A Rare Presentation of Basal Cell Carcinoma Arising within Trichoepithelioma: A Diagnostic Challenge

Differentiating between trichoepithelioma and basal cell carcinoma (BCC) is sometimes diagnostically challenging. We present a case of a 61-year-old male with a BCC arising within a trichoepithelioma, which is rarely reported in the literature. Clinical and histological diagnosis of trichoepithelioma is sometimes complicated by its many similarities to BCC. Therefore, immunohistochemical analysis and adequate tissue sampling are essential in suspicious lesions. In addition, as represented by our patient’s presentation, it is important for clinicians to remember that the presence of a concurrent malignant neoplasm may be masked by the benign nature of a trichoepithelioma and that a superficial shave biopsy may not be sufficient for accurately diagnosing such suspicious lesions.


Introduction
Trichoepithelioma is a benign hair follicle tumor with many of its clinical and histologic features similar to those of basal cell carcinoma (BCC). Thus, differentiating between these two entities is sometimes diagnostically challenging. We present a case of a 61-year-old male with a BCC arising within a trichoepithelioma, which is rarely reported in the literature (Poster and Abstract: Greywal T, Rubin A, Jiang SB. Basal Cell Carcinoma Arising within Trichoepithelioma: A Rare Presentation and Diagnostic Challenge. American Academy of Dermatology 76th Annual Meeting; Feb [16][17][18][19][20]2018).

Case Presentation
A 61-year-old man with no previous history of any type of skin cancer presented with a "spot" on his neck that had been present for 30 years. The lesion slowly increased in size and was associated with intermittent swelling. Cutaneous examination of the neck revealed a 1.5 cm by 2.3-cm multilobular plaque with overlying telangiectasias (Figure 1).

FIGURE 5: Bcl-2 immunohistochemistry
Bcl-2 immunohistochemistry demonstrating decoration of individual tumor cells along the periphery (as seen in trichoepithelioma) and with some areas of more diffuse expression (as seen in BCC) Histopathologic examination revealed basaloid islands within a cellular stroma, follicular differentiation with papillary mesenchymal bodies, minimal atypia and apoptotic bodies, and no retraction artifact. Immunohistochemical staining was positive for CD34 in stromal cells and Bcl-2 in the peripheral cells of the basaloid islands; CK20 was negative. These findings were most consistent with trichoepithelioma. However, due to the overlapping histologic features with BCCs, a conservative surgical excision was performed to completely remove the lesion.

FIGURE 11: Excisional biopsy, CK20 immunohistochemistry
Negative CK20 stain with no significant expression within the more superficial trichoepithelioma or deeper BCC BCC, basal cell carcinoma Some of the larger nodules contained cystic formations, necrosis, peripheral retraction artifact, and increased atypia; the smaller nodules showed follicular differentiation. Immunohistochemical staining was diffusely positive for Bcl-2 and CD10 in these larger nodular and cystic areas, and peripherally positive in areas with follicular differentiation. CK20 remained negative in all components. Overall, these findings were most consistent with a multifocal, infundibulocystic basal cell carcinoma arising within a trichoepithelioma. Since the lesion extended broadly into the deep margins, re-excision was recommended.
The patient subsequently underwent a third and final procedure with Mohs micrographic surgery (MMS) to achieve optimal clearance of the margins. The final defect was 7.2 cm by 8.0 cm after four stages of MMS ( Figure 12).

FIGURE 12: Final Mohs surgery defect
The final defect after four stages of Mohs micrographic surgery (7.2 cm by 8.0 cm) Following confirmation of negative margins, the resultant wound was repaired with an advancement flap.

Discussion
It is difficult to differentiate trichoepithelioma from BCC due to their many clinical and histologic similarities ( Table 1).   [1][2][3][4]. These tumors are thought to originate from follicular germinative cells and result from epithelial-mesenchymal origin cell proliferation [2,5]. Trichoepitheliomas can develop in any ethnicity or gender [1]. Males and females are equally affected, although some believe that women have a greater predilection for trichoepithelioma in inherited conditions, since men have lower levels of penetrance and expressivity [1][2]. By contrast, BCCs are the most common non-melanoma skin cancer that can originate from the epidermis or outer root sheath of a hair follicle; it has several histologic subtypes and is most prevalent in males [6][7].

Trichoepithelioma Basal Cell Carcinoma
Trichoepitheliomas usually present as a skin-colored papule or nodule on the central face of children and young adults [1][2][3][4]8]. They may also develop in other less common areas such as the neck, scalp, and trunk [1,4]. In addition, telangiectasia and central depression may be detected within these lesions [1,4,8]. BCC has a similar clinical appearance and is typically found on the head, neck, and other chronically sun-exposed areas in older individuals [6]. BCCs can present as large lesions, unlike trichoepitheliomas that grow slowly over time and typically range from 2 mm to 8 mm in size [2]. Our patient's lesion represents an unusual presentation of trichoepithelioma since this neoplasm rarely exceeds 1cm in size [4,8].
Immunohistochemistry is important in differentiating trichoepitheliomas from BCCs. Clinicians typically use Bcl-2, CD10, CD34, and CK20 immunohistochemical stains to aid in diagnosis. Bcl-2 is an anti-apoptotic protein that is diffusely expressed in BCCs, and only stains peripheral epithelial cells and papillary mesenchymal bodies in trichoepitheliomas [11][12]. In trichoepitheliomas, CD10 only stains stromal cells, particularly those surrounding tumor cells; conversely, CD10 stains both the stromal and tumor cells in BCCs and is classically positive along the periphery of the tumor [5,13]. Positive CD34 staining of the fibroblastic stroma surrounding nests of basaloid cells is present in trichoepithelioma and absent in BCC [2,11]. CK20 highlights Merkel cells, which are typically present in trichoepitheliomas and rarely found in BCCs [5,12,[14][15]. However, several studies question the efficacy of CK20 in differentiating trichoepithelioma and BCC, since the quantity of Merkel cells varies between their many histologic subtypes of trichoepitheliomas [12,[14][15]. In addition, since this marker highlights only scattered, single cells, it may not be reliable, especially when evaluating a small amount of tissue from a superficial shave biopsy [15].
Several studies have investigated the patterns of other immunohistochemical stains such as cytokeratin 19 (CK19), debrin, nestin, laminin-5, and PHLDA1. CK19 is expressed in germinative basaloid cells and can positively stain both BCCs and trichoepitheliomas [10]. However, one study evaluated patterns of CK19 staining and found diffuse, focal, and negative staining in 60%, 28%, and 12% of BCC cases, respectively [10]. They also showed diffuse, focal, and negative staining in 12%, 29%, and 59% of trichoepithelioma cases, respectively [10]. Therefore, CK19 will most likely diffusely stain BCCs, and remain negative in trichoepitheliomas. Debrin is an F-actin binding protein that appears to be highly and homogenously positive in BCCs and weakly present in a non-homogenous distribution within trichoepitheliomas [5]. Nestin is expressed in mesenchymal cells in hair follicles, and variable expression of nestin in trichoepitheliomas and BCCs is reported in the literature [11,16]. Stromal cells are usually positive in trichoepitheliomas and negative in BCCs [16]. However, certain histologic subtypes of BCC (nodular, superficial, infiltrative) show variable, weak nestin expression in their stromal cells [15]. Laminin-5 (laminin-5γ2 chain) was studied and shown to be positive in 96.2% of BCCs and in only 12% of trichoepitheliomas [11,17].
Finally, PHLDA1 (also known as TDAG51) is the most recent immunohistochemical stain that has been investigated for its role in differentiating trichoepithelioma and BCC. PHLDA1 is a proline-and glutamine-rich protein involved in apoptosis regulation and is expressed in melanocytes, the basal layer of the follicular bulge, and the lowermost portions of the inner root sheath and catagen follicles [12,14]. PHLDA1 is diffusely positive in trichoepithelioma and negative in BCC (although it may be positive near superficial ulcerations) [14][15]. Thus, some suggest PHLDA1 should replace CK20 since it can more easily and consistently differentiate trichoepithelioma and BCC, even in small biopsy specimens [14][15].
Since trichoepithelioma and BCC possess many similar features, it is important to realize that a superficial shave biopsy may provide inadequate tissue sampling for definitive diagnosis. Therefore, an excisional biopsy may be recommended in order to obtain more lesional tissue and to allow for a more accurate diagnosis.
Some cases have been reported in the literature describing the concomitant presence of a trichoepithelioma and a BCC, as seen in our patient [9,11,[18][19][20]. Most of these cases presented patients with both trichoepithelioma and BCC in the setting of genetic syndromes such as Brooke-Spiegler syndrome, familial cylindromatosis, or multiple familial trichoepithelioma [9,[18][19]. These conditions are all due to germline mutations of the cylindromatosis (CYLD) gene on chromosome 16q12-q13, which lead to uncontrolled activity of NF-κB, and ultimately, cell proliferation [1,[8][9].
Other case reports discuss the possibility of malignant transformation of trichoepithelioma to BCC, which usually arises in patients with multiple trichoepitheliomas [11,20]. Although trichoepitheliomas are generally thought to be benign neoplasms, they can rarely undergo malignant transformation, which is important for clinicians to consider when making diagnostic and therapeutic decisions [11,[19][20]. In addition, the coexistence of trichoepithelioma and BCC may be the result of two neoplasms (a collision tumor) independently developing in the same location [11,20]. Our patient illustrates a unique presentation of a BCC arising within a trichoepithelioma.
The treatment of trichoepithelioma includes laser, cryotherapy, dermal abrasion, electrodessication and curettage, radiation, and surgery [1][2][3]. Surgical removal can safely remove the lesion and is a particularly important modality when concomitant neoplasms or malignant transformation is suspected [2].

Conclusions
Trichoepithelioma is a tumor that seldom grows beyond 1 cm in size and rarely undergoes malignant transformation. However, clinical and histological diagnosis of trichoepithelioma is sometimes complicated by its many similarities to BCC. As such, immunohistochemical analysis and adequate tissue sampling are essential in suspicious lesions. Our patient presented with a BCC arising within a large, atypical trichoepithelioma. Therefore, it is important for clinicians to remember that trichoepitheliomas may co-exist with malignant neoplasms and that a superficial shave biopsy may not be sufficient for accurately diagnosing suspicious lesions.