2026 Poster Presentations
P200: GENOMIC CHARACTERIZATION OF METASTATIC PITUITARY NEUROENDOCRINE CARCINOMA (PITNET) IN TWO CASES
Shashank Rajkumar, MD; Brianna C Theriault, MD, PhD; R P Manes, MD; James E Hansen, MD; Ranjit S Bindra, MD, PhD; Ryan A Rimmer, MD; Silvio E Inzucchi, MD; E Z Erson-Omay, PhD; S B Omay, MD; Yale New Haven Hospital
Introduction: Due to their aggressiveness and rarity, metastatic PitNET remains difficult-to-manage.
Methods: We detail two patients with high-grade pituitary lesions who developed metastases isolated to the central nervous system. Whole exome sequencing (WES) was performed on all available lesions and matched blood samples. Deoxyribonucleic acid (DNA) target capture was performed using the Integrated DNA Technologies (IDT) xGen Exome Research Panel Version 2 with additional Genomics Organization for Academic Laboratories (GOAL) region spike-ins. Sequencing was performed with llumina NovaSeq 600. Downstream analysis to identify somatic single nucleotide variations (SNV), short insertion-deletions (INDEL), and copy number variations (CNV) was carried out following the Genome Analysis Toolkit (GATK) Best Practices Guidelines. A literature search was conducted to identify similar cases for comparison.
Results: Patient 1 was a 47-year-old male with pituitary tumor resected twice before who presented with headaches and visual disturbances. He was found to have a recurrent pituitary tumor and was treated with endoscopic endonasal resection (pathology showing pituitary adenoma with Ki-67 index 4-5%) and adjuvant fractionated radiotherapy (50.4 Gy). Surveillance imaging showed new brain lesions remote from the sella after 2.5 years. He underwent craniotomy for treatment of a left frontal lesion, for which pathology revealed neuroendocrine carcinoma, followed by stereotactic radiosurgery to the resection cavity and unresected lesions. Additional intracranial and spinal intramedullary metastases developed two years later, and he was advanced to craniospinal irradiation (CSI). Patient 2 was a 26-year-old female with history of prolactinoma treated with cabergoline (with poor compliance) who presented with symptomatic obstructive hydrocephalus with large pituitary tumor involving the third ventricle. She was treated with endoscopic endonasal resection and pathology showed neuroendocrine tumor with Ki-67 10-15%. She was lost to follow up and the lesion recurred in 6 months which required another resection followed by fractionated radiotherapy (50.4 Gy). On follow up she developed innumerable CNS metastases including brain and intradural extramedullary spinal lesions requiring palliative radiosurgery and spinal radiation. Somatic analysis of WES data revealed widespread genomic instability in both patients. In Patient 1, WES profiling of both the primary and recurrent tumors demonstrated >40% of the genome altered by CNVs, together with a frameshift mutation in DAXX, a nuclear protein involved in transcriptional repression, apoptosis, chromatin organization, telomere maintenance, and genomic instability. In Patient 2, CNV events affected 36% of the genome, accompanied by a deleterious TP53 missense mutation—consistent with the well-established role of TP53 loss in promoting chromosomal instability. Review of the literature confirms that metastatic PitNET remains a rare diagnosis with poor prognosis, often requiring adjuvant systemic therapy and radiation for treatment.
Conclusions: Metastatic PitNET is rare, and deleterious somatic alterations in key genomic stability regulators may underlie the aggressive biology of these otherwise typically benign tumors. When identified, they should prompt close surveillance for regrowth and development of metastases. Interdisciplinary care is crucial to plan adjuvant therapy for these patients. Future work should emphasize early diagnosis and aggressive management and the role of CSI in the management of patients with disease limited to the CNS.