal locations, including posterior head and cervical paraspinal neck, this tumor has distinctive morphologic, phenotypic and molecular features that generally distinguish it from other mesenchymal, neuroendocrine, meningothelial, or epithelial tumors.

A comprehensive review of the literature was conducted, focusing on clinical information, histopathological findings, immunohistochemical profiles, and molecular characteristics of pseudoendocrine sarcoma. Data was analyzed from 5 case reports and 2 series published between 2022 and 2025, and compared with differential diagnostic entities, for an analysis and update of pseudoendocrine sarcoma.

Including the seminal publication, with the novelty of this classification, 40 cases of pseudoendocrine sarcoma have been reported, with 21 cases involving the head and neck region.

Pseudoendocrine sarcoma presents as a deep-seated, sub-fascial soft tissue tumor, predominantly well delineated, with reports of secondary infiltration of bone, particularly in vertebral locations. Reported radiologic imaging reveals a hypoechoic mass with prominent vascularity on ultrasound and radiographic imaging studies. Histologically, pseudoendocrine sarcoma exhibits a neuroendocrine-like lobular or nested growth pattern of monotonous epithelioid to ovoid cells with well-dispersed, speckled chromatin. By immunohistochemistry, however, the tumor is notably positive for nuclear β-catenin and lacks neuroendocrine markers including INSM1, synaptophysin, and chromogranin. In addition, epithelial markers such as keratin, Cam 5.2, and EMA are also negative. By molecular methods, pseudoendocrine sarcoma harbors specific recurrent CTNNB1 hotspot mutations, unique to this entity that separates it from other tumors with this point mutation.

Distinguishing pseudoendocrine sarcoma from other benign and malignant entities is crucial, given its bland appearance and designation as an intermediate grade sarcoma in the upcoming 6th edition of the World Health Organization Classification of Bone and Soft Tissue Tumours, with a propensity for destructive local recurrence and metastasis to lung and rarely to lymph nodes (by direct extension) or liver. Awareness of its distinct clinical, histopathological, immunohistochemical, and molecular features is essential for accurate diagnosis and appropriate management.