Pituitary Adenoma (PTAD)

Overview

Pituitary adenoma (PTAD), now reclassified as pituitary neuroendocrine tumor (PitNET) by the 2022 WHO classification, is a typically benign tumor of the anterior pituitary gland. On OncoTree it is a child of SELT (Sellar Tumor). Most pituitary tumors are benign, but a minority become aggressive and treatment-refractory (requiring repeat surgery, radiation, and medical therapy). True pituitary carcinoma with metastasis is exceedingly rare.

Cohorts in the corpus

  • 92 PitNETs (26 retrospective aggressive/treatment-refractory, 66 prospective unselected) sequenced by MSK-IMPACT and whole-exome sequencing. 23 treatment-refractory vs. 69 benign in the analytic comparison. Dataset: ptad_msk_2024. PMID:38758238

Recurrent alterations

  • TP53 — somatic mutations in 52% (12/23) of treatment-refractory vs. 1.4% (1/69) of benign PitNETs (P=4.2e-8); clonal in 11/12 cases; associated with higher fraction of LOH. PMID:38758238
  • ATRX / DAXX — mutations unique to treatment-refractory corticotroph PitNETs; implicated in alternative lengthening of telomeres (ALT). PMID:38758238
  • TERT — mutations found exclusively in treatment-refractory corticotroph PitNETs. PMID:38758238
  • TSC2 — mutations found exclusively in treatment-refractory PitNETs. PMID:38758238
  • MSH2 / MSH6 / MLH1 — mismatch repair gene mutations in 5 treatment-refractory corticotroph PitNETs; 3 of 4 pre-treatment tumors were MSI-high. PMID:38758238
  • USP8 — canonical gain-of-function hotspot mutations rare in aggressive PitNETs (1/22); the one patient with USP8 hotspot had complete/durable response to radiation. PMID:38758238
  • CDKN2A / CDKN2B — loss acquired in a recurrent, metastatic tumor. PMID:38758238
  • Genome-wide LOH (fraction >0.11): highest importance feature for treatment-refractory behavior by random forest (AUC=0.87, accuracy=0.88, sensitivity=0.83, specificity=0.90). PMID:38758238

Subtypes

  • Treatment-refractory corticotroph PitNETs: recurrent chromosomal LOH pattern involving 12 specific chromosomes (1, 2, 3, 4, 6, 10, 11, 15, 17, 18, 21, 22) in 11/14 vs. 1/14 benign corticotrophs (P=1.7e-4). PMID:38758238
  • Benign PitNETs: USP8 gain-of-function mutations common; low LOH fraction; good response to surgery and radiation. PMID:38758238

Therapeutic landscape

  • Fraction of LOH >0.11 is a candidate biomarker for predicting treatment-refractory behavior at initial resection (NPV=0.95). PMID:38758238
  • MMR deficiency in treatment-refractory corticotroph PitNETs may render them responsive to pembrolizumab; dramatic responses have been reported in this context. PMID:38758238
  • Temozolomide is standard salvage therapy (used in 77% of retrospective patients); one tumor developed acquired MMR deficiency and hypermutation (93 mut/Mb) under temozolomide pressure. PMID:38758238
  • Recurrent chromosomal LOH phenotype resembles pancreatic neuroendocrine tumors and adrenocortical carcinoma, suggesting shared biology that may inform cross-tumor therapeutic strategies. PMID:38758238

Sources

  • PMID:38758238 — Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors (Acta Neuropathologica, 2024)

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