Multiple Familial Trichoepithelioma with an Adjacent Basal Cell Carcinoma, Transformation or Collision - A Case Report and Review of Literature.

Trichoepithelioma 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 skin disease. Malignant transformation is very rare. We describe here a case that developed malignant neoplasm in a setting of multiple trichoepithelioma.

What was known?

Trichoepithelioma is a benign adnexal neoplasm. Histologically its appearance is similar to basal cell carcinoma.

Introduction

Trichoepithelioma is a benign hamartomatous tumor of the pilo-sebaceous follicle that may occur either as a non-hereditary solitary lesion or as multiple lesions that are often dominantly inherited. Malignant transformation to basal cell carcinoma is rare and occurs late in the course of the disease.[1] There are many histological similarities shared by basal cell carcinoma and the follicle tumors, particularly trichoepithelioma. The correct diagnosis between these tumors is very important because basal cell carcinoma is locally aggressive neoplasm and requires total surgical excision with wide healthy margins. However, trichoepithelioma is a benign neoplasm which may be partially excised by shaving.[2]

Case Report

A 57-year-old female presented with multiple skin colored asymptomatic lesions developing over face since the age of 3 years. The lesions gradually increased in size and number and by the age of 25 year involved entire face including bilateral ears along with the loss of eye brows. The lesions also involved the bilateral upper limbs and upper chest since 2-3 years. About 6 months previously, two lesions, one on forehead and other on the nose, had shown rapid growth. The female had no significant history of any drug intake or radiation exposure. There was a family history with her father having similar lesions.

On local examination, patient's skin showed multiple skin colored to yellowish nodules varying in size from 0.5 × 0.5 to 1.5 × 1.5 cm coalescing with each other involving the entire face including bilateral ears and upper eyelids [Figure]. Few lesions over forehead, nose and cheek were crusted and surrounded by zone of telangiectasia along with loss of eyebrows. Similar lesions of size 0.5-0.8 cm were present over bilateral upper limbs, chest, back and scalp. General examination was normal with no lymphadenopathy. Radiographic studies were unremarkable. Subsequently, biopsies were performed from the lesions over forehead, nose and left cheek.

Figure 1

Photograph showing numerous skin-colored, dome-shaped nodules all over the face

Microscopic examination of lesions from forehead and left cheek revealed similar appearance which showed basaloid tumor islands, horn cysts filled with keratin and papillary mesenchymal bodies, with diagnosis consistent with trichoepithelioma [Figure 2]. However, the lesion from nose revealed a different microscopic appearance and represented by cells similar to those described earlier, although with irregular and voluminous nuclei with frequent mitotic figures. The tumor islands showed retraction pockets and peripheral palisading in some areas along with areas of follicular differentiation represented by tumor islands with keratinous material in the centre. We considered the differential diagnosis of malignant transformation of trichoepithelioma and basal cell carcinoma.

Figure 2

(a) Microphotograph of a lesion on forehead showing basaloid tumor islands, horn cysts filled with keratin and papillary mesenchymal bodies, consistent with trichoepithelioma (H and E, ×100). (b) Microphotograph of a lesion on nose showing basaloid tumor islands with retraction pockets and peripheral palisading in some areas along with frequent mitotic figure and areas of follicular differentiation represented by tumor islands with keratinous material in the centre (H and E, ×200)

Immunohistochemical stains including BCL-2, CD34 and Ki-67 were applied on these malignant tissue sections. The basaloid tumor islands showed diffuse positivity for BCL-2 whereas the peritumoral stromal cells were negative for CD34, positive in the endothelial lining of the blood vessels [Figure 3]. Ki-67 proliferative index was high being more than 10% [Figure 4]. Based on the light microscopic and immunohistochemical study, a final diagnosis of basal cell carcinoma was made. The malignant lesion was excised with wide margins and there was no evidence of distant metastasis. The patient is on regular follow-up every 6 months.

Figure 3

Photomicrograph of lesion on nose. (a) BCL-2 positivity in tumor cells (IHC, ×400). (b) CD34 negativity in the stromal cells with positive control in endothelial cells (IHC, ×400)

Figure 4

Photomicrograph of lesion on nose showing high Ki-67 proliferative index being more than 10% (IHC, ×400)

Discussion

Trichoepitheliomas are uncommon genodermatosis which develop from undifferentiated germinative cells of the follicular-sebaceous–apocrine unit.[3] In 1892, Brooke originally described it as epithelioma adenoids cysticum (EAC) and Fordyce as a multiple benign cystic epithelioma.[45] Two clinical forms are usually described: Multiple trichoepithelioma, which has a family history and starts to appear during puberty, affecting mainly the face; and giant solitary trichoepithelioma, which has no family history and generally appears in childhood.[3]

There is a genetic heterogenicity of multiple familial trichoepitheliomas. Initial reports linked multiple familial trichoepithelioma to chromosomes 9p21 but recent reports have found mutations in cylandromatosis tumor suppressor gene (CYLD), which maps to chromosome 16q12-q13 in most of the cases. Mutation in the CYLD gene gives rise to MFT indistinguishable from phenotype assigned to 9p21.[6] The exact prevalence of trichoepithelioma is unknown, however multiple trichoepitheliomas appear to be rather uncommon. Malignant transformation to basal cell carcinoma is rare and occurs late in the course of the disease.[1] Literature review showed that only 12 cases were reported up till now with the first case in 1959.[7]

A diagnostic dilemma accounts for a substantial number of extramural and intramural consultations in many institutions around the distinction between trichoepithelioma and basal cell carcinoma. In the majority of cases, this is not a difficult morphologic problem; however, the histologic appearance of the two tumors seems to merge and their separation is quite challenging. Obviously, a correct diagnosis is desirable when the differential diagnosis lies between a pultatively benign tumor entity and a destructive neoplasm.[8] Histologically, trichoepitheliomas consist of nests of basaloid cells with follicular differentiation embedded within tumor stroma that dissects through the collagen into the upper reticular dermis. Basal cell carcinomas can have a similar microscopic appearance. Contrasting histologic features are said to include papillary mesenchymal bodies which is a feature of trichoepitheliomas but the presence of clefting between the epithelial and stromal components of the tumor, peripheral palisading of keratinocytes, single cell necrosis, and brisk mitotic rate are associated with basal cell carcinoma and not ordinarily seen in trichoepitheliomas.[9]

A number of reports have been published claiming that immunohistochemical stains such as BCL-2 and CD34 that will help to distinguish basal cell carcinoma from trichoepithelioma.[8] The proto-oncogene BCL-2 encodes a protein that inhibits programmed cell death (apoptosis), and is expressed in normal basal keratinocytes but not in the superficial layers. BCL-2 expression has been demonstrated intracellularly in a wide variety of neoplasms, including basal cell carcinoma as in our case and also supported by Smoller et al., who examined 10 basal cell carcinomas and 10 trichoepitheliomas for BCL-2, found all basal cell carcinomas positive with prominent homogenous cytoplasmic staining throughout the lesions, whereas in trichoepitheliomas, without exception, staining of tumor cells was limited to the outermost basaloid cells.[1011] Trichoepitheliomas (TEs) are difficult to distinguish from basal cell carcinoma, however this distinction is necessary because of difference in management and outcome of these two conditions. The spindle-shaped stromal cells surrounding the tumor nests show focal strong positivity for CD34 but in case of basal cell carcinoma these cells are negative for CD34. The Ki-67 proliferative index is significantly higher in basal cell carcinoma as compared to trichoepithelioma as is in our case with Ki-67 proliferative index of >10%.[12]

In the original descriptions of EAC in 1892 by Brooke and Fordyce the benignity of the lesions was stressed.[45] An element of doubt was cast on the purported cases of malignant transformation in EAC by the clear establishment of nevoid basal cell carcinoma syndrome by Howell and Caro in 1959, raising the question as to whether the cases previously reported to be EAC with malignant degeneration were actually unrecognized cases of nevoid basal cell carcinoma syndrome.[13] The case of multiple trichoepithelioma with basal cell carcinoma in three of the ulcerated lesions was described by Pinkus in 1938 and found difficulties in knowing whether a pathological structure should be interpreted as “arising from” a normal structure or “differentiating toward” that structure, part of Pinkus’ description of his case could equally apply to the present case.[14]

Currently it is thought that transformation of trichoepithelioma to basal cell carcinoma is rare and usually arises in the setting of multiple trichoepitheliomas. Possible theories in our patient include transformation within a single lesion of a trichoepithelioma to a basal cell carcinoma or a collision of two independent neoplasms, basal cell carcinoma and trichoepithelioma. Alternatively this lesion may represent a primary basal cell carcinoma that has trichoepitheliomatous differentiation, although our immunohistochemical findings clearly show two separate staining patterns that have been reported to help distinguish lesion of basal cell carcinoma from trichoepitheliomas. However, EAC is basically a benign condition, it should not be a cause for complacency in patient follow-up, as, rarely, malignant lesions may arise.

What is new?

Trichoepitheliomas (TEs) are difficult to distinguish from basal cell carcinoma, however this distinction is necessary because of difference in management and outcome of these two conditions.