Trichoepithelioma

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Background

Trichoepithelioma is a benign adnexal neoplasm. Cases associated with Brooke-Spiegler syndrome are caused by mutations of the cylindromatosis oncogene (CYLD), which maps to 16q12-q13.[1, 2, 3] A 2006 study suggested that abnormalities in this gene might result in one of three syndromes: Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma.[4]  Furthermore, some cases of patients with multiple trichoepitheliomas appear to be sporadic and unrelated to familial incidence.[5]

A 2009 study reported a novel missense mutation in the CYLD gene, heterozygous nucleotide G→A transition at position 2,317 in exon 17, in a Chinese family with multiple familial trichoepithelioma.[6] Additionally, a novel splicing mutation in the CYLD gene (IVS12 + 1 G→A) was reported in a Taiwanese family with multiple familial trichoepithelioma.[7]

Treatment of trichoepithelioma is primarily surgical. (See Treatment.) Patients should be informed that some degree of scarring will be present after surgical therapy.

Pathophysiology

Studies have indicated that CYLD encodes a deubiquitinating enzyme that negatively regulates the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) pathways.[8] From the presence of significant numbers of Merkel cells within the tumor nest and the detection of a sheath of CD34-positive dendrocytes around the tumor nests, it appears that trichoepithelioma differentiates toward or derives from hair structures, particularly the hair bulge. Rare instances of tumors resembling trichoepithelioma have been reported in animals.[9]

Etiology

The gene involved in basal cell carcinoma (PTCH, human patched gene located on band 9q22.3) appears also to participate in the pathogenesis of trichoepithelioma.[10]

Brooke-Spiegler syndrome patients have a high incidence of multiple skin appendage tumors, such as cylindroma, trichoepithelioma, and spiradenoma. These patients may show mutations of CYLD (cylindromatosis gene) that map to 16q12-q13.[11]  A case report described multiple facial trichoepitheliomas caused by the p.Val835SerfsTer52 variant of CYLD.[12]  Another report cited the presence of a c.2686+1del CYLD mutation associated with overexpression of fibroblast growth factor (FGF) receptor (FGFR)-2.[13]

Epidemiology

One dermatopathology laboratory reported 2.14 and 2.75 cases of trichoepithelioma per year (9000 specimens).

Trichoepithelioma typically occurs in young to aging adults; however, the hereditary form may be seen in younger individuals. One case study reported a congenital lesion of desmoplastic trichoepithelioma.[14]

Because trichoepithelioma is inherited in an autosomal dominant fashion, males and females receive the gene equally; however, the lessened expressivity and penetrance in men means that most patients are women.

Prognosis

Slow growth is characteristic of trichoepithelioma. Partial removal may result in persistence or recurrence. In rare instances, patients with trichoepitheliomas can develop high-grade carcinomas and mixed (epithelial/sarcomatous) tumors.[15, 16] Familial trichoepithelioma patients have shown an aggressive, recurrent behavior in rare cases.

In cases of multiple trichoepitheliomas, the lesions may cause disfigurement because of involvement of the face. The rare cases of trichoepithelioma described as having aggressive behavior (eg, ulceration or recurrence) are probably follicular tumors within the basal cell nevus syndrome and not trichoepithelioma.

History

Slow-growing single or multiple papules or nodules are typically observed on the face (see the image below).



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Characteristic clinical morphologic features of trichoepithelioma. Note numerous small papules, predominantly close to midline.

The occurrence of multiple trichoepitheliomas is transmitted as an autosomal dominant trait. Lesions first appear in childhood and gradually increase in number. In patients with multiple trichoepitheliomas, it is important to interview the patient's family for a familial history of trichoepithelioma.

Physical Examination

The lesions are rounded, skin-colored, firm papules or nodules that range from 2 to 8 mm in diameter. They are located mainly on the nasolabial folds, the nose, the forehead, the upper lip, and the scalp; 50% of lesions occur on the face and the scalp. Occasionally, lesions also occur on the neck and the upper part of the trunk. Heller et al reported a rare case of trichoepithelioma of the vulva.[17]

Although trichoepitheliomas are often described in the literature as nonpigmented, a number of them may be pigmented to some degree.[18]

Ulceration is rare.

In the autosomal dominant form, multiple trichoepitheliomas may be present, usually on the nasolabial folds.

In some cases, the distribution is dermatomal. An association may exist with other cutaneous tumors (eg, cylindroma or Brooke-Spiegler syndrome, spiradenoma, basal cell carcinoma [BCC],[19] ungual fibromas) or dystrophia unguis congenita.

Trichoepithelioma may occur as part of the Rombo syndrome (ie, vermiculate atrophoderma, milia, hypotrichosis, trichoepithelioma, BCC, peripheral vasodilatation).

Solitary giant trichoepithelioma presents as a large polypoid lesion, usually in the lower part of the trunk or in the gluteal area.

Approach Considerations

In-vivo studies such as high-definition optical coherence tomography (HD-OCT) have been used to distinguish trichoepithelioma from other cutaneous tumors.[23] If necessary, genetic studies may be performed to detect the abnormalities in band 9p21 in trichoepithelioma patients.

Procedures

A shave or small punch biopsy should be performed to allow a histologic diagnosis of trichoepithelioma. In cases involving a solitary trichoepithelioma, it is important to ensure that the biopsy obtains a deep enough sample to allow the dermatopathologist to study most of the lesion, in particular its deep edge.

A shave biopsy of a plaquelike lesion on the lip may result in misidentifying the superficial portion of a microcystic adnexal carcinoma (an aggressive adnexal neoplasm) as a trichoepithelioma. Some adnexal carcinomas show a very limited degree of cytologic atypia. In such cases, it is only by examining the periphery of the lesion with the characteristic infiltrative pattern that the correct diagnosis can be made.

Histologic Findings

As many as 30% of trichoepitheliomas connect with the overlying epidermis, but in general, they are circumscribed dermal nodules.

In the upper dermis, multiple nodules are composed of uniform basaloid cells, frequently with central keratin-filled cysts (see the images below).



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Trichoepithelioma. Well-circumscribed superficial lesion composed of clusters of basaloid cells within fibrous stroma. This arrangement of epithelial ....



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Trichoepithelioma. Cystic spaces contain keratin. Note lack of mitotic figures or apoptotic bodies.

Peripheral palisading is present, but artifactual clefting is uncommon. Apoptotic and mitotic figures are rarely present; central necrosis and atypical mitotic figures are not features. The stroma is generally fibrous, with little myxoid component. Calcification is common, typically associated with the rupture of the keratinous cysts. A distinctive feature is the papillary-mesenchymal body (fibroblastic aggregate resembling abortive follicular papillae; see the image below).



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Trichoepithelioma. Papillary-mesenchymal bodies are structures associated with hair follicle differentiation. They are characterized by aggregate of s....

Because trichoepitheliomas recapitulate hair differentiation, they may contain scattered melanocytes (see the image below).



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Because trichoepitheliomas recapitulate follicular differentiation, they may contain cells commonly seen in hair follicles such as melanocytes. Image ....

Immunohistochemical studies reveal expression of the cytokeratins (CKs) associated with the outer root sheath (ie, CK5, CK6, CK8, and CK17) and expression of bcl-2, predominantly in the peripheral cell layer of the nests. The intervening stromal cells express CD34 (see the image below) and CD10.



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Trichoepithelioma. Immunohistochemical studies detect expression of CD34 by many dendritic cells surrounding tumor aggregates (anti-CD34, diaminobenzi....

Transforming growth factor (TGF)-β is expressed in most trichoepitheliomas. Some studies have shown that trichoepitheliomas frequently have Merkel cells (detectable with chromogranin or CK20).[24]  Merkel cells can be detected in all trichoepithelioma variants (see below). CK19 is reportedly more frequently detected in basal cell carcinoma (BCC) than in trichoepithelioma.[25] Trichoepitheliomas apparently lack expression of androgen receptors,[26] whereas many BCCs are positive. CD10, a marker commonly studied in hematopathology, is consistently expressed by the stromal cells in trichoepithelioma, but it is only rarely present in BCC cells.[27, 28]

Some trichoepitheliomas may develop high-grade carcinomas and biphasic tumors (epithelial and sarcomatous) with aggressive behavior (including metastasis)[15, 16] ; however, this is extremely rare.

Trichoepithelioma variants

The desmoplastic variant of trichoepithelioma, as its name indicates, is characterized by a prominent sclerotic stroma (see the image below).



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Desmoplastic variant of trichoepithelioma. Note that many aggregates of basaloid cells are small, resembling syringoma; however, they contain keratin ....

The  desmoplastic variant occurs in the same population as the classic type and presents as a plaque located in the same anatomic areas as the classic form. Histologically, it shows narrow strands of tumor cells, a desmoplastic stroma, and keratinous cysts (see the image below).



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High-powered view of desmoplastic trichoepithelioma. Note cluster of squamous cells surrounding small cystic area containing keratin. Intervening stro....

Pleomorphism, palisading, and peripheral clefting are not seen. Features favoring the diagnosis of desmoplastic trichoepithelioma include a rim of compact collagen around groups of epithelial cells, granulomas, calcification of cornified cells within cysts, absence of necrotic neoplastic cells, and only rare mitotic figures. In contrast to findings in BCC, fibroblasts surrounding trichoepithelioma nests do not express the matrix metalloproteinase stromelysin-3 (ST-3).

A possible pitfall is the observation of perineural involvement in some cases of desmoplastic trichoepithelioma, a feature more frequently associated with malignancy. Therefore, detection of perineural invasion in lesions with follicular differentiation should not be considered diagnostic of carcinoma.[29] Also noteworthy is the observation of pseudoepitheliomatous hyperplasia above desmoplastic trichoepitheliomas that may result in a misdiagnosis of squamous cell carcinoma (SCC).[30]

The solitary giant variant of trichoepithelioma is characterized by deep involvement of the reticular dermis and subcutaneous tissue.

Differential diagnoses based on histologic study

Features of BCC include a combination of basaloid cells, necrotic keratinocytes, mitotic figures, palisading and peripheral clefting, and myxoid stroma. The main differential features are stroma, clefting, and absence of papillary mesenchymal bodies. A study with a tissue microarray indicated that the best markers for differentiating trichoepithelioma from BCC include a combination of CD10, CK15, CK20, and D2-40. CK15 and D2-40 commonly are expressed in the peripheral layer of trichoepithelioma nests. CK20 Merkel cells are more common in trichoepitheliomas. CD10 is more commonly expressed in the stroma of trichoepithelioma and in the tumor cells of BCC.[31]

In microcystic adnexal carcinoma, small keratinous cysts are present in the upper portion; syringomalike small ducts in an infiltrative fashion are present in the deep dermis. A review indicated that invasion of skeletal muscle and subcutaneous tissue, perineural invasion, ductal differentiation, and expression of CK19 are much more common in microcystic adnexal carcinoma.[32]

In trichoadenoma, similarly sized clusters of basaloid cells contain numerous keratin cysts.

In tumor of follicular infundibulum (infundibuloma), platelike growth of basaloid cells having several points of attachment to the epidermis and the follicles is observed.

In basaloid follicular hamartoma, solitary localized linear/nevoid or generalized papules or plaques are observed. Thin anastomosing cords of basaloid cells, sometimes with peripheral palisading, may be seen. Occasionally, keratin cyst formation is present.

The malignant counterpart is distinctly uncommon. Such lesions are characterized by a poorly circumscribed infiltrative pattern of growth with areas of necrosis (see the image below).



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Malignant counterpart of trichepithelioma, trichilemmal carcinoma, typically shows areas with infiltrative growth and necrosis.

Tumor cells in these cases show pleomorphic nuclei and large, pale staining cytoplasm. Some cells may contain characteristic red cytoplasmic trichohyalin granules (see the image below).



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Trichilemmal carcinoma cells have large and lightly stained cytoplasm with large pleomorphic nuclei. As sign of follicular differentiation, some cells....

Approach Considerations

Treatment of the trichoepithelioma lesion is primarily surgical. Laser and radiofrequency (RF) ablation have been used, with diverse results.

A Brazilian study of several types of cutaneous tumors reported only a partial response for trichoepithelioma to 5% imiquimod cream.[33]

Other studies have suggested the possibility of targeted therapies, such as anti–tumor necrosis factor (TNF)-α[34] or targeting mammalian target of rapamycin (mTOR) and hypoxia signaling pathways.[35]

A 2022 case report described an 18-year-old female patient with multiple familial trichoepitheliomas that responded to treatment with topical benzoyl peroxide.[36]

Surgical Care

Solitary trichoepithelioma lesions can be excised. For multiple tumors, this surgical approach may not be feasible, though success has sometimes been reported.[37]

Split-thickness skin grafting, dermabrasion, and laser surgery have been proposed, but the results of these procedures have been variable.[38, 39, 40, 41]

Management of either form (ie, solitary or multiple/hereditary) by superficial biopsy is usually adequate.

A systematic review and meta-analysis (61 studies; N = 338) suggested that for the desmoplastic variant of trichoepithelioma, Mohs micrographic surgery might be the optimal treatment, with the lowest rate of recurrence.[42]

Recurrence of solitary trichoepithelioma is uncommon. When the multiple facial lesions are surgically flattened by means of dermabrasion or laser therapy, they tend to regrow into elevated papules or nodules. This regrowth may occur rapidly within months, or it may take several years. Some patients find a prolonged cosmetic improvement to be worthwhile even if repeated procedures are necessary.

It is important to ensure that the patient is informed about the possibility of scarring. As with many benign skin neoplasms, patients are mainly concerned about the aesthetic appearance of the lesion. All of the available methods for tumor removal have the potential to result in scarring. In cases involving multiple lesions, it may be helpful to treat one or two of the lesions initially and show the patient the final results before embarking on extensive aggressive therapy.

Complications

The persistence or recurrence of trichoepitheliomas is a complication, and scarring may occur after treatment.

What is trichoepithelioma?What is the pathophysiology of trichoepithelioma?What causes trichoepithelioma?What is the prevalence of trichoepithelioma in the US?What are the sexual predilections of trichoepithelioma?Which age groups have the highest prevalence of trichoepithelioma?What is the prognosis of trichoepithelioma?What is included in patient education about trichoepithelioma?Which clinical history findings are characteristic of trichoepithelioma?Which physical findings are characteristic of trichoepithelioma?What are the histologic differential diagnoses of trichoepithelioma?What are the differential diagnoses for Trichoepithelioma?Which studies are performed in the workup of trichoepithelioma?What is the role of biopsy in the diagnosis of trichoepithelioma?Which histologic findings are characteristic of trichoepithelioma?What are the histologic characteristics of trichoepithelioma variants?How is basal cell carcinoma differentiated from trichoepithelioma?How is microcystic adnexal carcinoma differentiated from trichoepithelioma?How is infundibuloma differentiated from trichoepithelioma?How is basaloid follicular hamartoma differentiated from trichoepithelioma?How is malignant trichilemmal carcinoma differentiated from trichoepithelioma?How is trichoepithelioma treated?What is the role of surgery in the treatment of trichoepithelioma?What are the possible complications of trichoepithelioma?How is trichoepithelioma prevented?

Author

Victor G Prieto, MD, PhD, Ferenc and Phyllis Gyorkey Chair for Research and Education in Pathology, Professor, Departments of Pathology and Dermatology, University of Texas MD Anderson Cancer Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Myriad / Castle (consultant regarding MyPath test in melanocytic lesions); Orlucent (consultant); .

Coauthor(s)

Christopher R Shea, MD, Eugene J Van Scott Professor in Dermatology, Chief, Section of Dermatology, Department of Medicine, University of Chicago, The Pritzker School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

References

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  23. Oliveira A, Arzberger E, Zalaudek I, Hofmann-Wellenhof R. Imaging of desmoplastic trichoepithelioma by high-definition optical coherence tomography. Dermatol Surg. 2015 Apr. 41 (4):522-5. [View Abstract]
  24. Hartschuh W, Schulz T. Merkel cells are integral constituents of desmoplastic trichoepithelioma: an immunohistochemical and electron microscopic study. J Cutan Pathol. 1995 Oct. 22 (5):413-21. [View Abstract]
  25. Bedir R, Sehitoglu I, Yurdakul C, Saygin I, Üstüner P, Dilek N. The importance of cytokeratin 19 expression in the differentiation of Basal cell carcinoma and trichoepithelioma. J Clin Diagn Res. 2015 Jan. 9 (1):EC01-4. [View Abstract]
  26. Izikson L, Bhan A, Zembowicz A. Androgen receptor expression helps to differentiate basal cell carcinoma from benign trichoblastic tumors. Am J Dermatopathol. 2005 Apr. 27 (2):91-5. [View Abstract]
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  28. Ramos-Ceballos FI, Pashaei S, Kincannon JM, Morgan MB, Smoller BR. Bcl-2, CD34 and CD10 expression in basaloid follicular hamartoma, vellus hair hamartoma and neurofollicular hamartoma demonstrate full follicular differentiation. J Cutan Pathol. 2008 May. 35 (5):477-83. [View Abstract]
  29. Jedrych J, Leffell D, McNiff JM. Desmoplastic trichoepithelioma with perineural involvement: a series of seven cases. J Cutan Pathol. 2012 Mar. 39 (3):317-23. [View Abstract]
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  31. Tebcherani AJ, de Andrade HF Jr, Sotto MN. Diagnostic utility of immunohistochemistry in distinguishing trichoepithelioma and basal cell carcinoma: evaluation using tissue microarray samples. Mod Pathol. 2012 Oct. 25 (10):1345-53. [View Abstract]
  32. Tse JY, Nguyen AT, Le LP, Hoang MP. Microcystic adnexal carcinoma versus desmoplastic trichoepithelioma: a comparative study. Am J Dermatopathol. 2013 Feb. 35 (1):50-5. [View Abstract]
  33. Alessi SS, Sanches JA, Oliveira WR, Messina MC, Pimentel ER, Festa Neto C. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo). 2009. 64 (10):961-6. [View Abstract]
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  35. Brinkhuizen T, Weijzen CA, Eben J, Thissen MR, van Marion AM, Lohman BG, et al. Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma. PLoS One. 2014. 9 (9):e106427. [View Abstract]
  36. Okamura S, Oyama N, Hasegawa M. The First Case Report of Multiple Familial Trichoepitheliomas Responding Successfully to Topical Benzoyl Peroxide: A Possible Therapeutic Action Underlying Structural Turnover and Antiinflammation. Indian J Dermatol. 2022 Jan-Feb. 67 (1):67-68. [View Abstract]
  37. Michael AI, Isamah CP, Ademola SA. Multiple Trichoepitheliomas: A Disfiguring Lesion Successfully Treated with Excision and Skin Grafting. West Afr J Med. 2024 Apr 30. 41 (4):481-484. [View Abstract]
  38. Sajben FP, Ross EV. The use of the 1.0 mm handpiece in high energy, pulsed CO2 laser destruction of facial adnexal tumors. Dermatol Surg. 1999 Jan. 25 (1):41-4. [View Abstract]
  39. Shaffelburg M, Miller R. Treatment of multiple trichoepithelioma with electrosurgery. Dermatol Surg. 1998 Oct. 24 (10):1154-6. [View Abstract]
  40. Richard A, Chevalier JM, Verneuil L, Sergent B, Tesnière A, Dolfus C, et al. [CO2 laser treatment of skin cylindromas in Brooke-Spiegler syndrome]. Ann Dermatol Venereol. 2014 May. 141 (5):346-53. [View Abstract]
  41. Thomas LW, Pham CT, Coakley B, Lee P. Treatment of Brooke-Spiegler Syndrome Trichoepitheliomas with Erbium: Yttrium-Aluminum-Garnet Laser: A Case Report and Review of the Literature. J Clin Aesthet Dermatol. 2020 Jul. 13 (7):41-44. [View Abstract]
  42. Nanda R, Srivastava D, Nijhawan RI. A Systematic Review of the Epidemiology, Clinical Characteristics, Treatment, and Outcomes for Desmoplastic Trichoepithelioma: Underscoring Mohs Micrographic Surgery in Management. Dermatol Surg. 2024 Aug 1. 50 (8):695-698. [View Abstract]

Characteristic clinical morphologic features of trichoepithelioma. Note numerous small papules, predominantly close to midline.

Trichoepithelioma. Well-circumscribed superficial lesion composed of clusters of basaloid cells within fibrous stroma. This arrangement of epithelial cells and stroma is described as organoid.

Trichoepithelioma. Cystic spaces contain keratin. Note lack of mitotic figures or apoptotic bodies.

Trichoepithelioma. Papillary-mesenchymal bodies are structures associated with hair follicle differentiation. They are characterized by aggregate of spindle stromal cells, closely apposed to hair bulb (arrow; darkly staining, basaloid epithelial cells).

Because trichoepitheliomas recapitulate follicular differentiation, they may contain cells commonly seen in hair follicles such as melanocytes. Image illustrates both melanocytes (black arrow) and dermal melanophages (white arrow).

Trichoepithelioma. Immunohistochemical studies detect expression of CD34 by many dendritic cells surrounding tumor aggregates (anti-CD34, diaminobenzidine, and hematoxylin).

Desmoplastic variant of trichoepithelioma. Note that many aggregates of basaloid cells are small, resembling syringoma; however, they contain keratin instead of eccrine secretion. Also, note characteristic markedly fibrous stroma.

High-powered view of desmoplastic trichoepithelioma. Note cluster of squamous cells surrounding small cystic area containing keratin. Intervening stroma is markedly fibrous.

Malignant counterpart of trichepithelioma, trichilemmal carcinoma, typically shows areas with infiltrative growth and necrosis.

Trichilemmal carcinoma cells have large and lightly stained cytoplasm with large pleomorphic nuclei. As sign of follicular differentiation, some cells may display characteristic cytoplasmic red trichohyalin granules (arrows).

Characteristic clinical morphologic features of trichoepithelioma. Note numerous small papules, predominantly close to midline.

Trichoepithelioma. Well-circumscribed superficial lesion composed of clusters of basaloid cells within fibrous stroma. This arrangement of epithelial cells and stroma is described as organoid.

Trichoepithelioma. Cystic spaces contain keratin. Note lack of mitotic figures or apoptotic bodies.

Trichoepithelioma. Papillary-mesenchymal bodies are structures associated with hair follicle differentiation. They are characterized by aggregate of spindle stromal cells, closely apposed to hair bulb (arrow; darkly staining, basaloid epithelial cells).

Because trichoepitheliomas recapitulate follicular differentiation, they may contain cells commonly seen in hair follicles such as melanocytes. Image illustrates both melanocytes (black arrow) and dermal melanophages (white arrow).

Trichoepithelioma. Immunohistochemical studies detect expression of CD34 by many dendritic cells surrounding tumor aggregates (anti-CD34, diaminobenzidine, and hematoxylin).

Desmoplastic variant of trichoepithelioma. Note that many aggregates of basaloid cells are small, resembling syringoma; however, they contain keratin instead of eccrine secretion. Also, note characteristic markedly fibrous stroma.

High-powered view of desmoplastic trichoepithelioma. Note cluster of squamous cells surrounding small cystic area containing keratin. Intervening stroma is markedly fibrous.

Malignant counterpart of trichepithelioma, trichilemmal carcinoma, typically shows areas with infiltrative growth and necrosis.

Trichilemmal carcinoma cells have large and lightly stained cytoplasm with large pleomorphic nuclei. As sign of follicular differentiation, some cells may display characteristic cytoplasmic red trichohyalin granules (arrows).