BASICS
DESCRIPTION
- A benign cutaneous neoplasm of the hair follicle
- Trichoepithelioma (TE) commonly presents as a solitary skin-colored papule or nodule on the face.
- Multiple lesions are seen in several autosomal dominant disorders including Brooke-Spiegler syndrome, Brooke disease, Rombo syndrome, and Bazex-Dupre-Christol syndrome (1).
- There are three variants of TE: (i) solitary, (ii) multiple familial trichoepithelioma (MFT), and (iii) desmoplastic trichoepithelioma (DTE).
- Can be mistaken for basal cell carcinoma (BCC) or Gorlin syndrome (multiple BCCs)
EPIDEMIOLOGY
- Predominantly occurs in young adults
- Multiple lesions may occur in children and adolescents with associated autosomal dominant disorders.
- A distinct variation known as giant solitary TE may occur in the elderly.
Incidence
Incidence unknown ‚
Prevalence
- Rare (affects <1 person per 2,000)
- Female > male (2:1)
ETIOLOGY AND PATHOPHYSIOLOGY
- The short arm of chromosome 9 is known to encode proteins that can arrest the cell cycle by binding CDK4/6. Tumorigenesis is believed to occur when deletion or rearrangements near 9p21 inactivates these proteins, causing decreased CDK4 kinase binding and increased phosphorylation of the retinoblastoma tumor suppressor protein (1,2).
- Familial cases of TE are due a mutation of CYLD gene, a tumor suppressor gene that plays a role in deubiquinating proteins. These proteins negatively regulate the nuclear factor- Ž ºB (NF- Ž ºB) signaling pathway. Loss of CYLD heterozygosity promotes tumor growth through continuous NF- Ž ºB activation, unregulated cell division, and resistance to apoptosis (1).
COMMONLY ASSOCIATED CONDITIONS
- Brooke-Spiegler syndrome
- Familial cylindromatosis
- BCC
- Gorlin syndrome
- Rombo syndrome (atrophoderma, milia, hypotrichosis, TE, BCC, peripheral vasodilatation [3])
Genetics
TE displays genetic heterogeneity; the two most prevalent mutations have been mapped to the following: ‚
- 9p21 ¢ † ’ Autosomal dominant mutation in a tumor suppressor gene gives rise to the familial form of TE (MFT) (3).
- 16q12 " “16q13 (CYLD gene) ¢ † ’ results in a spectrum of disease phenotypes including the following:
- MFT
- Familial cylindromatosis (FC)
- Brooke-Spiegler syndrome, which demonstrates features of MFT and FC (3)
RISK FACTORS
- Female gender (due to increased disease penetrance)
- Family history
DIAGNOSIS
HISTORY
- Solitary or multiple skin-colored papules or nodules presenting on the face, scalp, trunk, or lower extremities
- Typically appear as a solitary papule during the 2nd or 3rd decade of life and grow slowly
- May increase in size or number during puberty
- Lesions are painless and nonpruritic.
PHYSICAL EXAM
The characteristic features of TE include the following: ‚
- Dome-shaped papules with a translucent surface measuring 1 to 8 mm in diameter
- Skin-colored to pink, firm, and symmetrical lesions
- Possible coalescence to form plaques
- Predilection for the nasolabial folds and preauricular regions
- Commonly found on the cheeks and upper lip
- Rare reports of lesions as far down as the buttocks and genitals (4,5,6)
DIFFERENTIAL DIAGNOSIS
- BCC/Gorlin syndrome
- Trichoadenoma
- Trichoblastoma
- Cylindroma
- Milia
- Trichilemmoma
- Trichofolliculoma
- Syringoma
- Pilomatricoma
- Foreign body
- Sebaceous hyperplasia
- Scar
- Angiofibromas of tuberous sclerosis
- Molluscum contagiosum
- Microcystic adnexal carcinoma
- Steatocystoma multiplex
- Eruptive vellus hair cysts
- Sarcoidosis
- Epidermoid cyst
DIAGNOSTIC TESTS & INTERPRETATION
Dermatoscopy ‚
- TE appears as a white, structureless lesion with distinctive small, uniform, white clods superimposed on a pale background (represents milia-like dermal cysts of keratin).
- Nodule may also display linear branched vessels.
Diagnostic Procedures/Other
Shave or punch biopsy for histologic exam ‚
Test Interpretation
- Histologic exam shows well-circumscribed lesions with the following features:
- Uniform basaloid bulbar follicular germinative cells with peripheral palisading
- Variably sized nests with trabeculae/cribriform patterns surrounded by fibrous stroma
- Keratin-filled horn cysts that may rupture causing calcification
- Follicular germ and hair shaft formation
- Hyaline basement membrane
- A distinctive feature is the papillary-mesenchymal body, characterized by a mass of spindle and stromal cells next to the hair bulb.
- Presence of rare Merkel cells in all variants
- Lack tumor-stromal clefting seen in BCC
- Immunohistochemical features that distinguish TE from BCC are the following:
- Stromelysin 3 " “negative
- Positive CD10 and CD34 in stroma
- Positive Bcl-2 in peripheral cells
- Lack androgen receptors
- Positive CK15 and CK20 (3)
TREATMENT
Patients with multiple TEs should be monitored for the development of other adnexal tumors. Isolated TE is a benign condition that does not require treatment other than for cosmetic concerns. The mainstay of treatment is surgical excision. Variable results have been reported with the following medications. ‚
MEDICATION
- Topical 5% imiquimod
- Antitumor effects thought to be due to upregulation of interferon-α, leading to increased natural killer cell activity.
- Apply 3 to 7 times per week for 6 to 9 weeks (7)[B],(8)[C].
- Salicylic acid and adalimumab
- Novel treatment; may be used in disseminated or familial cases that are symptomatic and refractory to other treatments (9)[C]
- Antitumor effects thought to be due to blockage of tumor necrosis factor (TNF) activation of the NF- Ž ºB pathway (adalimumab acts on the TNF-α ligand and salicylic acid acts on the NF- Ž ºB transcription factor)
- Administration: 325 mg salicylic acid PO BID and SC adalimumab 40 mg every other week; increase to 40 mg weekly after 2 months
SURGERY/OTHER PROCEDURES
- Cryotherapy
- Dermabrasion
- Excision
- Mohs micrographic surgery
- Electrodesiccation and curettage
- Carbon dioxide laser: Treat every 3 months to 2 years with power set at 3 to 5W using continuous-wave vaporization (10)[C].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Malignant transformation of TE is extremely rare and occurs late in the disease. Patients should have skin lesions examined annually to monitor for this unusual complication. ‚
PROGNOSIS
- Solitary TE may be surgically excised with a relatively low recurrence rate and good prognosis.
- MFT and Brooke-Spiegler syndrome have no definitive cure. Lesions are typically slow-growing, increase in number and location over time, and pose minimal risk to the patient other than cosmetic concerns. All modalities of treatment have a very high recurrence rate and may cause facial scarring (1).
COMPLICATIONS
Although often mistaken for each other, TE can be complicated by BCC and should be vigilantly monitored for in all patients. ‚
REFERENCES
11 Lee ‚ DA, Grossman ‚ ME, Schneiderman ‚ P, et al. Genetics of skin appendage neoplasms and related syndromes. J Med Genet. 2005;42(11):811 " “819.22 Harada ‚ H, Hashimoto ‚ K, Ko ‚ MS. The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J Invest Dermatol. 1996;107(1):41 " “43.33 Ashinoff ‚ R, Jacobson ‚ M, Belsito ‚ DV. Rombo syndrome: a second case report and review. J Am Acad Dermatol. 1993;28(6):1011 " “1014.44 Lee ‚ KH, Kim ‚ JE, Cho ‚ BK, et al. Malignant transformation of multiple familial trichoepithelioma: case report and literature review. Acta Derm Venereol. 2008;88(1):43 " “46.55 Krishnamurthy ‚ J, Divya ‚ K. The cytology of giant solitary trichoepithelioma. J Cytol. 2010;27(3):99 " “101.66 Martinez ‚ CA, Priolli ‚ DG, Piovesan ‚ H, et al. Nonsolitary giant perianal trichoepithelioma with malignant transformation into basal cell carcinoma: report of a case and review of the literature. Dis Colon Rectum. 2004;47(5):773 " “777.77 Alessi ‚ SS, Sanches ‚ JA, Oliveira ‚ WR, et al. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo). 2009;64(10):961 " “966.88 Seo ‚ SH, Kim ‚ GW, Sung ‚ HW. Imiquimod as an adjuvant treatment measure for desmoplastic trichoepithelioma. Ann Dermatol. 2011;23(2):229 " “231.99 Fisher ‚ GH, Geronemus ‚ RG. Treatment of multiple familial trichoepitheliomas with a combination of aspirin and a neutralizing antibody to tumor necrosis factor alpha: a case report and hypothesis of mechanism. Arch Dermatol. 2006;142(6):782 " “783.1010 Rallan ‚ D, Harland ‚ CC. Brooke-Spiegler syndrome: treatment with laser ablation. Clin Exp Dermatol. 2005;30(4):355 " “357.
ADDITIONAL READING
- Alsaad ‚ KO, Obaidat ‚ NA, Ghazarian ‚ D. Skin adnexal neoplasms " ”part 1: an approach to tumours of the pilosebaceous unit. J Clin Pathol. 2007;60(2):129 " “144.
- Bettencourt ‚ MS, Prieto ‚ VG, Shea ‚ CR. Trichoepithelioma: a 19-year old clinicopathologic re-evaluation. J Cutan Pathol. 1999;26(8):398 " “404.
- Mamelak ‚ AJ, Goldberg ‚ LH, Katz ‚ TM, et al. Desmoplastic trichoepithelioma. J Am Acad Dermatol. 2010;62(1):102 " “106.
- Shehan ‚ JM, Huerter ‚ CJ. Desmoplastic trichoepithelioma: report of a case illustrating its natural history. Cutis. 2008;81(3):236 " “238.
- Sini ‚ MC, Manca ‚ A, Cossu ‚ A, et al. Molecular alterations at chromosome 9p21 in melanocytic naevi and melanoma. Br J Dermatol. 2008;158(2):243 " “250.
- Wallace ‚ ML, Smoller ‚ BR. Trichoepithelioma with an adjacent basal cell carcinoma, transformation or collision? J Am Acad Dermatol. 1997;37(2, Pt 2):343 " “345.
- Wang ‚ SH, Tsai ‚ RY, Chi ‚ CC. Familial desmoplastic trichoepithelioma. Int J Dermatol. 2006;45(6):756 " “758.
- Yiltok ‚ SJ, Echejoh ‚ GO, Mohammad ‚ AM, et al. Multiple familial trichoepithelioma: a case report and review of literature. Niger J Clin Pract. 2010;13(2):230 " “232.
CODES
ICD10
- D23.9 Other benign neoplasm of skin, unspecified
- D23.30 Other benign neoplasm of skin of unspecified part of face
- D23.4 Other benign neoplasm of skin of scalp and neck
- D23.39 Other benign neoplasm of skin of other parts of face
- D23.11 Oth benign neoplasm skin/ right eyelid, including canthus
- D23.12 Oth benign neoplasm skin/ left eyelid, including canthus
- D23.10 Oth benign neoplasm skin/ unsp eyelid, including canthus
ICD9
- 216.9 Benign neoplasm of skin, site unspecified
- 216.3 Benign neoplasm of skin of other and unspecified parts of face
- 216.4 Benign neoplasm of scalp and skin of neck
- 216.1 Benign neoplasm of eyelid, including canthus
SNOMED
- Trichoepithelioma
- Giant solitary trichoepithelioma
- Familial multiple trichoepitheliomata
- Desmoplastic trichoepithelioma (disorder)
CLINICAL PEARLS
- TE is a rare, slow-growing, benign adnexal neoplasm that commonly presents as single or multiple skin-colored papules or nodules measuring 1 to 8 mm in diameter in young adults and middle-aged patients.
- Generally involves the upper lip unlike the similarly appearing angiofibromas of tuberous sclerosis.
- The lesions of TE are often mistaken for BCC (or Gorlin syndrome when multiple). Family history, distribution of nodules, and absence of ulcerative lesions on history/physical may be clues favoring TE.
- Biopsy is required for definitive diagnosis.
- Observing family members with multiple papules in the nasolabial region can be helpful in making the diagnosis.
- There is currently no definitive treatment for this disease. Surgical excision is the mainstay for singular papules, and various medical therapies have shown some efficacy for lesions too numerous to excise.
- The benefit of removal of lesions should be weighed against the potential risk of scarring and pigmentary changes.
- Long-term prognosis is excellent despite the damaging effects on cosmetic appearance.
- Physicians should remain vigilant to examine skin lesions for any signs of malignant transformation to BCC late in the disease course.