Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma

Abstract

Background: Resectable adenocarcinomas in the pancreatic head, by definition "periampullary", originate from ampullary, duodenal, biliary, or ductal pancreatic epithelium. Typically, periampullary adenocarcinomas have either intestinal or pancreatobiliary type of differentiation, and the type of differentiation might be prognostically more important than the anatomic site of origin. The aim of the study was to determine whether the histologic type of differentiation is an independent prognostic factor in periampullary adenocarcinoma, and whether tumour origin predicts the prognosis in pancreatobiliary type carcinomas independently of resection margin involvement, tumour size, nodal involvement, perineural and vascular infiltration, and degree of differentiation.

Methods: Histopathologic variables in 114 consecutively resected periampullary adenocarcinomas of pancreatobiliary (n = 67) and intestinal (n = 47) type differentiation were evaluated using a standardized, systematic protocol for evaluation of the resected specimen (study group). Histologic type of differentiation and tumour origin were compared as predictors of survival, and the results were validated by comparison with a historical control group consisting of 99 consecutive pancreaticoduodenectomies performed before standardization of histopathologic evaluation. Associations between histopathologic variables were evaluated by Chi-square and Mann-Whitney tests. Survival was estimated by the Kaplan-Meier method, comparing curves using log-rank test, and by univariate and multivariable Cox regression analysis.

Results: Both in the study group (n = 114) and in the historical control group (n = 99), the histologic type of differentiation independently predicted survival, while tumour origin predicted survival only in univariate analysis. Independent adverse predictors of survival in the study group were pancreatobiliary type differentiation (p < 0.001; HR 3.1; CI 1.8-5.1), regional lymph node involvement (p < 0.001; HR 2.5; CI 1.5-4.4), vessel involvement (p = 0.012; HR 1.9; CI 1.2-3.1), and increasing tumour diameter (measured in cm, p = 0.011; HR 1.3; CI 1.1-1.5). For pancreatobiliary differentiated adenocarcinomas (n = 67), lymph node status, vessel involvement, and tumour diameter remained independent prognostic factors, while tumour origin did not independently predict the prognosis due to significant association with tumour size (p < 0.001) and lymph node involvement (p = 0.004).

Conclusion: Pancreatobiliary versus intestinal type of differentiation independently predicts poor prognosis after pancreaticoduodenectomy for periampullary adenocarcinoma. Lymph node involvement, vessel infiltration, and increasing tumour diameter are adverse predictors of survival in tumours with pancreatobiliary differentiation.

Figure 1

The two dominant types of histologic differentiation in periampullary adenocarcinomas: (A) The pancreatobiliary type typically has simple or branching glands and small solid nests of cells surrounded by a desmoplastic stroma, and cuboideal to low columnar epithelium arranged in a single layer without nuclear pseudostratification, the nuclei rounded but with marked variation in size and shape from one cell to the next. (B) The intestinal type typically resembles colon cancer, may consist of solid nests with cribriform areas, has tall and often pseudostratified columnar epithelium with oval nuclei located in the more basal aspects of the cytoplasm, and there may also often be presence of mucin.

Figure 2

Overall survival after pancreaticoduodenectomy for periampullary adenocarcinoma (n = 114) originating in duodenum (n = 16), ampulla (n = 41), distal bile duct (n = 17), and pancreas (n = 40) (p < 0.001).

Figure 3

Overall survival after pancreaticoduodenectomy: (A) Periampullary adenocarcinoma (n = 114) with intestinal (n = 47) and pancreatobiliary (n = 67) type of histologic differentiation (p < 0.001). (B) Ampullary adenocarcinoma (n = 41) with intestinal (n = 28) and pancreatobiliary (n = 13) type of histologic differentiation (p = 0.02).

Figure 4

Pancreaticoduodenectomy for pancreatobiliary type periampullary adenocarcinoma: (A) Univariate survival for patients with pancreatobiliary type periampullary adenocarcinomas (n = 67) originating in ampulla (n = 13), distal bile duct (n = 16), and pancreas (n = 38) (p = 0.009). (B) Boxplot of maximum tumour diameter in the same 67 tumours with pancreatobiliary differentiation (p < 0.001, pancreatic versus non-pancreatic). (C) Survival for patients with non-pancreatic (n = 12, of which 6 ampullary and 6 biliary) and pancreatic (n = 18) tumours of comparable size (2 cm ≤ maximum diameter ≤ 3 cm) (p = 0.851).