A peculiar mimicker of gastro-entero-pancreatic neuroendocrine tumors: Malignant Gastrointestinal Neuroectodermal Tumor-literature review and two clinical cases

Malignant gastrointestinal neuroectodermal tumor (GNET) is a distinctive and relatively newly described neoplasm that is seldom encountered in routine clinical practice. It is characterized by a predominantly monomorphic population of polyhedral to epithelioid cells, exhibiting pale eosinophilic or clear cytoplasm, rounded nuclei with vesicular chromatin, and occasionally prominent eosinophilic nucleoli. These cells are arranged in a heterogeneous pattern, forming small nests, compact solid areas, and pseudo-papillary or pseudo-microcystic structures. Within the tumor, osteoclast-like giant cells may be a notable feature, although their presence is variable. This tumor consistently demonstrates positivity for S100, SOX10, and vimentin, while it is invariably negative for Melan-A, HMB45, desmin, CD117, and pan-cytokeratin. Additionally, it exhibits variable expression of the following immunohistochemical markers: synaptophysin, chromogranin, CD56, neuron-specific enolase (NSE), and neurofilament protein (NFP). A specific mutation in the Ewing's sarcoma breakpoint region 1 (EWSR1) gene has been described for GNET, characterized by EWSR1-CREB1 and EWSR1-ATF1 fusions. This article discusses the clinical, pathological, immunophenotypic, and genetic features of two clinical cases of GNET, followed by a literature review of 127 cases published in the PubMed database, for which full-length articles were accessible. According to this review, approximately 10% of GNETs have been initially misdiagnosed, with about 6% being misclassified as neuroendocrine tumors or neuroendocrine carcinomas.