Utility of HNF-1B and a panel of lineage-specific biomarkers to optimize the diagnosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most common cancers with dismal prognosis. Definitive diagnosis of PDAC remains challenging due to the lack of specific biomarkers. A transcription factor essential for pancreatic development named HNF-1B can be a potential biomarker for PDAC. However, HNF-1B was not entirely specific for PDAC and can be expressed in cancers of Müllerian tract, kidney, lung, bladder and prostate. To solve this issue, we investigated the expression of a panel of well-established lineage-specific biomarkers for non-pancreatic origins, including TTF1 and Napsin A for lung, RCC for kidney, ER and PR for breast, NKX3.1 for prostate, PAX8 for Müllerian tract, GATA3 for breast and bladder, and keratin CK7 and CK20 in 149 PDACs, using immunohistochemistry and tissue microarray. A two-tier scoring system for HNF-1B expression in tumor cells was used. Chi-square and Fisher's exact tests were performed using SAS software version 9.4 to test the association between HNF-1B expression and tumor morphology and differentiation. The results showed that PAX8 was focally positive in 6 cases (4.0%). GATA3 was focally positive in 5 cases (3.4%). Napsin A was all negative except for 1 case with focal weak staining. All other lineage-specific markers such as TTF1, RCC, ER, PR and NKX3.1 were completely negative in all PDACs. Consistent with our previous result, the majority of PDACs (88.6%) was positive for HNF-1B, including 78 cases (59.1%) with "strong" and 54 cases (40.9%) with "weak" staining pattern. There was no significant association between HNF-1B expression and cytoplasmic clearing morphology. Addition of keratins may further aid the diagnosis of PDAC since the majority of PDACs (84.6%) was CK7+/CK20-, only a minority of PDACs (11.4%) was CK7+/CK20+, 2.7% were CK-/CK20-, and 1.3% were CK7-/CK20+. In conclusion, HNF-1B can serve as a useful biomarker to aid the diagnosis of PDAC when combined with other lineage-specific biomarkers to exclude the other origins.