Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma

Abstract

Background: Islet amyloid deposition and reduced β-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects. To date, the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma (PDAC) have not been specifically addressed.

Aim: To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences (proximal vs distal residual pancreas) are associated with islet amyloid deposition.

Methods: We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients, including 14 patients with normal glucose tolerance (NGT), 16 patients with prediabetes and 15 new-onset diabetes (NOD) patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020. Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans. Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows: (1) Hematoxylin and eosin for general histological appearance; (2) hematoxylin and insulin for the determination of fractional β-cell area (immunohistochemistry); and (3) quadruple insulin, glucagon, thioflavin T and DAPI staining for the determination of β-cell area, α-cell area and amyloid deposits.

Results: Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition, fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions, especially in the prediabetes and NOD groups. Consistent with this finding, the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group (37.35 ± 12.16 cm³ vs 69.79 ± 18.17 cm³, P < 0.001). As expected, islets that stained positive for amyloid (islet amyloid density) were found in the majority of PDAC cases. The proportion of amyloid/islet area (severity of amyloid deposition) was significantly higher in both prediabetes and NOD patients than in NGT patients (P = 0.002; P < 0.0001, respectively). We further examined the regional differences in islet amyloid deposits. Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups (3.98% ± 3.39% vs 0.50% ± 0.72%, P = 0.01; 12.03% vs 1.51%, P = 0.001, respectively).

Conclusion: In conclusion, these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation, which may be associated with the pathogenesis of NOD secondary to PDAC.

Keywords: Amyloid deposits; Diabetes; Islet amyloid polypeptide; Pancreatic ductal adenocarcinoma; Residual pancreas.

Figure 1

Preoperative magnetic resonance imaging image and histopathologic image of the surgical resection of pancreatic specimens of pancreatic ductal adenocarcinoma patients with new-onset diabetes. A and B: Magnetic resonance imaging images (A) and images of surgical specimens (B) from pancreatic ductal adenocarcinoma patients showed pancreatic head tumor invading the main pancreatic duct, leading to dilation of the pancreatic duct and atrophy of the body and tail of the pancreas; C and D: Representative images of hematoxylin and eosin staining from the proximal (C) or distal (D) pancreas.

Figure 2

Islet immunohistochemical and immunofluorescent analysis of the proximal/distal pancreas of pancreatic ductal adenocarcinoma patients with new-onset diabetes. A and B: Representative images of immunohistochemical staining for insulin from the proximal (A) or distal (B) pancreas; C and D: Representative quadruple insulin (red), glucagon (green), thioflavin T (white) and DAPI (blue) staining from the proximal (C) or distal (D) pancreas for the determination of β-cell area, α-cell area and amyloid deposits.