Are You Confident of the Diagnosis?
What you should be alert for in the history
The diagnosis of trichoepithelioma is considered when a patient presents with solitary and asymptomatic papules on the face.
If a patient presents with multiple asymptomatic papulonodules on the face, as well as other areas of the body including the trunk and the buttocks, the diagnosis of multiple-familial trichoepitheliomas or Brooke-Spiegler syndrome should be considered. A family history of these syndromes can usually be elicited and patients may complain of auditory and visual symptoms, as some of the lesions can be found in the external auditory canals and periorbital regions.
Multiple lesions associated with these two diseases can be very disfiguring, and are thus frequently associated with psychosocial problems. Therefore, patients frequently present with great cosmetic concerns.
In addition, patients with Brooke-Spiegler syndrome have multiple cylindromas, frequently found on the scalp, which can be associated with alopecia. Spiradenomas, in addition to cylindromas, are present simultaneously with trichoepitheliomas in Brooke-Spiegler syndrome, which distinguished it from multiple-familial trichoepitheliomas where only one type of tumor—trichoepitheliomas—are present. In multiple-familial trichoepitheliomas, the size of the lesions increases steadily for a limited time, but eventually stabilizes within a few years.
Characteristic findings on physical examination
Trichoepitheliomas are typically found on the face, but can also be found on other sites such as the neck. They are pearly skin-colored small papules or nodules that are generally less than 2cm in size.
Patients with multiple-familial trichoepitheliomas or Brooke-Spiegler syndrome have trichoepitheliomas predominantly in the nasolabial folds, but lesions can also be found on the nose, forehead, upper lip, external auditory canal, periorbital region, and sometimes on the scalp, neck, and upper trunk.
Multiple-familial trichoepitheliomas present as dome-shaped skin-colored firm papules that range in size from 5mm to 8mm (Figure 1).
The trichoepitheliomas in Brooke-Spiegler syndrome are very similar in size and clinical appearance to those found in multiple-familial trichoepitheliomas. Brooke-Spiegler syndrome patients may also have cylindromas, which are typically found on the scalp as nodules ranging 0.5-6cm in size, and spiradenomas, which can be painful and have a bluish appearance.
Expected results of diagnostic studies
Solitary trichoepitheliomas and trichoepitheliomas associated with multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome all have similar features on histology. On histology, trichoepitheliomas consist of abortive hair papilla, keratinous microcysts, and islands of basaloid cells arranged in a lace-like network in a collagenous, hypocellular stroma (Figure 2, Figure 3).
Trichoepitheliomas express CD34 antigen and stain positive on immunohistochemistry. Studies have also shown CD10 expression in the peritumoral stroma of trichoepitheliomas. Bcl-2 staining limited to the periphery of tumor nests is also consistent with the diagnosis of trichoepithelioma.
The desmoplastic trichoepithelioma is a histological variant of trichoepithelioma. It appears as small strands of basaloid cells with prominent oval nuclei in a desmoplastic stroma, with adjacent keratinaceous cysts attached to the basaloid cells. The cellular proliferations are primarily in the papillary and mid-reticular dermis, but can often extend deeper.
The differential diagnosis of trichoepithelioma includes other follicular tumors such as trichoadenoma, trichoblastoma as well as trichofolliculoma.
At present, there is no standardized classification system for trichogenic tumors, and several diagnostic terms have been proposed, but one should regard them as distinct entities until a universal classification system is established.
Some authors have suggested that trichoepithelioma is a variant of trichoblastoma. In 1993, Ackerman proposed a new classification and suggested that the term trichoblastoma encompass all adnexal neoplasms of follicular germinative cells that show benign features, including sharp circumscription, smooth borders, and symmetrical growth patterns.
Ackerman classified trichoblastomas into the following histopathologic types: adamantinoid (cutaneous lymphadenoma), columnar (desmoplastic trichoepithelioma), cribiform (trichoepithelioma), large nodular, small nodular, racemiform-retiform, rippled-pattern, subcutaneous, and superficial (common in nevus sebaceous). However, most agree that trichoblastoma is a distinct clinical entity, as it is larger than a trichoepithelioma, is located in the subcutaneous fat, and lacks keratinizing cysts. Trichoblastomas are typically found on the face and scalp and frequently develop within a nevus sebaceous.
Trichoadenomas are commonly placed in a spectrum of follicular neoplasms between trichoepithelioma and trichofolliculoma. Trichoadenomas express only cytokeratin 10 and 15, whereas trichofolliculomas do not express cytokeratin 10, but do express cytokeratin 15, 16, and 17. In addition, trichoepitheliomas express only cytokeratin 15.
Basal cell carcinomas may clinically appear similar to trichoepitheliomas, and the two entities can be easily confused. Histopathologic differentiation between the two entities is critical, as trichoepitheliomas are benign tumors that are typically managed conservatively, while basal cell carcinoma is a malignant tumor that requires complete removal of the tumor with margin control.
On histology, trichoepitheliomas have abortive hair papilla, keratinous microcysts, and collagenous hypocellular stroma. On the other hand, basal cell carcinomas have connections to the epidermis, necrosis, apoptosis, mitosis, in a loose, fibromyxoid stroma with peritumoral retraction spaces.
Rarely, the above histologic findings are not present, and diagnosis between trichoepitheliomas and basal cell carcinoma is difficult. In such cases, immunohistochemistry is a helpful tool.
Trichoepitheliomas have been shown to demonstrate CD10 expression mainly in the peritumoral stroma, while basal cell carcinoma had staining of the basaloid cells. In addition, CD34 is expressed in all cases of trichoepithelioma, but staining is negative in cases of basal cell carcinoma. Bcl-2 is another marker that has been studied to differentiate between trichoeitheliomas and basal cell carcinoma. Bcl-2 staining is limited to the periphery of tumor nests in cases of trichoepitheliomas, while there is diffuse staining throughout the tumor nests in basal cell carcinoma.
Nikolowski originally described trichoadenoma as a distinct entity. Since then, others have regarded it as a variant of desmoplastic trichoepithelioma. More recently, immunohistochemistry studies support that desmoplastic trichoepithelioma is indeed a distinct clinical entitiy from trichoadenoma.
In one study, immunohistochemistry was used to demonstrate expression pattern of cytokeratin 20, Ber-EP4, and androgen receptor in both trichoadenomas and desmoplastic trichoepitheliomas. The study found that cytokeratin 20 was expressed in both trichoadenomas and desmoplastic trichoepitheliomas; however, Ber-EP4 was expressed by desmoplastic trichoepitheliomas, but not expressed by trichoadenomas.
Who is at Risk for Developing this Disease?
Solitary trichoepitheliomas are nonfamilial and are more common than the inherited trichoepitheliomas associated with multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome. The exact incidence of these tumors is unknown. Solitary trichoepitheliomas occur in children or young adults. Sexual predilection has not been reported for the solitary nonfamilial trichoepitheliomas.
Multiple-familial trichoepithelioma is inherited in an autosomal dominant pattern and tends to appear in childhood or adolescence. Multiple-familial trichoepithelioma is more common in females, despite an autosomal dominant pattern of inheritance. It is thought that female preponderance is likely secondary to decreased expressivity and penetrance in males.
Similarly, Brooke-Spiegler syndrome is inherited in an autosomal dominant pattern, and tumors tend to start in early adulthood with a 2:1 female to male ratio.
Desmoplastic trichioepithelioma is more common in females.
What is the Cause of the Disease?
The etiology and pathogenesis of solitary trichoepitheliomas remains unclear; however, there have been studies linking solitary trichoepitheliomas to 9q22.3 (PTCH) gene locus. On the other hand, multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome are both linked to 16q12q13 (CYLD) gene.
It is important to note that one study has linked multiple-familial trichoepitheliomas to a gene located on the 9p21 locus; however, many subsequent studies have not replicated this.
Systemic Implications and Complications
Sporadic solitary trichoepitheliomas are benign and have no systemic implications or complications. Likewise, trichoepitheliomas associated with multiple-familial trichoepitheliomas rarely undergo malignant changes. However, there are obvious psychosocial problems due to the disfigurement associated with the disease. Also, the course of disease should be discussed, as an increase in size and number of lesions is expected. Patients should also be informed that some lesions of multiple-familial trichoepithelioma show spontaneous remission over the years.
If a patient is diagnosed with Brooke-Spiegler syndrome, multiple different tumors are likely to occur. While eccrine spiradenomas, trichoepitheliomas, and cylindromas are generally benign, parotid basal cell adenomas and adenocarcinomas have been reported. Although malignant transformation of cylindromas is rare, in the event of malignancy, metastases can frequently occur. Therefore, close follow up is recommended in any patient with Brooke-Spiegler syndrome or family history of it.
It is important to note that in both multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome, trichoepitheliomas may be present in the external auditory canals and periorbital regions, potentially impairing vision and hearing. These tumors should, therefore, be treated accordingly.
Since both multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome are autosomal dominant diseases, genetic counseling should be offered to the patients with family history of these diseases.
Patients with desmoplastic trichoepitheliomas should be informed that, despite the benign nature of the tumor, these tumors can penetrate widely and have aggressive histologic features, subclinical growth, and occurrence in cosmetically important areas.
Treatment options are summarized in Table I.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Topical*||Shave removal||Ablative laser surgery:|
|• 5-fluorouracil*||• Carbon dioxide laser alone|
|• tretinoin*||• Er:YAG (erbium:yittrium aluminum garnet) laser alone|
|• Combination of carbon dioxide laser and Er:YAG laser|
|Topical aspirin*||Punch excision||Radiotherapy|
|Scalp excision with split-thickness skin grafting|
*Topical treatments for trichoepitheliomas are generally unsuccessful.
Optimal Therapeutic Approach for this Disease
Several surgical modalities have been successful in removing these dermal tumors. Most patients are agreeable to surgery, as resultant scarring is usually more acceptable than the appearance of the lesion itself. Since the tumors are benign, tumor bulk reduction for good cosmetic outcomes should be the aim, regardless of the surgical modality chosen.
SUGGESTED TREATMENTS FOR SOLITARY TRICHOEPITHELIOMA
Complete surgical excision with histopathologic evaluation to rule out malignancy is the best option for definitive treatment of solitary trichoepitheliomas, if cosmetic outcomes allow. Deep shave of the lesion can be done, but dermal component may persist, increasing the chance of tumor recurrence. If the tumor is small, a punch excision around the visible tumor margins can be attempted.
Complete surgical excision is also recommended for desmoplastic trichoepithelioma, as it is a locally invasive tumor. It is advisable to perform complete surgical excision with frozen section margin control and observe for evidence of recurrence. Some authors have recommended Mohs micrographic surgery for desmoplastic trichoepitheliomas in order to ensure margin control, lower the chance of recurrence, and minimize the defect size in a cosmetically sensitive approach.
SUGGESTED TREATMENTS FOR SYNDROMES ASSOCIATED WITH MULTIPLE TRICHOEPITHELIOMAS
Primary excision is impractical for the multiple lesions associated with multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome. Other modalities may be attempted for multiple lesions as recommended below.
The combination of carbon dioxide and Er:YAG (erbium:yttrium aluminum garnet) laser ablation has been reported with good results. The Er:YAG laser ablates tissue with minimal thermal damage and allows debulking to an appropriate depth, thereby limiting the extent of scar formation.
Because the Er:YAG is not hemostatic, the carbon dioxide laser is useful for additional carbonization and hemostatic effect. Specific Er:YAG laser parameters to ablate tumor tissue to sublesional dermis reported by Rallan et al. were as follows: 2940nm wavelength, 2mm beam diameter, 0.4J/cm2 at 4pulses/sec. The carbon dioxide laser was then used in continuous mode at 2mm and 5W.
The next best option is to use carbon dioxide laser alone. This tool also offers great precision and is therefore recommended for small facial lesions. Tissue is vaporized in a controlled fashion with excellent hemostasis. In addition, it gives good cosmetic results compared to electrosurgery and no significant recurrence was noted at two years follow-up, according to several cases. One drawback with using the carbon dioxide laser alone is tissue carbonization, which necessitates wiping off the surgical area between passes.
Electrosurgery can also be used, but it is not recommended over laser modalities for multiple lesions covering over large areas because it has less precision and increased thermal effects.
THERAPIES THAT HAVE BEEN ATTEMPTED BUT HAVE PROVEN TO BE UNSUCCESSFUL
Medical therapy with topical chemotherapeutic agents such as tretinoin and 5-fluorouracil were tried in the past, with minimal improvement. Since the tumor has a dermal location, topical remedies are generally unsuccessful.
In the past, cryotherapy, dermabrasion, and electrodessication and curettage have been unsuccessful. In addition, some of these techniques have disadvantages.
There is significant bleeding associated with dermabrasion, which leads to loss of the surgeon’s visual field.
Due to the fibrotic nature of the tumor, electrodessication and curettage is difficult to perform and often leads to hypopigmented and depressed areas.
THERAPIES THAT SHOULD NOT BE ATTEMPTED
Since it is understood that the loss of wildtype allele of tumor suppressor genes is associated with tumor formation in multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome, radiotherapy is not recommended, as it could result in further tumor induction. In addition, radiotherapy results in poikiloderma and increases the risk of basal cell and squamous cell carcinomas.
THERAPIES THAT MAY PROVE BENEFICIAL BUT REQUIRE FURTHER STUDY
Topical aspirin has been tried in one trial, with equivocal results. It has been shown that the CYLD gene is associated with multiple-familial trichoepitheliomas and Brooke-Spiegler syndrome, and since it is now known that it is a negative regulator in the antiapoptotic nuclear factor kappa beta pathway (NFkB), topical aspirin may prove as an alternative medical therapy for these tumors. However, further research needs to be done before it can be recommended as a standard treatment.
THERAPIES FOR OTHER LESIONS OF BROOKE-SPIEGLER SYNDROME
Brooke-Spiegler syndrome has been associated with cylindromas and spiradenomas. In the past, loop diathermy has been used for cylindromas of the external auditory meatus, and scalp excision with split-thickness skin grafting has been used for scalp cylindromas. Both approaches have resulted in complications, and other conservative approaches should be considered. Spiradenomas can be removed successfully with small incisions.
Patients with multiple-familial trichoepithelioma and Brooke-Spiegler syndrome should be informed that treatment of existing trichoepitheliomas may be successful without recurrence, but occurrence of new trichoepitheliomas at a different site is not uncommon.
If the patient has multiple-familial trichoepitheliomas or Brooke-Spiegler syndrome, whether they have been treated or not, observation for malignant transformation of the benign tumors should be performed.
In addition, patients with Brooke-Spiegler syndrome are also at risk for developing tumors of the major and minor salivary glands. Basal cell adenomas and adenocarcinomas of the parotid glands and minor salivary glands have been reported in patients with Brooke-Spiegler syndrome. In one case, bilateral parotid gland basal cell adenocarcinomas have been reported. It is, therefore, important to monitor these patients closely.
Unusual Clinical Scenarios to Consider in Patient Management
It is rare to have malignant transformation of trichoepitheliomas associated with multiple-familial trichoepitheliomas. There is, however, one rare case of a 35-year-old Korean woman, with multiple-familial trichoepitheliomas, with malignant transformation of one trichoepithelioma lesion on her buttock. The trichoepithelioma was transformed into a trichoblastic carcinoma, which is a rare malignant neoplasm. The mass was excised, and 6-month follow-up showed no evidence of distant metastasis or recurrence.
What is the Evidence?
Rajan, N, Trainer, A, Burn, J, Langtry, JA. “A Familial cylindromatosis and Brooke-Spiegler syndrome: a review of current therapeutic approaches and the surgical challenges posed by two affected families”. Dermatol Surg. vol. 34. 2009. pp. 845-52. (A review of different therapeutic approaches to treat multiple trichoepitheliomas associated with Brooke-Spiegler syndrome. It also details the advantages and disadvantages of different therapeutic approaches.)
Shaffelburg, M, Miller, R. “Treatment of multiple trichoepithelioma with electrosurgery”. Dermatol Surg. vol. 24. 1998. pp. 1154-6. (A case report of a patient with multiple-familial trichoepitheliomas, successfully treated with electrosurgery. It reports detailed information about how the surgery was done and also gives information about successful treatment in the same patient with carbon dioxide laser. Advantages and disadvantages of other treatment modalities are also discussed in this article.)
Sawchuk, W, Heald, P. “CO2 laser treatment of trichoepithelioma with focused and defocused beam”. J Dermatol Surg Oncol. vol. 10. 1984. pp. 905-7. (A case report of a patient with multiple trichoepitheliomas occluding the external auditory canal, successfully treated with carbon dioxide laser. This case report also detailed the surgical procedure.)
Rallan, D, Harland, CC. “Brooke-Spiegler syndrome: treatment with laser ablation”. Clin Exp Dermatol. vol. 30. 2005. pp. 355-7. (This article gives a good explanation of different laser ablation options and their advantages and disadvantages. This is a case report of a patient with Brooke-Spiegler syndrome that was treated with the combined Er:YAG and carbon dioxide laser ablation.)
Mamelak, A, Goldberg, L, Katz, T, Graves, J, Arnon, O, Kimyai-Asadi, A. “Desmoplastic trichoepithelioma”. J Am Acad Dermatol. vol. 62. 2010. pp. 102-6. (A detailed review about desmoplastic trichoepithelioma and explanation of differences between desmoplastic trichoepithelioma and a trichoepithelioma. Treatment and differential diagnosis is also discussed extensively.)
Matt, D, Xin, H, Vortmeyer, A, Zhuang, Z, Burg, G, Boni, R. “Sporadic trichoepithelioma demonstrates deletions at 9q22.3”. Arch Dermatol. vol. 136. 2000. pp. 657-60. (This article used molecular biological techniques to demonstrate the PTCH gene at 9q22.3 locus is associated with sporadic trichoepitheliomas. The results of this study provide insight into the possible cause of sporadic trichoepitheliomas.)
Zhang, XJ, Liang, YH, He, PP, Yang, S, Wang, HY, Chen, JJ. “Identification of the cylindromatosis tumor-suppressor gene responsible for multiple-familial trichoepithelioma”. J Invest Dermatol. vol. 122. 2004. pp. 658-64. (This is a sophisticated study that genotyped members in the same family and performed mutation analysis of the CYLD gene in the 16q12-q13 locus. It also explained the clinical and histological aspects of the multiple-familial trichoepithelioma disease.)
Pham, TTN, Selim, MA, Burchette, JL, Madden, J, Turner, J, Herman, C. “CD10 expression in trichoepithelioma and basal cell carcinoma”. J Cutan Pathol. vol. 33. 2006. pp. 123-8. (This was an immunohistochemistry study using CD10 antigen to differentiate between basal cell carcinoma and trichoepithelioma. The results of the study are important in differentiating between the two entities, as one is malignant and other is benign but both can appear similar clinically as well as histologically.)
Lee, KH, Kim, JE, Cho, BK, Kim, YC, Park, CJ. “Malignant transformation of multiple-familial trichoepithelioma: case report and literature review”. Acta Derm Venereol. vol. 88. 2008. pp. 43-6. (A rare case report and literature review describing malignant transformation of trichoepithelioma associated with multiple-familial trichoepithelioma. This is an unusal presentation of multiple-familial trichoepithelioma.)
Kurokawa, I, Mizutani, H, Nishijima, S, Kato, N, Yasui, K, Tsubura, A. “Trichoadenoma: cytokeratin expression suggesting differentiation towards the follicular infundibulum and follicular bulge regions”. Br J Dermatol. vol. 153. 2005. pp. 1084-6. (This article was about using immunohistochemistry to determine the different cytokeratin staining pattern observed in trichofolliculomas and trichoepitheliomas, which are common differential diagnosis for trichoadenoma.)
Shimanovich, I, Krahl, D, Rose, C. “Trichoadenoma of Nikolowski is a distinct neoplasm within the spectrum of follicular tumors”. J Am Acad Dermatol. vol. 62. 2010. pp. 277-83. (Study differentiating desmoplastic trichoepithelioma from trichoadenoma, using immunohistochemistry. Three different antigens were used, including cytokeratin 20, Ber-EP4, and androgen receptor. Expression patterns in trichoadenoma were compared with desmoplastic trichoepithelioma.)
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