Objective: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS).
Background: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm.
Methods: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression.
Results: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas.
Conclusions: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.
*Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
†Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
‡Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
§Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
¶Departments of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
||Departments of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
**ARC-Net applied research on cancer center, University and Hospital Trust of Verona, Verona, Italy.
Reprints: Christopher L. Wolfgang, MD, PhD, Blalock 240, 600 N. Wolfe Street, Baltimore, MD 21287. E-mail: email@example.com.
The correspondence should be addressed to C.L.W. and L.D.W.
Funding was received from NIH grants P50CA62924, R01CA176828, 3P30CA006973; Pancreatic Cancer Action Network Research Acceleration Network grant; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; Rolfe Pancreatic Cancer Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Sigma Beta Sorority; Tampa Bay Fisheries Inc; Susan Wojcicki and Dennis Troper; Fondazione Italiana Malattie Pancreas (FIMP- Ministero Salute, CUP_J33G13000210001); Associazione Italiana Ricerca sul Cancro (Grant no. 12182); Italian Cancer Genome Project (FIRB RBAP10AHJB); European Community 7 Framework Programme Cam-Pac (Grant no. 602783).
L.D.W. is a paid consultant for Personal Genome Diagnostics.
The authors report no conflicts of interest.
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A.P., J.Y., and N.R. contributed equally to this study.