Abstract
Simple SummaryThe pathogenesis of pancreatic cancer-associated diabetes mellitus is poorly understood. We analyzed tumor infiltration into Langerhans islets and characterized it systematically for the first time, identifying four different main patterns of islet invasion. In a cohort of 68 pancreatic ductal adenocarcinoma (PDAC) patients, these islet invasion patterns were not related to occurrence of diabetes mellitus. However, severe islet invasion was associated with worsened overall survival.Background: Pancreatic cancer-associated diabetes mellitus (PC-DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri-insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo-insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV) adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, more research on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.
Highlights
To improve the prognosis of pancreatic cancer, early detection is urgently needed.Diabetes mellitus or hyperglycemia occurs in up to 80% of all pancreatic ductal adenocarcinoma (PDAC) patients, which usually emerges 2–3 years before the diagnosis of cancer [1,2,3]
We analyzed the infiltration of pancreatic cancer cells into pancreatic islets via doubleimmunolabeling of human pancreatic cancer tissues with insulin or glucagon and the pancreatic cancer cell marker cytokeratin 19 (CK-19) or Mucin-1 (MUC1)
In the four following categories: (I) peri-insular invasion defined as tumor cells directly touching the round islet boundary without penetrating the islet (Figure 1A), (II) endo-insular invasion with tumor cells found inside the round islet, but still respecting the shape of the islet (Figure 1B), (III) distorted islet structure as cancer infiltration into the islet with distortion of the round islet morphology, yet still reminiscent of an islet (Figure 1C) and, (IV)
Summary
Diabetes mellitus or hyperglycemia occurs in up to 80% of all pancreatic ductal adenocarcinoma (PDAC) patients, which usually emerges 2–3 years before the diagnosis of cancer [1,2,3]. This time period offers a perspective for using new-onset diabetes as a strategy for early detection [4,5]. Destruction of the pancreatic tissue containing the islets of Langerhans due to infiltrating tumor cells is a further possible explanation for pancreatic cancer-induced diabetes. We aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells
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