Expansion of the MEN1 tumor spectrum: convergent molecular evidence of MEN1 inactivation in a fibromyxosarcoma, VIPoma, and gastric neuroendocrine carcinoma

Background Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor predisposition syndrome primarily characterized by parathyroid, pituitary, and pancreaticoduodenal neuroendocrine tumors. Although several non-endocrine neoplasms have been associated with MEN1, the role of MEN1 inactivation in rare mesenchymal tumors remains incompletely understood. Case presentation We report a woman with genetically confirmed MEN1 carrying the pathogenic germline MEN1 variant c.249_252delGTCT ( p.Ile85Serfs* 33, exon 2), identified in a large MEN1 kindred. The patient presented with primary hyperparathyroidism, a non-functioning pituitary microadenoma, a pancreatic vasoactive intestinal peptide-producing neuroendocrine tumor (VIPoma), and a poorly differentiated gastric neuroendocrine carcinoma. The VIPoma was successfully cured by gastroduodenopancreatectomy, with complete resolution of the WDHA syndrome and normalization of serum VIP levels. In contrast, the gastric neuroendocrine carcinoma followed an aggressive clinical course, leading to disease recurrence and death 30 months after surgery. In addition, the patient developed a recurrent low-grade odontogenic fibromyxosarcoma of the maxilla. Immunohistochemistry demonstrated complete loss of nuclear menin expression in the fibromyxosarcoma, pancreatic VIPoma, and gastric neuroendocrine carcinoma. Molecular analyses of the fibromyxosarcoma revealed allelic imbalance at the MEN1 locus by Sanger sequencing, with apparent absence of the wild-type allele at exon 2 and exclusive detection of the T allele of an informative heterozygous synonymous MEN1 variant ( c.1269C>T ; p.Asp418= , exon 9). Targeted next-generation sequencing confirmed marked enrichment of the mutant MEN1 allele in the fibromyxosarcoma (VAF 81.8%) and demonstrated enrichment of the mutant allele in the VIPoma (VAF 68.2%) and gastric neuroendocrine carcinoma (VAF 70.6%). Together with loss of menin expression by immunohistochemistry, these findings support somatic MEN1 inactivation across all three tumors. Conclusions This report provides convergent genetic and immunohistochemical evidence supporting low-grade odontogenic fibromyxosarcoma as a potential MEN1-associated neoplasm. In addition, the demonstration of MEN1 inactivation across three exceptionally rare tumors arising in the same patient provides evidence for a broader role of menin loss across distinct tumor types and supports the possibility that the phenotypic spectrum of MEN1 extends beyond currently recognized manifestations.