Prognostic value of tumor-infiltrating lymphocytes in distal extrahepatic bile duct carcinoma

Abstract

Background

The assessment of tumor-infiltrating lymphocytes (TILs) has led to the development of various immunotherapies beyond their predictive potential in gastrointestinal malignancies. However, the clinicopathologic and prognostic values of TILs have yet to be well elucidated in distal extrahepatic bile duct carcinoma (DBDC).

Patients and methods

We evaluated stromal TILs (sTILs) and intraepithelial TILs (iTILs) in 405 surgically resected DBDCs to analyze their correlations with overall survival (OS) and recurrence-free survival (RFS) and with clinicopathologic parameters according to the eighth edition of the American Joint Committee on Cancer scheme.

Results

High levels of sTIL density (sTIL^High; >5%) and iTIL count (iTIL^High; >3) were found in 245 (61%) and 74 cases (18%), respectively. sTIL^High was more commonly found in larger tumors (P = 0.048) diffusely involving both intra- and extrapancreatic bile ducts (P = 0.013), in tumors with lower T category (P = 0.002), and in tumors without pancreatic (P = 0.003) or duodenal invasion (P < 0.001). iTIL^High was associated with tumors with papillary or nodular growth pattern (P < 0.001) without perineural invasion (P = 0.006). Both sTIL^High and iTIL^High significantly predicted better OS (P = 0.009 and 0.036, respectively) and RFS (P = 0.003 and 0.026, respectively). sTIL consistently provided prognostic predictability in OS, even when tested with different quantitative cut-offs and prognostically stratified OS (P = 0.006) and RFS (P = 0.005) on multivariate analysis. The survival benefit of sTIL^High persisted regardless of the stage in both OS (P = 0.010 for lower stages I and II and P = 0.001 for higher stages III and IV) and RFS (P = 0.004 and 0.025 for lower- and higher-stage tumors, respectively).

Conclusions

sTILs were superior to iTILs in predicting survival, and it was shown to be a strong prognosticator for DBDC patients regardless of the stage. The utility of sTILs may extend beyond prognostication to aid in predicting therapeutic responses in DBDC patients.