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IgG4-associated disease

Wednesday 19 November 2003

hyper-IgG4 disease, IMAD, IgG4 syndrome, IgG4 disease, IgG4-associated multifocal systemic fibrosclerosis, IgG4-associated immune complex multiorgan autoimmune disease, IgG4-related plasmacytic disease, hyper-IgG4 disease, multifocal systemic fibrosclerosis (MSF), systemic multifocal fibrosclerosis, inflammatory fibrotic disease, IgG4-Related Disease; IgG4-assotiated diseases; IgG4-related disease

Definition: The IMAD or ’hyper-IgG4 disease’ is a chronic inflammatory disease, characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. IgG4-related disease has been identified in various organs, but whether or not there are organ-specific characteristics related to the etiologic factors is still unknown.


- In lacrymal glands

Multifocal systemic fibrosclerosis (MSF) is a multisystem disease, which often mimics malignancy.

A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis.


On the basis of the location of the lesions, the patients can be classified into 5 groups:
- head and neck (20%)
- thoracic (10%)
- hepatic and pancreatobiliary (20%)
- retroperitoneal (10%)
- systemic (30%).

All groups have similar clinicopathologic features in various aspects. However, there are some organ-specific features: for example, the proportion of the female patients was significantly higher in the head and neck group, serum IgG4 concentrations were significantly higher in the head/neck and systemic groups, and all kidney lesions were associated with extrarenal disease.

Unique pathologic features were dense fibrosis in dacryoadenitis, numerous lymph follicles in sialadenitis and dacryoadenitis, and obliterative arteritis in lung lesions.

In addition, an epithelioid granuloma and rheumatoid nodule can be noted within IgG4-related lesions in rare patients (history of tuberculosis or rheumatoid arthritis).

Malignant tumors (lung cancers, malignant lymphoma) can beidentified after the diagnosis of IgG4-related disease in some patients, all in the systemic group.


- multisystemic fibrosis

  • sclerosing cholangitis
  • sclerosing cholecystitis
  • retroperitoneal fibrosis (16426926, 16938531)
  • mediastinal fibrosis (16426926, 16938531)
  • mesenteric fibrosis
  • pelvic fibrosis
  • Riedel thyroiditis
  • fibrotic pseudotumor of the orbit
  • fibrosis of the salivary glands
  • sclerosing pancreatitis (autoimmune pancreatitis) (AIP)
  • sclerosing dacryoadenitis

- IgG4 immune-complex tubulointerstitial nephritis (17895762)
- membranous glomerulopathy
- autoimmune hypophysitis (17954209)

  • panhypopituitarism
  • central diabetes insipidus

- Mikulicz disease
- constrictive pericarditis (17727980)
- prostatitis
- interstitial pneumonia
- pulmonary vasculitis (17539856)
- lymphadenopathy with increased IgG4+ plasma cells
- inflammatory pseudotumors (17895762)

- pachymeningitis and intracranial fibrosis (14606716)
- IgG4 periaortitis (18223321)

- idiopathic retroperitoneal fibrosis
- sclerosing pancreatitis
- inflammatory pseudotumor of the breast (15644785)

Microscopical synopsis

- intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils
- eosinophilic aggregates
- venulitis
- obliterative arteritis
- majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles
- significant increase in IgG4-positive plasma cells compared with controls

Differential diagnosis

- inflammatory pseudotumour
- inflammatory myofibroblastic tumour
- plasma cell granuloma
- systemic fibrosis
- xanthofibrogranulomatosis
- multifocal fibrosclerosis

See also

- fever
- severe systemic disease
- retroperitoneal fibrosis
- IgG4-expressing plasma cells
- fibrotic diseases

Open references

Applying the consensus statement on the pathology of IgG4-related disease to lacrimal gland lesions.
Andrew N, Kearney D, Selva D.
Mod Pathol. 2013 Aug;26(8):1150-1. doi : 10.1038/modpathol.2013.46. No abstract available
PMID: 23903493 [PubMed - indexed for MEDLINE]


- Applying the consensus statement on the pathology of IgG4-related disease to lacrimal gland lesions. Andrew N, Kearney D, Selva D. Mod Pathol. 2013 Aug;26(8):1150-1. doi : 10.1038/modpathol.2013.46 PMID: 23903493 [Free]

- Consensus statement on the pathology of IgG4-related disease. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Klöppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH. Mod Pathol. 2012 May 18. PMID: 22596100

- Eosinophilic Angiocentric Fibrosis Is a Form of IgG4-related Systemic Disease. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Am J Surg Pathol. 2011 May;35(5):701-6. PMID: 21502911

- IgG4-Related Disease: A Cross-sectional Study of 114 Cases. Zen Y, Nakanuma Y. Am J Surg Pathol. 2010 Dec;34(12):1812-9. PMID: 21107087

- Kasashima S, Zen Y, Kawashima A, Konishi K, Sasaki H, Endo M, Matsumoto Y, Kawakami K, Kasashima F, Moriya M, Kimura K, Ohtake H, Nakanuma Y. Inflammatory Abdominal Aortic Aneurysm: Close Relationship to IgG4-related Periaortitis. Am J Surg Pathol. 2008 Feb;32(2):197-204. PMID: 18223321

- Wong S, Lam WY, Wong WK, Lee KC. Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol. 2007 Nov;38(11):1720-3. PMID: 17954209

- Cornell LD, Chicano SL, Deshpande V, Collins AB, Selig MK, Lauwers GY, Barisoni L, Colvin RB. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol. 2007 Oct;31(10):1586-97. PMID: 17895762

- Cheuk W, Yuen HK, Chan JK.Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease? Am J Surg Pathol. 2007 Apr;31(4):643-5. PMID: 17414116

- Kojima M, Sipos B, Klapper W, Frahm O, Knuth HC, Yanagisawa A, Zamboni G, Morohoshi T, Klöppel G. Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells. Am J Surg Pathol. 2007 Apr;31(4):521-8. PMID: 17414098

- Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, Colvin RB, Lauwers GY. Autoimmune pancreatitis: a systemic immune complex mediated disease.Am J Surg Pathol. 2006 Dec;30(12):1537-45. PMID: 17122509

- Watson SJ, Jenkins DA, Bellamy CO. Nephropathy in IgG4-related systemic disease. Am J Surg Pathol. 2006 Nov;30(11):1472-7. PMID: 17063091

- Cornell LD, Chicano SL, Deshpande V, Collins AB, Selig MK, Lauwers GY, Barisoni L, Colvin RB. Pseudotumors due to IgG4 Immune-Complex Tubulointerstitial Nephritis Associated With Autoimmune Pancreatocentric Disease. Am J Surg Pathol. 2007 Oct;31(10):1586-1597. PMID: 17895762

- Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med. 2006 Oct 6;4:23. PMID: 17026742

- 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 Sep;37(9):1237-9; PMID: 16938531

- 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 Feb;37(2):239-43. PMID: 16426926

- Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Fujimura M, Nakanuma Y. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol. 2005 Jul;36(7):710-7. PMID: 16084938