BCC & SCC Mimickers: Histologic Pitfalls for Mohs Surgeons

The Mohs surgeon serves simultaneously as surgeon and pathologist, interpreting frozen sections in real time to guide complete tumor extirpation with maximal tissue conservation. This dual role demands not only the ability to identify carcinoma but also the ability to confidently exclude benign and reactive processes that may closely resemble malignancy. Tumor mimickers represent one of the most challenging aspects of Mohs histopathology, and their misinterpretation has direct clinical consequences. Overcalling a benign adnexal tumor (such as trichoepithelioma or trichoblastoma) as BCC leads to additional unnecessary Mohs stages, removal of normal tissue, larger defects, more complex reconstructions, and potential functional compromise, particularly in cosmetically and functionally sensitive areas such as the nose, eyelids, and lips. Undercalling residual carcinoma as a benign mimicker results in incomplete tumor clearance, leading to local recurrence that may require re-excision with even larger tissue loss. The frozen section environment amplifies these diagnostic challenges: tissue processing artifacts (freeze artifact, crush artifact, tangential sectioning) degrade histologic detail compared to permanent sections, and the surgeon is under time pressure to render a diagnosis while the patient waits under anesthesia.

Trichoepithelioma is the most clinically significant BCC mimicker encountered during Mohs surgery. It is a benign follicular hamartoma/neoplasm composed of basaloid cells with follicular differentiation, arising most commonly on the central face. The same anatomic region where BCCs are most frequent. Trichoepitheliomas present clinically as skin-colored to pink papules, typically 2-8 mm in diameter, and can be solitary or multiple (the latter seen in Brooke-Spiegler syndrome and familial trichoepithelioma syndromes, caused by mutations in CYLD). Histologically, trichoepithelioma shows basaloid islands with peripheral palisading and a characteristic fibrotic stroma. Features that overlap significantly with nodular BCC. However, several key features help distinguish trichoepithelioma from BCC: trichoepitheliomas typically show horn cysts (small keratinous cysts with abrupt keratinization), papillary mesenchymal bodies (small clusters of fibroblasts surrounded by basaloid cells resembling follicular papillae), CK20-positive Merkel cells scattered within the tumor periphery, and absent or very rare mitotic figures. The stroma in trichoepithelioma is characteristically fibrotic and often shows a lamellar pattern, whereas BCC stroma is typically myxoid or mucin-rich. Retraction artifact. The characteristic separation of tumor islands from surrounding stroma. Is much more prominent in BCC than trichoepithelioma.

Trichoblastoma is a benign follicular neoplasm that presents a significant diagnostic challenge during Mohs surgery due to its basaloid cytomorphology and often large, deeply extending architecture. Trichoblastomas are generally larger than trichoepitheliomas and extend more deeply into the dermis and subcutis, often reaching 1-3 cm in diameter. They most commonly present on the face and scalp as solitary, flesh-colored to blue-gray dermal or subcutaneous nodules. Histologically, trichoblastoma is composed of basaloid cells arranged in large nodular aggregates, cribriform patterns, or racemiform (branching cord-like) configurations. Like trichoepithelioma, trichoblastoma represents follicular germinative differentiation and shows many features of hair follicle development. Papillary mesenchymal bodies, follicular bulb-like structures, and a characteristic fibroblastic stroma distinct from the mucinous stroma of BCC. Trichoblastoma was historically classified as a subtype of trichoepithelioma, but it is now recognized as a distinct entity in the WHO classification of skin tumors. The clinical significance in Mohs surgery is considerable: a large, deeply extending basaloid tumor on the face can be mistaken for nodular or nodular-infiltrative BCC, leading to extensive and unnecessary surgery if the surgeon does not recognize the follicular nature of the lesion.

Beyond trichoepithelioma and trichoblastoma, several other benign lesions can mimic BCC on frozen sections during Mohs surgery. While individually less common than trichoepithelioma, their collective frequency makes awareness essential. These mimickers share one common feature: basaloid cytomorphology or follicular architecture that can be confused with BCC, particularly on suboptimal frozen section preparations where tissue artifact degrades histologic detail.

Keratoacanthoma (KA) is the most important and controversial SCC mimicker in dermatologic surgery. The fundamental question. Whether KA is a benign, self-resolving reactive process or a variant of well-differentiated SCC. Has been debated for decades and remains unresolved. The clinical behavior of KA is distinctive: rapid growth over 4-8 weeks to a dome-shaped, 1-3 cm nodule with a central keratotic plug, followed by spontaneous involution over 2-6 months in classic cases. However, a significant minority of KAs do not involute, and some clearly progress to invasive SCC. The concept of "KA-type SCC" has emerged as a practical framework that acknowledges the SCC-like features of many KAs while recognizing their generally favorable biology. Most Mohs surgeons treat KA as SCC, proceeding with complete excision including Mohs when indicated by location or other risk factors.

Pseudoepitheliomatous hyperplasia (PEH) is a reactive squamous epithelial proliferation that can closely mimic well-differentiated SCC on frozen sections. PEH represents an exuberant, non-neoplastic proliferation of the epidermis and follicular epithelium in response to various underlying stimuli. Chronic inflammation, infection, wound healing, or underlying neoplasm (most classically granular cell tumor). The clinical significance in Mohs surgery is considerable: PEH can appear at the peripheral margins of an SCC excision (reactive to the surgery itself or the underlying inflammatory condition) or may be the sole pathology in a lesion that was biopsied as "SCC" when the underlying cause (e.g., deep fungal infection, granular cell tumor) was not recognized. On frozen sections, the irregular downgrowth of squamous epithelium into the dermis can be virtually indistinguishable from well-differentiated SCC, making this one of the most treacherous diagnostic pitfalls for the Mohs surgeon.

Beyond keratoacanthoma and pseudoepitheliomatous hyperplasia, several additional benign and low-grade lesions can mimic SCC on frozen sections during Mohs surgery. These mimickers share the common feature of squamous proliferation. Either reactive or neoplastic. Without true invasive malignant behavior.

Immunohistochemistry (IHC) is an invaluable adjunct to frozen section interpretation when morphology alone is insufficient to distinguish a mimicker from true carcinoma. In a well-equipped Mohs laboratory, IHC can be performed on frozen section tissue with results available within 30-60 minutes, allowing real-time diagnostic decision-making during surgery. The key to effective IHC use is selecting the right panel for the right clinical question and interpreting results in context. No single stain is 100% sensitive or specific, and a panel-based approach is always preferred. The decision to request IHC should be made early during the procedure when doubt first arises, as the 30-60 minute processing time can be utilized for patient care or other cases rather than causing prolonged delays.