Multiple familial trichoepithelioma with malignant transformation.

Trichoepithelioma (TE) is a benign tumor of follicular origin that presents as small, skin-colored papules predominantly on the face. When more than one family member is affected, the disease is known as multiple familial trichoepithelioma (MFT). It is a rare autosomal dominant (AD) skin disease. Malignant transformation is very rare. We present a case of MFT in a female patient and her father with malignant transformation to basal cell carcinoma (BCC) in the father. We summarized the main histological differential parameters between TE and BCC and applied immunophenotyping for both by administration of Bcl2, CD34, CD10 and androgen receptor (AR) antibodies.

What was known?

Malignant transformation may occur in MFT

This malignant change denotes loss of heterozygosity in CLYD gene

The differentiation between BCC and immature TE represents a diagnostic challenge

Introduction

Trichoepithelioma (TE) is a benign adnexal neoplasm. Lesions are rounded, skin-colored, firm papules or nodules, 2-8 mm in diameter. They are located mainly on nasolabial folds, nose, forehead, upper lip, and scalp.[12]

Multiple familial trichoepithelioma (MFT) is an autosomal dominant (AD) disorder beginning in childhood and progresses slowly. Malignant transformation of such lesions is quite rare.[3]

Case History

Case 1

A 38-year-old female presented with a 27 years history of asymptomatic, skin colored papules. Lesions were firm in consistency, ranging from 5 to 10 mms in diameter and were distributed on her face; around eyes, on the nose, nasolabial folds and upper lip [Figure 1a and b]. General examination revealed no abnormality. Dermatological examination revealed normal skin and mucous membranes. Patient's father had similar lesions but there was no affection of other family members. Routine investigations including hemogram, urine analysis, liver and renal function tests were non contributary.

Figure 1

First patient presented by skin colored papules on: (a) periorbital region (b) nose, nasolabial folds and upper lip

Excisional biopsy of a representative lesion was done after taking patient consent. Histopathological examination of hematoxylin and eosin (H and E)-stained sections revealed superficial dermal, well circumscribed, non capsulated, symmetrical lesion. This lesion was formed of solid aggregates of uniform basaloid cells with peripheral palisading but lacked epidermal connection, pilar differentiation and retraction artifacts. They were surrounded by a stroma with increased number of fibroblasts [Figure 2a]. Cells were uniform, with large nuclei and scanty cytoplasm and lacked cytological atypia, mitoses or necrosis [Figure 2b]. Aggregations of fibroblasts, representing abortive attempts to form papillary mesenchyme (papillary mesenchymal bodies), were detected, that are characteristic of TE [Figure 2c]. Small foreign body granuloma was detected [Figure 2d].

Figure 2

(a) Trichoepithelioma showing superficial dermal solid basaloid masses with peripheral palisading and lacked the epidermal connection, epithelial stromal retraction artifact, mitosis or cytologic atypia (b) An intrastromal cleft (arrow) was observed around the solid aggregates that were tightly encircled by fibroblasts (H and E, ×200 “a and b”) (c) Aggregations of fibroblasts, representing abortive attempts to form papillary mesenchyme (papillary mesenchymal bodies) (arrow) (d) Foreign body granuloma (arrows) adjacent to a basaloid mass (asterisk) (H and E, ×400 “c and d”)

Based on clinical and histopathological criteria, the diagnosis of immature TE was reached. However the presence of solid basaloid aggregates with peripheral palisading may lead to a misdiagnosis of BCC. Thus, we performed immunohistochemical (IHC) staining for Bcl2, CD10, CD34 and androgen receptor (AR) antibodies. The outermost epithelial cells showed positivity for Bcl2 [Figure 3a]. Both CD10 and CD34 stained the stromal cells but not the basaloid cells [Figure 3b and c]. Both tumor cells and stroma did not show any AR immunoreactivity [Figure 3d]. The final diagnosis was TE. The patient was treated by CO2 laser with no recurrence for one year.

Figure 3

Trichoepithelioma IHC staining profile: (a) The outermost epithelial cells showed positivity for Bcl2 (arrows) (b) CD10 stained the stromal cells but not the basaloid cells (arrow) (c) CD34 stained the stromal cells (colored arrows) but not the basaloid cells (asterisk), It also stained blood vessel (internal control) (black arrow) (d) Both tumor cells and stroma lacked any Androgen receptor immunoreactivity (Immunoperoxidase ×400 for a, b, c and d)

Case 2

A 65-year-old male, the father of the first patient, was presented similarly by papulo-nodular lesions with the same distribution and morphology described in his daughter but larger in size [Figure 4a]. These lesions appeared since 57 years but were neglected as they were asymptomatic. One month before reaching us, one of those nodules enlarged markedly to reach a size of 6 cm with repeated bleeding, ulceration and crustation [Figure 4b].

Figure 4

Patient's father presented by similar but larger lesions on (a): periorbital region and nose with ulcerated crusted nodule on the left side of the nose (b)

Excisional biopsy was taken from a representative papule and incisional biopsy was taken from the enlarging nodule after taking patient consent.

For the former biopsy, examination of H and E-stained sections and immunohistochemical-stained sections of the same antibodies revealed the same results as the first case.

For the latter biopsy, islands of basaloid cells extending from the epidermis to the dermis with peripheral palisading and prominent stromal epithelial retraction artifacts were observed. Cells were large, with uniform large nuclei and scanty cytoplasm. So the diagnosis of BCC was suggested. Immunohistochemical staining revealed that, the basaloid cells stained diffusely with Bcl2 [Figure 5a], CD10 [Figure 5b] and focally with AR antibodies [Figure 5c]. CD34 immunostaining was negative [Figure 5d].

Figure 5

Basal cell carcinoma IHC staining profile: (a) The basaloid cells stained diffusely with Bcl2. (b) The tumor cells stained diffusely with CD10. (c) CD34 immunostaining was negative in basaloid cells and fibrous stroma but stained the blood vessels (internal control) (arrows). (d) Androgen receptor stained the basaloid cells (Immunoperoxidase ×400 for a, b, c and d)

Discussion

TE is a benign neoplasm of follicular germinative cells.[1] Clinically, this tumor occurs either as a solitary lesion without any familial association or as multiple lesions in MFT.[3] Lesions develop as firm, non-ulcerated, flesh-colored papules with a propensity for the face and rarely exceed 0.5 cm in size.[2]

MFT was initially described in 1892 under the names “multiple benign cystic epithelioma” and “epithelioma adenoides cysticum”.[3]

In most cases, lesions appear in childhood and gradually increase in number and size. Ulceration may occur rarely.[1] The gene associated with the familial type of TE links to the short arm of chromosome 9. It encodes tumor suppressor genes and if altered, cellular proliferation may be upregulated.[4] However, other reports documented defects of a tumor repressor gene on chromosome 16, CYLD.[5] To date, 17 mutations of this gene have been described to be associated with MFT.[6] Males and females receive the gene equally, but because of lessened expressivity and penetrance in men, most patients are women.[4]

Biopsy is diagnostic. TE contains adenoid network or solid aggregates of basaloid cells, horn cysts, and abortive hair papillae. Horn cysts are the most characteristic tumor component.[1] However, some lesions show relatively little differentiation towards hair structures with very few or even absent horn cysts.[3] These lesions considered as immature TE as in our cases.

The histopathological findings found in our cases were summarized in Table 1.

Table 1

Histopathological differences observed between TE and BCC

TE is a benign lesion that may be excised by a small margin of healthy tissue, thereby facilitating surgical repair; however, BCC is a locally malignant tumor treated by excision of the lesion with 3-4 mm margins. So the differentiation between both is mandatory. Diagnosis may be assisted in a given case by clinical data, and the presence of hereditary transmission.[7] The distinction between BCC and immature TE on histopathologic basis is quite difficult especially in small superficially shaved specimens. This is due to the subtle morphologic differences between the two entities. Immunohistochemistry has been considered for the differential diagnosis between both tumors. Bcl-2 expression has been found to be limited to the outermost basaloid cells in tumor nests of TE and to be diffuse in BCC. CD10 gives positive stromal staining in TE and epithelial staining in BCC.[8] CD34 is considered to be a good candidate because the stroma is positive in TE and negative in BCC.[9]

More recent studies have shown AR expression in a number of mature epithelial structures and epithelial neoplasms including BCC. In contrast, AR expression was absent in mature hair follicles or the few trichogenic neoplasms studied to date. These findings suggested that AR expression might be a useful adjunct in the histologic differential diagnosis between BCC and TE.[10]

The immunhistochemical staining of the used antibodies were summarized in Table 2. Our results were in accordance with others.[8910]

Table 2

Immunostaining markers that differentiate TE and BCC

Malignant transformation of TE to BCC is rare.[7] Literature review showed that only 12 cases were reported up till now with the first case in 1959.[11] Malignant transformation denotes loss of heterozygosity in CLYD gene in the 9p21 and 9q22 chromosomal regions.[7] Matt et al.,[12] had indicated that there is a common gatekeeper between TE and BCC. Tan and his associates[13] concluded that BCC arising on top of MFT lesions may represent a novel contagious gene syndrome.

Multiple treatment modalities had been suggested for TE, including surgical excision and grafting, chemical peeling and CO2 laser.[126] The first case had been treated by Co2 laser. Regarding the treatment of BCC in the second case, it had been surgically excised but he was not interested in treating TE lesions.

What is new?

We presented the thirty fourth case of MFT and also the thirteenth case of malignant transformation of TE to BCC.

The histopathological and immunohistochemical differences between TE and BCC were summarized and tabulated.

We recommend the administration of the suggested immunohistochemical antibodies to differentiate between BCC and immature TE.