Cutaneous Angiofibroma

Etiology

Tuberous sclerosis is caused by mutations in the tuberous sclerosis complex 1 (TSC 1) gene, which encodes the protein hamartin, and the tuberous sclerosis complex 2 (TSC 2) gene, which encodes the protein tuberin.[5] These proteins normally suppress the activation of the mammalian target of rapamycin (mTOR); however, when mutated, they cause unregulated proliferation of cell growth followed by the formation of multiorgan hamartomas. 

MEN-1 is due to a mutation in the MEN1 gene, which encodes the protein menin. Birt-Hogg-Dubé syndrome is caused by a mutation in the FLCN gene, which encodes the protein folliculin.[6]

Epidemiology

About 75% of individuals with tuberous sclerosis eventually develop angiofibromas. Although periungual angiofibromas are less common in children, their incidence rises to 40% in adults, and they occur in 30% to 60% of patients with tuberous sclerosis. Oral fibromas are present in 30% to 70% of individuals with tuberous sclerosis, with a higher prevalence in adults than in children. Additionally, pearly penile papules are found in approximately 30% of postpubertal males.

Pathophysiology

Tuberous sclerosis is caused by mutations in the genes TSC 1, which encodes the protein hamartin, and TSC 2, which encodes the protein tuberin. These proteins normally suppress the activation of the mTOR; however, when mutated, they cause unregulated proliferation of cell growth and lead to the formation of multiorgan hamartomas. In facial angiofibromas, mTOR is activated in the proliferating fibroblast-like cells. These cells produce an epidermal growth factor called epiregulin, which stimulates epidermal cell proliferation so that they are produced at a faster rate. Additionally, angiofibromas associated with tuberous sclerosis exhibit vascular proliferation due to increased expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), which further stimulates mTOR.[7][8][9]

Histopathology

All cutaneous angiofibromas comprise a dermal proliferation of fibroblasts within a collagenous stroma, accompanied by an increase in thin-walled, dilated blood vessels. Collagen fibers are arranged concentrically around hair follicles and blood vessels, while elastic fibers may be decreased, and the epidermis can be atrophic. Fibroblasts are stellate in shape and may be multinucleated. Immunohistochemistry reveals positivity for factor XIIa and negativity for S100 protein in these cells.[10]

History and Physical

Fibrous papules are solitary, dome-shaped, skin-colored to red papules typically found on the central face, particularly around the nose and malar eminences. These papules may have tiny telangiectatic vessels on their surface. In tuberous sclerosis, angiofibromas often appear symmetrically on the cheeks, nasolabial folds, nose, and chin. They may begin as erythematous macules that evolve into red or red-brown papules, which can coalesce into plaques. Rarely, angiofibromas may also be present on the scalp.[11]

Periungual angiofibromas in tuberous sclerosis typically appear from late childhood to early adulthood. They arise from the lateral or proximal nail fold, commonly affecting the toes, and can be painful, often distorting the shape of the nail. Oral fibromas most commonly occur on the gingiva but can also appear on the buccal or labial mucosa and occasionally on the tongue. Pearly penile papules are pearly, white, dome-shaped, and closely aggregated, located circumferentially on the glans penis in a multilayered manner around the corona.

Clinical findings in Birt-Hogg-Dubé syndrome include fibrofolliculomas, perifollicular fibromas (some authorities relate to angiofibromas), and trichodiscomas. These lesions typically appear as skin-colored to hypopigmented papules on the head, neck, or upper trunk.

Evaluation

The diagnosis of angiofibroma is based on history, physical examination, and skin biopsy.[10] If tuberous sclerosis, MEN-1, or Birt-Hogg-Dubé syndrome is suspected, genetic testing should be performed along with an extensive workup to identify any associated tumors according to the specific condition.

Treatment / Management

As cutaneous angiofibromas are benign lesions, they should only be removed for cosmesis or if they cause compression and pain in adjacent structures to prevent morbidity and improve outcomes. Current treatment options for angiofibromas include shave excision, cryotherapy, electrodesiccation, radiofrequency ablation, dermabrasion, and lasers such as ablative fractional laser resurfacing and pulsed dye laser. Topical podophyllotoxin is also used. Although these treatments have proven to be effective, they can result in scarring, postinflammatory hyperpigmentation, and pain.[12] (B2)

The recurrence rate of angiofibromas can be up to 80%, often requiring follow-up treatments. Topical rapamycin, an mTOR inhibitor, appears to be a safe and effective treatment for angiofibromas, although long-term studies are still needed. Combination treatments, such as fractional laser resurfacing and pulsed dye laser, can be used alongside topical medications, such as timolol or rapamycin, to effectively manage these lesions.[13][14][15](A1)

Rapamycin has recently gained popularity for treating angiofibromas. By binding to mTOR, it inhibits its activity, which reduces cell proliferation and decreases VEGF production by downregulating VEGF-stimulated endothelial cell proliferation. Several case series, case reports, and a randomized controlled trial have been published verifying the effectiveness of topical rapamycin at various concentrations and frequencies, including 0.1% used once or twice daily, 0.2% used 5 times weekly, and 0.4% used 3 times weekly. Angiofibromas typically clear while the medication is in use, with the longest reported follow-up being 3 years.

Many have used crushed rapamycin tablets mixed with Vaseline to achieve the desired concentration, though this method does not provide a standardized dose. In 2011, DeKlotz et al proposed a standardized formulation for making 0.1% topical rapamycin. Few adverse effects occur from the topical medication, primarily mild irritation and erythema. Park et al showed that topical rapamycin can effectively treat lesions smaller than 4 mm in size.[16] However, for lesions larger than 4 mm, ablative resurfacing was needed in conjunction with rapamycin. Using topical rapamycin to treat angiofibromas can be costly due to the lengthy treatment schedules required to achieve sufficient results, with expenses ranging from several hundred to several thousand dollars out of pocket.(B3)

Beta-blockers have been used for many years to treat vascular lesions. Oral propranolol has been successful in treating hemangiomas in the pediatric population, though adverse effects such as hypoglycemia limit its use in certain patients. Topical timolol 0.5% solution or gel, applied 2 to 3 times daily, has effectively treated superficial hemangiomas. The mechanism of action for beta-blockers involves blocking the conversion of renin to angiotensin II, thereby preventing the formation of VEGF, which is necessary for the conversion of endothelial stem cells to endothelial cells, thus reducing capillary development. Additionally, beta-blockers inhibit matrix metalloproteinase-9, a key enzyme in angiogenesis, and promote osteoprotegerin production, leading to apoptosis of mesenchymal and endothelial cells, further decreasing angiogenesis.[16][17](B3)

Differential Diagnosis

The differential diagnosis of cutaneous angiofibroma includes several dermatological conditions with similar clinical presentations. These include fibrous papules of the face, which are often solitary and smaller, and dermatofibromas, which are firm nodules typically found on the extremities. Basal cell carcinoma can also resemble angiofibromas but is usually more pearly and may ulcerate. Sebaceous hyperplasia presents as yellowish papules with central umbilication, often mistaken for angiofibromas. Additionally, trichoepitheliomas, benign tumors arising from hair follicles, and neurofibromas associated with neurofibromatosis should be considered. 

For facial lesions, angiofibromas can be confused with acne, acrochordons, intradermal melanocytic nevi, basal cell carcinoma, and adnexal tumors. Periungual angiofibromas can resemble verruca vulgaris and subungual exostosis. Pearly penile papules can be mistaken for condyloma acuminatum and molluscum contagiosum. Accurate diagnosis often requires clinical evaluation, dermoscopy, and histopathological examination to differentiate these conditions and ensure appropriate management. 

Prognosis

The prognosis of cutaneous angiofibroma is generally favorable, as these lesions are benign proliferations. While they often persist once they appear, they do not pose a significant health risk. However, when multiple, angiofibromas can cause significant disfigurement, bleeding, pruritus, and erythema, necessitating effective treatment.

Treatment for cutaneous angiofibromas is typically sought for cosmetic reasons or if the angiofibromas cause discomfort due to their size or location. Although various treatment options, such as laser therapy, cryotherapy, and topical medications like rapamycin, are effective, recurrences are common, with rates as high as 80%. Long-term management may require multiple treatments to maintain cosmetic outcomes. Overall, individuals with cutaneous angiofibromas can expect a good quality of life with appropriate care and monitoring.

Complications

Lesions in angiofibroma are prone to secondary bacterial infections and can bleed easily, causing chronic ulceration. In syndromic cases like tuberous sclerosis, angiofibromas are associated with severe systemic complications, such as renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and neurological issues, including epilepsy and cognitive impairment.

Some treatment-related complications from laser therapy or surgical excision include scarring, postinflammatory hyperpigmentation, and potential lesion recurrence. Systemic treatments, such as mTOR inhibitors, may cause immunosuppression and other adverse effects.