Trichoepithelioma 

Updated: Sep 25, 2018
Author: Victor G Prieto, MD, PhD; Chief Editor: William D James, MD 

Overview

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 has suggested that abnormalities in this gene may result in one of 3 syndromes: Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma.[4]  Furthermore, some cases of patients with multiple trichoepitheliomas appear to be sporadic and not related with familial incidence.[5]

A 2009 study reports 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) has been reported in a Taiwanese family with multiple familial trichoepithelioma.[7]

Pathophysiology

Studies have indicated that CYLD encodes a deubiquitinating enzyme that negatively regulates the nuclear factor (NF)–kappaB and c-Jun N-terminal kinase (JNK) pathways.[8] Due to 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 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 the CYLD gene (cylindromatosis gene) that map to 16q12-q13.[11]

Epidemiology

US frequency

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

Sex

Since trichoepithelioma is inherited in an autosomal dominant fashion, males and females receive the gene equally, but because of lessened expressivity and penetrance in men, most patients are women.

Age

Trichoepithelioma typically occurs in young to aging adults; however, the hereditary form may be seen in younger individuals. A single case study has reported a congenital lesion of desmoplastic trichoepithelioma.[12]

Prognosis

Slow growth is characteristic of trichoepithelioma. Partial removal may result in persistence or recurrence. Although rare, trichoepitheliomas can develop high-grade carcinomas and mixed (epithelial/sarcomatous) tumors.[13, 14] Familial trichoepithelioma has 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 (ie, ulceration, recurrence) are probably follicular tumors within the basal cell nevus syndrome and not trichoepithelioma.

Patient Education

Inform the patient that some degree of scarring will be present after trichoepithelioma treatment.

 

Presentation

History

Slow-growing, single or multiple papules or nodules are typically observed on the face, as demonstrated in the image below.

Characteristic clinical morphologic features. Noti Characteristic clinical morphologic features. Notice the numerous, small papules, predominantly close to the 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, interview the patient's family for a familial history of trichoepithelioma.

Physical Examination

The lesions are rounded, skin-colored, firm papules or nodules that are 2-8 mm in diameter.

The lesions 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 report a rare case of trichoepithelioma of the vulva.[15]

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, ungual fibromas) or dystrophia unguis congenita.

Trichoepithelioma may be part of the Rombo syndrome (ie, vermiculate atrophoderma, milia, hypotrichosis, trichoepithelioma, basal cell carcinoma, peripheral vasodilatation).

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

 

DDx

Diagnostic Considerations

Histologic differential diagnoses (see Histologic Findings) are as follows:

Differential Diagnoses

 

Workup

Approach Considerations

In vivo studies such as high-definition optical coherence tomography have been applied to distinguish trichoepithelioma from other cutaneous tumors.[16] If necessary, genetic studies may be used to detect the abnormalities in band 9p21 in trichoepithelioma patients.

Procedures

Perform a shave or small punch biopsy to allow a histologic diagnosis of trichoepithelioma. Ensure that the biopsy sample is sufficiently deep to allow the dermatopathologist to study most of the lesion in cases of a solitary trichoepithelioma. In particular, a shave biopsy of a plaquelike lesion on the lip may result in identifying the superficial portion of a microcystic adnexal carcinoma (an aggressive adnexal neoplasm) as a trichoepithelioma. Some adnexal carcinomas may show a very limited degree of cytologic atypia. In such cases, only by examining the periphery of the lesion with the characteristic infiltrative pattern allows correct diagnosis.

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, as in the images below.

Well-circumscribed, superficial lesion composed of Well-circumscribed, superficial lesion composed of clusters of basaloid cells within a fibrous stroma. This arrangement of epithelial cells and stroma is described as organoid.
The cystic spaces contain keratin. Notice the lack The cystic spaces contain keratin. Notice the 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 or atypical mitotic figures are not a feature. 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), as shown in the image below.[17]

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

Because trichoepitheliomas recapitulate hair differentiation, they may contain scattered melanocytes, as shown in the image below.

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

Immunohistochemical studies reveal expression of the cytokeratins associated with the outer root sheath (ie, cytokeratins 5, 6, 8, and 17) and expression of bcl-2, predominantly in the peripheral cell layer of the nests. The intervening stromal cells express CD34, as shown in the image below.

Immunohistochemical studies detect expression of C Immunohistochemical studies detect expression of CD34 by many of the dendritic cells that surround the tumor aggregates (anti-CD34, diaminobenzidine, and hematoxylin).

Transforming growth factor-beta is expressed in most trichoepitheliomas. Merkel cells can be detected in all trichoepithelioma variants. Some studies have shown that trichoepitheliomas frequently have Merkel cells (detectable with chromogranin or cytokeratin 20).[18] CK19 is reportedly more frequently detected in basal cell carcinoma than in trichoepithelioma.[19] Trichoepitheliomas apparently lack expression of androgen receptors,[20] while many basal cell carcinomas 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 those cells of basal cell carcinoma.[21, 22]

Although extremely rare, some trichoepitheliomas may develop high-grade carcinomas and biphasic tumors (epithelial and sarcomatous) with aggressive behavior (including metastasis).[13, 14]

Trichoepithelioma variants

The desmoplastic variant, as its name indicates, is characterized by a prominent, sclerotic stroma, as shown in the image below.[23]

Desmoplastic variant. Notice that many of the aggr Desmoplastic variant. Notice that many of the aggregates of basaloid cells are small, resembling a syringoma; however, they contain keratin instead of eccrine secretion. Also notice the characteristic markedly fibrous stroma.

It occurs in the same population as the classic type and presents as a plaque located in the same anatomical areas as the classic form. Histologically, it shows narrow strands of tumor cells, a desmoplastic stroma, and keratinous cysts, as shown in the image below.

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

Pleomorphism, palisading, or peripheral clefting are not seen. Features favoring 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 basal cell carcinoma, fibroblasts surrounding trichoepithelioma nests do not express the matrix metalloproteinase stromelysin-3 (ST-3).[24, 25]

A possible pitfall is the observation of perineural involvement in some cases of desmoplastic trichoepithelioma, a feature more frequently associated with malignancy.[26] Also interesting is the observation of pseudoepitheliomatous hyperplasia above desmoplastic trichoepitheliomas that may result in a misdiagnosis of squamous cell carcinoma.[27]

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

Differential diagnoses based on histologic study

Features of basal cell carcinoma 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.[28, 29, 30] A study with a tissue microarray indicated that the best markers to differentiate between trichoepithelioma and basal cell carcinoma include a combination of CD10, cytokeratin 15, cytokeratin 20, 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 in basal cell carcinoma.[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, as shown in the image below.

The malignant counterpart, trichilemmal carcinoma, The malignant counterpart, 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, as shown in the image below.

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

Treatment

Approach Considerations

Treatment of the trichoepithelioma lesion is primarily surgical. Laser and radiofrequency 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 suggest the possibility of targeted therapies, such as antitumor necrosis factor-alpha[34] or targeting mammalian target of rapamycin (mTOR) and hypoxia signaling pathways.[35]

Surgical Care

Solitary lesions can be excised. In the case of multiple tumors, this surgical approach may not be feasible.

Split-thickness skin grafting, dermabrasion, and laser surgery have been proposed, but the results of these procedures vary.[36, 37, 38]

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

Recurrence of solitary trichoepithelioma is uncommon. When the multiple facial lesions are surgically flattened by 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.

Ensure that the patient is informed about the possibility of scarring. As with many benign skin neoplasms, the patient is mainly concerned about the aesthetic appearance of the lesion. Scarring may result from all available methods for tumor removal. In patients with multiple lesions, treating 1 or 2 of the lesions and showing the patient the final result may be helpful before embarking on extensive aggressive therapy.

Complications

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

Prevention

No preventive measures for trichoepithelioma are known.

 

Questions & Answers

Overview

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?

Presentation

Which clinical history findings are characteristic of trichoepithelioma?

Which physical findings are characteristic of trichoepithelioma?

DDX

What are the histologic differential diagnoses of trichoepithelioma?

What are the differential diagnoses for Trichoepithelioma?

Workup

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?

Treatment

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?