Yonsei Med J.  2012 Jan;53(1):15-34. 10.3349/ymj.2012.53.1.15.

IgG4-Related Sclerosing Disease, an Emerging Entity: A Review of a Multi-System Disease

• Divatia M
• Kim SA
• Ro JY

• KMID: 1779683
• DOI: http://doi.org/10.3349/ymj.2012.53.1.15

Abstract

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently defined emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. IgG4-RSD usually affects middle aged and elderly patients, with a male predominance. It is associated with an elevated serum titer of IgG4, which acts as a marker for this recently characterized entity. The prototype is IgG4-related sclerosing pancreatitis or autoimmune pancreatitis (AIP). Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, however practically any organ can be involved, including upper aerodigestive tract, lung, aorta, mediastinum, retroperitoneum, soft tissue, skin, central nervous system, breast, kidney, and prostate. Fever or constitutional symptoms usually do not comprise part of the clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). IgG4-RSD may potentially be rarely associated with the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies.

Keyword

IgG4-related sclerosing disease; IgG4; autoimmune pancreatitis; sclerosing cholangitis; inflammatory fibrosclerosing lesion; inflammatory pseudotumor; lymphadenopathy; salivary gland; lacrimal gland

MeSH Terms

Autoimmune Diseases/*immunology
Cholangitis, Sclerosing/*immunology
Humans
Immunoglobulin G/*immunology
Lacrimal Apparatus/immunology
Lymphatic Diseases/*immunology
Pancreatitis, Chronic/*immunology
Salivary Glands/immunology
Sclerosis/immunology

Figure

• 

  Fig. 1 The gross photograph of pancreas shows an ill-defined firm lesion in the head of the pancreas (arrow) with yellow-tan and fibrotic cut surface. The lesion extends into the peripancreatic fat tissue.

• 

  Fig. 2 Microscopic features of IgG4-related sclerosing pancreatitis. (A) Pancreatic lobules are replaced by severe inflammatory cell infiltration and fibrosis. Sclerosis of interlobular septa enhances lobular architecture of pancreas (H&E stain, original magnification ×40). (B) The lobular interstitium is infiltrated by plasma cells, lymphocytes, and a variable number of eosinophils. Residual atrophic pancreatic acini are identified (right upper corner, arrow; H&E stain, original magnification ×400). (C) Obliterative phlebitis is characterized by perivenular and intravenular inflammatory cell infiltrate with fibrous obliteration of the lumen (H&E stain, original magnification ×200). (D) IgG4 immunostain shows markedly increased IgG4-positive plasma cells (>50 plasma cells/HPF; immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4; HPF, high-power fields.

• 

  Fig. 3 Microscopic features of IgG4-related sclerosing cholangitis. (A) Intrahepatic bile ducts are infiltrated by lymphoplasmacytes with variable numbers of eosinophils, intermixed with collagen fibers (H&E stain, original magnification ×400). (B) Lymphoplasmacytes are infiltrating in the perivenular soft tissue of large veins, resulting in vascular wall destruction and luminal obliteration (H&E stain, original magnification ×200). (C) The bile duct lumen undergoes stenosis due to the periductal fibrosis and inflammation (H&E stain, original magnification ×40). (D) Numerous plasma cells are positive for IgG4 (immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4.

• 

  Fig. 4 Microscopic features of IgG4-associated inflammatory pseudotumor of ureter. (A) Fibroinflammatory lesion involves the entire ureteral wall and extends into periureteral adipose tissue (H&E stain, original magnification ×12.5). (B) Abundant plasma cells are intermixed with scattered histiocytes, fibroblasts and collagen fibers (H&E stain, original magnification ×400). (C) Obliterative phlebitis is identified in the periureteral adipose tissue (H&E stain, original magnification ×100). (D) A significant subset of plasma cells is positive for IgG4 (immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4.

• 

  Fig. 5 Microscopic features of IgG4-related lymphadenopathy, type I. (A) Multicentric Castleman disease-like pattern with interfolicular expansion (H&E stain, ×40). (B) Perivascular sclerosis and hyalinized venules in lymphoid follicles are identified (H&E stain, ×100). (C) The interfollicular area is infiltrated by plasma cells intermixed with collagen fibers (H&E stain, ×400). (D) Many plasma cells are positive for IgG4 (immunohistochemical stain, ×200). IgG4, immunoglobulin G4.

Reference

1. Nirula A, Glaser SM, Kalled SL, Taylor FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol. 2011. 23:119–124.

2. Meulenbroek AJ, Zeijlemaker WP. Human IgG Subclasses: useful diagnostic markers for immunocompetence [online]. 1996. Sanquin: Laboratory for Experimental and Clinical Immunology University of Amsterdam, the Netherlands;(http://www.xs4all.nl/_ednieuw/IgGsubclasses/subkl.htm).

3. Aucouturier P, Danon F, Daveau M, Guillou B, Sabbah A, Besson J, et al. Measurement of serum IgG4 levels by a competitive immunoenzymatic assay with monoclonal antibodies. J Immunol Methods. 1984. 74:151–162.

4. French MA. Serum IgG subclasses in normal adults. Monogr Allergy. 1986. 19:100–107.

5. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009. 39:469–477.

6. Tao MH, Smith RI, Morrison SL. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J Exp Med. 1993. 178:661–667.

7. Brekke OH, Michaelsen TE, Aase A, Sandin RH, Sandlie I. Human IgG isotype-specific amino acid residues affecting complement-mediated cell lysis and phagocytosis. Eur J Immunol. 1994. 24:2542–2547.

8. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998. 160:3555–3561.

9. Horner AA, Widhopf GF, Burger JA, Takabayashi K, Cinman N, Ronaghy A, et al. Immunostimulatory DNA inhibits IL-4-dependent IgE synthesis by human B cells. J Allergy Clin Immunol. 2001. 108:417–423.

10. Jones CC, Hamilton RG, Jordon RE. Subclass distribution of human IgG autoantibodies in pemphigus. J Clin Immunol. 1988. 8:43–49.

11. Futei Y, Amagai M, Ishii K, Kuroda-Kinoshita K, Ohya K, Nishikawa T. Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus. J Dermatol Sci. 2001. 26:55–61.

12. Hawrylowicz CM, O'Garra A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol. 2005. 5:271–283.

13. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas--an autonomous pancreatic disease? Am J Dig Dis. 1961. 6:688–698.

14. 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. 40:1561–1568.

15. Okazaki K, Chiba T. Autoimmune related pancreatitis. Gut. 2002. 51:1–4.

16. Zamboni G, Lüttges 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. 445:552–563.

17. Aparisi L, Farre A, Gomez-Cambronero L, Martinez J, De Las Heras G, Corts J, et al. Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut. 2005. 54:703–709.

18. Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000. 118:573–581.

19. Deshpande V, Mino-Kenudson M, Brugge W, Lauwers GY. Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology. Arch Pathol Lab Med. 2005. 129:1148–1154.

20. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006. 41:613–625.

21. Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002. 122:1264–1269.

22. Sood S, Fossard DP, Shorrock K. Chronic sclerosing pancreatitis in Sjögren's syndrome: a case report. Pancreas. 1995. 10:419–421.

23. 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. 22:387–395.

24. Ectors N, Maillet B, Aerts R, Geboes K, Donner A, Borchard F, et al. Non-alcoholic duct destructive chronic pancreatitis. Gut. 1997. 41:263–268.

25. Yadav D, Notahara K, Smyrk TC, Clain JE, Pearson RK, Farnell MB, et al. Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and natural history after resection. Clin Gastroenterol Hepatol. 2003. 1:129–135.

26. Wakabayashi T, Kawaura Y, Satomura Y, Watanabe H, Motoo Y, Sawabu N. Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment. Pancreas. 2005. 30:31–39.

27. 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. 27:1119–1127.

28. Sah RP, Chari ST, Pannala R, Sugumar A, Clain JE, Levy MJ, et al. Differences in clinical profile and relapse rate of type 1 versus type 2 autoimmune pancreatitis. Gastroenterology. 2010. 139:140–148.

29. Kamisawa T, Funata N, Hayashi Y. Lymphoplasmacytic sclerosing pancreatitis is a pancreatic lesion of IgG4-related systemic disease. Am J Surg Pathol. 2004. 28:1114.

30. Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol. 2007. 20:23–28.

31. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010. 17:303–332.

32. 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. 30:1537–1545.

33. Mino-Kenudson M, Smyrk TC, Deshpande V, Fujisawa M, Shimizu M, Uehara T, et al. Autoimmune pancreatitis: West vs. East. Mod Pathol. 2008. 21:Suppl 1. A312.

34. Okazaki K, Kawa S, Kamisawa T, Naruse S, Tanaka S, Nishimori I, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006. 41:626–631.

35. Kim KP, Kim MH, Kim JC, Lee SS, Seo DW, Lee SK. Diagnostic criteria for autoimmune chronic pancreatitis revisited. World J Gastroenterol. 2006. 12:2487–2496.

36. Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis. J Gastroenterol. 2008. 43:403–408.

37. Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006. 4:1010–1016.

38. Frulloni L, Scattolini C, Falconi M, Zamboni G, Capelli P, Manfredi R, et al. Autoimmune pancreatitis: differences between the focal and diffuse forms in 87 patients. Am J Gastroenterol. 2009. 104:2288–2294.

39. Sugumar A, Klöppel G, Chari ST. Autoimmune pancreatitis: pathologic subtypes and their implications for its diagnosis. Am J Gastroenterol. 2009. 104:2308–2310.

40. 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. 344:732–738.

41. Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003. 52:683–687.

42. 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. 38:982–984.

43. 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. 32:1770–1779.

44. Kamisawa T, Yoshiike M, Egawa N, Nakajima H, Tsuruta K, Okamoto A, et al. Chronic pancreatitis in the elderly in Japan. Pancreatology. 2004. 4:223–227.

45. Kim KP, Kim MH, Song MH, Lee SS, Seo DW, Lee SK. Autoimmune chronic pancreatitis. Am J Gastroenterol. 2004. 99:1605–1616.

46. Nishimori I, Tamakoshi A, Otsuki M. Research Committee on Intractable Diseases of the Pancreas, Ministry of Health, Labour, and Welfare of Japan. Prevalence of autoimmune pancreatitis in Japan from a nationwide survey in 2002. J Gastroenterol. 2007. 42:6–8.

47. Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, Abraham SC, Yeo CJ, Lillemoe KD. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg. 2003. 237:853–858.

48. Abraham SC, Wilentz RE, Yeo CJ, Sohn TA, Cameron JL, Boitnott JK, et al. Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all 'chronic pancreatitis'? Am J Surg Pathol. 2003. 27:110–120.

49. Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010. 62:1755–1762.

50. Suda K, Nishimori I, Takase M, Oi I, Ogawa M. Autoimmune pancreatitis can be classified into early and advanced stages. Pancreas. 2006. 33:345–350.

51. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol. 2004. 28:1193–1203.

52. Ito T, Nishimori I, Inoue N, Kawabe K, Gibo J, Arita Y, et al. Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune pancreatitis in Japan. J Gastroenterol. 2007. 42:50–58.

53. 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. 41:643–652.

54. Kamisawa T, Okamoto A, Funata N. Clinicopathological features of autoimmune pancreatitis in relation to elevation of serum IgG4. Pancreas. 2005. 31:28–31.

55. Raina A, Krasinskas AM, Greer JB, Lamb J, Fink E, Moser AJ, et al. Serum immunoglobulin G fraction 4 levels in pancreatic cancer: elevations not associated with autoimmune pancreatitis. Arch Pathol Lab Med. 2008. 132:48–53.

56. Ghazale A, Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol. 2007. 102:1646–1653.

57. Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor). Am J Surg Pathol. 2005. 29:783–791.

58. Wang WL, Farris AB, Lauwers GY, Deshpande V. Autoimmune pancreatitis-related cholecystitis: a morphologically and immunologically distinctive form of lymphoplasmacytic sclerosing cholecystitis. Histopathology. 2009. 54:829–836.

59. Chandan VS, Iacobuzio-Donahue C, Abraham SC. Patchy distribution of pathologic abnormalities in autoimmune pancreatitis: implications for preoperative diagnosis. Am J Surg Pathol. 2008. 32:1762–1769.

60. Moon SH, Kim MH, Park do H, Song TJ, Eum J, Lee SS, et al. IgG4 immunostaining of duodenal papillary biopsy specimens may be useful for supporting a diagnosis of autoimmune pancreatitis. Gastrointest Endosc. 2010. 71:960–966.

61. Geyer JT, Ferry JA, Harris NL, Stone JH, Zukerberg LR, Lauwers GY, et al. Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010. 34:202–210.

62. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol. 2006. 41:1197–1205.

63. Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor). Am J Surg Pathol. 2005. 29:783–791.

64. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010. 34:1812–1819.

65. Cheuk W, Yuen HK, Chan JK. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease? Am J Surg Pathol. 2007. 31:643–645.

66. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol. 2008. 32:671–681.

67. Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, Nakanuma Y. A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol. 2006. 37:239–243.

68. Cheuk W, Lee KC, Chong LY, Yuen ST, Chan JK. IgG4-related Sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol. 2009. 33:1713–1719.

69. Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, Masuda S, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol. 2005. 36:710–717.

70. Cheuk W, Chan AC, Lam WL, Chow SM, Crowley P, Lloydd R, et al. IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases. Am J Surg Pathol. 2009. 33:1058–1064.

71. Kasashima S, Zen Y, Kawashima A, Konishi K, Sasaki H, Endo M, et al. Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis. Am J Surg Pathol. 2008. 32:197–204.

72. Kakudo K, Li Y, Hirokawa M, Ozaki T. Diagnosis of Hashimoto's thyroiditis and IgG4-related sclerosing disease. Pathol Int. 2011. 61:175–183.

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

74. Lara LP, Chari ST. Autoimmune pancreatitis. Curr Gastroenterol Rep. 2005. 7:101–106.

75. Saeki T, Saito A, Hiura T, Yamazaki H, Emura I, Ueno M, et al. Lymphoplasmacytic infiltration of multiple organs with immunoreactivity for IgG4: IgG4-related systemic disease. Intern Med. 2006. 45:163–167.

76. Shinji A, Sano K, Hamano H, Unno H, Fukushima M, Nakamura N, et al. Autoimmune pancreatitis is closely associated with gastric ulcer presenting with abundant IgG4-bearing plasma cell infiltration. Gastrointest Endosc. 2004. 59:506–511.

77. Kamisawa T. IgG4-related sclerosing disease. Intern Med. 2006. 45:125–126.

78. Bateman AC, Deheragoda MG. IgG4-related systemic sclerosing disease - an emerging and under-diagnosed condition. Histopathology. 2009. 55:373–383.

79. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int. 2010. 60:247–258.

80. Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med. 2006. 4:23.

81. 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. 22:1287–1295.

82. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008. 134:706–715.

83. Kamisawa T, Nakajima H, Egawa N, Funata N, Tsuruta K, Okamoto A. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology. 2006. 6:132–137.

84. Nakazawa T, Ohara H, Sano H, Ando T, Aoki S, Kobayashi S, et al. Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis. Pancreas. 2005. 30:20–25.

85. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007. 37:S478–S486.

86. Nakanuma Y, Harada K, Katayanagi K, Tsuneyama K, Sasaki M. Definition and pathology of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999. 6:333–342.

87. Oseini AM, Chaiteerakij R, Shire AM, Ghazale A, Kaiya J, Moser CD, et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology. 2011. 06. 14. doi:10.1002/hep.24487 [Epub ahead of print].

88. Erkelens GW, Vleggaar FP, Lesterhuis W, van Buuren HR, van der Werf SD. Sclerosing pancreato-cholangitis responsive to steroid therapy. Lancet. 1999. 354:43–44.

89. Nakazawa T, Ohara H, Yamada T, Ando H, Sano H, Kajino S, et al. Atypical primary sclerosing cholangitis cases associated with unusual pancreatitis. Hepatogastroenterology. 2001. 48:625–630.

90. Kojima E, Kimura K, Noda Y, Kobayashi G, Itoh K, Fujita N. Autoimmune pancreatitis and multiple bile duct strictures treated effectively with steroid. J Gastroenterol. 2003. 38:603–607.

91. Kuroiwa T, Suda T, Takahashi T, Hirono H, Natsui M, Motoyama H, et al. Bile duct involvement in a case of autoimmune pancreatitis successfully treated with an oral steroid. Dig Dis Sci. 2002. 47:1810–1816.

92. Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006. 101:2070–2075.

93. Webster GJ, Pereira SP, Chapman RW. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis--overlapping or separate diseases? J Hepatol. 2009. 51:398–402.

94. Abraham SC, Cruz-Correa M, Argani P, Furth EE, Hruban RH, Boitnott JK. Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis. Am J Surg Pathol. 2003. 27:441–451.

95. Jessurun J, Bolio-Solis A, Manivel JC. Diffuse lymphoplasmacytic acalculous cholecystitis: a distinctive form of chronic cholecystitis associated with primary sclerosing cholangitis. Hum Pathol. 1998. 29:512–517.

96. Zen Y, Fujii T, Sato Y, Masuda S, Nakanuma Y. Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease. Mod Pathol. 2007. 20:884–894.

97. Kanno A, Satoh K, Kimura K, Masamune A, Asakura T, Unno M, et al. Autoimmune pancreatitis with hepatic inflammatory pseudotumor. Pancreas. 2005. 31:420–423.

98. Travis WD, Elisabeth B, Muller-Hermelink HK, Harris CC, editors. Pathology and Genetics of Tumours of the Lung, Pleural, Thymus and Heart. 2004. Lyon: IARC Press.

99. Cheuk W, Chan JK, Shek TW, Chang JH, Tsou MH, Yuen NW, et al. Inflammatory pseudotumor-like follicular dendritic cell tumor: a distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association. Am J Surg Pathol. 2001. 25:721–731.

100. Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007. 46:463–471.

101. Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, et al. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007. 56:1471–1472.

102. Kuttner H. Uber entzundiche Tumoren der Submaaxillar-speicheldruse. Bruns Beitr Klin Chir. 1896. 15:815–834.

103. Pilch BZ. Head and Neck Surgical Pathology. 2001. Philadelphia: Lippincott Williams and Wilkin.

104. Tiemann M, Teymoortash A, Schrader C, Werner JA, Parwaresch R, Seifert G, et al. Chronic sclerosing sialadenitis of the submandibular gland is mainly due to a T lymphocyte immune reaction. Mod Pathol. 2002. 15:845–852.

105. Cheuk W, Chan JK. Kuttner tumor of the submandibular gland: fine-needle aspiration cytologic findings of seven cases. Am J Clin Pathol. 2002. 117:103–108.

106. Kamisawa T, Nakajima H, Hishima T. Close correlation between chronic sclerosing sialadenitis and immunoglobulin G4. Intern Med J. 2006. 36:527–529.

107. Chan JK. Kuttner tumor (chronic sclerosing sialadenitis) of the submandibular gland: an underrecognized entity. Adv Anat Pathol. 1998. 5:239–251.

108. Yamamoto M, Takahashi H, Sugai S, Imai K. Clinical and pathological characteristics of Mikulicz's disease (IgG4-related plasmacytic exocrinopathy). Autoimmun Rev. 2005. 4:195–200.

109. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009. 68:1310–1315.

110. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006. 16:335–340.

111. Yamamoto H, Yamaguchi H, Aishima S, Oda Y, Kohashi K, Oshiro Y, et al. Inflammatory myofibroblastic tumor versus IgG4-related sclerosing disease and inflammatory pseudotumor: a comparative clinicopathologic study. Am J Surg Pathol. 2009. 33:1330–1340.

112. Comings DE, Skubi KB, VanEyes J, Motulsky AG. Familial multifocal fibrosclerosis. Findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel's thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med. 1967. 66:884–892.

113. Klisnick A, Fourcade J, Ruivard M, Baud O, Souweine B, Boyer L, et al. Combined idiopathic retroperitoneal and mediastinal fibrosis with pericardial involvement. Clin Nephrol. 1999. 52:51–55.

114. Graal MB, Lustermans FA. A patient with combined mediastinal, mesenteric and retroperitoneal fibrosis. Neth J Med. 1994. 44:214–219.

115. Owen K, Lane H, Jones MK. Multifocal fibrosclerosis: a case of thyroiditis and bilateral lacrimal gland involvement. Thyroid. 2001. 11:1187–1190.

116. Morris WR, Haik BG, Osborn D, Fleming JC. Intraocular involvement in multifocal fibrosclerosis. Ophthalmology. 2000. 107:962–966.

117. Levey JM, Mathai J. Diffuse pancreatic fibrosis: an uncommon feature of multifocal idiopathic fibrosclerosis. Am J Gastroenterol. 1998. 93:640–642.

118. Fukuda W, Kimura M, Akaogi T, Sako M, Ohiwa K, Yamamoto Y, et al. Multifocal fibrosclerosis: retroperitoneal fibrosis associated with a suprasellar tumor and pachymeningitis. Intern Med. 2003. 42:1006–1010.

119. Pacini D, Leone O, Turci S, Camurri N, Giunchi F, Martinelli GN, et al. Incidence, etiology, histologic findings, and course of thoracic inflammatory aortopathies. Ann Thorac Surg. 2008. 86:1518–1523.

120. Miller DV, Isotalo PA, Weyand CM, Edwards WD, Aubry MC, Tazelaar HD. Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant. Am J Surg Pathol. 2006. 30:1150–1158.

121. Burke AP, Tavora F, Narula N, Tomaszewski JE, Virmani R. Aortitis and ascending aortic aneurysm: description of 52 cases and proposal of a histologic classification. Hum Pathol. 2008. 39:514–526.

122. Dehner LP, Coffin CM. Idiopathic fibrosclerotic disorders and other inflammatory pseudotumors. Semin Diagn Pathol. 1998. 15:161–173.

123. Clark A, Zeman RK, Choyke PL, White EM, Burrell MI, Grant EG, et al. Pancreatic pseudotumors associated with multifocal idiopathic fibrosclerosis. Gastrointest Radiol. 1988. 13:30–32.

124. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002. 359:1403–1404.

125. 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. 33:1833–1839.

126. Chen TS, Montgomery EA. Are tumefactive lesions classified as sclerosing mesenteritis a subset of IgG4-related sclerosing disorders? J Clin Pathol. 2008. 61:1093–1097.

127. Matsumoto Y, Kasashima S, Kawashima A, Sasaki H, Endo M, Kawakami K, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol. 2008. 39:975–980.

128. Sakata N, Tashiro T, Uesugi N, Kawara T, Furuya K, Hirata Y, et al. IgG4-positive plasma cells in inflammatory abdominal aortic aneurysm: the possibility of an aortic manifestation of IgG4-related sclerosing disease. Am J Surg Pathol. 2008. 32:553–559.

129. Qian Q, Kashani KB, Miller DV. Ruptured abdominal aortic aneurysm related to IgG4 periaortitis. N Engl J Med. 2009. 361:1121–1123.

130. Ito H, Kaizaki Y, Noda Y, Fujii S, Yamamoto S. IgG4-related inflammatory abdominal aortic aneurysm associated with autoimmune pancreatitis. Pathol Int. 2008. 58:421–426.

131. Ishida M, Hotta M, Kushima R, Asai T, Okabe H. IgG4-related inflammatory aneurysm of the aortic arch. Pathol Int. 2009. 59:269–273.

132. Stone JH, Khosroshahi A, Deshpande V, Stone JR. IgG4-related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care Res (Hoboken). 2010. 62:316–322.

133. Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, Yoshizawa K, et al. High prevalence of hypothyroidism in patients with autoimmune pancreatitis. Dig Dis Sci. 2005. 50:1052–1057.

134. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, et al. Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int. 2009. 59:636–641.

135. Li Y, Nishihara E, Hirokawa M, Taniguchi E, Miyauchi A, Kakudo K. Distinct clinical, serological, and sonographic characteristics of hashimoto's thyroiditis based with and without IgG4-positive plasma cells. J Clin Endocrinol Metab. 2010. 95:1309–1317.

136. Drieskens O, Blockmans D, Van den Bruel A, Mortelmans L. Riedel's thyroiditis and retroperitoneal fibrosis in multifocal fibrosclerosis: positron emission tomographic findings. Clin Nucl Med. 2002. 27:413–415.

137. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken). 2010. 62:1312–1318.

138. Zhang L, Smyrk TC. Autoimmune pancreatitis and IgG4-related systemic diseases. Int J Clin Exp Pathol. 2010. 3:491–504.

139. Shrestha B, Sekiguchi H, Colby TV, Graziano P, Aubry MC, Smyrk TC, et al. Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology. Am J Surg Pathol. 2009. 33:1450–1462.

140. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009. 33:1886–1893.

141. Yamashita K, Haga H, Kobashi Y, Miyagawa-Hayashino A, Yoshizawa A, Manabe T. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature. Am J Surg Pathol. 2008. 32:1620–1626.

142. Kobayashi H, Shimokawaji T, Kanoh S, Motoyoshi K, Aida S. IgG4-positive pulmonary disease. J Thorac Imaging. 2007. 22:360–362.

143. Zen Y, Kasahara Y, Horita K, Miyayama S, Miura S, Kitagawa S, 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. 2005. 29:275–278.

144. Watson SJ, Jenkins DA, Bellamy CO. Nephropathy in IgG4-related systemic disease. Am J Surg Pathol. 2006. 30:1472–1477.

145. Cornell LD, Chicano SL, Deshpande V, Collins AB, Selig MK, Lauwers GY, et al. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol. 2007. 31:1586–1597.

146. Dhobale S, Bedetti C, Killian P, Ilyas M, Liput J, Jasnosz K, et al. IgG4 related sclerosing disease with multiple organ involvements and response to corticosteroid treatment. J Clin Rheumatol. 2009. 15:354–357.

147. Takeda S, Haratake J, Kasai T, Takaeda C, Takazakura E. IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant. 2004. 19:474–476.

148. Saeki T, Nishi S, Ito T, Yamazaki H, Miyamura S, Emura I, et al. Renal lesions in IgG4-related systemic disease. Intern Med. 2007. 46:1365–1371.

149. Kuroda N, Nakamura S, Miyazaki K, Inoue K, Ohara M, Mizuno K, et al. Chronic sclerosing pyelitis with an increased number of IgG4-positive plasma cells. Med Mol Morphol. 2009. 42:236–238.

150. Kim SA, Lee SR, Huh J, Shen SS, Ro JY. IgG4-associated inflammatory pseudotumor of ureter: clinicopathologic and immunohistochemical study of 3 cases. Hum Pathol. 2011. 42:1178–1184.

151. Hori M, Makita N, Andoh T, Takiyama H, Yajima Y, Sakatani T, et al. Long-term clinical course of IgG4-related systemic disease accompanied by hypophysitis. Endocr J. 2010. 57:485–492.

152. Shimatsu A, Oki Y, Fujisawa I, Sano T. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J. 2009. 56:1033–1041.

153. Wong S, Lam WY, Wong WK, Lee KC. Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol. 2007. 38:1720–1723.

154. Osawa S, Ogawa Y, Watanabe M, Tominaga T. Hypophysitis presenting with atypical rapid deterioration: with special reference to immunoglobulin G4-related disease-case report-. Neurol Med Chir (Tokyo). 2009. 49:622–625.

155. Tanabe T, Tsushima K, Yasuo M, Urushihata K, Hanaoka M, Koizumi T, et al. IgG4-associated multifocal systemic fibrosis complicating sclerosing sialadenitis, hypophysitis, and retroperitoneal fibrosis, but lacking pancreatic involvement. Intern Med. 2006. 45:1243–1247.

156. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A case of Mikulicz's disease (IgG4-related plasmacytic disease) complicated by autoimmune hypophysitis. Scand J Rheumatol. 2006. 35:410–411.

157. Chan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009. 33:1249–1252.

158. Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ. Idiopathic hypertrophic pachymeningitis. Neurology. 2004. 62:686–694.

159. Riku S, Kato S. Idiopathic hypertrophic pachymeningitis. Neuropathology. 2003. 23:335–344.

160. Lui PC, Fan YS, Wong SS, Chan AN, Wong G, Chau TK, et al. Inflammatory pseudotumors of the central nervous system. Hum Pathol. 2009. 40:1611–1617.

161. Sato Y, Kojima M, Takata K, Morito T, Asaoku H, Takeuchi T, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease. Mod Pathol. 2009. 22:589–599.

162. Sugimoto T, Morita Y, Isshiki K, Yamamoto T, Uzu T, Kashiwagi A, et al. Constrictive pericarditis as an emerging manifestation of hyper-IgG4 disease. Int J Cardiol. 2008. 130:e100–e101.

163. Uehara T, Hamano H, Kawakami M, Koyama M, Kawa S, Sano K, et al. Autoimmune pancreatitis-associated prostatitis: distinct clinicopathological entity. Pathol Int. 2008. 58:118–125.

164. Taniguchi T, Kobayashi H, Fukui S, Ogura K, Saiga T, Okamoto M. A case of multifocal fibrosclerosis involving posterior mediastinal fibrosis, retroperitoneal fibrosis, and a left seminal vesicle with elevated serum IgG4. Hum Pathol. 2006. 37:1237–1239. author reply 1239.

165. Ikeda R, Awataguchi T, Shoji F, Oshima T. A case of paranasal sinus lesions in IgG4-related sclerosing disease. Otolaryngol Head Neck Surg. 2010. 142:458–459.

166. Ishida M, Hotta M, Kushima R, Shibayama M, Shimizu T, Okabe H. Multiple IgG4-related sclerosing lesions in the maxillary sinus, parotid gland and nasal septum. Pathol Int. 2009. 59:670–675.

167. Cheuk W, Tam FK, Chan AN, Luk IS, Yuen AP, Chan WK, et al. Idiopathic cervical fibrosis--a new member of IgG4-related sclerosing diseases: report of 4 cases, 1 complicated by composite lymphoma. Am J Surg Pathol. 2010. 34:1678–1685.

168. Lopes J, Hochwald SN, Lancia N, Dixon LR, Ben-David K. Autoimmune esophagitis: IgG4-related tumors of the esophagus. J Gastrointest Surg. 2010. 14:1031–1034.

169. Martel M, Cheuk W, Lombardi L, Lifschitz-Mercer B, Chan JK, Rosai J. Sclerosing angiomatoid nodular transformation (SANT): report of 25 cases of a distinctive benign splenic lesion. Am J Surg Pathol. 2004. 28:1268–1279.

170. Nagai Y, Hayama N, Kishimoto T, Furuya M, Takahashi Y, Otsuka M, et al. Predominance of IgG4+ plasma cells and CD68 positivity in sclerosing angiomatoid nodular transformation (SANT). Histopathology. 2008. 53:495–498.

171. Kashiwagi S, Kumasaka T, Bunsei N, Fukumura Y, Yamasaki S, Abe K, et al. Detection of Epstein-Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen. Virchows Arch. 2008. 453:275–282.

172. Kojima M, Miyawaki S, Takada S, Kashiwabara K, Igarashi T, Nakamura S. Lymphoplasmacytic infiltrate of regional lymph nodes in Kuttner's tumor (chronic sclerosing sialadenitis): a report of 3 cases. Int J Surg Pathol. 2008. 16:263–268.

173. Boulanger E, Fuentes V, Meignin V, Mougenot B, Labaume S, Gouilleux-Gruart V, et al. Polyclonal IgG4 hypergammaglobulinemia associated with plasmacytic lymphadenopathy, anemia and nephropathy. Ann Hematol. 2006. 85:833–840.

174. Kojima M, Nakamura N, Tsukamoto N, Otuski Y, Shimizu K, Itoh H, et al. Clinical implications of idiopathic multicentric castleman disease among Japanese: a report of 28 cases. Int J Surg Pathol. 2008. 16:391–398.

175. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005. 106:2627–2632.

176. Kojima M, Hosomura Y, Itoh H, Johshita T, Yoshida K, Nakamura S, et al. Reactive proliferative lesions in lymph nodes from rheumatoid arthritis patients. A clinicopathological and immunohistological study. Acta Pathol Jpn. 1990. 40:249–254.

177. Kojima M, Nakamura S, Morishita Y, Itoh H, Yoshida K, Ohno Y, et al. Reactive follicular hyperplasia in the lymph node lesions from systemic lupus erythematosus patients: a clinicopathological and immunohistological study of 21 cases. Pathol Int. 2000. 50:304–312.

178. Koo CH, Nathwani BN, Winberg CD, Hill LR, Rappaport H. Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy). Medicine (Baltimore). 1984. 63:274–290.

179. Ioachim HL, Medeiros LJ. Ioachim's Lymph Node Pathology. 2009. 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins;186–189.

180. Moran CA, Suster S, Abbondanzo SL. Inflammatory pseudotumor of lymph nodes: a study of 25 cases with emphasis on morphological heterogeneity. Hum Pathol. 1997. 28:332–338.

181. Cheuk W, Yuen HK, Chan AC, Shih LY, Kuo TT, Ma MW, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol. 2008. 32:1159–1167.

182. Takahashi N, Ghazale AH, Smyrk TC, Mandrekar JN, Chari ST. Possible association between IgG4-associated systemic disease with or without autoimmune pancreatitis and non-Hodgkin lymphoma. Pancreas. 2009. 38:523–526.

183. Motosugi U, Ichikawa T, Yamaguchi H, Nakazawa T, Katoh R, Itakura J, et al. Small invasive ductal adenocarcinoma of the pancreas associated with lymphoplasmacytic sclerosing pancreatitis. Pathol Int. 2009. 59:744–747.

184. Witkiewicz AK, Kennedy EP, Kennyon L, Yeo CJ, Hruban RH. Synchronous autoimmune pancreatitis and infiltrating pancreatic ductal adenocarcinoma: case report and review of the literature. Hum Pathol. 2008. 39:1548–1551.

185. 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. 12:6225–6228.

186. Inoue H, Miyatani H, Sawada Y, Yoshida Y. A case of pancreas cancer with autoimmune pancreatitis. Pancreas. 2006. 33:208–209.

187. Joo M, Chang SH, Kim H, Gardner JM, Ro JY. Primary gastrointestinal clear cell sarcoma: report of 2 cases, one case associated with IgG4-related sclerosing disease, and review of literature. Ann Diagn Pathol. 2009. 13:30–35.

188. Gill J, Angelo N, Yeong ML, McIvor N. Salivary duct carcinoma arising in IgG4-related autoimmune disease of the parotid gland. Hum Pathol. 2009. 40:881–886.

189. Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007. 45:1538–1546.

190. Chang MC, Chang YT, Wei SC, Kuo CH, Liang PC, Wong JM. Autoimmune pancreatitis associated with high prevalence of gastric ulcer independent of Helicobacter pylori infection status. Pancreas. 2009. 38:442–446.

191. Kountouras J, Zavos C, Chatzopoulos D. A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis. J Cell Mol Med. 2005. 9:196–207.

192. Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med. 2005. 9:741–744.

193. Okazaki K, Uchida K, Fukui T. Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis. J Gastroenterol. 2008. 43:409–418.

194. Tanaka A, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Maehara T, et al. Th2 andregulatory immune reactions contributes to IgG4 production and the initiation of Mikulicz's disease. Arthritis Rheum. 2011. 09. 06. doi: 10.1002/art.33320 [Epub ahead of print].

195. 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. 45:732–741.

196. Nakashima H, Miyake K, Moriyama M, Tanaka A, Watanabe M, Abe Y, et al. An amplification of IL-10 and TGF-beta in patients with IgG4-related tubulointerstitial nephritis. Clin Nephrol. 2010. 73:385–391.

197. Akitake R, Watanabe T, Zaima C, Uza N, Ida H, Tada S, et al. Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease. Gut. 2010. 59:542–545.

198. Frulloni L, Lunardi C, Simone R, Dolcino M, Scattolini C, Falconi M, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009. 361:2135–2142.