Background: The differentiation between pancreatic head cancer (PHC) and distal cholangiocarcinoma (DCC) can be challenging because of their anatomical and histopathological similarity. This is an important problem, because the distinction has important implications for the treatment of these malignancies. However, there are no biomarkers for the differential diagnosis of PHC and DCC. The present study aimed to identify novel diagnostic immunohistochemical biomarkers to distinguish PHC from DCC. Methods: Liquid chromatography tandem mass spectrometry (LC-MS/MS) was employed to detect candidate proteins. Ten PHC and 8 DCC specimens were analyzed by LC-MS/MS. Selected proteins were evaluated, using immunohistochemical analysis, to determine whether they would be appropriate biomarkers. Finally, we generated biomarker panels to improve diagnostic accuracy. We applied these panels to clinically difficult cases (cases in which different diagnoses were made before and after operation). Results: Consequently, 1820 proteins were detected using LC-MS/MS. Fifteen differentially expressed proteins were selected as candidates based on semi-quantitative comparison. We first performed immunohistochemical staining on samples from the small cohort group (12 PHCs and 12 DCCs) using 15 candidates. KRT17, ANXA10, TMEM109, PTMS, and ATP1B1 showed favorable performances and were tested in the next large cohort group (72 PHCs and 74 DCCs). Based on immunohistochemical analysis, KRT17 performed best for the diagnosis of PHC as a single marker; additionally, PTMS exhibited good performance for the diagnosis of DCCs. Moreover, we indicated the KRT17+/ANXA10+/PTMS- staining pattern as a biomarker panel for the correct diagnosis of PHC and KRT17−/ANXA10−/PTMS+ for the diagnosis of DCC. After immunohistochemical staining for examining samples from the clinically difficult cases, these panels showed satisfactory diagnostic performance with 85.7% (6/7) accuracy. Conclusions: We conclude that 5 proteins and 2 biomarker panels are promising for distinguishing PHC from DCC, and patients with an equivocal diagnosis would benefit from the application of these biomarkers. Confirmatory studies are needed to generalize these findings to other populations.
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