A 30-year-old woman has pituitary adenoma causing Cushing disease. After transsphenoidal resection, she goes into remission. Five years later, cortisol rises again. Pituitary MRI shows a new lesion in the same region. Molecular analysis of the recurrent tumor reveals loss of the USP8 mutation present in the original tumor and emergence of a new BRAF V600E mutation. This scenario best illustrates:

• A A de novo second primary corticotroph adenoma
• B Clonal evolution with acquisition of additional driver mutations ✓
• C Transformation to corticotroph carcinoma via BRAF mutation
• D Radiation-induced mutagenesis from prior adjuvant radiotherapy

Explanation

This scenario demonstrates clonal evolution (tumor progression) within the original neoplastic clone. USP8 (ubiquitin-specific protease 8) mutations are found in ~40% of corticotroph adenomas causing Cushing disease; they impair EGFR degradation, causing persistent EGFR signaling and POMC/ACTH overproduction. The recurrent tumor lacking USP8 mutation but harboring BRAF V600E suggests outgrowth of a resistant subclone with different driver mutations. Corticotroph adenoma recurrence/progression can involve acquisition of new mutations. Loss of the original mutation indicates that the founding clone may have been eliminated, but a minor subclone with BRAF V600E (perhaps pre-existing at low frequency) expanded under selection pressure.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.