12477 Non-functioning Pituitary Neuroendocrine Tumor In A Patient With Neurofibromatosis Type 1
Authors: Aguilar-Soto Mercedes , Zuarth-Vázquez Julia M , Leyva-Figueroa Laura , Zarco-Ávila Karla , Rebollar-Vega Rosa G , Gamboa-Domínguez Armando , Hernández-Ramírez Laura C 
Published: October 2024

Abstract
Disclosure: M. Aguilar-Soto: None. J.M. Zuarth-Vázquez: None. L. Leyva-Figueroa: None. K. Zarco-Ávila: None. R.G. Rebollar-Vega: None. A. Gamboa-Domínguez: None. L.C. Hernández-Ramírez: None.
Introduction. Aside from other manifestations, neurofibromatosis type 1 (NF1) entails an increased risk for various neoplasms. Multiple cases of pituitary neuroendocrine tumors (PitNETs) in the setting of NF1 have been documented in the literature. Based on these findings, a role for NF1 (17q11.2) loss-of-function (LOF) variants in pituitary tumorigenesis has been hypothesized, but causality remains unclear. Aim. To report a case of a PitNET associated with a germline NF1 defect and to characterize the NF1 genotype and expression in this lesion.Methods. The patient was recruited via an ongoing prospective study of individuals with neuroendocrine neoplasms. Genetic testing was carried out by means of two next generation sequencing (NGS) panels. DNA and/or RNA were extracted from blood and PitNET samples. Loss-of-heterozygosity was investigated via Sanger sequencing and NF1 expression was analyzed via droplet digital polymerase chain reaction (ddPCR). Similar cases were searched in the literature. Results. A 54-year-old-man underwent a magnetic resonance imaging due to new-onset seizures. The study identified a 16 mm pituitary lesion, which was clinically non-functioning. A transsphenoidal resection was performed uneventfully, with histopathological report of a plurihormonal PitNET (positive for prolactin, GH, and ACTH) with Ki67&lt;1%. This individual had a personal and family history compatible with NF1, and carried a germline pathogenic NF1 variant (NM_001042492.3: c.147C&gt;A, p.Y49*), detected via targeted NGS. The same heterozygous defect was confirmed in DNA from peripheral blood and both fresh frozen and FFPE tumor tissue. Additional NGS ruled out germline defects in PitNET-associated genes. By ddPCR, NF1 was significantly overexpressed in the tumor, compared with another non-functioning PitNET (ACTB-normalized absolute quantification 0.07 vs 0.03, P=0.0381), but not in blood (P=0.4063). At least 14 well-documented cases of PitNETs occurring in the context of NF1 exist in the literature, with mean age at diagnosis of 34.7 ±21.5 years. Nine tumors were macroadenomas, seven were somatotropinomas, and all patients, except one, had clinical NF1. The diagnosis was genetically confirmed in seven cases and LOH was negative in the two cases where it was investigated. Two individuals developed multiple endocrine neoplasia-like phenotypes, but tested negative for other relevant genetic defects. Conclusions. We found NF1 upregulation in the PitNET tissue, probably due compensatory increased transcription of the normal allele. Preserved heterozygosity at the affected locus was also observed, in line with previous data showing that LOH is not required for the development of benign tumors in this setting. Further research is required to determine if NF1 defects might indeed drive pituitary tumorigenesis.
Presentation: 6/1/2024