Epigenomic profiling suggests a common origin of both components in mixed gangliocytoma-pituitary neuroendocrine tumors

Mixed gangliocytoma-pituitary neuroendocrine tumors (GC-PitNETs) are rare pituitary tumors composed of neuroendocrine and gangliocytic elements. Recent studies have demonstrated shared features between neuroendocrine and gangliocytic cells. Specifically, co-expression of neuronal-associated cytoskeletal proteins and pituitary cell lineage transcription factors supports the hypothesis of a common origin of the cells in these tumors. In this multi-institutional study, we characterize the epigenomic profiles of a series of GC-PitNETs by DNA methylation analyses. Twenty-two cases, classified according to the 2022 WHO Classification, were studied including 13 somatotroph, 4 corticotroph, 4 mixed somatotroph-lactotroph, and 1 lactotroph GC-PitNETs. DNA methylation profiles of 21 tumors were analyzed using CNS tumor classifiers (Epignostix Heidelberg v12.8 and NCI Bethesda v 3.1), and unsupervised dimensionality reduction methods. The analysis revealed that all 21 evaluated GC-PitNETs exhibited epigenomic profiles aligning strictly with PitNET/adenoma classes matching their WHO histological diagnoses and showing no epigenomic affiliation with neuronal or glioneuronal reference tumors. These findings indicate that the gangliocytic component of GC-PitNETs lacks a distinct epigenomic signature, supporting the hypothesis that these cells may represent transdifferentiated neuroendocrine cells. Consequently, we propose reclassifying GC-PitNETs within tumors of the anterior pituitary neuroendocrine system and be renamed "pituitary neuroendocrine tumor (subtype) with gangliocytic differentiation."