Zhang M Lisa, Meredith David M, Bellizzi Andrew M, Nowak Jonathan A, Papke David J
Department of Pathology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
Virchows Arch. 2025 Jul 16. doi: 10.1007/s00428-025-04167-6.
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.
复合性神经节细胞瘤/神经瘤与神经内分泌肿瘤（CoGNET，之前称为“神经节细胞性副神经节瘤”）是一种罕见的肿瘤类型，起源于壶腹/壶腹周围十二指肠，发病机制不明。在此，我们报告了11例CoGNET病例，其中女性6例（55%），男性5例（中位年龄：55岁；范围：28 - 69岁），均位于壶腹或十二指肠。肿瘤具有三相性，包含不同比例的：（1）神经内分泌巢；（2）梭形细胞神经鞘区域；（3）神经节样细胞。免疫组化显示，神经节样细胞表达广谱角蛋白、生长抑素、神经丝蛋白（NFP）和胰岛-1，且不表达PAX2B。神经内分泌巢弥漫性表达ARX、胰岛-1、胰多肽和生长抑素，且不表达CDX2和PDX1。梭形细胞表达NFP和S-100。对4例肿瘤进行靶向DNA测序，发现2例存在15号染色体缺失，1例存在多个拷贝数改变。对5例肿瘤进行全外显子组DNA测序，发现1例有NF1移码突变的临界证据。8例患者（73%）有临床随访数据（中位随访时间：7.0年；范围：1.3个月 - 13.9年）。1例接受胰十二指肠切除术的患者出现区域淋巴结转移，12.3年后仍无疾病复发。术后无患者出现复发或转移。内分泌激素和转录因子的表达模式使CoGNET与其他胰腺和十二指肠神经内分泌肿瘤亚型相区别。神经节样细胞表达角蛋白且不表达PAX2B，表明其免疫表型与真正的神经节细胞不同。因此，我们建议考虑使用替代命名“神经节样神经内分泌肿瘤”或“复合性神经节样神经内分泌肿瘤”。相对缺乏致病突变提示这些肿瘤可能存在表观遗传驱动因素。
