CTNNB1-mutated High-grade Endometrioid Carcinoma With Extensive Squamous and Shadow Cell Differentiation Can Mimic Pilomatrix Carcinoma

To the Editor:

Response to Bueno et al. “Vulvar Pilomatrix Carcinoma: Morphologic and Molecular Features.” International Journal of Gynecologic Pathology. 2021 September;40(5):482–486.

We write in response to a recent case report, noted above, of an aggressive pilomatrix carcinoma of the vulva with pathogenic mutations in CTNNB1, PTEN, PIK3CA, and ARID1A. Although alterations in CTNNB1 is a known molecular driver of pilomatrix carcinoma ¹, alterations in PTEN, PIK3CA, and ARID1A have not been reported in pilomatrix tumors or other follicular-based neoplasms. Indeed, these genes are commonly described in endometrioid carcinomas ², which may display pilomatrix-like morphology ³. We, therefore, propose the possibility that the tumor described in the aforementioned case report may represent a pilomatrix-like endometrioid carcinoma rather than a true pilomatrix carcinoma.

Pilomatrix carcinoma is an exceedingly rare adnexal tumor seen mostly in white, older men around the head and neck region. The tumor is known to be locally aggressive with only rare cases of metastatic disease ^4,5. Histologically, pilomatrix carcinoma is composed of basaloid cells with conspicuous necrosis and shadow cell formation. However, these findings are not specific, and histologic mimics have been reported in several visceral carcinomas, including endometrioid, transitional cell, and colonic carcinomas ⁶. Consequently, several cases of visceral carcinoma misdiagnosed as pilomatrixoma or pilomatrix carcinoma have been reported. For instance, Lalich et al. ⁷ described an upper extremity skin lesion initially diagnosed as pilomatrixoma. However, further review showed a minor component of classic endometrioid carcinoma with squamous morules, similar to the patient’s prior ovarian endometrioid carcinoma. Scheck et al. ⁸ also reported a case initially diagnosed as pilomatrixoma of the vagina, which was then revealed as metastatic endometrioid carcinoma with further studies.

Recently, Weisman et al. ³ described 5 cases of aggressive endometrial endometrioid carcinomas with morphologic and immunophenotypic similarities to pilomatrix carcinomas. The tumors showed solid growth pattern with basaloid tumor cells, conspicuous necrosis, and shadow cell formation. The cells had aberrant β-catenin expression with negative ER and PAX8. Molecular testing revealed an exon 3 CTNNB1 mutation in 2 tested cases, along with mutations in PTEN and PIK3CA in 1 case.

The tumor described by Bueno and colleagues is unusual in its location, demographics, and aggressive clinical course. Furthermore, while activating mutations in the exon 3 of CTNNB1 have been consistently detected in pilomatrix carcinoma ¹, it is not specific and have been reported in other tumors, such as endometrioid carcinoma ^2,3. In contrast, alterations in PTEN, PIK3CA, and ARID1A have not been reported in pilomatrical tumors but are commonly described in endometrioid carcinoma ². Given these unusual features, we submit the possibility that the case may represent a high-grade endometrioid carcinoma rather than a true pilomatrix carcinoma. The tumor is described to extend to the upper vagina; however, there is no description of the uterus or adnexa. Without examination of the endometrium and ovaries, it is difficult to rule out the more common endometrioid carcinoma with extension/metastasis to the vagina and vulva.

Differentiating between pilomatrix carcinoma and metastatic visceral carcinoma has both prognostic and therapeutic implications. Ultimately, it is important to note that pilomatrix carcinoma of the vulva is an exceedingly rare diagnosis, warranting extensive clinical and pathologic work-up to rule out other primary carcinomas.