Dermal Interstitial Glycogenosis and Stromal Senescence-Associated Marker Expression in Fibrofolliculomas: Implications for Pathogenesis and mTOR-Targeted Therapy.

Abstract

Abstract: Fibrofolliculomas, benign adnexal tumors often associated with Birt-Hogg-Dubé syndrome, exhibit characteristic perifollicular epithelial and stromal proliferation. Although their clinicopathologic features are well established, the molecular and metabolic drivers of stromal remodeling remain poorly understood, particularly in sporadic cases. We investigate the presence of dermal interstitial glycogenosis (DIG) and stromal senescence in fibrofolliculomas, exploring potential mechanistic parallels with pulmonary interstitial glycogenosis and mammalian target of rapamycin (mTOR)-driven cutaneous lesions. Archival skin biopsy specimens diagnosed as fibrofolliculoma between 2015 and 2025 (n = 13) were analyzed using Periodic acid-Schiff ± diastase staining and immunohistochemistry for p53, GLB1 (β-galactosidase), CD68, and phospho-S6 and compared with age-matched, sex-matched, and site-matched controls (n = 3). Clinical data, including imaging and genetic testing, were reviewed in cases of fibrofolliculoma. All fibrofolliculomas exhibited diastase-sensitive Periodic acid-Schiff-positive stromal granules consistent with glycogen accumulation. Stromal cells demonstrated immunoreactivity for GLB1, p53, and phospho-S6 in the absence of CD68 expression, indicating nonhistiocytic stromal senescence and mTOR activation. Birt-Hogg-Dubé syndrome was suspected in 4 of 10 patients but unconfirmed; DIG and senescence markers were present regardless of clinical context. Glycogenosis and cellular senescence markers were absent in controls. These findings identify DIG and stromal senescence as conserved features of fibrofolliculomas, suggesting a metabolic-senescence axis driven by mTOR signaling, and provide a rationale for mTOR-targeted therapies, including topical rapamycin, in the treatment of fibrofolliculomas.