Combined tumor epithelial and stromal histopathology with keratin 81 expression predicts prognosis for pancreatic ductal adenocarcinoma

Background: Development of a pragmatic pathologic classifier of pancreatic ductal adenocarcinoma (PDAC) that reflects biological behavior is needed. Methods: The tumor epithelial and stromal features of PDAC and molecular subtype-related markers were evaluated in three independent cohorts. Results: In the non-neoadjuvant therapy cohort (n = 108), regarding tumor-epithelial feature, non-gland-forming type showed worse prognosis compared to gland-forming type (P < .001). For tumor-stromal feature, in gland-forming type, the prognosis was good in order of inactivated stroma-rich, stroma-poor, and activated stroma-rich (P = .027). Whereas, non-gland-forming type revealed no difference of prognosis according to tumor stroma. Of molecular subtype-related markers, keratin 81 expression was correlated with non-gland-forming type and poor prognosis (P = .005 and P = .021, respectively). Other markers (HNF1A, c-MET, and p53) showed no significant differences in prognosis. In the neoadjuvant therapy cohort (n = 68), non-gland-forming type was correlated with high residual tumor volume (>= 20%) (P < .001) and gland-forming/stroma-poor type was not present. In the next-generation sequencing cohort (n = 55), non-gland-forming type was correlated with a higher number of the KRAS, TP53, CDKN2A, and SMAD4 mutations (P = .038). Conclusion: Combined tumor epithelial and stromal histopathology with keratin 81 expression is suggested to be useful for predicting prognosis of PDAC.