Fibrous Papule of the Face, Similar to Tuberous Sclerosis Complex-Associated Angiofibroma, Shows Activation of the Mammalian Target of Rapamycin Pathway: Evidence for a Novel Therapeutic Strategy?

Jung-Yi Lisa Chan,Kuo-Hsien Wang,Wei-Yu Chen,Chia-Lang Fang,H Peter Soyer

doi:10.1371/journal.pone.0089467

Abstract

Fibrous papules of the face are hamartomas characterized by stellate-shaped stromal cells, multinucleated giant cells, and proliferative blood vessels in the dermis. The pathogenesis of fibrous papules remains unclear. There is a striking microscopic resemblance between fibrous papules and tuberous sclerosis complex (TSC)-associated angiofibromas. A germline mutation of the TSC1 or TSC2 gene, leading to activation of the mammalian target of rapamycin (mTOR) pathway, accounts for the pathogenesis of TSC-associated angiofibromas. Activated mTOR subsequently activates p70 ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (S6) by phosphorylation. Rapamycin, a mTOR inhibitor, is effective in treating TSC-associated angiofibromas. The aim of this study was to understand whether the mTOR pathway is activated in fibrous papules. We studied immunoexpressions of phosphorylated (p-) mTOR effectors in fibrous papules, TSC-associated angiofibromas, and normal skin controls. P-mTOR, p-p70S6K and p-S6 were highly expressed in dermal stromal cells and epidermal keratinocytes in fibrous papules and TSC-associated angiofibromas but not in fibroblasts and epidermal keratinocytes of normal skin controls (p<0.001). The results suggest topical rapamycin may be a novel treatment option for fibrous papules.

Highlights

Fibrous papules (FPs) of the face/nose, known as sporadic angiofibromas (AFs), are very common cutaneous hamartomas which predominantly occur singly on the nose, but occasionally several lesions may exist [1,2]
Dermal stromal cells in FPs were clearly demonstrated to originate from dermal fibroblasts or fibrohistiocytic cells, the underlying molecular mechanisms leading to the formation of FPs remain completely unknown [5,6,7]
Clinical findings The 40 lesions of FP were excised from 40 patients (10–66 years; median age: 38 years)

Summary

Introduction

Fibrous papules (FPs) of the face/nose, known as sporadic angiofibromas (AFs), are very common cutaneous hamartomas which predominantly occur singly on the nose, but occasionally several lesions may exist [1,2]. FPs appear domeshaped or polypoid with spindle- to stellate-shaped stromal cells, multinucleated giant stromal cells, fibrosis, mononuclear inflammatory cell infiltrate, and proliferative thin-walled vessels with dilated lumina in the dermis [1,2,3]. Collagen fibers commonly show a concentric, laminated arrangement around hair follicles. Hyperkeratosis, hypergranulosis, and flattening of rete ridges are seen in the epidermis. The amount of melanin pigment and the number of melanocytes are commonly increased in the basal layer of the epidermis. In addition to the classic type of FPs, several histologic variants including hypercellular, inflammatory, pigmented, clear-cell, and pleomorphic types, were described [2,4]. Dermal stromal cells in FPs were clearly demonstrated to originate from dermal fibroblasts or fibrohistiocytic cells, the underlying molecular mechanisms leading to the formation of FPs remain completely unknown [5,6,7]

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