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?

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.

Figure 1. Fibrous papule (FP), tuberous sclerosis complex (TSC)-associated angiofibroma (AF), normal skin (NS), and their expressions of phosphorylated mammalian target of rapamycin (mTOR) effectors.

A to C, Stellate-shaped stromal cells and fibrosis in the dermis of FP and TSC-associated AF but not in the dermis of NS. Insets in A and B show the histologic features of stellate-shaped stromal cells in FP and TSC-associated AF compared with fibroblasts in normal skin (inset in C). D to L, Phosphorylated mTOR (p-mTOR), phosphorylated p70 ribosomal protein S6 kinase (p-p70S6K) and phosphorylated ribosomal protein S6 (p-S6) in the dermal stromal cells of FP and TSC-associated AF but not in the fibroblasts of NS. Insets in D to L highlight positive p-mTOR, p-p70S6K and p-S6 immunoreactivity in stellate-shaped stromal cells of FP and TSC-associated AF but not in fibroblasts of normal skin. P-mTOR, p-p70S6K, and p-S6 are also highly expressed in epidermal keratinocytes in FP and TSC-associated AF. Expressions of these markers are limited to granular layers of the epidermis in NS. (A to C, hematoxylin-eosin stain (H&E); original magnification: X200. D to F, P-mTOR immunostaining; original magnification: X200. G to I, P-p70S6K immunostaining; original magnification: X200. J to L, P-S6 immunostaining; original magnification: X200. Insets in D to L, original magnification: x400.)

Figure 2. Fibrous papule (FP) variants and their expression of phosphorylated ribosomal protein S6 (p-S6).

A and B, Hypercellular FP with closely compacted dermal stromal cells which are immunoreactive for pS6. The epidermal keratinocytes are also positive for p-S6. C and D, Inflammatory FP with stellate stromal cells admixed with lymphocytes in the dermis. The stromal cells and epidermal keratinocytes are immunoreactive for p-S6. E and F, Pigmented FP with melanocyte hyperplasia in the dermoepidermal junction and melanin incontinence. Note p-S6 expression in the stromal cells and epidermal keratinocytes. G and H, Pleomorphic FP with mononucleate and multinucleate stromal cells with enlarged, pleomorphic nuclei. The inset reveals pleomorphic stromal cells with hyperchromatic nuclei and occasional prominent nucleoli. The pleomorphic stromal cells and epidermal keratinocytes are immunoreactive for p-S6. I and J, Clear-cell FP with stromal cells which are immunoreactive for p-S6. The inset in I shows stromal cells with abundant clear cytoplasm. The insets in B, D, F, H, and J highlight positive p-S6 staining in the dermal stromal cells of FP variants. The epidermal keratinocytes are also positive for p-S6. (A, C, E, G, and I: hematoxylin-eosin stain (H&E); original magnification: x200. B, D, F, H, and J: p-S6 immunostaining; original magnification: x200. Insets in A to J, original magnification: x400.)