Pancreatic lesions are abnormal growths in the pancreas, the gland behind the stomach that produces digestive juices and hormones that regulate blood sugar levels. Until recently, it was thought that these lesions were relatively rare. However, new evidence suggests that pancreatic lesions may occur more frequently than previously thought.
Researchers found pancreatic intraepithelial neoplasia (PanIN) lesions in healthy pancreata from deceased donors of diverse ages, according to a study in Cancer Discovery. PanIN lesions are precancerous lesions that share features with pancreatic cancer. Pancreatic cancer is often diagnosed at advanced stages, and identifying PanIN lesions earlier could lead to earlier detection and treatment.
“Understanding how pancreatic tissue evolves as it transitions from normal to precancerous to cancerous will be key to identifying strategies for early detection, prevention, and treatment of pancreatic cancer,” said Marina Pasca di Magliano, Ph.D., one of the co-corresponding authors of the study, a researcher at the Rogel Cancer Center, and a professor of surgery and cell and developmental biology at Michigan Medicine at the University of Michigan.
“Unfortunately, it has been difficult to understand the baseline characteristics of the pancreas due to a lack of normal pancreatic tissue available for research.”
“Since there is no reason to biopsy or resect a physiologically normal pancreas, researchers have had to rely on the tissue surrounding pancreatic tumors as the so-called normal,” explained Timothy Frankel, MD, co-corresponding author, a researcher at the Rogel Cancer Center, and an associate professor and surgical oncologist at Michigan Medicine at the University of Michigan.
“However, it is clear that the tissue adjacent to tumors is very abnormal looking and is not a reliable surrogate for true, healthy pancreatic tissue.”
Pancreata from healthy brain-dead donors were obtained and studied, revealing PanIN lesions in most individuals irrespective of age. The microenvironment of the adult human pancreas and PanIN lesions were characterized using multiplex immunohistochemistry, single-cell RNA sequencing, and spatial transcriptomics.
The transcriptomic signatures in fibroblasts and macrophages were distinct in healthy pancreata compared to pancreatic cancer and peritumoral tissue. PanIN epithelial cells in healthy pancreata were transcriptionally similar to cancer cells, indicating that neoplastic pathways are initiated early in tumorigenesis.
Researchers partnered with Gift of Life Michigan to obtain healthy pancreata from 30 recently deceased donors and found PanIN lesions in 18 of them. Histopathologic analysis revealed the PanIN microenvironment was distinct from normal pancreatic tissue and rich in fibroblasts, myeloid cells, and T cells.
The gene expression pattern of PanINs was similar to pancreatic tumors but had distinct microenvironments. PanINs had higher levels of acinar and endothelial cells and fewer macrophages and CD4+ T cells than tumors.
“By analyzing true normal pancreata, we found that PanINs were commonly found in individuals of diverse age and race and may have already acquired some features of malignant cells,” summarized Carpenter, who is a researcher at the Rogel Cancer Center and a gastroenterologist and assistant professor at Michigan Medicine at the University of Michigan.
“Given that pancreatic cancer is exceedingly rare, the widespread occurrence of PanINs in individuals of various ages and races challenges the paradigm that PanINs always evolve into cancer.”
“Prior efforts at early detection have focused on finding the PanIN lesions, with the assumption that individuals with PanINs would be the ones at risk of developing pancreatic cancer, but our findings suggest that additional factors are involved,” said Frankel.
“Understanding why some PanINs evolve to cancer and others will not be important to predict who is at risk of pancreatic cancer accurately and to develop techniques for cancer interception,” Pasca di Magliano said. “The composition of the microenvironments surrounding PanINs might be a key factor.”
The authors noted that “a limitation of the study was the inability to observe changes in the pancreas over time or to examine the impact of therapeutic interventions. The tissue we examined provided only a snapshot of the pancreas at the time of the donor’s death,” said Pasca di Magliano. An additional limitation was the small sample size.
In conclusion, while the exact prevalence of pancreatic lesions is still being studied, new evidence suggests that they may occur more frequently than previously thought. Early detection and treatment are essential for improving patient outcomes with pancreatic lesions. Continued research is needed to understand the causes of this condition better and develop more effective treatments.
- Carpenter E.L., Baybutt T.R., Baker A.F., et al. Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions. Cancer Discovery. DOI: 10.1158/2159-8290.CD-22-0155