Alcian blue‐positive stromal phenotype in basal cell carcinoma is associated with progression on first‐line hedgehog inhibitors

Abstract Basal cell carcinoma (BCC) is the most frequent malignancy in fair‐skinned populations. Although curable in most cases, approximately 4% of patients develop locally advanced or metastatic disease (advBCC) requiring systemic therapy. Hedgehog pathway inhibitors (HHIs; vismodegib/sonidegib) constitute standard first‐line treatment, yet individual responses vary and no histopathological biomarker predicting therapeutic outcome exists. We conducted a retrospective, multicenter analysis of 70 BCCs encompassing clinically common and advanced stages. Routine hematoxylin and eosin and Alcian blue (AB; pH 2.5) staining was evaluated using a 17‐parameter, numerically encoded histopathology matrix spanning tumor morphology, stromal composition, and immune contexture. Data were mapped by unsupervised hierarchical clustering. Distinct AB staining patterns were observed: superficial and nodular BCCs typically exhibited an AB‐positive peritumoral border, whereas infiltrative and sclerosing subtypes displayed a diffuse AB‐positive desmoplastic stroma. The latter also correlated with advanced EADO clinical stages (correlation coefficients 0.46–0.48; p < 0.001). In a subset of 30 advBCCs obtained before or during HHI therapy, AB‐positive stroma was the only parameter independently associated with shorter progression‐free survival (multivariable hazard ratio = 23.8; 95% CI 4.02–141.3; p < 0.001). Established clinical or histological features failed to associate with outcome. Our findings identify diffuse AB‐positive stroma as a readily detectable feature of histologically aggressive BCC and as a candidate biomarker associated with progression under HHI treatment. Because AB staining is routine, inexpensive, and easily standardized, this phenotype represents an immediately implementable readout for prospective validation and a potential link between extracellular‐matrix remodeling and therapy resistance in BCC.