Abstract
Autoimmune pancreatitis (AIP) is a unique form of pancreatitis in which the pathogenesis is suspected to involve autoimmune mechanisms. AIP sometimes mimics pancreatic cancer in its presentation, but as AIP responds dramatically to steroid therapy, accurate diagnosis is necessary. AIP is currently diagnosed on the basis of a combination of characteristic clinical, serological, morphological and histopathological features. However, its diagnosis remains a clinical challenge and there are no internationally agreed diagnostic criteria. Another type of AIP called 'idiopathic duct-centric chronic pancreatitis' or 'AIP with granulocytic epithelial lesion' has been reported in Western countries. IgG4-related sclerosing disease is a systemic disease in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs. Organs with tissue fibrosis and obliterative phlebitis, such as the pancreas, salivary gland and retroperitoneum, show clinical manifestations; AIP seems to represent one manifestation of IgG4-related sclerosing disease. As a mass is formed in most cases of IgG4-related sclerosing disease, a malignant tumor is frequently suspected on initial presentation. Clinicians should consider IgG4-related sclerosing disease in the differential diagnosis to avoid unnecessary surgery.
Key Points
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Autoimmune pancreatitis (AIP) should be diagnosed on the basis of a combination of characteristic clinical, serological, morphological and histopathological features
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Given than AIP responds dramatically to steroid therapy, accurate differentiation from pancreatic cancer is important
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IgG4-related sclerosing disease is a systemic disease, in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs
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AIP may be one manifestation of IgG4-related sclerosing disease
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References
Kawaguchi, K. et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum. Pathol. 22, 387–395 (1991).
Okazaki, K. et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J. Gastroenterol. 41, 626–631 (2006).
Okazaki, K. et al. Japanese clinical guidelines for autoimmune pancreatitis. Pancreas 38, 849–866 (2009).
Sarles, H., Sarles, J. C., Muratoren, R. & Guien, C. Chronic inflammatory sclerosing of the pancreas—an autonomous pancreatic disease? Am. J. Dig. Dis. 6, 688–698 (1961).
Yoshida, K. et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig. Dis. Sci. 40, 1561–1568 (1995).
Finkelberg, D. L., Sahani, D., Deshpande, V. & Brugge, W. R. Autoimmune pancreatitis. N. Engl. J. Med. 355, 2670–2676 (2006).
Kamisawa, T. et al. A new clinicopathological entity of IgG4-related autoimmune disease. J. Gastroenterol. 38, 982–984 (2003).
Kamisawa, T. et al. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 6, 132–137 (2006).
Kamisawa, T. & Okamoto, A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J. Gastroenterol. 41, 613–625 (2006).
Kamisawa, T. & Okamoto, A. IgG4-related sclerosing disease. World J. Gastroenterol. 14, 3948–3955 (2008).
Nishimori, I. et al. Prevalence of autoimmune pancreatitis in Japan from a nationwide survey in 2002. J. Gastroenterol. 42 (Suppl. 18), 6–8 (2007).
Shimosegawa, T. & Kanno, A. Autoimmune pancreatitis in Japan: overview and perspective. J. Gastroenterol. 44, 503–517 (2009).
Gardner, T. B. & Chari, S. T. Autoimmune pancreatitis. Gastroenterol. Clin. N. Am. 37, 439–460 (2008).
Weber, S. M. et al. Lymphoplasmacytic sclerosing pancreatitis: inflammatory mimic of pancreatic carcinoma. J. Gastrointest. Surg. 7, 129–137 (2003).
Abraham, S. C. et al. Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all 'chronic pancreatitis'? Am. J. Surg. Pathol. 27, 110–120 (2003).
Farnell, M. B. et al. A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 138, 618–628 (2005).
Kawa, S. et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 122, 1264–1269 (2002).
Park, H. et al. Substitution of aspartic acid at position 57 of the DQβ1 affects relapse of autoimmune pancreatitis. Gastroenterology 134, 440–446 (2008).
Chang, M. C. et al. T-cell regulatory gene CTLA-4 polymprphism/haplotype association with autoimmune pancreatitis. Clin. Chem. 53, 1700–1705 (2007).
Umemura, T. et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am. J. Gastroenterol. 103, 588–594 (2008).
Okazaki, K. et al. Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2-type cellular immune response. Gastroenterology 118, 573–581 (2001).
Asada, M. et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas 33, 20–26 (2006).
Endo, T. et al. Amylase alpha-2A autoantibodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes. Diabetes 58, 732–737 (2009).
Frulloni, L. et al. Identification of a novel antibody associated with autoimmune pancreatitis. N. Engl. J. Med. 361, 2135–2142 (2009).
Zen, Y. et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 45, 1538–1546 (2007).
Okazaki, K., Uchida, K. & Fukui, T. Recent advanced in autoimmune pancreatitis: concept, diagnosis, and pathogenesis. J. Gastroenterol. 43, 409–418 (2008).
Miyoshi, H. et al. Circulating naive and CD4+CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas 36, 133–140 (2008).
Kamisawa, T. et al. Allergic manifestations in autoimmune pancreatitis. Eur. J. Gastroenterol. Hepatol. 21, 1136–1139 (2009).
Mukai, T. et al. Autoimmune pancreatitis and complement activation system. Pancreas 32, 16–21 (2006).
Kawa, S. et al. A novel immunoglobulin-immunoglobulin interaction in autoimmunity. PLoS ONE 3, e1637 (2008).
Kamisawa, T. et al. Chronic pancreatitis in the elderly in Japan. Pancreatology 4, 223–227 (2004).
Chari, S. T. et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin. Gastroenterol. Hepatol. 10, 1097–1103 (2009).
Sandanayake, N. B. et al. Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis. Clin. Gastroenterol. Hepatol. 7, 1089–1096 (2009).
Ryu, J. K. et al. Review of 67 patients with autoimmune pancreatitis in Korea. A multicenter nationwide study. Pancreas 37, 377–385 (2008).
Kamisawa, T. et al. Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy. Pancreas 27, 235–238 (2003).
Kamisawa, T. et al. Digestion and absorption of patients with autoimmune pancreatitis. Hepatogastroenterology 53, 138–140 (2006).
Kamisawa, T., Egawa, N., Nakajima, H., Tsuruta, K. & Okamoto, A. Extrapancreatic lesions in autoimmune pancreatitis. J. Clin. Gastroenterol. 39, 904–907 (2005).
Hamano, H. et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N. Engl. J. Med. 344, 732–738 (2001).
Tabata, T. et al. Serum IgG4 concentrations and IgG4-related sclerosing disease. Clin. Chim. Acta 408, 25–28 (2009).
Raina, A. et al. Serum immunoglobulin G fraction 4 levels in pancreatic cancer. Elevations not associated with autoimmune pancreatitis. Arch. Pathol. Lab. Med. 132, 48–53 (2008).
Ghazale, A. et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am. J. Gastroenterol. 102, 1646–1653 (2007).
Kamisawa, T. et al. Clinical difficulties in the differentiation of autoimmune pancreatitis and pancreatic carcinoma. Am. J. Gastroenterol. 98, 2694–2699 (2003).
Sahani, D. V. et al. Autoimmune pancreatitis: imaging features. Radiology 233, 345–352 (2004).
Bodily, K. D. et al. Autoimmune pancreatitis: pancreatic and extrapancreatic imaging findings. AJR Am. J. Roentgenol. 192, 431–437 (2009).
Kamisawa, T. et al. MRCP and MRI findings in 9 patients with autoimmune pancreatitis. World J. Gastroenterol. 12, 2919–2922 (2006).
Kamisawa, T. et al. Differentiation of autoimmune pancreatitis from pancreatic cancer by diffusion-weighted, MRI. Am. J. Gastroenterol. doi: 10.1038/ajg.2010.87.
Kamisawa, T. et al. Involvement of pancreatic and bile ducts in autoimmune pancreatitis. World J. Gastroenterol. 12, 612–614 (2006).
Hoki, N. et al. Diagnosis of autoimmune pancreatitis using endoscopic ultrasonography. J. Gastroenterol. 44, 154–159 (2009).
Kamisawa, T. et al. Can MRCP replace ERCP for the diagnosis of autoimmune pancreatitis? Abdom. Imaging 34, 381–384 (2009).
Kamisawa, T. Angiographic findings in patients with autoimmune pancreatitis. Radiology 236, 371 (2005).
Kamisawa, T. et al. FDG-PET/CT findings of autoimmune pancreatitis. Hepatogastroenterology (in press).
Lee, T. Y. et al. Utility of 18F-FDG PET/CT for differentiation of autoimmune pancreatitis with atypical pancreatic imaging findings from pancreatic cancer. AJR Am. J. Roentogenol 193, 343–348 (2009).
Kamisawa, T. et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 52, 683–687 (2003).
Song, H. M. et al. Regression of pancreatic fibrosis after steroid therapy in patients with autoimmune chronic pancreatitis. Pancreas 30, 83–86 (2005).
Detlefsen, S., Drewes, A. M., Vyberg, M. & Kloppel, G. Diagnosis of autoimmune pancreatitis by core needle biopsy: application of six microscopic criteria. Virchows Arch. 454, 531–539 (2009).
Mizuno, N. et al. Histological diagnosis of autoimmune pancreatitis using EUA-guided trucut biopsy: a comparison study with EUS-FNA. J. Gastroenterol. 44, 742–750 (2009).
Kim, K. P. et al. Diagnostic criteria for autoimmune chronic pancreatitis revised. World J. Gastroenterol. 12, 2487–2496 (2006).
Chari, S. T. et al. Diagnosis of autoimmune pancreatitis: The Mayo Clinic experience. Clin. Gastroenterol. Hepatol. 4, 1010–1016 (2006).
Otsuki, M. et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan–Korea symposium on autoimmune pancreatitis. J. Gastroenterol. 43, 403–408 (2008).
Kamisawa, T. et al. Strategy for differentiating autoimmune pancreatitis from pancreatic cancer. Pancreas 37, e62–e67 (2008).
Sugumar, A. & Chari, S. Distinguishing pancreatic cancer from autoimmune pancreatitis: a comparison of two strategies. Clin. Gastroenterol. Hepatol. 7, S59–S62 (2009).
Kamisawa, T. et al. Usefulness of biopsing the major duodenal papilla to diagnose autoimmune pancreatitis: a prospective study using IgG4-immunostaining. World J. Gastroenterol. 12, 2031–2033 (2006).
Kamisawa, T., Tu, Y., Egawa, N., Tsuruta, K. & Okamoto, A. A new diagnostic endoscopic tool for autoimmune pancreatitis. Gastrointest. Endosc. 68, 358–361 (2008).
Noon, S. H. et al. Is a 2-week steroid trial after initial negative investigation for malignancy useful in differentiating autoimmune pancreatitis from pancreatic cancer? A prospective outcome study. Gut 57, 1704–1712 (2008).
Kamisawa, T. et al. Standard steroid treatment for autoimmune pancreatitis. Gut 58, 1504–1507 (2009).
Kamisawa, T. et al. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol. 45, 471–477 (2010).
Kamisawa, T., Anjiki, H., Takuma, K., Egawa, N. & Kubota, N. The natural course of autoimmune pancreatitis. Hepatogastroenterology 56, 866–870 (2009).
Ghazale, A. et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to steroids. Gastroenterology 134, 706–715 (2008).
Kamisawa, T., Okamoto, A., Wakabayashi, T., Watanabe, H. & Sawabu, N. Appropriate steroid therapy for autoimmune pancreatitis based on long-term outcome. Scand. J. Gastroenterol. 43, 609–613 (2008).
Kamisawa, T. & Okamoto, A. Prognosis of autoimmune pancreatitis. J. Gastroenterol. 42 (Suppl. 18), 59–62 (2007).
Kawa, S. et al. Long-term follow-up of autoimmune pancreatitis: characteristics of chronic disease and recurrence. Clin. Gastroenterol. Hepatol. 7, S18–S22 (2009).
Kamisawa, T. et al. Frequent and significant K-ras mutation in the pancreas, the bile duct, and the gallbladder in autoimmune pancreatitis. Pancreas 38, 890–895 (2009).
Kamisawa, T. et al. K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis. J. Gastroenterol. doi: 10.1007/s00535-010-0211-y.
Notohara, K., Burgart, L. J., Yadav, D., Chari, S. & Smyrk, T. C. Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration. Clinicopathologic features of 35 cases. Am. J. Surg. Pathol. 27, 1119–1127 (2003).
Zamboni, G. et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch. 445, 552–563 (2004).
Park, D. H., Kim, M. H. & Chari, S. T. Recent advances in autoimmune pancreatitis. Gut 58, 1680–1689 (2009).
Sugumar, A., Kloppel, G. & Chari, S. T. Autoimmune pancreatitis: pathologic subtypes and their implications for its diagnosis. Am. J. Gastroenterol. 104, 2308–2310 (2009).
Frulloni, L. et al. Autoimmune pancreatitis: differences between the focal and diffuse forms in 87 patients. Am. J. Gastroenterol. 104, 2288–2294 (2009).
Kamisawa, T., Wakabayashi, T. & Sawabu, N. Autoimmune pancreatitis in young patients. J. Clin. Gastroenterol. 40, 847–850 (2006).
Sah, R. P. et al. Difference in clinical profiles and relapse rate of type 1 vs type 2 autoimmune pancreatitis. Gastroenterology doi: 10.1053/j.gastro.2010.03.054.
Kamisawa, T., Notohara, K. & Shimosegawa, T. Two clinicopathological subtypes of autoimmune pancreatitis: LPSP and IDCP. Gastroenterology (in press).
Kamisawa, T., Imai, M., Egawa, N., Tsuruta, K. & Okamoto, A. Serum IgG4 levels and extrapancreatic lesions in autoimmune pancreatitis. Eur. J. Gastroenterol. Hepatol. 20, 1167–1170 (2008).
Kamisawa, T., Okamoto, A. & Funata, N. Clinicopathological features of autoimmune pancreatitis in relation to elevation of serum IgG4. Pancreas 31, 28–31 (2005).
Okazaki, K. et al. How to diagnose autoimmune pancreatitis by the revised Japanese clinical criteria. J. Gastroenterol. 42 (Suppl. 18), 32–38 (2007).
Raina, A. et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am. J. Gastroenterol. 104, 2295–2306 (2009).
Comings, D. E., Skubi, K. B., Eyes, J. V. & Motulsky, A. G. Familial multifocal fibrosclerosis. Ann. Intern. Med. 66, 884–892 (1967).
Dehner, L. P. & Coffin, C. M. Idiopathic fibrosclerotic disorders and other inflammatory pseudotumors. Semin. Diagn. Pathol. 15, 161–173 (1998).
Masaki, Y. et al. Proposal for a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann. Rheum. Dis. 68, 1310–1315 (2009).
Yamamoto, M. et al. A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease. Mod. Rheumatol. 16, 335–340 (2006).
Kamisawa, T. et al. Sclerosing cholangitis associated with autoimmune pancreatitis differs from primary sclerosing cholangitis. World J. Gastroenterol. 15, 2357–2360 (2009).
Bjornsson, E., Chari, S. T., Smyrk, T. C. & Lindor, K. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 45, 1538–1546 (2007).
Kamisawa, T. et al. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J. Gastroenterol. 12, 3736–3739 (2006).
Wang, W. L., Farris, A. B., Lauwers, G. Y. & Deshpande, V. Autoimmune pancreatitis-related cholecystitis: a morphologically and immunologically distinctive form of lymphoplasmacytic sclerosing cholecystitis. Histopathology 54, 829–836 (2009).
Kamisawa, T., Nakajima, H. & Hishima, T. Close relationship between chronic sclerosing sialadenitis and IgG4. Intern. Med. J. 36, 527–529 (2006).
Takahira, M. et al. IgG4-related chronic sclerosing dacryoadenitis. Arch. Ophthalmol. 125, 1575–1578 (2007).
Takuma, K., Kamisawa, T., Anjiki, H., Egawa, N. & Igarashi, Y. Metachronous extrapancreatic lesions in autoimmune pancreatitis. Intern. Med. 49, 529–533 (2010).
Kamisawa, T. et al. The relationship of salivary gland function to elevated serum IgG4 in autoimmune pancreatitis. Intern. Med. 46, 435–439 (2007).
Kamisawa, T. et al. Lacrimal gland function in autoimmune pancreatitis. Intern. Med. 48, 1–5 (2009).
Kamisawa, T., Chen, P. Y., Tu, Y., Nakajima, H. & Egawa, N. Autoimmune pancreatitis metachronously associated with retroperitoneal fibrosis with IgG4-positive plasma cell infiltration. World J. Gastroenterol. 12, 2955–2957 (2006).
Saeki, T. et al. Renal lesions in IgG4-related systemic disease. Intern. Med. 46, 1365–1371 (2007).
Takahashi, N. et al. Renal involvement in patients with autoimmune pancreatitis. CT and MR imaging findings. Radiology 242, 791–801 (2007).
Kamisawa, T. & Tabata, T. Response to “Renal lesions in autoimmune pancreatitis aid the differentiation from pancreatic adenocarcinoma”. Pancreas 38, 833–834 (2009).
Kobayashi, H., Shimokawaji, T., Kanoh, S., Motoyoshi, K. & Aida, S. IgG4-positive pulmonary disease. J. Thorac. Imaging 22, 360–362 (2007).
Tsushima, K. et al. Pulmonary involvement of autoimmune pancreatitis. Eur. J. Clin. Invest. 39, 714–722 (2009).
Uchida, K. et al. Inflammatory pseudotumors of the pancreas and liver with infiltration of IgG4-positive plasma cells. Intern. Med. 46, 1409–1412 (2007).
Zen, Y. et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum. Pathol. 36, 710–717 (2005).
Zen, Y. et al. Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level. Histologic similarity to sclerosing pancreatitis. Am. J. Surg. Pathol. 29, 275–278 (2005).
Wong, S. et al. Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum. Pathol. 38, 1720–1723 (2007).
Hamano, H. et al. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J. Gastroenterol. 41, 1197–1205 (2006).
Cheuk, W. et al. Lymphadenopathy of IgG4-related sclerosing disease. Am. J. Surg. Pathol. 32, 671–681 (2008).
Uehara, T. et al. Autoimmune pancreatitis-associated prostatitis: distinct clinicopathological entity. Pathol. Int. 58, 118–125 (2008).
Kasashima, S. et al. A new clinicopathological entity of IgG4-related inflammatory abdominal aortic aneurysm. J. Vasc. Surg. 49, 1264–1271 (2009).
Kamisawa, T. et al. Gastrointestinal findings in patients with autoimmune pancreatitis. Endoscopy 37, 1127–1130 (2005).
Ueno, K. et al. IgG4-related autoimmune pancreatitis involving the colonic mucosa. Eur. J. Gastroenterol. Hepatol. 20, 1118–1121 (2008).
Kaji, R. et al. Autoimmune pancreatitis presenting with IgG4-positive multiple gastric polyps. Gastrointest. Endosc. 71, 420–422 (2010).
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This work was partially supported by a grant-in-aid for refractory pancreatic disease from the Ministry of Health, Labor and Welfare of Japan.
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Kamisawa, T., Takuma, K., Egawa, N. et al. Autoimmune pancreatitis and IgG4-related sclerosing disease. Nat Rev Gastroenterol Hepatol 7, 401–409 (2010). https://doi.org/10.1038/nrgastro.2010.81
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DOI: https://doi.org/10.1038/nrgastro.2010.81
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