背景:胰岛淀粉样蛋白沉积和β细胞量减少是2型糖尿病受试者的病理标志。迄今为止,胰腺导管腺癌(PDAC)继发糖尿病患者胰岛的病理特征尚未得到具体解决.
目的:进一步了解PDAC患者残余胰腺的胰岛淀粉样蛋白沉积之间的关系,并探讨区域差异(近端和远端残余胰腺)是否与胰岛淀粉样蛋白沉积有关。
方法:我们回顾性收集了45例PDAC患者的临床资料和胰腺组织,包括14例糖耐量正常(NGT)患者,2017年7月至2020年6月,华西医院通过口服葡萄糖耐量试验诊断为16例糖尿病前期患者和15例新发糖尿病(NOD)患者。通过将每个图像切片上的胰腺组织的估计面积乘以基于腹部计算机断层扫描的切片之间的间隔来计算胰腺体积。来自远离肿瘤的近端和/或远端区域的石蜡包埋的胰腺标本的几个切片染色如下:(1)苏木精和伊红用于一般组织学外观;(2)苏木精和胰岛素用于确定部分β细胞面积(免疫组织化学);和(3)四重胰岛素,胰高血糖素,硫黄素T和DAPI染色测定β细胞面积,α细胞面积和淀粉样蛋白沉积。
结果:胰腺组织学特征的筛查显示,导管阻塞伴有胰岛淀粉样蛋白沉积,纤维化和明显的腺泡萎缩在远端胰腺区域是强大的,但在近端区域则不那么强大,尤其是在糖尿病前期和NOD组中。与这一发现一致,与NGT组相比,NOD组的残余胰腺体积显着减少了近一半(37.35±12.16cm3vs69.79±18.17cm3,P<0.001)。不出所料,在大多数PDAC病例中发现了淀粉样蛋白染色阳性的胰岛(胰岛淀粉样蛋白密度)。糖尿病前期和NOD患者的淀粉样蛋白/胰岛面积比例(淀粉样蛋白沉积的严重程度)均明显高于NGT患者(分别为P=0.002;P<0.0001)。我们进一步检查了胰岛淀粉样蛋白沉积物的区域差异。与糖尿病前期和NOD组的近端区域相比,远端区域的胰岛淀粉样沉积物密度强劲增加约8倍(3.98%±3.39%vs0.50%±0.72%,P=0.01;12.03%vs1.51%,分别为P=0.001)。
结论:结论:这些发现表明,由于肿瘤引起的远端胰腺的强烈改变可以干扰胰岛淀粉样蛋白形成的胰岛功能和结构,这可能与PDAC继发NOD的发病机制有关。
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.
OBJECTIVE: 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).
CONCLUSIONS: 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.