Composite gangliocytoma/neuroma and neuroendocrine tumor: a clinicopathologic, immunohistochemical, and molecular genetic study of 11 cases.

Composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET, previously "gangliocytic paraganglioma"), is a rare tumor type of uncertain pathogenesis in the ampulla/periampullary duodenum. Here, we present 11 CoGNETs in 6 females (55%) and 5 males (median age: 55 years; range: 28-69 years), all in the ampulla or duodenum. Tumors were triphasic with variable proportions of (1) neuroendocrine nests, (2) spindle cell nerve sheath regions, and (3) ganglion-like cells. By immunohistochemistry, ganglion-like cells expressed broad-spectrum keratins, somatostatin, NFP, and islet-1, and they lacked expression of PHOX2B. Neuroendocrine nests diffusely expressed ARX, islet-1, pancreatic polypeptide, and somatostatin, and they lacked expression of CDX2 and PDX1. Spindle cells expressed NFP and S-100. Targeted DNA sequencing of four tumors demonstrated 15q loss in two and multiple copy number alterations in one. Whole-exome DNA sequencing of five tumors showed borderline evidence of an NF1 frameshift mutation in one. Clinical follow-up was available for 8 patients (73%; median length: 7.0 years; range: 1.3 months-13.9 years). One Whipple resection showed regional lymph node metastases in a patient who remained disease-free 12.3 years later. No patients experienced recurrence or metastasis following surgery. The expression pattern of endocrine hormones and transcription factors distinguished CoGNET from other pancreatic and duodenal neuroendocrine tumor subtypes. The ganglion-like cells expressed keratins and not PHOX2B, demonstrating immunophenotypic divergence from true ganglion cells. Therefore, we propose that alternative nomenclature "gangliocytoid neuroendocrine neoplasm" or "composite gangliocytoid neuroendocrine neoplasm" be considered. The relative lack of pathogenic mutations raises the possibility that these tumors might harbor epigenetic drivers.