Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Trichilemmoma usually presents as a solitary skin-colored papule on the face of older adults, especially the nose and cheeks. It is slow growing and asymptomatic. Occasionally, the surface may be hyperkeratotic or verrucous. Rarely, it can present at the base of a cutaneous horn or on the genitals.
The presence of six or more facial papules, of which three or more are trichilemmomas, is considered pathognomonic for Cowden syndrome (CS) and occurs in 83%-86% of patients.
Cowden syndrome, also known as Cowden disease or multiple hamartoma syndrome, is a rare autosomal dominant disorder affecting the skin, breast, thyroid, gastrointestinal tract, endometrium, and brain. Eighty percent of patients have an autosomal dominant PTEN (phosphatase and tensin homologue) gene deletion on chromosome 10. Nearly all patients exhibit mucocutaneous lesions, including multiple facial trichilemmomas, oral verrucoid papules, and acral keratoses. Associated malignancies include breast cancer, nonmedullary thyroid cancer, and endometrial cancer, and these malignancies usually occur after the onset of mucocutaneous lesions.
Even in CS patients with the characteristic presentation of multiple facial trichilemmomas, not all of the facial papules may be trichilemmomas. Studies have found that CS patients also present with multiple facial papillomatous papules or viral warts coexisting with multiple facial trichilemmomas.
Expected results of diagnostic studies
A skin biopsy is needed for a definitive diagnosis of trichilemmoma, whether solitary or multiple. On histopathology, trichilemmoma is a neoplasm of the cells of the outer root sheath. Biopsy shows epidermal tumor lobules with glycogen-rich clear cells, peripheral palisading, and a thickened basement membrane. The lobules may localize around a hair follicle and are CD34-positive. The surface displays epidermoid—not trichilemmal—keratinization, which contains a granular layer and can give rise to a cutaneous horn (Figure 1).
The differential diagnosis of trichilemmoma includes the following:
– basal cell carcinoma (distinguished clinically by a more translucent appearance, characteristic pearly rolled edge, and distinct histology)
– benign keratosis (lacks glycogen-containing cells on biopsy)
– verruca vulgaris (most lack glycogen-containing cells on biopsy)
– cutaneous horn (though trichilemmoma can present at the base of a cutaneous horn)
It is also important to distinguish trichilemmoma from other adnexal tumors such as:
– desmoplastic trichilemmoma (also with CD34-positive cells on histopathology, but the center shows cells with a random pattern of cords and strands)
– trichilemmal carcinoma (histopathology like trichilemmoma but with trichilemmal keratinization, more cytologic atypia and high mitotic activity)
– trichoepithelioma (keratin-containing horn cysts on biopsy)
– trichofolliculoma (keratin-containing cystic cavity on biopsy)
Who is at Risk for Developing this Disease?
The exact incidence of trichilemmoma appearing as a solitary tumor is unknown. Men and women appear to be equally affected.
Cowden syndrome is thought to affect 1/200,000 to 1/250,000 people. The penetrance of this autosomal dominant disorder is nearly complete, with almost 90% of patients affected with mucocutaneous lesions by age 20; however, the onset of skin signs can vary from 4 to 75 years.
What is the Cause of the Disease?
Trichilemmoma is a benign neoplasm of the outer root sheath. One theory as to its etiology is that the human papillomavirus (HPV) causes the morphologic changes seen in such tumors. Studies have shown the presence of DNA from epidermodysplasia verruciformis (EV)-associated HPVs (supergroup B) in trichilemmomas, but not for other types of HPV. As the hair follicle is believed to be a source of HPV DNA and the site of trichilemmomas, it is unknown whether HPV infection and trichilemmomas are related to each other or independently associated with the hair follicle.
In cases of CS in which multiple facial trichilemmomas are present, 80% patients have an autosomal dominant PTEN gene deletion on chromosome 10. PTEN tumor suppressor gene encodes a dual specificity phosphatase whose role is not yet completely understood but is known to be involved in cellular regulation and apoptosis.
Defects in the PTEN pathway have been associated with CS, Bannayan-Riley-Ruvalcaba syndrome, Proteus or Proteus-like syndrome, adult Lhermitte-Duelos disease, and autism-like disorders associated with macrocephaly. While the exact relationship between PTEN gene mutations and the development of trichilemmomas is unknown, defects in the PTEN pathway cause disordered cellular growth, which is likely involved in the pathogenesis of trichilemmomas.
Systemic Implications and Complications
In patients with multiple facial trichilemmomas in which CS is suspected, it is important to discuss genetic testing and appropriate cancer screening.
Mucocutaneous lesions, such as multiple facial trichilemmomas, oral verrucoid papules, and acral keratoses, usually present prior to the onset of malignancies. It is estimated that breast cancer affects 25%-50% of women with CS (vs. 12% for the general population), thyroid cancer affects 3%-10% of CS patients (vs. <1% in the general population), and endometrial cancer affects 5%-10% of CS females (vs. 2.5% in the general population). Therefore, astute clinicians who diagnose the mucocutaneous lesions of CS have the potential to identify high-risk cancer patients prior to the onset of advanced malignant disease.
Treatment options are summarized in Table I.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Topical 5-fluorouracil||Shave biopsy||Cryotherapy with liquid nitrogen|
|Oral retinoids||Surgical excision||Carbon dioxide laser|
Optimal Therapeutic Approach for this Disease
In cases of solitary trichilemmoma, every effort should be made to preserve histopathology in order to rule out malignancy, especially if the diagnosis is questionable. Surgical removal is thus diagnostic and therapeutic, and nonsurgical treatments are not recommended. The decision between a shave biopsy and surgical excision is based on optimizing cosmetic results.
Once biopsy results are obtained, explain to patients that trichilemmoma is a benign growth of part of the hair follicle. No further management is needed after surgical removal in cases of solitary trichilemmoma.
Unusual Clinical Scenarios to Consider in Patient Management
In CS patients with multiple facial trichilemmomas, surgical removal of every lesion is often not feasible. Observation is appropriate if lesions are asymptomatic, as progression to trichilemmal carcinoma is extremely rare. Treatment modalities such as topical 5-fluorouracil, oral retinoids, cryotherapy with liquid nitrogen, and carbon dioxide laser have been used in anecdotal reports, but often with temporary benefits. Patient preferences and cosmetic results must be taken into account when selecting treatment.
In CS patients, the most important concern is that patients are offered genetic testing and screened for cancer, specifically cancer of the breast and thyroid. Since mucocutaneous lesions usually present prior to the onset of malignancy, asute clinicians have the potential to identify high-risk cancer patients prior to the onset of advanced malignant disease.
What is the Evidence?
Pilarski, R. “Cowden syndrome: a critical review of the clinical literature”. J Genet Counsel. vol. 18. 2009. pp. 13-27. (A thorough review of CS, its genetics, diagnostic criteria, and component cancers)
Hildenbrand, C, Burgdorf, WHC, Lautenschlager, S. “Cowden syndrome—diagnostic skin signs”. Dermatol. vol. 202. 2001. pp. 362-6. (A case report and review of the literature for CS, with mention of treatment of facial papules in patients with CS)
Brownstein, MH, Mehregan, AH, Bikowski, JB, Lupulescu, A, Patterson, JC. “The dermatopathology of Cowden’s syndrome”. Br J Dermtaol. vol. 100. 1979. pp. 667-73. (In a study of 89 biopsies from 19 patients with CS, all patients showed multiple trichilemomas but sometimes several biopsy specimens were required to confirm a diagnosis of trichilemmoma. Oral and acral biopsies were also studied.)
Starink, TM, Hausman, R. “The cutaneous pathology of facial lesions in Cowden’s disease”. J Cutan Pathol. vol. 11. 1984. pp. 331-7. (A study of 11 facial lesions from 7 patients with CS shows that the most distinctive lesions were trichilemmomas, but other lesions fall on a spectrum of follicular malformations.)
Tardio, JC. “CD34-reactive tumors of the skin. An updated review of an ever-growing list of lesions”. J Cutan Pathol. vol. 35. 2008. pp. 1079-92. (An excellent review of cutaneous tumors expressing CD34. The authors comment that both trichilemmoma and desmoplastic trichilemmoma express CD34. CD34 positivity can thus help differentiate desmoplastic trichilemmoma from other cutaneous tumors with dense collagenous stroma.)
Tellechea, O, Reis, JP, Baptista, AP. “Desmoplastic trichilemmoma”. Am J Dermatopath. vol. 14. 1992. pp. 107-14. (A summary of seven cases of desmoplastic trichilemmoma, with emphasis on histopathology, including how desmoplastic trichilemmoma differs from trichilemmoma. All cases were surgically excised with no signs of recurrence in the follow-up period ranging from 15 months to 7 years.)
Simpson, W, Garner, A, Collin, JRO. “Benign hair-follicle derived tumours in the differential diagnosis of basal-cell carcinoma of the eyelids: a clinicopathological comparison”. Br J Ophthalmol. vol. 73. 1989. pp. 347-53. (A good review of 117 cases of eyelid tumors, discussing how basal cell carcinoma can easily be confused with benign eyelid tumors like trichilemmoma, trichoepithelioma, trichofolliculoma, and pilomatrixoma)
Rohwedder, A, Keminer, O, Hendricks, C, Schaller, J. “Detection of HPV DNA in trichilemmomas by polymerase chain reaction”. J Med Virol. vol. 51. 1997. pp. 119-25. (The first study demonstrating HPV positivity in trichilemmomas. By using polymerase chain reaction, the authors show evidence of epidermodysplasia verruciformis (EV)-associated HPVs (supergroup B) in all 11 trichilemmomas investigated.)
Stierman, S, Chen, S, Nuovo, G, Thomas, J. “Detection of human papillomavirus infection in trichilemmomas and verrucae using in situ hybridization”. J Cutan Pathol. vol. 37. 2010. pp. 75-80. (In an analysis of nine trichilemmomas, 31 warts, and six inverted follicular keratoses, the trichilemmomas were negative for HPV types 1 ([supergroup E] and 2 [supergroup A] as tested by in situ hybridization with comparison to warts serving as positive controls. Therefore, these specific HPV types are not thought to be involved in the pathogenesis of trichilemmomas.)
Phillips, ME, Ackerman, AB. ““Benign” and “malignant” neoplasms associated with verrucae vulgares”. Am J Dermatopath. vol. 4. 1982. pp. 61-84. (A review of 80 neoplasms showing morphologic features of verrucae vulgares, such as trichilemmoma. The authors conclude that warts may induce such lesions, even if no viral particles are demonstrated, since papilloma virus is not always seen in old verrucae.)
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