Thirty-two new cases of SAF confirm this tumor as a reproducible entity. Occurrence in the heel, a new site for this tumor, was reported in four cases. Recurrence rate of this tumor may exceed 20%.
Systemic cyclosporin A and tacrolimus are effective treatments for psoriasis. Cyclosporin A and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor nuclear factor of activated T cells (NFAT). Inhibition of T cell activation is thought to account for their therapeutic action in psoriasis. We investigated whether nonimmune cells in human skin express calcineurin and NFAT1 and whether cyclosporin A and tacrolimus block activation of calcineurin/NFAT in epidermal keratinocytes. The expression patterns of the principal components of calcineurin/NFAT signaling pathway in normal human skin and psoriasis were determined by immunohistochemistry. We assessed calcineurin/NFAT activation in cultured keratinocytes by measuring the degree of nuclear localization of calcineurin and NFAT1 using immunofluorescence/confocal microscopy and assessed if cyclosporin A and tacrolimus blocked nuclear translocation of these proteins. A variety of cell types in normal and psoriatic skin expressed calcineurin and NFAT1, but expression was particularly prominent in keratinocytes. The principal cyclosporin A and tacrolimus binding proteins cyclophilin A and FKBP12 were also expressed by keratinocytes and nonimmune cells in skin. NFAT1 was predominantly nuclear in normal basal epidermal keratinocytes. Increased nuclear localization of NFAT1 was observed in suprabasal keratinocytes within lesional and to a lesser extent nonlesional psoriatic epidermis compared to normal skin (p = 0.001 and p = 0.03, respectively), suggesting increased activation of calcineurin in psoriatic epidermal keratinocytes. Agonists that induce keratinocyte differentiation, specifically 12-0-tetradecanoyl-phorbol-13-acetate (TPA) plus ionomycin, TPA, and raised extracellular calcium, induced nuclear translocation of NFAT1 and calcineurin in keratinocytes that was inhibited by pretreatment with cyclosporin A or tacrolimus. In contrast in human dermal fibroblasts, TPA plus ionomycin or TPA did not significantly alter the proportion of nuclear-associated NFAT1. These data provide the first evidence that calcineurin is functionally active in human keratinocytes inducing nuclear translocation of NFAT1 and also indicate that regulation of NFAT1 nuclear translocation in skin is cell type specific. Inhibition of this pathway in epidermal keratinocytes may account, in part, for the therapeutic effect of cyclosporin A and tacrolimus in skin diseases such as psoriasis.
Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.
We describe a large series of 41 cases of SAF showing that it is a distinct entity with typical clinical, histological and immunohistochemical features. Follow-up was available only in 12 patients, precluding a firm comment on recurrence. However, complete excision and follow-up review is recommended.
Recently described macular arteritis presents as asymptomatic hyperpigmented macules, runs a chronic, indolent course, and shows lymphocytic arteritis at various stages of evolution ranging from fibrinoid necrosis to endarteritis obliterans. Herein, we present another case that was clinically suspected to be unilateral plantar pompholyx. A 47-year-old male presented with a 2-month history of persistent, reticulated, asymptomatic, nonblanching erythematous and brawny macules, and scattered, slightly scaly papules over the plantar instep of his left foot. Two punch biopsies extending to the subcutis revealed healed arteritis (endarteritis obliterans with fragmented elastic lamina) in the subcutis in one biopsy and purpura and hemosiderin deposition surrounding small subcutaneous arterioles and venules in the second. Additional histologic features included lymphocytic eccrine hidradenitis and chronic spongiotic dermatitis. Extensive laboratory work did not reveal evidence of systemic disease. Despite topical corticosteroid therapy, he has had persistent, asymptomatic disease after 6 months follow-up. The differential diagnoses considered included pigmented purpuric dermatitis, perniosis (chilblains), plantar eccrine hidradenitis, Buerger disease, livedo vasculopathy, and cutaneous polyarteritis nodosa. Cutaneous polyarteritis nodosa also runs a benign course and is denoted by muscular vessel vasculitis, which can resolve with retiform hyperpigmentation. Based on these overlapping clinical-pathologic features, macular arteritis might represent a latent, non-nodule forming chronic variant of cutaneous polyarteritis nodosa.
PGBS are rare and mainly occur in the gallbladder body in middle-aged females. They generally present with acute cholecystitis and have a very poor prognosis. A variety of sarcoma types are found with MFH being the predominant variant.
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