Continuing Education Activity

Cutaneous angiofibroma is a benign skin tumor characterized by the presence of fibrovascular tissue. These growths typically manifest as small, firm, reddish, or flesh-colored papules, often appearing on the face, particularly around the nose and cheeks. Although generally noncancerous, cutaneous angiofibromas are associated with certain genetic conditions, such as tuberous sclerosis complex, where multiple angiofibromas may be observed. The condition is primarily of cosmetic concern, but in some cases, surgical removal or laser therapy may be considered for symptomatic or aesthetic reasons. Diagnosis involves a thorough clinical evaluation and may require a biopsy. Genetic testing and an extensive workup are necessary if associated syndromes are suspected. Understanding the nature and implications of cutaneous angiofibromas is essential for accurate diagnosis and effective treatment. 

This activity offers an in-depth exploration of cutaneous angiofibroma, covering its pathophysiology, clinical presentation, diagnosis, and management strategies. This activity provides insights into the latest research on genetic associations, particularly with conditions such as tuberous sclerosis complex, and explores current treatment options, including both surgical and nonsurgical interventions. This activity also highlights the role of an interprofessional healthcare team in applying clinical strategies to improve patient care and outcomes for affected individuals.

Objectives:

• Identify the clinical and histological features of cutaneous angiofibromas to diagnose the condition accurately.

• Implement appropriate treatment modalities, including surgical excision, cryotherapy, and laser therapy, to treat cutaneous angiofibroma based on individual patient needs and lesion characteristics.

• Select appropriate diagnostic and therapeutic approaches, including biopsy and genetic testing, to ensure accurate diagnosis and effective management.

• Collaborate with dermatologists, geneticists, and other healthcare professionals to address the complex needs of patients with cutaneous angiofibromas and associated syndromes.

Introduction

Cutaneous angiofibroma is a benign skin tumor characterized by fibrovascular tissue and presents as a group of lesions with varied clinical appearances but consistent histological features. These benign fibrous neoplasms exhibit a proliferation of stellate and spindled cells, thin-walled blood vessels with dilated lumina in the dermis, and concentric collagen bundles. These growths typically manifest as small, firm, reddish, or flesh-colored papules, most commonly on the face (often referred to as fibrous papules or adenoma sebaceum), particularly around the nose and cheeks. However, they can also appear on other parts of the body, including the penis (as pearly penile papules), under the nails (as periungual angiofibromas or Koenen tumors), and in the mouth (as oral fibromas).

Facial angiofibromas are one of the most prominent clinical signs of tuberous sclerosis—an autosomal dominant disorder that affects the skin, kidneys, heart, brain, and lungs. In tuberous sclerosis, these angiofibromas typically emerge on the face during childhood or early adulthood (see Image. Facial Angiofibromas Observed in Tuberous Sclerosis).[1] The presence of 3 or more facial angiofibromas or 2 or more periungual angiofibromas is major diagnostic criteria for the condition. Multiple facial angiofibromas are also observed in multiple endocrine neoplasia type 1 (MEN-1) and Birt–Hogg–Dubé syndrome.[2][3][4]

Pearly penile papules are chronic, asymptomatic papules found on the coronal margin and sulcus of the penis and are more commonly observed in uncircumcised men.

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] 

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]

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.

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]

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.

Deterrence and Patient Education

Patients should be educated on the importance of regular dermatologic evaluations to monitor for new lesions and manage existing ones, reducing the risk of complications such as bleeding, infection, and ulceration. Emphasis on gentle skin care and avoiding trauma to lesions can prevent secondary infections and minimize bleeding. Patients should be informed about treatment options, including laser therapy, surgical excision, and the use of topical or systemic medications such as mTOR inhibitors. They should also be made aware of potential adverse effects and the need for ongoing follow-up.

Education on the genetic nature of the condition and the potential for associated systemic complications is essential, prompting regular surveillance for renal, pulmonary, and neurological involvement in syndromic cases. Providing psychological support and resources to address the psychosocial impact of visible lesions can improve quality of life. Encouraging patients to connect with support groups and organizations can offer additional emotional support. 

Enhancing Healthcare Team Outcomes

Effective management of cutaneous angiofibromas requires an interprofessional approach involving physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals. Physicians and advanced practitioners develop diagnostic skills to accurately identify cutaneous angiofibromas, differentiate them from other dermatological conditions, and master various treatment modalities such as laser therapy, cryotherapy, and topical medications.

Dermatologists and geneticists address the complex needs of patients, especially those with underlying genetic conditions such as tuberous sclerosis. Nurses provide wound care and patient education to support posttreatment recovery and adherence to management plans. Pharmacists offer expertise in dermatological pharmacotherapy, particularly in the use of topical treatments such as rapamycin, to ensure safe and effective medication use. 

Treatment plans must be tailored to individual patient needs, considering both medical and cosmetic outcomes to enhance quality of life. The team collaboratively monitors treatment efficacy and potential recurrences, adjusting the management plan as necessary. By fostering a collaborative, informed, and patient-centered approach, healthcare professionals can significantly enhance the management of cutaneous angiofibromas, leading to improved clinical outcomes, increased safety, and better team performance.