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Background Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified. Objective To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety. Methods A literature search was performed in January 2017. Reports of all studies investigating the use of topical mTOR inhibitors in any dermatology diseases were included. The exclusion criteria were systemic use and mucosal administration. Results We included 40 studies with a total of 262 patients. In all, 11 dermatologic conditions were found, the most frequent being angiofibromas linked to tuberous sclerosis complex (157 patients). Topical mTOR inhibitors were significantly more efficient than placebo for angiofibromas (relative risk, 2.52; 95% confidence interval, 1.27-5.00; I2 = 0%). The median concentration of sirolimus was 0.1%, with a median treatment duration of 12 weeks. Topical mTOR inhibitors were well tolerated, with only mild or moderate local side effects (mostly irritative) reported. Blood level of sirolimus was not detected in 90% of patients. Limitations High heterogeneity in most studies. Conclusion This systematic review supports the efficacy of topical sirolimus for angiofibromas linked to tuberous sclerosis complex, with only local side effects reported. Other indications require further research.

Background Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC). Objective We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects. Methods A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. Results Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment). Limitations This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis. Conclusion Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients; 6% of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The "ash leaf" macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a "Fitzpatrick patch." Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. Learning objective After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.

Patients with multiple endocrine neoplasia type I (MEN-I) frequently develop skin lesions including collagenomas, angiofibromas, and lipomas. We report a patient with MEN-I who exhibited rapid growth of multiple collagenomas after pancreatic enucleation of a vasoactive intestinal peptide-secreting tumor (VIPoma) and excision of multiple pancreatic masses. Five of the collagenomas were protuberant, with the bulk of the lesion protruding above the skin. Histologic analysis of the collagenomas revealed broad collagen bundles in a haphazard arrangement and decreased elastic fibers. Rapid growth of protuberant collagenomas appears to be unusual in MEN-I, but we suggest that MEN-I be considered in patients with apparent eruptive collagenoma.

Background: Facial angiofibromas in tuberous sclerosis have been managed with various treatment modalities, including carbon dioxide (CO 2 ) laser resurfacing. Objective: Our purpose was to perform a long-term clinicopathologic assessment of CO 2 laser treatment of angiofibromas. Methods: This was a retrospective case review of 10 patients treated with a scanning CO 2 laser to flatten lesions. Baseline clinical photographs and those taken at 6, 12, and 24 months after the operation were assessed by a blinded observer. Patients also evaluated outcomes. Biopsy specimens taken immediately and at 4 months after the operation were reviewed. Results: Three groups of patients were identified: the first comprised 2 patients with sustained excellent and good outcomes. A second group (3 patients) had excellent outcomes in the early and medium term but then demonstrated partial deterioration. The last group (5 patients) had a range of early results with invariably poor outcomes at 24 months. In contrast, patients' self-assessment at 24 months was good or excellent in 8 of 10 cases. All biopsy specimens taken immediately after the procedure demonstrated ablation extending into the papillary dermis. Residual angiofibromas were present in 6 biopsy specimens. At 4 months, all biopsy specimens showed a band of superficial dermal fibrosis, but distinguishing between this and adjacent angiofibromas was often difficult. Long-term side effects included 2 cases of subtle hypopigmentation. Conclusion: The long-term results of CO 2 laser treatment of angiofibromas are unpredictable. The marked improvement obtained at 6 months is sustained in only a minority of cases at 24 months. Despite this, patient satisfaction appears relatively high. Initial clinical improvement may be the result of a combination of destruction of angiofibromas and their sequestration under postoperative fibrosis. The benefits of therapy should be weighed against both early morbidity and the risks of long-term complications such as scarring and hypopigmentation. (J Am Acad Dermatol 2001;45:731-5.)

her brain as well as in numerous other organs. 1 In time, additional patients with this inherited disease were studied and found to have benign tumors in virtually every organ, including the brain (cortical tubers, subependymal nodules, and giant cell astrocytomas), eyes (retinal hamartomas), kidneys (angiomyolipomas, cysts), heart (cardiac rhabdomyomas), lungs (lymphangioleiomyomatosis), and skin. Recent molecular investigations have revealed that this potpourri of seemingly unrelated findings, called tuberous sclerosis complex (TSC),results from a dysregulated signaling pathway. These discoveries have profound clinical implications. The skin is paradigmatic for TSC. TSC presents a variable clinical picture, and the skin lesions are no less variable. TSC skin lesions range from subtle to disfiguring. A patient may have one or several types of skin lesions, and each type may be single or multiple. Many of the skin and internal tumors in TSC are hamartomas that are highly vascular. Both skin tumors and internal tumors occur in characteristic locations with typical ages of onset. Proclivity of skin tumors for certain regions of the body is indicated by the names of lesions, such as facial angiofibromas, periungual fibromas, and forehead plaques. In contrast, hypopigmented macules seemingly occur at random locations, and exhibit differences in size and shape (ash leaf vs confetti-like), location (hypopigmented macule vs poliosis), and extent. Hypomelanotic macules are typically present at birth or appear during early infancy. Angiofibromas usually develop at about 3 to 5 years, while periungual fibromas emerge in the teen years or later. 2 Skin lesions may be a presenting feature and can form the basis for the diagnosis of TSC. Among the diagnostic criteria, mucocutaneous lesions comprise 4 major features (angiofibromas or forehead plaque, subungual or periungual fibromas, hypomelanotic macules, and the shagreen patch) and 3 minor features (confetti-like hypopigmentation, gingival fibromas, and multiple dental pits). 3 These 1998 criteria were modified from earlier versions to accommodate recent observations. Multiple facial angiofibromas are no longer considered pathognomonic for TSC, as they are also observed in multiple endocrine neoplasia type 1. More than 3 hypomelanotic macules must be observed to qualify as a major feature of TSC, because solitary lesions are commonly observed in the general population. Finally, consideration is given to the fact that single ungual fibromas may occur in the general popu

Background Giant angiofibromas in patients with tuberous sclerosis complex (TSC) are rare. Objective We sought to report two patients who had TSC with unusually large and disfiguring facial angiofibromas and to identify underlying histopathologic changes that may possibly explain the clinical features. Methods We performed a clinicopathologic, immunohistochemical, and molecular biologic study using 42 lesional specimens and peripheral blood from one of the two patients. The immunohistochemical investigations were mainly focused on the vascular moiety of the lesions. TSC1 and TSC2 alterations were studied using multiplex ligation-dependent probe amplification for large deletion/duplication mutations, whereas screening for small mutations was performed using polymerase chain reaction amplification of individual coding exons and exon-intron junctions of both genes followed by an analysis on denaturation gradient gel electrophoresis. Results Histopathologic examination revealed, in addition to findings typical of angiofibroma, several unusual features including multinucleated giant cells containing multiple intracytoplasmic vacuoles, Touton-like cells, emperipolesis, pagetoid dyskeratosis, vacuolar alteration at the dermoepidermal junction, Civatte bodies, and melanophages in the subjacent dermis. Numerous dilated lymphatic vessels were detected indicating localized lymphostasis, probably caused by secondary lymphedema. The lymphatic nature of the vessels was confirmed by immunohistochemical study. Genetic testing for TSC1 and TSC2 gene mutations revealed a substitution on position c.2251C>T resulting in a nonsense mutation R751X in fragment 20.2. Limitations Histopathologic specimens and peripheral blood were available from only one patient. Conclusion Localized lymphedema may contribute to the formation of large disfiguring angiofibromas in patients with TSC.

Multiple endocrine neoplasia type 1 (MEN 1) predisposes affected persons to neoplasms of the parathyroid glands, the endocrine pancreas, the anterior pituitary, and the duodenum. We report the first case of adult-onset multiple angiofibromas of the central face associated with MEN 1. Seven siblings also developed adult-onset angiofibromas, none with evidence of tuberous sclerosis. Basic fibroblast growth factor (BFGF) is elevated in many patients with MEN 1 and may play a pathogenetic role.

Angiofibromas occur commonly as solitary le­ sions (fibrous papules) on the face of adults, and they also appear extensively on patients with tuberous sclerosis. Fibrous papules are generally smooth, firm, dome-shaped, and skin colored, but they may have a rim of erythema or be slightly pigmented. Although many authors believe that fibrous papules and angiofibromas are identical, others classify them individually.' Angiofibromasoccurinapproximately 90% ofpatients with tuberous sclerosis and are vari­ ably colored, reflecting the amount ofvascular ecta­ SIa. Angiofibromas contain a variable number of spindle-shaped stellate fibroblasts in the papillary dermis and increased numbers of blood vessels that are frequently dilated. 1 The cause of these angiofi­

The large stellate and polygonal cells observed in eleven fibrous papules and two angiofibromas were examined immunohistochemically for alpha 1-antitrypsin and lysozyme. The positive findings suggest that these cells are related to histiocytes rather than nevomelanocytes.