Background: Pancreatic ductal adenocarcinoma (PDAC) tumor inter-patient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intra-patient heterogeneity has been reported but has not yet been extensively studied due to the lack of standardized, reproducible and easily accessible high throughput methods. Material and Methods: We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multi-step process. The successive stages of i) an in-silico selection from a review literature and a bulk transcriptome analysis of 309 PDACs, ii) a tumor-specific selection from 30 patient-derived xenografts followed by iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n=95, whole-slide, n=148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based-analysis in tumor and pre-neoplastic epithelial areas and a k-means clustering to identify relevant marker combinations. Results: Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: 1 classical, 1 intermediate (KRT17+) and 2 basal-like (MUC16+ vs S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival, even in classical predominant PDACs (HR=2.36, p=0.01). Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis may follow a progressive evolution from classical toward a basal through an early intermediate phenotype. Conclusion: Our IHC panel redefined and easily assessed the high degree of intra- and inter-tumoral heterogeneity of PDAC.