A Bilayer Is Not a Lineage: Testing Myoepithelial Mimicry in EWSR1::BEND2-Fused Fenestrating Adenocarcinoma

Fenestrating adenocarcinoma is an emerging EWSR1::BEND2-associated malignancy of the pharyngeal region whose reported architectural diversity includes apparently biphasic arrangements, basal/squamoid differentiation and hyalinised pseudorosettes. These observations expose a specific diagnostic uncertainty: does apparent epithelial–myoepithelial organisation represent genuine neoplastic myoepithelial differentiation, or can it arise through basal/squamoid mimicry or incorporation of native glandular structures? The distinction remains unresolved because the published cases have not undergone a uniform, compartment-resolved assessment of cellular differentiation and neoplastic membership. This Perspective proposes a three-gate pathological framework separating anatomical compartment identification, differentiation assignment and molecular attribution of neoplastic identity. Four competing explanations are considered: genuine biphasic differentiation, basal/squamoid mimicry, non-neoplastic glandular entrapment and regional phenotypic heterogeneity. Serial-section morphology, spatially registered complementary immunohistochemistry and, where feasible, compartment-directed fusion analysis could discriminate among these possibilities. Neither p63/p40 expression nor individual negative myoepithelial markers independently determine lineage; similarly, a shared EWSR1::BEND2 fusion establishes molecular relatedness without proving differentiation. Reproducible demonstration of a distinct, fusion-associated abluminal population with coherent myoepithelial differentiation would challenge the proposed mimicry explanation. The immediate significance is diagnostic: apparent bilayering in a rare pharyngeal carcinoma must not automatically establish epithelial–myoepithelial carcinoma or another recognised biphasic neoplasm. The framework offers a falsifiable approach to refining tumour characterisation without prematurely modifying classification or clinical management.