The differential diagnosis includes epidermal cysts, pilomatrixoma, basal cell carcinoma with matrical differentiation, trichoblastoma/trichoblastic carcinoma, and trichilemmal carcinoma. Pilomatrix carcinomas frequently are mistaken for epidermal cysts on clinical examination. Such a distinction can be easily resolved by histopathologic evaluation. The more challenging differential diagnosis is with pilomatrixoma. Histologically, pilomatrixomas consist of a distinct population of cells including basaloid, squamoid, transitional, and shadow cells in variable proportions. The basaloid cells transition to shadow cells in an organized zonal fashion.16 Compared to pilomatrixomas, pilomatrix carcinomas often show predominance of the basaloid cells; marked cytologic atypia and pleomorphism; numerous mitotic figures; deep infiltrative pattern into subcutaneous fat, fascia, and skeletal muscle; stromal desmoplasia; necrosis; and neurovascular invasion (Tables 1 and 2). Furthermore, the shadow cells tend to form a small nested pattern in pilomatrix carcinoma instead of the flat sheetlike pattern usually observed in pilomatrixoma.16 Basal cell carcinoma with matrical differentiation can pose a diagnostic challenge in the differential diagnosis; basal cell carcinoma usually exhibits a peripheral palisade of the basaloid cells accompanied by retraction spaces separating the tumor from the stroma. Trichoblastoma/trichoblastic carcinoma with matrical differentiation can be distinguished by its exuberant stroma, prominent primitive hair follicles, and papillary mesenchymal bodies. Trichilemmal carcinomas are recognized by their connection to the overlying epidermis, peripheral palisading, and presence of clear cells, while pilomatrix carcinoma lacks connection to the surface epithelium.
Immunohistochemical stains have little to no role in the differential diagnosis, and morphology is the mainstay in making the diagnosis. Rarely, pilomatrix carcinoma can be confused with poorly differentiated sebaceous carcinoma and poorly differentiated squamous cell carcinoma. Although careful scrutiny of the histologic features may help identify mature sebocytes in sebaceous carcinoma, evidence of keratinization in squamous cell carcinoma and ghost cells in pilomatrix carcinoma, using a panel of immunohistochemical stains can be helpful in reaching the final diagnosis (Table 3).
The development of hair matrix tumors have been known to harbor mutations in exon 3 of the catenin beta-1 gene, CTNNB1, that encodes for β-catenin, a downstream effector in the Wnt signaling pathway responsible for differentiation, proliferation, and adhesion of epithelial stem cells.17-21 In a study conducted by Kazakov et al,22 DNA was extracted from 86 lesions: 4 were pilomatrixomas and 1 was a pilomatrix carcinoma. A polymerase chain reaction assay revealed 8 pathogenic variants of the β-catenin gene. D32Y (CTNNB1):c.94G>T (p.Asp32Tyr) and G34R (CTNNB1):c.100G>C (p.Gly34Arg) were the mutations present in pilomatrixoma and pilomatrix carcinoma, respectively.22 In addition, there are several proteins that are part of the Wnt pathway in addition to β-catenin—LEF-1 and CDX-2.
Tumminello and Hosler23 found that pilomatrixomas and pilomatrix carcinomas were positive for CDX-2, β-catenin, and LEF-1 by immunohistochemistry. These downstream molecules in the Wnt signaling pathway could have the potential to be used as diagnostic and prognostic markers.2,13,15,23
Although the pathogenesis is unclear, there are 2 possible mechanisms by which pilomatrix carcinomas develop. They can either arise as de novo tumors, or it is possible that initial mutations in β-catenin result in the formation of pilomatrixomas at an early age that may undergo malignant transformation in elderly patients over time with additional mutations.2