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Hillary Johnson MD PhD, Mirin Robles MD, Hideko Kamino MD, Ruth F Walters MD, Arnold Lee MD PhD, Miguel Sanchez MD
Dermatology Online Journal 14 (10): 5

Department of Dermatology, New York University


A 29-year-old man presented with a long-standing history of asymptomatic, skin-colored, facial papules and nodules. Histopathologic examination of a representative papule demonstrated trichoepithelioma. The patient had a history of a brother with a similar phenotype, which suggests a diagnosis of familial trichoepithelioma. Linkage and mutational analyses support genetic heterogeneity of familial trichoepithelioma, possibly sharing a clinical spectrum with Brooke-Spiegler syndrome and familial cylindromatosis since each entity has been associated with mutations the CYLD gene.


A 29-year-old Puerto Rican man presented to the Dermatology Clinic at Bellevue Hospital Center in September, 2007, with multiple, skin-colored, facial papules that began to first appear in childhood and then increased in size and number during adolescence. The papules have been intermittently pruritic and slightly tender only after scratching. He reported that his brother and mother had similar lesions. The patient denied a family history of additional cutaneous disorders or neoplasms. He has been otherwise healthy without medical problems, medications, or any systemic complaints upon review of systems. The patient presented with a biopsy specimen from a facial papule from a private dermatologist. Past treatment using an unknown laser therapy was unsuccessful.

Figure 1Figure 2

Physical Examination

Numerous, 2-to-3-mm, skin-colored, dome-shaped papules were present on the forehead, cheeks, nose, and chin. Larger 3-to-4-mm papules coalescing to plaques were concentrated bilaterally on the mid-face along the nasal creases and the cutaneous upper lip. The trunk, buttocks, and extremities were unaffected.




In the reticular dermis, there are aggregates and branching strands of uniform basaloid cells with peripheral palisading of the nuclei arranged within a prominent fibrous stroma. One focus exhibits a papillary mesenchymal body with hair bulb formation. Stromal clefts and cysts lined by squamous epithelium with infundibular keratinization are present. The tumor shows no connection to an unremarkable epidermis.


Trichoepithelioma is a benign adnexal neoplasm that is considered a hamartoma of folliculo-sebaceous differentiation. It may erupt sporadically as solitary lesions or in multiplicity. Numerous trichoepitheliomas occur in an autosomal dominantly inherited genodermatosis called multiple familial trichoepithelioma (MFT) or familial trichoepithelioma (FT). Historically, epithelioma adenoids cysticum and Brooke-Fordyce or Brooke syndrome have been ascribed to this disorder [1, 2].

Multiple familial trichoepithelioma, familial cylindromatosis (FC), and Brooke-Spiegler syndrome (BSS in which patients are predisposed to trichoepithelioma, cylindroma, and spiradenoma) each have been associated with missense mutations in the cylindromatosis (CYLD) gene on chromosome 16q12-q13 in a number of families [3, 4, 5, 6]. Current evidence indicates that these inherited skin disorders may exist on a clinical spectrum rather as than distinct entities. Families have been described in which the identical germline mutation in the CYLD gene produces either the MFT or the FC phenotype [7, 8, 9, 10, 11]. However, MFT may be even more genetically heterogeneous since one family with MFT possessed a defect mapped to chromosome 9p21 in genetic linkage analysis that has not been reproduced in other lineages, and no gene mutations in this locus have yet been identified [12]. CYLD has been postulated to function as a tumor suppressor since loss of heterozygosity of a wild-type allele has been associated with development of trichoepithelioma. A deubiquitinating enzyme, CYLD has been shown to regulate signal transduction pathways whose activities are responsive to levels of ubiquitination of component proteins in the NF-kB and JNK signaling pathways. For example, CYLD can remove K63-linked polyubiquitin chains from tumor necrosis factor receptors TRAF2, TRAF6, and NEMO and thereby negatively regulate the cytokine-induced NF-kB pathway for cellular homeostasis [13, 14].

Classically, MFT presents with numerous, skin-colored, firm, well-demarcated papules or small nodules that are often distributed symmetrically on the face, with increased concentration on the nose and along the central face. The center of the papule may be depressed or umbilicated. Occasionally, trichoepitheliomas will occur on the scalp, neck, or upper trunk. They commonly appear in childhood or adolescence. There is no apparent predilection for gender or ethnicity [15]. While typically unassociated with malignant conditions, rare association with basal-cell carcinoma has been reported [16, 17, 18, 19]. One Japanese family included members with MFT, who also experienced fatal cerebrovascular accidents although the clinical association may not be generalized [20]. Patients with MFT often present with disfigurement since the trichoepitheliomas tend to grow in size and number over time and contribute to psychosocial challenges.

Histopathologic diagnosis of classical trichoepithelioma (non-desmoplastic) is usually made based on established criteria. Papillary mesenchymal bodies (follicular germinative differentiation) and keratinizing cystic spaces surrounded by keratinocytes (follicular infundibular or isthmic differentiation) are surrounded by an adherent fibrocystic stroma. Overall, the specimen displays relative symmetry and lack of atypia. Difficulties can arise in distinguishing trichoepithelioma, particularly in small biopsy specimens, from less typical keratotic variants of basal-cell carcinoma. Staining with lymphoid markers (CD34, CD23), cytokeratin expression (CK5, CK14, CK17, and CK19), cell membrane glycoproteins (Ber-Ep-4), and cell-cycle regulatory protreins (Ki-67, PCNA, p53, and bcl2) have been used to distinguish these neoplasms with variable success and reproducibility [21, 22].

Treatment of MFT relies on a variety of ablative techniques with variable results and the risk of scars. Report of clinical improvement, with minimizing the appearance of the lesions, has been demonstrated after several treatments using the high energy pulsed or continuous wave carbon dioxide lasers. Other destructive methods, which include cryotherapy, dermabrasion, electrodesiccation and curettage, and radiation, have been employed with modest results [23, 24]. One case report showed lessening of lesions without scars in an 11-year-old girl treated with topical imiquimod cram and tretinoin 1 percent gel over a three-year period [25]. In another report, treatment with isotretinoin for 12 weeks failed to affect the trichoepitheliomas of a patient with concurrent cystic acne [26]. However, additional evidence is needed to determine the utility of these potential therapies.


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