Evaluation of tumor budding, desmoplastic reaction, and lymphocytic infiltration in predicting survival for pancreatic ductal adenocarcinoma

Abstract

Background: Although previous findings indicated that pathological assessment of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may play a role in determining tumor behavior in many malignancies, the relationship between TB, DR, and TILs in patients with pancreatic ductal adenocarcinoma (PDAC) is still unknown.

Aim: To evaluate relationships of TB, DR, and TILs with histopathological parameters and determine their prognostic value in patients with PDAC.

Methods: The study cohort comprised 100 patients diagnosed with PDAC. Peritumoral budding (PTB) and intratumoral budding (ITB) were assessed according to the International Tumor Budding Consensus Conference guidelines. DR was classified based on stromal maturation. TILs were evaluated semiquantitatively with a 5% cutoff. Additionally, cases were categorized into two groups according to lymphocyte density: No/Low lymphocytes and medium/high lymphocytes.

Results: A significant correlation was observed between ITB and PTB (r = 0.890). Higher PTB was associated with fewer TILs and immature stroma (P < 0.001). PTB and TILs were significantly related to tumor dimension, lymphovascular invasion, lymph node metastasis (LNM), and stage (P < 0.005). ITB was also associated with the presence of lymph node involvement. The results of the univariate analysis revealed a significant correlation between poor survival rates and the presence of lymphovascular invasion, LNM, PTB, ITB, and TILs according to scoring (P < 0.001). The multivariate analysis revealed LNM, PTB, ITB, and TILs according to scoring as independent prognostic factors.

Conclusion: TB assessment stratified patients with PDAC. PTB-ITB correlation showed diagnostic relevance of ITB in biopsy specimens. The prognostic significance of DR and interplay with TIL subsets warrant further investigation.

Keywords: Desmoplastic reaction; Pancreatic ductal adenocarcinoma; Prognostic factors; Tumor budding; Tumor microenvironment; Tumor-infiltrating lymphocytes.

Figure 1

Tumor budding, desmoplastic reaction, and tumor-infiltrating lymphocytes. The grade was assessed according to the International Tumor Budding Consensus Conference recommendations. A: Tumor budding (TB) 1 (1-4 tumor bud/hot spot), × 200; B: TB2 (5-9 tumor bud/hot spot), × 200; C: TB3 (10 tumor bud/hot spot), × 200; D: Desmoplastic reaction (DR) 1. Mature stroma composed of tightly packed collagen fibers, × 400; E: DR2, intermediate stroma consisting of areas of collagen that resemble keloids, × 400; F: DR3, immature stroma with myxoid alterations; G: Pancreatic ductal adenocarcinoma with high tumor-infiltrating lymphocytes in the tumor stroma (≥ 5%), × 100; H: Pancreatic ductal adenocarcinoma with low tumor-infiltrating lymphocytes (< 5%), × 200. Hematoxylin-eosin staining. Black arrows indicate tumor buds.

Figure 2

Kaplan-Meier survival analyses in the cohort. A: Peritumoral tumor budding (log-rank test, P < 0.001); B: Intratumoral budding (log-rank test, P < 0.001); C: Tumor infiltrating lymphocytes according to the scoring (log-rank test, P < 0.05). PTB: Peritumoral tumor budding; ITB: Intratumoral budding; sTILs: Tumor infiltrating lymphocytes according to the scoring.