Are You Confident of the Diagnosis?
Fibrous papule (aka solitary angiofibroma) is a common benign skin growth. As a solitary lesion, there are no associated systemic implications. When multiple angiofibromas are seen in an individual, particularly clustered over the central face, the differential diagnosis should include the tuberous sclerosis complex, and appropriate evaluation should ensue to assess the patient for tuberous sclerosis. Multiple facial angiofibromas may also be seen as the presenting sign or in association with multiple endocrine neoplasia type 1.
Characteristic findings on physical examination
Solitary fibrous papule presents as a red to skin-colored firm papule arising on the face, most commonly on the nose (Figure 1). It is usually small, less than 5 mm, and found in middle-aged adults. Fibrous papules are most commonly dome-shaped, but rarely can be pedunculated.
Expected results of diagnostic studies
Histopathology shows an increased number of dilated blood vessels and a proliferation of fibroblasts surrounded by coarse collagen (Figure 2).The fibroblasts are often plump, spindle or stellate shaped, and can be multinucleate. A lymphocytic inflammatory infiltrate may also be present. Overlying epidermal changes include flattened rete ridges, melanocytic hyperplasia, acanthosis, and hyperkeratosis.
Although the majority of fibrous papules exhibit the classic histology, other histologic variants include hypercellular, clear cell (Figure 3), pigmented, pleomorphic, and inflammatory. Clinically it may be difficult to differentiate a fibrous papule from a basal cell carcinoma, adnexal neoplasm, or dermal melanocytic nevus. A biopsy may be performed to rule out basal cell carcinoma or adnexal neoplasm, and confirms the diagnosis.
Adenoma sebaceum is the term for the multiple angiofibromas distributed on the central face and nasolabial grooves in patients with tuberous sclerosis (Figure 4). Adenoma sebaceum is a misnomer, as the lesions are not adenomas or related to sebaceous glands.
Tuberous sclerosis is the second most common neurocutaneous syndrome, behind neurofibromatosis. The patient may have a history of seizures or mental retardation, and there may be a family history of tuberous sclerosis since it is inherited in an autosomal dominant pattern. Therefore, the physician should perform a skin examination on the parent as well as the patient. However, more than two-thirds of tuberous sclerosis cases are thought to be sporadic mutations.
The multiple angiofibromas in adenoma sebaceum appear as pink to red papules in childhood or early puberty, and are sometimes mistaken by the patient for acne. The skin examination of a patient with tuberous sclerosis is of great importance since it is non-invasive and can provide valuable clues to the diagnosis. The patient may also possess ash-leaf spots (hypopigmented macules; the earliest finding), shagreen patches (connective tissue nevi), forehead plaques, and periungual fibromas, which histologically are also angiofibromas. Clinical criteria used to diagnose the tuberous sclerosis complex require two major criteria, or one major and two minor criteria.
Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibroma
Hypomelanotic macules, more than three
Multiple retinal nodular hamartomas
Subependymal giant cell astrocytoma
Pits in dental enamel
Hamartomatous rectal polyps
Cerebral white matter migration lines
Retinal achromic patch
“Confetti” skin lesions
Multiple renal cysts
In the majority of cases, the diagnosis of adenoma sebaceum is made clinically, negating the need for biopsy. With paler or more flesh-colored lesions in which the differential diagnosis could include a trichoepithelioma (multiple hereditary trichoepitheliomas, Brooke-Spiegler syndrome), or trichodiscoma/fibrofolliculoma (Birt-Hogg-Dubé syndrome), a biopsy is recommended.
Histologic examination of adenoma sebaceum reveals a fibrovascular proliferation identical to fibrous papule or angiofibroma. Lesions are more commonly larger or pedunculated as compared to solitary fibrous papule of the nose (Figure 5). Plump, stellate, and multinucleate fibroblasts are seen along with an increased number of dilated blood vessels (Figure 6). The fibrous forehead plaques and periungual fibromas of patients with tuberous sclerosis complex also exhibit the histologic features of an angiofibroma. Genetic testing is available for the diagnosis of tuberous sclerosis complex.
Similar to tuberous sclerosis, multiple facial angiofibromas commonly occur in patients with multiple endocrine neoplasia type 1. These angiofibromas may be the only sign of this autosomal dominant inherited cancer syndrome.
When multiple facial angiofibromas are seen without other presenting signs or symptoms, the diagnosis of MEN 1 should be considered. It is important to gather a family history of endocrine tumors or other cancers, and to obtain a more extensive history and physical to rule out MEN 1.
Classically, patients with MEN 1 will develop parathyroid, pancreatic/gastrointestinal, and pituitary adenomas. At least two of these three tumor types must be present to diagnose MEN 1 in sporadic cases, and in familial cases at least one of the tumor types and a first degree relative with MEN 1 must be present.
The differential diagnosis and histopathology is similar to adenoma sebaceum. Typically, the angiofibromas of MEN 1 are fewer in number when compared to those of tuberous sclerosis. Other cutaneous manifestations of MEN 1 include collagenomas, cafe au lait macules, lipomas, multiple gingival papules, and confetti-like hypopigmented macules. Genetic testing for MEN 1 is available, but usually not performed unless the diagnosis MEN 1 is questioned.
Who is at Risk for Developing Angiofibroma?
Solitary fibrous papules are found in the middle aged population and are distributed evenly between both sexes.
Patients with a family history of the tuberous sclerosis complex are at risk for tuberous sclerosis and adenoma sebaceum, since the mode of inheritance is autosomal dominant . Tuberous sclerosis is estimated to occur in 1 every 6000 live births.
Multiple endocrine neoplasia type 1 is rare and may be a sporadic mutation or inherited as autosomal dominant. There is an equal distribution among sexes. Patients with a family history are at risk for developing this cancer syndrome and multiple facial angiofibromas.
What is the Cause of the Disease?
Fibrous papules were originally thought to be a product of an involuting nevus; however, more recently they are considered to be of histiocytic or dermal dendritic origin.
Adenoma sebaceum occurs in association with to tuberous sclerosis. Tuberous sclerosis has been mapped to two gene defects, TSC1 and TSC2, located at 9q34 and 16p13.3, respectively. They are thought to be tumor suppressor genes and their defect leads to dysregulation of the mTOR pathway. Inheritance is autosomal dominant with complete penetrance, but there is variable expression within families and a large number of cases are attributed to sporadic mutations. It is imperative to identify tuberous sclerosis so that the patient can be referred for appropriate screening tests.
Multiple facial angiofibromas are seen in a majority of patients diagnosed with multiple endocrine neoplasia type 1. MEN 1 is an autosomal dominantly inherited syndrome with very high penetrance, and it has been mapped to chromosome 11q13. The MEN1 gene is a tumor suppressor gene and its loss is responsible for the high predisposition to development of the endocrine tumors. As with tuberous sclerosis, identification of MEN1 is important so appropriate screening may be carried out.
Systemic Implications and Complications
Fibrous papules are normally asymptomatic, although they may bleed if traumatized. There are no associated systemic complications.
Adenoma sebaceum is related to a multitude of systemic complications in the tuberous sclerosis complex. These can involve: neurologic manifestations, including seizures, mental retardation, autism, and brain lesions (cortical tubers, subependymal nodules, giant cell astrocytomas); kidney abnormalities, including angiomyolipomas and renal cysts; ophthalmologic abnormalities, including retinal hamartomas and retinal achromic patches; cardiac rhabdomyomas; dental pits and gingival fibromas; and bone cysts.
Multiple angiofibromas in the setting of MEN 1 are related to the systemic complications of this cancer syndrome. Primary hyperparathyroidism is seen in almost all patients with MEN 1. Pituitary adenomas are common as well, and present with signs and symptoms of increased secretion of prolactin, growth hormone, or adrenocorticotropin hormone. Patients may have symptoms of peptic ulcer disease from a gastrinoma (Zollinger-Ellison syndrome), or can present with other gastrointestinal complaints from vasoactive intestinal polypeptide secreting tumors. Insulinomas, glucagonomas, and other tumors may also been seen in MEN 1.
Treatment options are summarized in Table I and Table II.
|Medical Treatment||Surgical Treatment||Physical Modalities|
|None||Shave excision, punch biopsy, or curettage||None|
|Medical Treatment||Surgical Treatment||Physical Modalities|
|Topical rapamycin||Surgical excision||Mechanical dermabrasion|
Optimal Therapeutic Approach for Angiofibroma
Fibrous papules do not require treatment, since the majority of lesions are asymptomatic. For symptomatic or cosmetically unacceptable lesions, shave excision may be performed using a scalpel or bendable blade. Curettage may be performed, but this often renders the biopsy difficult to interpret and is not recommended.
Adenoma sebaceum does not require treatment, since it does not lead to malignant transformation. It usually remains stable or mildly improves over time. However, the multitude of angiofibromas can be cosmetically distressing and disfiguring, which leads many patients to request treatment. Successful treatment of the lesions is difficult because they tend to recur. The multiple angiofibromas found in patients with MEN 1 may be treated similar to adenoma sebaceum.
Surgical excision (shave excision) and mechanical dermabrasion have been reported with good results. The procedure is normally performed under general anesthesia by a plastic surgeon. The larger papules or nodules are first removed by shave excision and then mechanical dermabrasion is performed to sculpt the face. Unfortunately, recurrence is still common over a period of years.
The procedure has been reported in a darker-skinned patient without hypopigmentation. There is a risk for scarring, infection, bleeding, and pigmentation changes. If the patient has an underlying seizure disorder, they may not be able to tolerate general anesthesia, making this treatment option impractical.
Laser therapy has been reported in multiple cases. Carbon dioxide, copper vapor, argon, pulsed dye, potassium titanyl phosphate, and Nd:YAG lasers have been used alone or in combination. Carbon dioxide laser seems to provide superior results; however, there are no systematic reviews comparing the various treatments. There is a risk for scarring and hypopigmentation with use of laser treatment. Use of a carbon dioxide laser with flashscanner at 16W, on/off time: 0.2/0.4 seconds using a 200-mm handpiece at a repeat mode under regional nerve block has been reported.
Topical rapamycin, an mTOR inhibitor, holds promise to be the first line treatment for adenoma sebaceum, but clinical trials and long-term follow-up are needed to further evaluate its use in clinical practice. In one case report, topical rapamycin 1% ointment was applied twice a day using 0.5g of ointment with each application (total of 5mg rapamycin each application). The patient had a favorable response and improvement in skin texture after using the product for 3 months. At the time of the published report the patient continued to use the product every day and did not have any side effects. Blood counts were stable and serum levels of rapamycin were undetectable during this time.
Discontinuation of the topical rapamycin eventually leads to recurrence of lesions. Oral rapamycin, at doses used for immunosuppressive therapy after transplant, have also been shown to improve facial angiofibromas, but the systemic side effects would prohibit its use for a mostly cosmetic condition.
Radiofrequency ablation has been reported in an Indian patient with clinically acceptable improvement. The procedure was performed with the Megasurg Gold by Dermaindia with a frequency of 0.2-2.93 MHz, 230 volts, using both cut (70% cut, 30% coagulation) and coagulation (60% coagulation, 40% cut) modes. Local anesthesia was used. Minimal scarring was reported with overall improvement of severe adenoma sebaceum.
There was also mild hyperpigmentation reported in the butterfly area of the face.
Topical podophyllin has been reported in one case as improving facial angiofibromas. Podophyllin extract 25% in benzoin tincture was applied directly to the surface of each angiofibroma, left on for 4 hours and then washed off with soap and water. These treatments were repeated once monthly for 3 months. There was no recurrence in one case at follow-up 1 year later. The only reported side effect was some burning at the site of application.
The management of fibrous papule should begin with reassuring the patient that the lesion is benign and is unlikely to grow greater than 5 mm. The physician should educate the patient that fibrous papules have not been associated with systemic or local complications, and that they tend to remain stable over time. After ruling out a malignancy, the lesion does not need to be followed.
The importance of recognizing adenoma sebaceum is to diagnose the tuberous sclerosis complex. Once the patient has been diagnosed with tuberous sclerosis, they should be followed by a multidisciplinary team including a neurologist, ophthalmologist, and genetics counselor, as well as other physicians according to the symptoms present. The dermatologist plays an integral part in recognizing this diagnosis.
If the patient wishes to have treatment for cosmetic or functional reasons, the dermatologist should recommend treatment options and discuss the risk and benefits of each option. Management of adenoma sebaceum can be frustrating because the lesions tend to be difficult to treat and often recur. The patient should be counseled on what reasonable expectations are for each treatment, and must be educated that lesions are likely to recur.
As discussed above, the importance of recognizing multiple facial angiofibromas is to rule out an underlying association or cause. If tuberous sclerosis has been ruled out, the physician must then be suspicious for MEN 1. Management of a patient with MEN 1 is usually done by an endocrinologist or the patient’s primary care physician, as well as a surgeon when indicated. The role of the dermatologist is similar to that played in the diagnosis and treatment of adenoma sebaceum.
Unusual Clinical Scenarios to Consider in Patient Management
Pearly penile papules are small angiofibromas found on the corona of the penis. Less commonly, they can be found on the shaft or glans of the penis and should not be confused with genital warts.
Periungual fibromas (Koenen tumors) are angiofibromas found in association with the tuberous sclerosis complex. They are more commonly found on the toes and present as a flesh colored papule extending from the edge of the nail plate or causing nail distortion.
Single periungual fibromas unrelated to tuberous sclerosis have been reported due to trauma or other etiology. However, rarely a single ungual or periungual fibroma can be the only presenting sign of tuberous sclerosis. Tuberous sclerosis should be considered in the differential diagnosis of an individual with a single periungual fibroma, but further investigation into the family history and other diagnostic criteria must be undertaken.
Angiofibromas have been shown to occur in association with other familial syndromes. Adult onset central facial angiofibromas have been reported with multiple endocrine neoplasia type 1 and multiple angiofibromas have also been noted in a case of neurofibromatosis type 2.
What is the Evidence?
Meigel, WN, Ackerman,, AB. “Fibrous papule of the face”. Am J Dermatopathol. vol. 1. 1979. pp. 329-40. (A review discussing the histologic and clinical features of the fibrous papule. A table is presented that describes the major histologic features of fibrous papules and adenoma sebaceum.)
Bansal, C, Stewart, D, Li, A, Cockerell, CJ. “Histologic variants of the fibrous papule”. J Cutan Pathol. vol. 32. 2005. pp. 424-8. (The investigators microscopically examined 212 fibrous papule specimens and discussed the histologic variants that were seen. The majority of the fibrous papules were found to display some histologic variant, and the point was made that dermatopathologists should be aware of these variants as not to misdiagnosis this benign lesion.)
Sanchez, NP, Wick, MR, Perry, HO. “Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related entities”. J Cutan Pathol. vol. 8. 1981. pp. 395-403. (A review of the histologic features of adenoma sebaceum and comparison to similar angiofibromatous lesions. Also discussed is the association of adenoma sebaceum with tuberous sclerosis complex and the other skin findings expected with this neurocutaneous syndrome.)
Curatolo, P, Bombardieri, R, Jozwiak, S. “Tuberous sclerosis”. Lancet. vol. 372. 2008. pp. 657-68. (A nice review of tuberous sclerosis that covers the clinical features, both physical and neurological. The diagnosis criteria were outlined and the management was discussed. The pathophysiology and genetic abnormalities were also reviewed.)
Darling, TN, Skarulis, MC, Steinburg, SM, Marx, SJ, Spiegel, AM, Turner, M. ” Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1″. Arch Dermatol. vol. 133. 1997. pp. 853-7. (The National Institutes of Health surveyed 32 individuals during a 3-year period for the presence of skin lesions related to a diagnosis of multiple endocrine neoplasia type 1. They reported the types and frequency of skin lesions found in association with MEN 1.)
Song, MG, Park, KB, Lee, ES. “Resurfacing of facial angiofibromas in tuberous sclerosis patients using CO2 laser with flashscanner”. Dermatol Surg. vol. 25. 1999. pp. 970-73. (A report of two patients treated with a CO2 laser with flashscanner with good short term clinical outcomes. There is a nice review of the literature describing different types of lasers used in treatment of angiofibromas of the face.)
Haemel, AK, O’Brian, AL, Teng, JM. “Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis”. Arch Dermatol. vol. 146. 2010. pp. 715-8. (A case report of the use of topical rapamycin on facial angiofibromas of tuberous sclerosis. The mechanism of rapamycin, an mTOR inhibitor, is discussed. The patient exhibited good response and no side effects from topical rapamycin. The use of topical rapamycin over oral rapamycin for facial angiofibromas is preferred due to the lack of systemic side effects.)
Swaroop, MR, Nischal, KC, Rajesh Gowda, CM, Umashankar, NU, Basavaraj, HB, Sathyanarayana, BD. “Radiofrequency ablation of adenoma sebaceum”. J Cutan Aesthet Surg. vol. 1. 2008. pp. 89-91. (A report of treating adenoma sebaceum with radiofrequency ablation in an Indian patient.)
Turkmen, M, Ertam, I, Unal, I, Dereli, T. “Facial angiofibromas of tuberous sclerosis: successful treatment with podophyllin”. J Eur Acad Dermatol Venereol. vol. 23. 2009. pp. 713-4. (A report of the successful treatment of facial angiofibromas with podophyllin. Follow-up of the one patient revealed no recurrence. The only side effect reported was burning at the site of application, and the response was to treatment was favorable.)
Quist, SR, Franke, I, Sutter, C, Bartram, CR, Gollnick, HP, Leverkus, M. “Periungual fibroma (Koenen tumors) as isolated sign of tuberous sclerosis complex with tuberous sclerosis complex 1 germline mutation”. J Am Acad Dermatol. vol. 62. 2010. pp. 159-61. (A case report of the rare circumstance (second reported case) where the only presenting sign of tuberous sclerosis complex was a periungual fibroma. The report highlights the importance of family history in the diagnosis of tuberous sclerosis. The report reminds the physician that tuberous sclerosis must be kept in the differential when a single periungual fibroma is present.)
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