Pancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases

doi:10.1053/j.gastro.2008.09.029

Gastroenterology

Volume 136, Issue 1, January 2009, Pages 177-186.e1

https://doi.org/10.1053/j.gastro.2008.09.029 Get rights and content

Background & Aims

Chronic pancreatitis (CP) and pancreatic adenocarcinoma (PCa) are characterized by intrapancreatic neural alterations and pain. Our aims were to: (a) Investigate whether neuropathic changes like pancreatic neuritis, increased neural density, and hypertrophy are phenomena only in CP or whether they are also evident in other pancreatic disorders as well, (b) study possible variations in neural cancer cell invasion among malignant pancreatic tumors, and (c) explore whether these neuropathic changes contribute to pain sensation.

Methods

Neuropathic changes were studied in PCa (n = 149), in CP (n = 141), in pancreatic tumors (PTm) including serous/mucinous cystadenomas, invasive/noninvasive intraductal papillary mucinous neoplasias, benign/malignant neuroendocrine tumors, ampullary cancers (n = 196), and in normal pancreas (n = 60). The results were correlated with GAP-43 expression, tissue inflammation, pancreatic neuritis, neural invasion, fibrosis, desmoplasia, pain, and patient survival.

Results

Increased neural density and hypertrophy were only detected in PCa and CP and were strongly associated with GAP-43 over expression and abdominal pain. The severity of pancreatic neuritis was strongest in PCa and was closely linked to changes in neural density and hypertrophy. The aggressiveness of neural cancer cell invasion was most prominent in PCa and was related to neuropathic changes, desmoplasia, and pain. Severe and enduring pain were strongly associated with poor prognosis in PCa patients.

Conclusions

Enhanced neural density and hypertrophy are only typical features of CP and PCa among all investigated pancreatic disorders. Such neuropathic changes, including damage to nerves by inflammatory and/or cancer cells, seem to enhance and generate pancreatic neuropathic pain.

Section snippets

Patients and Tissues

Pancreatic tissue samples were collected from patients following tumor resection: Pancreatic adenocarcinoma (PCa; n = 149), chronic pancreatitis (CP; n = 141) and other pancreatic tumors (PTm; n = 195) including mucinous (n = 12) and serous cystadenoma (n = 39), invasive intraductal papillary mucinous neoplasia (IPMNi; n = 40) and noninvasive intraductal papillary mucinous neoplasia (IPMN; n = 33), benign neuroendocrine tumor (NTb; n = 17) and malignant neuroendocrine tumor (NTm; n = 35), and

Increased Neural Density and Hypertrophy Are Typical Features of Pancreatic Cancer and Chronic Pancreatitis

Patients with PCa (12,500 ± 4500 μm²) and CP (7000 ± 930 μm²) had a 14- and 8-fold increase in neural area, respectively, when compared to normal pancreas (900 ± 90 μm²; Figure 1A). In contrast, no difference between PTms (1600 ± 230 μm²) and NP was found (Figure 1A). Neural density was highest in PCa (1.2 ± 0.09/mm²) and in CP (1.0 ± 0.09/mm²) when compared to NP (0.6 ± 0.05/mm²) and PTm (0.4 ± 0.05/mm²; Figure 1B). The number of nerves in PTm was noticeably smaller than in NP (P < .01, Figure

Discussion

Our recent study demonstrates that both CP and PCa seem to have “neurotrophic” attributes that induce changes in nerve morphology and plasticity and constitute a specific pancreatic neuropathy.

Concerning pancreatic neuropathy and pain, initially Bockman et al concluded that increase in mean nerve diameter may argue against pain being solely caused by constriction due to fibrosis in CP.¹² This hypothesis was supported by others demonstrating that increase of GAP-43 immunoreactivity in

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: The authors disclose no conflicts.

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Clinical—Liver, Pancreas, and Biliary TractPancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Tissues

Increased Neural Density and Hypertrophy Are Typical Features of Pancreatic Cancer and Chronic Pancreatitis

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Lancet Neurol

Best Pract Res Clin Gastroenterol

Gastroenterology

Am J Surg

Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer

Pancreas

Neural invasion in pancreatic carcinoma

Hepatobiliary Pancreat Dis Int

Perineural invasion in pancreatic cancer

Pancreas

Pancreatic carcinoma

N Engl J Med

Innervation of the pancreas from the perspective of perineural invasion of pancreatic cancer

Pancreas

Perineural invasion by ductal adenocarcinoma of the pancreas

J Surg Oncol

Abdominal pain in patients with resectable pancreatic cancer with reference to clinicopathologic findings

Pancreas

Pancreas head carcinoma: frequency of invasion to soft tissue adherent to the superior mesenteric artery

Am J Surg Pathol

Cancer statistics, 2006

CA Cancer J Clin

Most pancreatic cancer resections are R1 resections

Ann Surg Oncol

Neuropathology of chronic pancreatitis in humans

Can J Surg

Neural alterations in surgical stage chronic pancreatitis are independent of the underlying aetiology

Gut

The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis

Gut

Clinical—Liver, Pancreas, and Biliary Tract
Pancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases