Characterizing Paratesticular Neoplasms in Proteus Syndrome

Area of Science:

• Genetics and Oncology
• Pathology
• Endocrinology

Background:

• Proteus syndrome is a rare mosaic overgrowth disorder linked to somatic AKT1 variants.
• It increases the risk of benign and malignant neoplasms, including paratesticular masses.
• Paratesticular tumors in Proteus syndrome are poorly understood.

Purpose of the Study:

• To document the clinicopathologic features of paratesticular tumors in males with Proteus syndrome.
• To investigate the histological spectrum and immunohistochemical profile of these tumors.
• To determine the association with the AKT1 gene variant.

Main Methods:

• Longitudinal natural history study of 64 males with genetically confirmed Proteus syndrome.
• Surgical and histopathological review of 12 paratesticular masses.
• Immunohistochemistry and exome sequencing of tumor samples.

Main Results:

• 19% of males developed paratesticular masses, typically unilateral, small, and slow-growing.
• Tumors showed diverse histology, frequently Müllerian-type (papillary cystadenomas, adenocarcinomas, Brenner tumor).
• Consistent PAX8, WT1, ER, and PR expression supported Müllerian lineage; all sequenced tumors harbored the AKT1 c.49G>A variant.

Conclusions:

• Paratesticular tumors are a significant component of the Proteus syndrome phenotype.
• These tumors exhibit Müllerian differentiation and are associated with the AKT1 c.49G>A variant.
• Recurrence and atypical histology highlight the need for vigilant follow-up.