ArticleThe journal of pathology. Clinical research2026
Mechanosensitive TRPV4 immunohistochemistry improves deep learning-based classification of ductal carcinoma in situ beyond H&E morphology.
Article in The journal of pathology. Clinical research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Ductal carcinoma in situ (DCIS) spans a biologic continuum from atypical ductal hyperplasia (ADH) to high-grade lesions with variable risk of progression to invasive ductal carcinoma (IDC), yet morphologic assessment by hematoxylin and eosin (H&E) remains diagnostically limited, particularly at the benign versus ADH/low-grade DCIS boundary. TRPV4, a mechanosensitive ion channel with pathology-dependent subcellular localization in DCIS, offers a biologically motivated immunohistochemical (IHC) marker that may refine classification beyond routine H&E assessment. We tested whether deep learning models trained on TRPV4 IHC outperform H&E-based models across the DCIS progression spectrum. We assembled a multi-institutional cohort of H&E and TRPV4 IHC whole-slide images from 108 patients, comprising an internal development cohort (n = 69), an external test cohort (n = 39), yielding 24,248 annotated tiles. Histopathological tiles from annotated regions were grouped into four ordered classes: normal/benign, ADH/low-grade DCIS, high-grade DCIS, and IDC. Xception and EfficientNet-B0 convolutional neural networks were trained with patient-level three-fold cross-validation on the development cohort and evaluated as ensembles on the external test cohort. On external patient-level testing, H&E ensembles achieved macro-F1 values of 0.43-0.44 and macro-AUC values of 0.73-0.80, whereas TRPV4 IHC ensembles improved performance to macro-F1 values of 0.68-0.72 and macro-AUC values of 0.91-0.92, corresponding to a 54.5-67.4% relative improvement in patient-level macro-F1. Patient-level per-class analyses showed the largest AUC gains with TRPV4 IHC versus H&E for ADH/low-grade DCIS (0.94-0.95 versus 0.61-0.70) and IDC (0.77-0.85 versus 0.61-0.69). Per-class analyses showed the largest gains with TRPV4 IHC versus H&E for ADH/low-grade DCIS (AUC, 0.83-0.84 versus 0.70-0.81) and IDC (AUC, 0.74-0.79 versus 0.65-0.66). These findings support TRPV4 IHC as a mechanistically grounded complement to H&E that improves patient-level discrimination across the DCIS progression spectrum, with the strongest gains for ADH/low-grade DCIS and IDC, in a pilot multi-institutional setting.
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