Hu R, Zhang HC, Zhang XF. Perineural invasion in pancreatic ductal adenocarcinoma: Molecular mechanisms and clinical significance. World J Gastrointest Oncol 2026; 18(11): 124427 [DOI: 10.4251/wjgo.124427]
Corresponding Author of This Article
Xiao-Feng Zhang, MD, Chief Physician, Professor, Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University; Hangzhou Institute of Digestive Diseases; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, No. 261, Huansha Road, Hangzhou 310006, Zhejiang Province, China. zhangxiaofeng@hospital.westlake.edu.cn
Research Domain of This Article
Oncology
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastrointest Oncol. Nov 15, 2026; 18(11): 124427 Published online Nov 15, 2026. doi: 10.4251/wjgo.124427
Perineural invasion in pancreatic ductal adenocarcinoma: Molecular mechanisms and clinical significance
Rong Hu, Hong-Chen Zhang, Xiao-Feng Zhang
Rong Hu, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
Rong Hu, Hong-Chen Zhang, Xiao-Feng Zhang, Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University; Hangzhou Institute of Digestive Diseases; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Hangzhou 310006, Zhejiang Province, China
Co-first authors: Rong Hu and Hong-Chen Zhang.
Author contributions: Hu R and Zhang HC contributed equally to this article, they are the co-first authors of this manuscript; Hu R drafted most of the manuscript and prepared the initial tables; Zhang HC drafted the original manuscript, substantially rewrote and revised the manuscript after peer review, redesigned and revised the tables, prepared the figures, and drafted the responses to reviewers; Zhang XF designed the manuscript outline and coordinated its preparation; and all authors thoroughly reviewed and endorsed the final manuscript.
AI contribution statement: Some graphic elements in the Figure 1 come from the BioRender standard materials/icons library and were used in accordance with BioRender’s license.
Supported by the Construction Fund of Key Medical Disciplines of Hangzhou, No. 2025HZGF05; Zhejiang Provincial Key Research and Development Program, No. 2024C03048; and Zhejiang Provincial Key Discipline of Integrated Traditional Chinese and Western Medicine (Digestive Diseases), No. 2024-XK-61.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Xiao-Feng Zhang, MD, Chief Physician, Professor, Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University; Hangzhou Institute of Digestive Diseases; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, No. 261, Huansha Road, Hangzhou 310006, Zhejiang Province, China. zhangxiaofeng@hospital.westlake.edu.cn
Received: June 15, 2026 Revised: August 12, 2026 Accepted: September 21, 2026 Published online: November 15, 2026 Processing time: 134 Days and 11 Hours
Abstract
Pancreatic ductal adenocarcinoma is an aggressive malignancy in which perineural invasion (PNI) is frequent and associated with adverse clinical outcomes. This article reframes PNI as an active, spatially organized invasive process within a neural-immune-stromal-metabolic niche rather than an isolated histopathological finding. It integrates interactions among tumor cells, nerves, Schwann cells, and immune and stromal compartments through neurotrophic tumor-nerve convergence, extracellular-matrix remodeling, metabolic and RNA regulation, and neural signaling across distinct evidence levels. PNI-associated pain reflects overlapping mechanical injury or compression and chemical and neuroimmune sensitization, although PNI does not explain all pain in pancreatic ductal adenocarcinoma. Histopathology remains the diagnostic reference, whereas quantitative pathology, radiomics, artificial intelligence-assisted pathology, and experimental imaging occupy different stages of maturity. No PNI-specific disease-modifying therapy has been clinically validated, and symptom control must remain distinct from interventions intended to modify neural invasion or disease outcomes. Spatial transcriptomics and multiplex imaging can refine biological characterization while preserving spatial context, but their application to PNI remains research-stage. Prospective validation, standardized annotation, independent cohorts, and PNI-specific endpoints are required before emerging diagnostic, prognostic, or therapeutic concepts can support routine care.
Core Tip: This article organizes perineural invasion in pancreatic ductal adenocarcinoma around a spatially organized neural-invasion niche, integrating neural-immune-stromal-metabolic crosstalk while preserving differences in evidence strength. Its key contribution is to connect this niche framework with a dual pain model that distinguishes mechanical injury and compression from chemical and neuroimmune sensitization. Clinical implications remain evidence-bounded: Spatial omics is research-stage, and diagnostic or therapeutic translation requires prospective validation with perineural invasion-specific endpoints.
