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The similarity of Type 1 autoimmune pancreatitis to pancreatic ductal adenocarcinoma with significant IgG4-positive plasma cell infiltration

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

High serum immunoglobulin G4 (IgG4) levels and infiltration of IgG4-positive cells are characteristic of Type 1 autoimmune pancreatitis (AIP). We previously reported that increased regulatory T cells (Tregs) may regulate IgG4 production in AIP. Although an increased serum IgG4 concentration is observed in some patients with pancreatic ductal adenocarcinoma (PDA), clarification is still necessary. We have therefore studied the correlations between IgG4-positive cells and Tregs in patients with PDA.

Subjects and methods

A total of 21 PDA and nine AIP patients were enrolled in our study. The numbers and ratios of Tregs, IgG4-positive, and IgG-positive cells immunohistochemically stained with anti-Foxp3, IgG4, and IgG antibodies, respectively, were counted in three areas of resected pancreata in PDA, peritumoral pancreatitis (PT), and obstructive pancreatitis (OP).

Results

In PDA, PT, OP area, the number of IgG4-Positive cells (5.183 ± 1.061, 2.250 ± 0.431, 4.033 ± 1.018, respectively; p < 0.05) and the ratio of IgG4/IgG (0.391 ± 0.045, 0.259 ± 0.054, 0.210 ± 0.048, respectively; p < 0.05) were significantly lower than those in AIP (21.667 ± 2.436 and 0.306 ± 0.052, respectively). The numbers of IgG4-positive cells did not differ significantly among the three areas of resected pancreata examined. However, the IgG4/IgG (0.391 ± 0.045) and Foxp3/monocyte (0.051 ± 0.008) ratios in PDA area were significantly (p < 0.05) higher than those in OP area (IgG4/IgG: 0.210 ± 0.048; oxp3/monocyte: 0.0332 ± 0.005), but not in PT area. Of the 21 cases of PDA, the ratio of IgG4/IgG was >40 % in nine (43 %), six (29 %) and three (14 %) cases in PDA, PT and OP area, respectively. Foxp3 and IgG4 were positively correlated in OP area, but not in PDA and PT area.

Conclusions

Clinicians should be careful when basing a differential diagnosis of PDA and AIP on the numbers of IgG4-positive cells and the ratio of IgG4/IgG, especially when determined using a small biopsied sample.

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References

  1. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas—an autonomous pancreatic disease? Am J Dig Dis. 1961;6:688–98.

    Article  PubMed  CAS  Google Scholar 

  2. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22:387–95.

    Article  PubMed  CAS  Google Scholar 

  3. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561–8.

    Article  PubMed  CAS  Google Scholar 

  4. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–8.

    Article  PubMed  CAS  Google Scholar 

  5. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982–4.

    Article  PubMed  CAS  Google Scholar 

  6. Ito T, Nakano I, Koyanagi S, Miyahara T, Migita Y, Ogoshi K, et al. Autoimmune pancreatitis as a new clinical entity. Three cases of autoimmune pancreatitis with effective steroid therapy. Dig Dis Sci. 1997;42:1458–68.

    Article  PubMed  CAS  Google Scholar 

  7. Horiuchi A, Kawa S, Akamatsu T, Aoki Y, Mukawa K, Furuya N, et al. Characteristic pancreatic duct appearance in autoimmune chronic pancreatitis: a case report and review of the Japanese literature. Am J Gastroenterol. 1998;93:260–3.

    Article  PubMed  CAS  Google Scholar 

  8. Uchida K, Okazaki K, Konishi Y, Ohana M, Takakuwa H, Hajiro K, et al. Clinical analysis of autoimmune-related pancreatitis. Am J Gastroenterol. 2000;95:2788–94.

    Article  PubMed  CAS  Google Scholar 

  9. Okazaki K, Uchida K, Chiba T. Recent concept of autoimmune-related pancreatitis. J Gastroenterol. 2001;36:293–302.

    Article  PubMed  CAS  Google Scholar 

  10. Zamboni G, Luttges J, Capelli P, Frulloni L, Cavallini G, Pederzoli P, et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch. 2004;445:552–63.

    Article  PubMed  Google Scholar 

  11. Notohara K, Burgart LJ, Yadav D, Chari S, Smyrk TC. Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Am J Surg Pathol. 2003;27:1119–27.

    Article  PubMed  Google Scholar 

  12. Chari ST, Kloeppel G, Zhang L, Notohara K, Lerch MM, Shimosegawa T. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas. 2010;39:549–54.

    Article  PubMed  CAS  Google Scholar 

  13. Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352–8.

    Article  PubMed  Google Scholar 

  14. Okazaki K, Kawa S, Kamisawa T, Shimosegawa T, Tanaka M. Japanese consensus guidelines for management of autoimmune pancreatitis: I. Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol. 2010;45:249–65.

    Article  PubMed  Google Scholar 

  15. Kamisawa T, Chen PY, Tu Y, Nakajima H, Egawa N, Tsuruta K, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol. 2006;12:6225–8.

    PubMed  CAS  Google Scholar 

  16. Aoki S, Nakazawa T, Ohara H, Sano H, Nakao H, Joh T, et al. Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients’ sera. Histopathology. 2005;47:147–58.

    Article  PubMed  CAS  Google Scholar 

  17. Chandan VS, Iacobuzio-Donahue C, Abraham SC. Patchy distribution of pathologic abnormalities in autoimmune pancreatitis: implications for preoperative diagnosis. Am J Surg Pathol. 2008;32:1762–9.

    Article  PubMed  Google Scholar 

  18. Deheragoda MG, Church NI, Rodriguez-Justo M, Munson P, Sandanayake N, Seward EW, et al. The use of immunoglobulin G4 immunostaining in diagnosing pancreatic and extrapancreatic involvement in autoimmune pancreatitis. Clin Gastroenterol Hepatol. 2007;5:1229–34.

    Article  PubMed  Google Scholar 

  19. Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol. 2006;30:1537–45.

    Article  PubMed  Google Scholar 

  20. Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52:683–7.

    Article  PubMed  CAS  Google Scholar 

  21. Kojima M, Sipos B, Klapper W, Frahm O, Knuth HC, Yanagisawa A, et al. Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells. Am J Surg Pathol. 2007;31:521–8.

    Article  PubMed  Google Scholar 

  22. Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol. 2007;20:23–8.

    Article  PubMed  CAS  Google Scholar 

  23. Dhall D, Suriawinata AA, Tang LH, Shia J, Klimstra DS. Use of immunohistochemistry for IgG4 in the distinction of autoimmune pancreatitis from peritumoral pancreatitis. Hum Pathol. 2010;41:643–52.

    Article  PubMed  CAS  Google Scholar 

  24. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4 + CD25 high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.

    PubMed  CAS  Google Scholar 

  25. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001;193:1303–10.

    Article  PubMed  CAS  Google Scholar 

  26. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285–94.

    Article  PubMed  CAS  Google Scholar 

  27. Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001;193:1295–302.

    Article  PubMed  CAS  Google Scholar 

  28. Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, et al. CD4 + CD25 bright T cells in human intestinal lamina propria as regulatory cells. J Immunol. 2004;173:3119–30.

    PubMed  CAS  Google Scholar 

  29. Stephens LA, Mottet C, Mason D, Powrie F. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol. 2001;31:1247–54.

    Article  PubMed  CAS  Google Scholar 

  30. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E. Characterization of human CD25 + CD4 + T cells in thymus, cord and adult blood. Immunology. 2002;106:190–9.

    Article  PubMed  CAS  Google Scholar 

  31. Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg. 2008;206:849–54.

    Article  PubMed  Google Scholar 

  32. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res. 2007;67:8344–50.

    Article  PubMed  CAS  Google Scholar 

  33. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3 + regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006;12:5423–34.

    Article  PubMed  CAS  Google Scholar 

  34. Kusuda T, Uchida K, Miyoshi H, Koyabu M, Satoi S, Takaoka M, et al. Involvement of inducible costimulator- and interleukin 10-positive regulatory T cells in the development of IgG4-related autoimmune pancreatitis. Pancreas. 2011;40:1120–30.

    Article  PubMed  CAS  Google Scholar 

  35. Koyabu M, Uchida K, Miyoshi H, Sakaguchi Y, Fukui T, Ikeda H, et al. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases. J Gastroenterol. 2010;45:732–41.

    Article  PubMed  CAS  Google Scholar 

  36. Miyoshi H, Uchida K, Taniguchi T, Yazumi S, Matsushita M, Takaoka M, et al. Circulating naive and CD4 + CD25 high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2008;36:133–40.

    Article  PubMed  CAS  Google Scholar 

  37. Sarles H. Revised classification of pancreatitis—Marseille 1984. Dig Dis Sci. 1985;30:573–4.

    Article  PubMed  CAS  Google Scholar 

  38. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707.

    Article  PubMed  CAS  Google Scholar 

  39. Suda K, Mogaki M, Oyama T, Matsumoto Y. Histopathologic and immunohistochemical studies on alcoholic pancreatitis and chronic obstructive pancreatitis: special emphasis on ductal obstruction and genesis of pancreatitis. Am J Gastroenterol. 1990;85:271–6.

    PubMed  CAS  Google Scholar 

  40. Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor). Am J Surg Pathol. 2005;29:783–91.

    Article  PubMed  Google Scholar 

  41. Deshpande V, Sainani NI, Chung RT, Pratt DS, Mentha G, Rubbia-Brandt L, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009;22:1287–95.

    Article  PubMed  CAS  Google Scholar 

  42. Zen Y, Onodera M, Inoue D, Kitao A, Matsui O, Nohara T, et al. Retroperitoneal fibrosis: a clinicopathologic study with respect to immunoglobulin G4. Am J Surg Pathol. 2009;33:1833–9.

    Article  PubMed  Google Scholar 

  43. Geyer JT, Ferry JA, Harris NL, Stone JH, Zukerberg LR, Lauwers GY, et al. Chronic sclerosing sialadenitis (Kuttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010;34:202–10.

    Article  PubMed  Google Scholar 

  44. Uehara T, Hamano H, Kawa S, Sano K, Oki K, Kobayashi Y, et al. Chronic gastritis in the setting of autoimmune pancreatitis. Am J Surg Pathol. 2010;34:1241–9.

    Article  PubMed  Google Scholar 

  45. Sepehr A, Mino-Kenudson M, Ogawa F, Brugge WR, Deshpande V, Lauwers GY. IgG4 + to IgG + plasma cells ratio of ampulla can help differentiate autoimmune pancreatitis from other “mass forming” pancreatic lesions. Am J Surg Pathol. 2008;32:1770–9.

    Article  PubMed  Google Scholar 

  46. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64:237–43.

    Article  PubMed  Google Scholar 

  47. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30.

    Article  PubMed  CAS  Google Scholar 

  48. Yoshizawa K, Abe H, Kubo Y, Kitahara T, Aizawa R, Matsuoka M, et al. Expansion of CD4(+)CD25(+)FoxP3(+) regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma. Hepatol Res. 2010;40:179–87.

    Article  PubMed  CAS  Google Scholar 

  49. Sakaki M, Hiroishi K, Baba T, Ito T, Hirayama Y, Saito K, et al. Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis. Hepatol Res. 2008;38:354–61.

    Article  PubMed  CAS  Google Scholar 

  50. Kandulski A, Wex T, Kuester D, Peitz U, Gebert I, Roessner A, et al. Naturally occurring regulatory T cells (CD4+, CD25high, FOXP3+) in the antrum and cardia are associated with higher H. pylori colonization and increased gene expression of TGF-beta1. Helicobacter. 2008;13:295–303.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was partially supported by (1) Grant-in-Aid for Scientific Research (C) of the Ministry of Culture and Science of Japan (20590810, 24591020), (2) the Research Program on Intractable Diseases, from the Ministry of Labor and Welfare of Japan, and (3) grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, from CREST Japan Science and Technology Agency.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan

    Yuri Fukui, Kazushige Uchida, Kimi Sumimoto, Takeo Kusuda, Hideaki Miyoshi, Masanori Koyabu, Tsukasa Ikeura, Yutaku Sakaguchi, Masaaki Shimatani, Toshiro Fukui, Mitsunobu Matsushita, Makoto Takaoka, Akiyoshi Nishio & Kazuichi Okazaki

  2. Department of Pathology, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan

    Nobuaki Shikata, Noriko Sakaida & Yoshiko Uemura

  3. Department of Surgery, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan

    Sohei Satoi & A-hon Kwon

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  1. Yuri Fukui
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  2. Kazushige Uchida
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  3. Kimi Sumimoto
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Correspondence to Kazuichi Okazaki.

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Fukui, Y., Uchida, K., Sumimoto, K. et al. The similarity of Type 1 autoimmune pancreatitis to pancreatic ductal adenocarcinoma with significant IgG4-positive plasma cell infiltration. J Gastroenterol 48, 751–761 (2013). https://doi.org/10.1007/s00535-012-0677-x

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  • DOI: https://doi.org/10.1007/s00535-012-0677-x

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