Every one of 13 archival fibrofolliculoma specimens displayed diastase-sensitive PAS-positive glycogen granules in stromal cells — a pattern termed dermal interstitial glycogenosis (DIG) — alongside co-expression of GLB1 (β-galactosidase), p53, and phospho-S6, markers of cellular senescence and active mTOR signaling. Critically, CD68 was absent, ruling out macrophage infiltration and confirming a non-histiocytic stromal senescence phenotype. Age-, sex-, and site-matched controls showed none of these features. The findings held regardless of whether Birt-Hogg-Dubé syndrome (FLCN mutation) was confirmed, suggesting the pathway is not syndromic-exclusive.
This small but carefully controlled case series (n=13, n=3 controls) elevates fibrofolliculomas from purely descriptive entities into mechanistically actionable ones. The convergence of glycogen hoarding, senescence-associated secretory phenotype markers, and mTOR hyperactivation mirrors what has been documented in pulmonary interstitial glycogenosis and TSC-related cutaneous lesions — pointing toward a unified metabolic-senescence axis. FLCN, the Birt-Hogg-Dubé tumor suppressor, is a known negative regulator of mTORC1; its loss plausibly explains stromal mTOR activation even in apparently sporadic cases.
Practically, the phospho-S6 positivity provides a biomarker rationale for trialing topical rapamycin, already used off-label in facial angiofibromas in tuberous sclerosis. The sample size is modest and causality unproven, but the 100% penetrance of the DIG-senescence signature is striking. For a rare benign tumor without effective pharmacotherapy, this is a meaningful mechanistic foundation — incremental in scope but potentially paradigm-shifting for clinical management.