Volume 136, Issue 1, Pages 177-186.e1 (January 2009) Pancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases  Güralp O. Ceyhan, Frank Bergmann, Mustafa Kadihasanoglu, Burak Altintas, Ihsan E. Demir, Ulf Hinz, Michael W. Müller, Thomas Giese, Markus W. Büchler, Nathalia A. Giese, Helmut Friess  Gastroenterology  Volume 136, Issue 1, Pages 177-186.e1 (January 2009) DOI: 10.1053/j.gastro.2008.09.029 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 Pancreatic tissue sections from patients with NP, PCa, CP, and various pancreatic disorders were analyzed for changes in nerve area (A) and number (B). Entirely scanned tissue sections of NP (C) and PCa (D) demonstrate the enormous increase of neural density and area in PCa. Intrapancreatic nerves are immuno-labeled with the pan-neural-marker PGP9.5 (black arrows). Semiquantitative neural-immunoreactivity (E) and QRT-PCR analysis (F) of GAP-43 were analyzed within the 3 groups. The results of GAP-43 neural-immunoreactivity are presented as percent change (mean ± SEM) and GAP-43 mRNA data as mean ± SEM. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 Immunohistochemical analysis of GAP-43 in NP and NTb (A) compared to NTm (B): CP, serous (SC) and mucinous (MC) cystadenoma, IPMN, and IPMNi, NTb and NTm, PCa, and AmpC. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions

Figure 3 (A) Representative picture of pancreatic neuritis in PCa. (B) Severity of pancreatic neuritis was compared between the PCa, CP, and PTm groups. The severity of pancreatic neuritis was correlated with neural hypertrophy (C) and neural density (D) in PCa and in CP, respectively (E and F). Data are presented as mean ± SEM. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions

Figure 4 (A) Representative pictures of the severity of neural invasion of cancer cells in pancreatic malignancies: PCa, NTm, IPMNi, and AmpC. Intrapancreatic nerves were immunolabeled with the pan-neural marker PGP9.5. (B) The degree of neural cancer cell invasion was compared between the PCa, IPMNi, NTm, and AmpC groups. The severity of neural invasion was associated with neural hypertrophy (C) and neural density (D) in PCa. (E) The severity of neural invasion of cancer cells was related to severity of pain in pancreatic adenocarcinoma (PCa). Data are presented as mean ± SEM. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions

Figure 5 (A) The severity of desmoplastic reaction was significantly pronounced in PCa compared to the other pancreatic tumors (*P < .001). The severity of fibrosis was associated with neural hypertrophy (B) and neural density (C) in CP. (D) The severity of pancreatic neuritis was related to the severity of fibrosis in CP. (E) The severity of desmoplastic reactions in PCa were related to the neural invasion score. (F) Representative picture of enhanced neural invasion (arrows) in areas of dense desmoplastic reactions. Intrapancreatic nerves were immunolabeled with the pan-neural marker PGP9.5. Data are presented as mean ± SEM. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions

Figure 6 The severity of pain was associated with neural hypertrophy and neural density in PCa (A and C) and in CP (B and D). Data are presented as mean ± SEM. (E) Kaplan–Meier analysis of postoperative survival was performed according to the severity of pain in patients with PCa. Gastroenterology 2009 136, 177-186.e1DOI: (10.1053/j.gastro.2008.09.029) Copyright © 2009 AGA Institute Terms and Conditions