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Extrapancreatic findings of IgG4-related disease
Clinical Radiology 69 (2014) 209e218
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Extrapancreatic findings of IgG4-related disease T.J. Tan a, b, *, Y.L. Ng a, D. Tan c, W.S. Fong d, A.S.C. Low a, ** a
Department of Diagnostic Radiology, Singapore General Hospital, Singapore Department of Diagnostic Radiology, Changi General Hospital, Singapore c Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore d Department of Rheumatology and Immunology, Singapore General Hospital, Singapore b
art icl e i nformat ion Article history: Received 1 July 2013 Received in revised form 18 September 2013 Accepted 23 September 2013
IgG4-related disease is a systemic fibro-inflammatory condition, which includes autoimmune pancreatitis as part of the disease spectrum. Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis. Recognizing the wide spectrum of extrapancreatic manifestations of IgG4-related disease coupled with a high clinical index of suspicion will allow for an accurate and timely diagnosis to be made, thus avoiding unnecessary invasive procedures and ensuring that early effective corticosteroid therapy is commenced. This review aims to serve as a concise reference tool for both clinicians and radiologists in the diagnosis of extrapancreatic IgG4-related disease. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction IgG4-related disease is a systemic fibro-inflammatory condition, which was first recognized by Kamisawa et al.1 in 2003, who proposed that autoimmune pancreatitis was a part of the disease spectrum. Autoimmune pancreatitis itself is now considered to encompass two separate disorders according to international consensus diagnostic criteria: lymphoplasmacytic sclerosing pancreatitis (type 1, or “classic” autoimmune pancreatitis), which is associated with IgG4-related disease; and idiopathic duct-centric pancreatitis (type 2 autoimmune pancreatitis), which has substantial clinical overlap with type 1, but is characterized by distinctive histopathological features.2 Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis.3 Although the * Guarantor and correspondent: T.J. Tan, Department of Diagnostic Radiology, Changi General Hospital, 2 Simei Street 3, Singapore 529889. Tel.: þ65 6850 4849; fax: þ65 6260 1703. ** Guarantor and correspondent: A.S.C. Low, Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore 169608. Tel.: þ65 6321 4069; fax: þ65 6223 6386. E-mail addresses: [email protected] (T.J. Tan), albert.low.s.c@sgh. com.sg (A.S.C. Low).
extrapancreatic imaging findings of IgG4-related disease on their own are non-specific, the imaging identification of these extrapancreatic sites of disease and a high clinical index of suspicion are crucial in establishing a clinical diagnosis of IgG4-related disease. The reported extrapancreatic sites of involvement include the biliary tree, gall bladder, kidneys, retroperitoneum, mesentery, thyroid gland, lacrimal glands, periorbital tissues, meninges, salivary glands, lymph nodes, lungs, gastrointestinal tract, and blood vessels.4,5 Although concurrent autoimmune pancreatitis is present in the majority of patients, IgG4related disease has been reported in patients with no pancreatic involvement.4 The histological features of IgG4-related disease are similar across the various affected organ systems, regardless of the site of disease. These include dense lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and occasional infiltration by eosinophils of the affected organs.4 A dramatic response to corticosteroid therapy is also usually seen in patients with IgG4-related disease, although spontaneous resolution may occur in a minority of patients.4 However, there is no general consensus for the regimen or duration of steroid treatment to date. Disease
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2013.09.021
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recurrence occurs in 20e40% of patients during tapering or following cessation of steroid treatment. The management of recurrent disease is also controversial, but most clinicians administer a repeat course of corticosteroids with an additional immunomodulating agent, such as azathioprine. In this article, the diverse imaging findings of extrapancreatic involvement of IgG4-related disease are discussed based on the authors’ clinical experience with 26 patients seen at the Singapore General Hospital over the past 9 years. All available computed tomography (CT) and magnetic resonance imaging (MRI) examinations of these patients were retrospectively reviewed. Combined 2-[18F]-fluoro-2deoxy-D-glucose (FDG) positron-emission tomography and computed tomography (FDG PET/CT) is an emerging tool in the detection of systemic involvement in patients with IgG4-related disease,6 and these imaging studies, if available, were also perused. The Mayo Clinic’s HISORt criteria (histology, imaging, serology, other organ involvement, response to therapy) as described by Chari et al.7 was used for the diagnosis of autoimmune pancreatitis prior to the year 2011: (a) periductal lymphoplasmacytic infiltrate associated with storiform fibrosis and obliterative phlebitis, or if the lymphoplasmacytic infiltrate demonstrates abundant (>10/ high power field) IgG4-positive plasma cells; (b) typical CT or MRI features of a diffusely enlarged pancreas with delayed (rim) enhancement, as well as a diffusely irregular and attenuated pancreatic duct on pancreatography; (c) serology showing an abnormally elevated serum IgG4 level; (d) evidence of other organ involvement, which includes intra- and extrahepatic biliary strictures, salivary gland involvement, mediastinal lymphadenopathy and retroperitoneal fibrosis; (d) marked improvement or resolution of pancreatic and extrapancreatic manifestations with corticosteroid therapy. The recently published international consensus diagnostic criteria for autoimmune pancreatitis, which is also based on histology, imaging findings, serology, other organ involvement, and response to steroid therapy,2 was used from 2011. Further classification into types 1 and 2 autoimmune pancreatitis (comprising of both definitive and probable cases) by the new international consensus diagnostic criteria was made in an effort to describe the clinical profiles associated with lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP), respectively.2
Figure 1 Contrast-enhanced coronal T1-weighted MRI image of a 42year-old man, which demonstrates diffuse mural thickening and enhancement involving the CBD as well as of the right and left main hepatic ducts (white arrows). The diagnosis of IgG4-related sclerosing cholangitis was confirmed following endoscopic biopsy of the ampulla of Vater.
The affected segments of the biliary tree in patients with IgG4-related sclerosing cholangitis may demonstrate focal or diffuse mural thickening, increased post-contrast enhancement, luminal irregularity, and stenoses (Fig 1).8 The intrapancreatic segment of the common bile duct
Extrapancreatic IgG4-related disease Biliary and gallbladder disease The biliary tree is the most common extrapancreatic site of involvement in IgG4-related disease, manifesting as IgG4-related sclerosing cholangitis.5 Although best depicted on magnetic resonance cholangiopancreatography (MRCP) or endoscopic cholangiopancreatography (ERCP), biliary tree involvement in the majority of cases is usually first identified on CT at the time of initial presentation.
Figure 2 A 61-year-old man with biopsy proven IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma. Coronal T2weighted (top) and contrast-enhanced T1-weighted (bottom) MRI images show an enhancing soft-tissue mass at the hepatic confluence (white arrowheads).
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Figure 3 Coronal T2-weighted (top) and contrast-enhanced T1weighted (bottom) MRI images of a 40-year-old man, which show abrupt truncation of the mid-CBD and enhancing periductal soft tissue (white arrows), mimicking cholangiocarcinoma. IgG4-related sclerosing cholangitis was diagnosed histopathologically following Whipple’s surgery.
(CBD) is most commonly involved, and this usually leads to upstream biliary ductal dilatation and obstructive jaundice,9 although in practical terms, this is considered as part of the spectrum of pancreatic IgG4-related disease or autoimmune pancreatitis. When a suprapancreatic, intrahepatic, or extrahepatic biliary stricture is present, especially with an associated soft-tissue mass, the overall appearance mimics that of a ductal cholangiocarcinoma (Figs 2e4).10 Multifocal intrahepatic short-segment biliary strictures with alternating normal or slightly dilated segments giving rise to a beaded or pruned-tree appearance is occasionally seen in IgG4-related sclerosing cholangitis (Fig 5). This may mimic primary sclerosing cholangitis and makes differentiation between the two conditions difficult based on imaging findings alone. However, primary sclerosing cholangitis is more frequently diagnosed in younger patients (30e40 years) than those with IgG4-related sclerosing cholangitis, with a more gradual disease progression occurring in the latter condition.11 Resolution of symptoms, imaging, and biochemical abnormalities in patients with IgG4-related sclerosing cholangitis also often occurs with corticosteroid treatment. In addition, the presence of extrabiliary disease especially with the involvement of the
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Figure 4 A 70-year-old woman with intrahepatic IgG4-related sclerosing cholangitis. Coronal T2-weighted (top) and contrast-enhanced axial T1-weighted (bottom) MRI images demonstrate mass-like ductal mural thickening and enhancement within the left hepatic lobe (white arrows) mimicking cholangiocarcinoma, associated with upstream biliary ductal dilatation (open white arrows).
pancreas or kidneys, is also highly suggestive of IgG4related sclerosing cholangitis.11 IgG4-related sclerosing cholangitis may be self-limiting, or it may progress and lead to biliary cirrhosis without treatment. With corticosteroid therapy, biliary tree involvement often demonstrates a favourable response, although relapses do occur while patients are receiving maintenance corticosteroid therapy.12 Infiltration by IgG4-positive plasma cells and transmural fibrosis may also result in diffuse gall bladder wall thickening in some patients with IgG4-related disease.13 The diffusely thickened gallbladder wall appears hypoechoic on ultrasound, hypointense on T2-weighted MRI images, and demonstrates contrast enhancement that persists on delayed phase images (Fig 5).
Renal disease Approximately a third of patients diagnosed with autoimmune pancreatitis are also found to have renal involvement.14,15 Histological analysis of sites of renal involvement reveals interstitial nephritis, which may improve after corticosteroid therapy,15 albeit with some degree of scar formation. Four disease patterns have been described: round or wedge-shaped renal cortical lesions (Fig 6), small (subcentimetre) peripheral cortical nodules (Fig 7), diffuse patchy involvement, and renal pelvis involvement (Fig 8).15
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Figure 5 Coronal T2-weighted MIP reconstructed MRI image (top) of a 56-year-old man with intrahepatic IgG4-related sclerosing cholangitis reveals multifocal intrahepatic short-segment biliary strictures (white arrow) with alternating normal or slightly dilated segments (open arrow). This gives rise to a beaded or pruned-tree appearance, mimicking primary sclerosing cholangitis. The same patient also had diffuse mural thickening and enhancement of the gall bladder wall as demonstrated by the contrast-enhanced axial T1-weighted MRI image (bottom). Histopathological analysis was used to confirm the diagnosis of IgG4-related disease following cholecystectomy.
Renal cortical lesions are usually multiple, bilateral, and are composed of lymphoplasmacytic infiltrates. Focal pyelonephritis or metastases are differential diagnoses if round or wedge-shaped nodules are present, although these can be readily excluded in the appropriate clinical context. Rarely, renal involvement in IgG4-related disease may manifest as a solitary lesion, which may mimic a neoplasm. Renal lesions are typically hypo-attenuating relative to the native renal parenchyma on contrast-enhanced CT images, with mild enhancement seen in the delayed phase images. On MRI, renal lesions appear iso- or hypointense relative to the native renal parenchyma on T1-weighted images, hypointense on T2-weighted images, and demonstrate mild contrast enhancement after contrast medium administration.
Figure 6 Contrast-enhanced axial CT image of a 73-year-old woman (top) with renal involvement from IgG4-related disease reveals round hypodense cortical lesions in both kidneys (black arrows). Contrastenhanced axial CT image of a 42-year-old man (bottom) with bilateral renal involvement from IgG4-related disease demonstrates a hypodense wedge-shaped right renal cortical lesion (black arrow), as well as more diffuse hypodense change of the left kidney (black asterisk).
prominent, homogeneously enhancing, non-necrotic, and non-calcified cervical, intra-thoracic (mediastinal and hilar), abdominal (including peri-pancreatic, para-aortic and mesenteric) as well as inguinal (Fig 9) lymph nodes in patients with IgG4-related disease have been previously
Lymphadenopathy Dense infiltration of lymph nodes by IgG4-positive plasma cells in patients with IgG4-related disease produces lymphadenopathy of varying sizes. The finding of
Figure 7 A 70-year-old man with IgG4-related renal involvement. Contrast-enhanced coronal CT image shows multiple small hypodense peripheral cortical lesions in both kidneys (white arrows).
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Figure 8 A 51-year-old man with renal pelvis involvement from IgG4-related disease. Axial T2-weighted MRI image (top) demonstrates hypointense urothelial thickening of the renal pelves bilaterally (white arrows). Corresponding MRI image following steroid therapy (bottom) shows significant interval reduction in the urothelial thickening (white arrows), which was one of the criteria used for diagnosis. 5,16
reported. Lymphadenopathy in these patients usually responds to corticosteroid therapy.
Head and neck disease The salivary glands are the most frequently involved organs in IgG4-related disease of the head and neck, usually manifesting as homogeneous swelling of the salivary glands bilaterally on imaging.17 The salivary glands demonstrate dense lymphoplasmacytic infiltration with IgG4-positive plasma cells, which eventually results in interstitial fibrosis, acinar atrophy, and subsequent impaired glandular excretory function. Salivary gland involvement is often associated with cervical or mediastinal lymphadenopathy and usually improves following the administration of corticosteroids. Many head and neck diseases that have long been viewed as being confined to single organ systems are now considered to be part of the spectrum of IgG4-related disease. These conditions include chronic sclerosing sialade€ ttner tumour), chronic dacryoadenitis, and nitis (Ku Mikulicz disease (Fig 10), a condition characterized by painless bilateral lacrimal and salivary gland swelling.18e20 € gren’s disease, granulomatosis with polyLymphoma, Sjo angiitis, as well as sarcoidosis should, however, be considered in the differential diagnosis in patients presenting with
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Figure 9 IgG4-related inguinal lymphadenopathy in a 56-year-old man. Contrast-enhanced axial CT image (top) reveals a prominent, homogeneously enhancing left inguinal lymph node (white arrow). There was avid FDG uptake by the enlarged left inguinal lymph node on PET/CT (bottom). Biopsy of the lymph node was used to confirm the diagnosis.
lacrimal and salivary gland enlargement. Orbital inflammatory pseudotumour (Fig 11), pituitary infundibulohypophysitis, and hypertrophic pachymeningitis (Fig 12) have also been reported as extrapancreatic manifestations of IgG4-related disease.21 Hypothyroidism is fairly common in patients with autoimmune pancreatitis. It is now acknowledged that Riedel’s thyroiditis, and probably a fibrosing variant of Hashimoto’s thyroiditis fall within the spectrum of IgG4related disease.22,23 IgG4-related thyroiditis demonstrates a higher degree of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration as compared to non-IgG4-related thyroiditis, although both forms manifest similarly as a diffusely hypoechoic and vascular thyroid gland on ultrasound.24
Retroperitoneal fibrosis and vascular disease There have been several reports of IgG4-related retroperitoneal fibrosis, periarteritis, and periaortitis in the reviewed published literature.25e27 The characteristic radiological findings include abnormal soft-tissue thickening and fat stranding confined to the retroperitoneum, which is usually of low to intermediate T1-weighted and variable T2-weighted signal intensity on MRI, depending on the degree of active inflammation. Enhancement on contrast-enhanced images also varies with the degree of
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Figure 10 A 42-year-old man with Mikulicz’s disease. Contrast-enhanced coronal (left, centre) and axial (right) CT images show diffuse enlargement of the homogeneously enhancing lacrimal (black arrows), parotid, and submandibular glands, respectively (black asterisks). The same patient had biopsy-proven IgG4-related sclerosing cholangitis.
maturity of fibrous tissue. The abnormal soft tissue often surrounds the abdominal aorta and its branches, which in turn show arterial wall thickening in association with luminal stenosis or dilatation (Fig 13). Histological analysis of the arterial lesions has revealed diffuse lymphoplasmacytic infiltration with numerous
Figure 11 IgG4-related orbital inflammatory pseudotumour. Contrast-enhanced axial T1-weighted MRI image in a 37-year-old man (top) demonstrates enhancing intraconal soft tissue surrounding the right optic nerve (white arrow) and extending towards the orbital apex. Biopsy of a left lower eyelid mass (not shown) and elevated serum levels of IgG4 were used to establish the diagnosis. Contrastenhanced axial T1-weighted MRI image in a 61-year-old woman (bottom) reveals enhancing periorbital and intra-orbital, extraconal soft tissue masses (black arrows). Enhancing intraconal soft tissue was noted in the left orbit as well (black asterisk). Histopathological diagnosis of IgG4-related disease was made following biopsy of the periorbital masses.
Figure 12 A 37-year-old man with IgG4-related pituitary infundibulo-hypophysitis and hypertrophic pachymeningitis (same patient as in the top image of Fig 11). Contrast-enhanced axial T1weighted MRI images reveal (top) enlargement of the enhancing pituitary stalk (white arrow) and (bottom) focal dural thickening within the floor of the middle cranial fossa on the left side (white arrow).
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Figure 13 A 54-year-old man with IgG4-related retroperitoneal fibrosis. Axial contrast-enhanced T1-weighted MRI image demonstrates a sliver of enhancing soft tissue (white arrows) partially encasing the abdominal aorta (Ao) and inferior vena cava (IVC).
IgG4-positive plasma cells predominantly involving the adventitia, with attenuation or disruption of the media. Lymphoplasmacytic infiltrates and fibroblast proliferation have also been observed in and around the walls of veins draining the pancreas, resulting in an obliterative phlebitis in patients with autoimmune pancreatitis.
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Figure 15 Contrast-enhanced axial CT image from a 52-year-old man with right internal iliac periarteritis secondary to histopathologically proven IgG4-related disease. The thick cuff of perivascular soft tissue (black arrow) enhances almost to the same degree as the encased right internal iliac artery, the intima of which is partially outlined by a sliver of atherosclerotic calcification.
Although IgG4-related disease involving the aorta and its large branches is relatively common (Figs 14 and 15), coronary artery involvement (Fig 16) is rare, with only a handful of published case reports available in the reviewed literature to the authors’ knowledge.28e30 Mass-like softtissue lesions surrounding the right or left coronary arteries were found in these cases involving individuals over 60 years of age. There were also associated findings of mural thrombi, aneurysmal dilatation, and stenosis.
Paravertebral masses Paravertebral masses can occur in cases of extrapancreatic IgG4-related disease (Fig 17), but usually do not affect the adjacent spine.8 The differential diagnoses include lymphoma, granulomatosis with polyangiitis, extramedullary myeloma or haematopoiesis, and metastasis. Histological correlation is usually necessary for exclusion of malignancy.
Pulmonary disease
Figure 14 Contrast-enhanced axial T1-weighted MRI image (top) from a 56-year-old man with periarteritis secondary to IgG4-related disease shows a thin perivascular cuff of enhancing soft tissue partially encasing the superior mesenteric artery (white arrow). Corresponding MRI image following steroid therapy (bottom) shows interval reduction in the perivascular soft tissue, which was one of the criteria used for diagnosis.
The reported incidence of IgG4-related pulmonary disease in patients with autoimmune pancreatitis is approximately 13%. Pulmonary lesions may be the only extrapancreatic site of involvement, although extrapulmonary lesions often precede pulmonary lesions.31 Pulmonary involvement in IgG4-related disease may manifest as a myriad of imaging findings, which include solid parenchymal nodules (Fig 18) or mass-like lesions; multiple foci of round ground-glass opacities, which mimic bronchioloalveolar carcinoma; a bronchovascular pattern showing thickening of bronchovascular bundles (Fig 18) and interlobular septa, which may appear similar to a lymphoproliferative disorder or sarcoidosis; an alveolar interstitial type associated with bronchiectasis, honeycombing, and areas of diffuse ground-glass opacification, which may resemble non-specific interstitial pneumonia; as well as air-space consolidation.32 Mediastinal or hilar
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Figure 17 Paravertebral mass and periaortitis in a 55-year-old man. Contrast-enhanced axial CT image (top) reveals paravertebral softtissue thickening (white arrow) associated with a periaortic softtissue cuff (open white arrow) partially encasing the thoracic aorta (Ao). FDG PET/CT image (bottom) shows avid uptake by both the paravertebral (white arrow) and periaortic (open white arrow) soft tissue. Note normal FDG uptake by the myocardium (Myo). Histopathological diagnosis of IgG4-related disease was made following imaging guided biopsy of the paravertebral soft tissue.
lymphadenopathy is also a common a feature in patients with IgG4-related pulmonary disease. Parenchymal nodules seen in IgG4-related disease often have spiculated margins, are often confined to one lobe, and mimic the appearance of malignancy. The alveolar interstitial and bronchovascular patterns of disease involvement usually involve all lung zones. Histologically, these pulmonary lesions are characterized by diffuse infiltration with IgG4-positive plasma cells. Figure 16 A 52-year-old man with coronary artery involvement in IgG4-related disease (same patient as in Fig 15). CT coronary angiogram images (a) demonstrate conglomerate soft-tissue masses (black asterisk) surrounding the right coronary artery (RCA) in association with coronary arterial aneurysmal dilatation (black arrow) and luminal stenosis (white arrow). Similar soft-tissue masses were seen surrounding the left coronary artery. CT coronary angiogram images (b) prior (top) and following (bottom) steroid therapy revealed interval reduction in size of the soft-tissue masses surrounding the RCA and left coronary artery (LCA), which was one of the criteria used for diagnosis.
Sclerosing mesenteritis and inflammatory bowel disease Sclerosing mesenteritis is a rare condition characterized by inflammation of the root of the small bowel mesentery. An association with IgG4-related disease has been suggested, with Akram et al. finding marked infiltration with IgG4-positive plasma cells in four out of 12 patients (33%) with sclerosing mesenteritis who had undergone immunohistochemical studies.33 Sclerosing mesenteritis usually
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Figure 18 Axial CT image (lung window; top) demonstrates discrete subcentimetre pulmonary nodules within the right lung base in a 42year-old man with biopsy proven IgG4-related sclerosing cholangitis (white arrows). Peribronchial soft-tissue thickening in the lower lobes of both lungs (white arrows) as well as subcarinal lymphadenopathy (black arrow) are seen in this contrast-enhanced axial CT image (soft-tissue window; bottom) of a 73-year-old woman with IgG4-related autoimmune pancreatitis.
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Figure 19 An 18-year-old man with IgG4-related autoimmune pancreatitis. Contrast-enhanced axial (top) and coronal (bottom) CT images demonstrate diffuse mild colonic wall thickening (white arrows). Colonoscopy confirmed the presence of a pancolitis.
Conclusion appears as mass-like soft-tissue thickening encasing the mesenteric vessels on cross-sectional imaging, usually in the root of the small bowel mesentery. Inflammatory bowel disease (Fig 19) has also been found to be more frequently associated with IDCP (type II autoimmune pancreatitis) as compared to LPSP (type I autoimmune pancreatitis).34
Other organ involvement Although gastritis and gastric ulcers can be associated with IgG4-related disease and autoimmune pancreatitis, rare cases of extrapancreatic IgG4-related disease manifesting as a focal gastric mass have also been reported.35 There are also a few histologically confirmed cases of extrapancreatic IgG4-related disease involving the omentum, ureters, prostate, seminal vesicles, testicles, and breast in the published literature.35e41 Histopathological findings in these cases are similar to those of other organs affected by IgG4-related disease and typically show partial or total parenchymal replacement with dense stromal fibrosis and IgG4-positive plasma cells.
Autoimmune pancreatitis is the most common manifestation of IgG4-related disease and typical imaging findings have been extensively described in the published literature. However, it is important for the reporting radiologist to also recognize the myriad of extrapancreatic manifestations of this multisystem disorder. This will allow for an accurate and timely diagnosis to be made, avoiding unnecessary invasive procedures, and ensuring that early effective corticosteroid therapy is commenced.
References 1. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982e4. 2. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the international association of pancreatology. Pancreas 2011;40:352e8. 3. Procter RD, Rofe CJ, Bryant TJC, et al. Autoimmune pancreatitis: an illustrated guide to diagnosis. Clin Radiol 2013;68:422e32. 4. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539e51. 5. Vlachou PA, Khalili K, Jang HJ, et al. IgG4-related sclerosing disease: autoimmune pancreatitis and extrapancreatic manifestations. RadioGraphics 2011;31:1379e402.
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6. Nakatani K, Nakamoto Y, Togashi K. Utility of FDG PET/CT in IgG4-related systemic disease. Clin Radiol 2012;67:297e305. 7. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010e6. 8. Horger M, Lamprecht H-G, Bares R, et al. Systemic IgG4-related sclerosing disease: spectrum of imaging findings and differential diagnosis. AJR Am J Roentgenol 2012;199:276e82. 9. Kawamoto S, Siegelman SS, Hruban RH, et al. Lymphoplasmacytic sclerosing pancreatitis (autoimmune pancreatitis): evaluation with multidetector CT. RadioGraphics 2008;28:157e70. 10. Bodily KD, Takahashi N, Fletcher J, et al. Autoimmune pancreatitis: pancreatic and extrapancreatic imaging findings. AJR Am J Roentgenol 2009;192:431e7. 11. Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroenterol 2008;14:3948e55. 12. Takahashi N, Fletcher JG, Fidler JL, et al. Dual-phase CT of autoimmune pancreatitis: a multireader study. AJR Am J Roentgenol 2008;190:280e6. 13. Kamisawa T, Tu Y, Nakajima H, et al. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J Gastroenterol 2006;12:3736e9. 14. Khalili K, Doyle DJ, Chawla TP, et al. Renal cortical lesions in patients with autoimmune pancreatitis: a clue to differentiation from pancreatic malignancy. Eur J Radiol 2008;67:329e35. 15. Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology 2007;242:791e801. 16. Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol 2010;76:228e38. 17. Fujita A, Sakai O, Chapman MN, et al. IgG4-related disease of the head and neck: CT and MR imaging manifestations. RadioGraphics 2012;32:1945e58. 18. Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell € ttner’s tuinfiltration characterizes chronic sclerosing sialadenitis (Ku mor). Am J Surg Pathol 2005;29:783e91. 19. Kamisawa T, Takuma K, Kuruma S, et al. Lacrimal gland function in autoimmune pancreatitis. Intern Med 2009;48:939e43. 20. Yamada K, Kawano M, Inoue R, et al. Clonal relationship between infiltrating immunoglobulin G4 (IgG4)-positive plasma cells in lacrimal glands and circulating IgG4-positive lymphocytes in Mikulicz’s disease. Clin Exp Immunol 2008;152:432e9. 21. Toyoda K, Oba H, Kutomi K, et al. MR imaging of IgG4-related disease in the head and neck and brain. AJNR Am J Neuroradiol 2012;33:2136e9. 22. Dahlgren M, Khosroshahi A, Nielsen GP, et al. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res 2010;62:1312e8. 23. Deshpande V, Huck A, Ooi E, et al. Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease. J Clin Pathol 2012;65:725e8. 24. Li Y, Nishihara E, Hirokawa M, et al. Distinct clinical, serological, and sonographic characteristics of Hashimoto’s thyroiditis based with and
25.
26.
27. 28.
29.
30.
31. 32. 33.
34. 35.
36.
37.
38.
39. 40.
41.
without IgG4-positive plasma cells. J Clin Endocrinol Metab 2010;95:1309e17. Fukukura Y, Fujiyoshi F, Nakamura F, et al. Autoimmune pancreatitis associated with idiopathic retroperitoneal fibrosis. AJR Am J Roentgenol 2003;181:993e5. Kasashima S, Zen Y, Kawashima A, et al. Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis. Am J Surg Pathol 2008;32:197e204. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related periaortitis and periarteritis: CT findings in 17 patients. Radiology 2011;261:625e33. Matsumoto Y, Kasashima S, Kawashima A, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol 2008;39:975e80. Ikutomi M, Matsumura T, Iwata H, et al. Giant tumorous lesions surrounding the right coronary artery associated with immunoglobulinG4-related systemic disease. Cardiology 2011;120:22e6. Kusumoto S, Kawano H, Takeno M, et al. Mass lesions surrounding coronary artery associated with immunoglobulin G4-related disease. J Cardiol Cases 2012;5:e150e4. Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 2009;33:1886e93. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology 2009;251:260e70. Akram S, Pardi DS, Schaffner JA, et al. Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients. Clin Gastroenterol Hepatol 2007;5:589e96. Park DH, Kim MH, Chari ST. Recent advances in autoimmune pancreatitis. Gut 2009;58:1680e9. Kim JH, Byun JH, Lee SS, et al. Atypical manifestations of IgG4-related sclerosing disease in the abdomen: imaging findings and pathologic correlations. AJR Am J Roentgenol 2013;200:102e12. Kim SA, Lee SR, Huh J, et al. IgG4-associated inflammatory pseudotumour of ureter: clinicopathologic and immunohistochemical study of 3 cases. Hum Pathol 2011;42:1178e84. Uehara T, Hamano H, Kawakami M, et al. Autoimmune pancreatitisassociated prostatitis: distinct clinicopathological entity. Pathol Int 2008;58:118e25. Taniguchi T, Kobayashi H, Fukui S, et al. A case of multifocal fibrosclerosis involving posterior mediastinal fibrosis, retroperitoneal fibrosis and a left seminal vesicle with elevated serum IgG4. Hum Pathol 2006;37:1237e9. € smu € ller H, von Weyhern CH, Adam P, et al. Paratesticular fibrous pseuBo dotumor d an IgG4-related disorder? Virchows Arch 2011;458:109e13. Zen Y, Kasahara Y, Horita K, 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;29:275e8. Cheuk W, Chan ALC, Lam WL, et al. IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases. Am J Surg Pathol 2009;33:1058e64.
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Extrapancreatic findings of IgG4-related disease T.J. Tan a, b, *, Y.L. Ng a, D. Tan c, W.S. Fong d, A.S.C. Low a, ** a
Department of Diagnostic Radiology, Singapore General Hospital, Singapore Department of Diagnostic Radiology, Changi General Hospital, Singapore c Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore d Department of Rheumatology and Immunology, Singapore General Hospital, Singapore b
art icl e i nformat ion Article history: Received 1 July 2013 Received in revised form 18 September 2013 Accepted 23 September 2013
IgG4-related disease is a systemic fibro-inflammatory condition, which includes autoimmune pancreatitis as part of the disease spectrum. Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis. Recognizing the wide spectrum of extrapancreatic manifestations of IgG4-related disease coupled with a high clinical index of suspicion will allow for an accurate and timely diagnosis to be made, thus avoiding unnecessary invasive procedures and ensuring that early effective corticosteroid therapy is commenced. This review aims to serve as a concise reference tool for both clinicians and radiologists in the diagnosis of extrapancreatic IgG4-related disease. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction IgG4-related disease is a systemic fibro-inflammatory condition, which was first recognized by Kamisawa et al.1 in 2003, who proposed that autoimmune pancreatitis was a part of the disease spectrum. Autoimmune pancreatitis itself is now considered to encompass two separate disorders according to international consensus diagnostic criteria: lymphoplasmacytic sclerosing pancreatitis (type 1, or “classic” autoimmune pancreatitis), which is associated with IgG4-related disease; and idiopathic duct-centric pancreatitis (type 2 autoimmune pancreatitis), which has substantial clinical overlap with type 1, but is characterized by distinctive histopathological features.2 Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis.3 Although the * Guarantor and correspondent: T.J. Tan, Department of Diagnostic Radiology, Changi General Hospital, 2 Simei Street 3, Singapore 529889. Tel.: þ65 6850 4849; fax: þ65 6260 1703. ** Guarantor and correspondent: A.S.C. Low, Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore 169608. Tel.: þ65 6321 4069; fax: þ65 6223 6386. E-mail addresses: [email protected] (T.J. Tan), albert.low.s.c@sgh. com.sg (A.S.C. Low).
extrapancreatic imaging findings of IgG4-related disease on their own are non-specific, the imaging identification of these extrapancreatic sites of disease and a high clinical index of suspicion are crucial in establishing a clinical diagnosis of IgG4-related disease. The reported extrapancreatic sites of involvement include the biliary tree, gall bladder, kidneys, retroperitoneum, mesentery, thyroid gland, lacrimal glands, periorbital tissues, meninges, salivary glands, lymph nodes, lungs, gastrointestinal tract, and blood vessels.4,5 Although concurrent autoimmune pancreatitis is present in the majority of patients, IgG4related disease has been reported in patients with no pancreatic involvement.4 The histological features of IgG4-related disease are similar across the various affected organ systems, regardless of the site of disease. These include dense lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and occasional infiltration by eosinophils of the affected organs.4 A dramatic response to corticosteroid therapy is also usually seen in patients with IgG4-related disease, although spontaneous resolution may occur in a minority of patients.4 However, there is no general consensus for the regimen or duration of steroid treatment to date. Disease
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2013.09.021
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recurrence occurs in 20e40% of patients during tapering or following cessation of steroid treatment. The management of recurrent disease is also controversial, but most clinicians administer a repeat course of corticosteroids with an additional immunomodulating agent, such as azathioprine. In this article, the diverse imaging findings of extrapancreatic involvement of IgG4-related disease are discussed based on the authors’ clinical experience with 26 patients seen at the Singapore General Hospital over the past 9 years. All available computed tomography (CT) and magnetic resonance imaging (MRI) examinations of these patients were retrospectively reviewed. Combined 2-[18F]-fluoro-2deoxy-D-glucose (FDG) positron-emission tomography and computed tomography (FDG PET/CT) is an emerging tool in the detection of systemic involvement in patients with IgG4-related disease,6 and these imaging studies, if available, were also perused. The Mayo Clinic’s HISORt criteria (histology, imaging, serology, other organ involvement, response to therapy) as described by Chari et al.7 was used for the diagnosis of autoimmune pancreatitis prior to the year 2011: (a) periductal lymphoplasmacytic infiltrate associated with storiform fibrosis and obliterative phlebitis, or if the lymphoplasmacytic infiltrate demonstrates abundant (>10/ high power field) IgG4-positive plasma cells; (b) typical CT or MRI features of a diffusely enlarged pancreas with delayed (rim) enhancement, as well as a diffusely irregular and attenuated pancreatic duct on pancreatography; (c) serology showing an abnormally elevated serum IgG4 level; (d) evidence of other organ involvement, which includes intra- and extrahepatic biliary strictures, salivary gland involvement, mediastinal lymphadenopathy and retroperitoneal fibrosis; (d) marked improvement or resolution of pancreatic and extrapancreatic manifestations with corticosteroid therapy. The recently published international consensus diagnostic criteria for autoimmune pancreatitis, which is also based on histology, imaging findings, serology, other organ involvement, and response to steroid therapy,2 was used from 2011. Further classification into types 1 and 2 autoimmune pancreatitis (comprising of both definitive and probable cases) by the new international consensus diagnostic criteria was made in an effort to describe the clinical profiles associated with lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP), respectively.2
Figure 1 Contrast-enhanced coronal T1-weighted MRI image of a 42year-old man, which demonstrates diffuse mural thickening and enhancement involving the CBD as well as of the right and left main hepatic ducts (white arrows). The diagnosis of IgG4-related sclerosing cholangitis was confirmed following endoscopic biopsy of the ampulla of Vater.
The affected segments of the biliary tree in patients with IgG4-related sclerosing cholangitis may demonstrate focal or diffuse mural thickening, increased post-contrast enhancement, luminal irregularity, and stenoses (Fig 1).8 The intrapancreatic segment of the common bile duct
Extrapancreatic IgG4-related disease Biliary and gallbladder disease The biliary tree is the most common extrapancreatic site of involvement in IgG4-related disease, manifesting as IgG4-related sclerosing cholangitis.5 Although best depicted on magnetic resonance cholangiopancreatography (MRCP) or endoscopic cholangiopancreatography (ERCP), biliary tree involvement in the majority of cases is usually first identified on CT at the time of initial presentation.
Figure 2 A 61-year-old man with biopsy proven IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma. Coronal T2weighted (top) and contrast-enhanced T1-weighted (bottom) MRI images show an enhancing soft-tissue mass at the hepatic confluence (white arrowheads).
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Figure 3 Coronal T2-weighted (top) and contrast-enhanced T1weighted (bottom) MRI images of a 40-year-old man, which show abrupt truncation of the mid-CBD and enhancing periductal soft tissue (white arrows), mimicking cholangiocarcinoma. IgG4-related sclerosing cholangitis was diagnosed histopathologically following Whipple’s surgery.
(CBD) is most commonly involved, and this usually leads to upstream biliary ductal dilatation and obstructive jaundice,9 although in practical terms, this is considered as part of the spectrum of pancreatic IgG4-related disease or autoimmune pancreatitis. When a suprapancreatic, intrahepatic, or extrahepatic biliary stricture is present, especially with an associated soft-tissue mass, the overall appearance mimics that of a ductal cholangiocarcinoma (Figs 2e4).10 Multifocal intrahepatic short-segment biliary strictures with alternating normal or slightly dilated segments giving rise to a beaded or pruned-tree appearance is occasionally seen in IgG4-related sclerosing cholangitis (Fig 5). This may mimic primary sclerosing cholangitis and makes differentiation between the two conditions difficult based on imaging findings alone. However, primary sclerosing cholangitis is more frequently diagnosed in younger patients (30e40 years) than those with IgG4-related sclerosing cholangitis, with a more gradual disease progression occurring in the latter condition.11 Resolution of symptoms, imaging, and biochemical abnormalities in patients with IgG4-related sclerosing cholangitis also often occurs with corticosteroid treatment. In addition, the presence of extrabiliary disease especially with the involvement of the
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Figure 4 A 70-year-old woman with intrahepatic IgG4-related sclerosing cholangitis. Coronal T2-weighted (top) and contrast-enhanced axial T1-weighted (bottom) MRI images demonstrate mass-like ductal mural thickening and enhancement within the left hepatic lobe (white arrows) mimicking cholangiocarcinoma, associated with upstream biliary ductal dilatation (open white arrows).
pancreas or kidneys, is also highly suggestive of IgG4related sclerosing cholangitis.11 IgG4-related sclerosing cholangitis may be self-limiting, or it may progress and lead to biliary cirrhosis without treatment. With corticosteroid therapy, biliary tree involvement often demonstrates a favourable response, although relapses do occur while patients are receiving maintenance corticosteroid therapy.12 Infiltration by IgG4-positive plasma cells and transmural fibrosis may also result in diffuse gall bladder wall thickening in some patients with IgG4-related disease.13 The diffusely thickened gallbladder wall appears hypoechoic on ultrasound, hypointense on T2-weighted MRI images, and demonstrates contrast enhancement that persists on delayed phase images (Fig 5).
Renal disease Approximately a third of patients diagnosed with autoimmune pancreatitis are also found to have renal involvement.14,15 Histological analysis of sites of renal involvement reveals interstitial nephritis, which may improve after corticosteroid therapy,15 albeit with some degree of scar formation. Four disease patterns have been described: round or wedge-shaped renal cortical lesions (Fig 6), small (subcentimetre) peripheral cortical nodules (Fig 7), diffuse patchy involvement, and renal pelvis involvement (Fig 8).15
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Figure 5 Coronal T2-weighted MIP reconstructed MRI image (top) of a 56-year-old man with intrahepatic IgG4-related sclerosing cholangitis reveals multifocal intrahepatic short-segment biliary strictures (white arrow) with alternating normal or slightly dilated segments (open arrow). This gives rise to a beaded or pruned-tree appearance, mimicking primary sclerosing cholangitis. The same patient also had diffuse mural thickening and enhancement of the gall bladder wall as demonstrated by the contrast-enhanced axial T1-weighted MRI image (bottom). Histopathological analysis was used to confirm the diagnosis of IgG4-related disease following cholecystectomy.
Renal cortical lesions are usually multiple, bilateral, and are composed of lymphoplasmacytic infiltrates. Focal pyelonephritis or metastases are differential diagnoses if round or wedge-shaped nodules are present, although these can be readily excluded in the appropriate clinical context. Rarely, renal involvement in IgG4-related disease may manifest as a solitary lesion, which may mimic a neoplasm. Renal lesions are typically hypo-attenuating relative to the native renal parenchyma on contrast-enhanced CT images, with mild enhancement seen in the delayed phase images. On MRI, renal lesions appear iso- or hypointense relative to the native renal parenchyma on T1-weighted images, hypointense on T2-weighted images, and demonstrate mild contrast enhancement after contrast medium administration.
Figure 6 Contrast-enhanced axial CT image of a 73-year-old woman (top) with renal involvement from IgG4-related disease reveals round hypodense cortical lesions in both kidneys (black arrows). Contrastenhanced axial CT image of a 42-year-old man (bottom) with bilateral renal involvement from IgG4-related disease demonstrates a hypodense wedge-shaped right renal cortical lesion (black arrow), as well as more diffuse hypodense change of the left kidney (black asterisk).
prominent, homogeneously enhancing, non-necrotic, and non-calcified cervical, intra-thoracic (mediastinal and hilar), abdominal (including peri-pancreatic, para-aortic and mesenteric) as well as inguinal (Fig 9) lymph nodes in patients with IgG4-related disease have been previously
Lymphadenopathy Dense infiltration of lymph nodes by IgG4-positive plasma cells in patients with IgG4-related disease produces lymphadenopathy of varying sizes. The finding of
Figure 7 A 70-year-old man with IgG4-related renal involvement. Contrast-enhanced coronal CT image shows multiple small hypodense peripheral cortical lesions in both kidneys (white arrows).
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Figure 8 A 51-year-old man with renal pelvis involvement from IgG4-related disease. Axial T2-weighted MRI image (top) demonstrates hypointense urothelial thickening of the renal pelves bilaterally (white arrows). Corresponding MRI image following steroid therapy (bottom) shows significant interval reduction in the urothelial thickening (white arrows), which was one of the criteria used for diagnosis. 5,16
reported. Lymphadenopathy in these patients usually responds to corticosteroid therapy.
Head and neck disease The salivary glands are the most frequently involved organs in IgG4-related disease of the head and neck, usually manifesting as homogeneous swelling of the salivary glands bilaterally on imaging.17 The salivary glands demonstrate dense lymphoplasmacytic infiltration with IgG4-positive plasma cells, which eventually results in interstitial fibrosis, acinar atrophy, and subsequent impaired glandular excretory function. Salivary gland involvement is often associated with cervical or mediastinal lymphadenopathy and usually improves following the administration of corticosteroids. Many head and neck diseases that have long been viewed as being confined to single organ systems are now considered to be part of the spectrum of IgG4-related disease. These conditions include chronic sclerosing sialade€ ttner tumour), chronic dacryoadenitis, and nitis (Ku Mikulicz disease (Fig 10), a condition characterized by painless bilateral lacrimal and salivary gland swelling.18e20 € gren’s disease, granulomatosis with polyLymphoma, Sjo angiitis, as well as sarcoidosis should, however, be considered in the differential diagnosis in patients presenting with
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Figure 9 IgG4-related inguinal lymphadenopathy in a 56-year-old man. Contrast-enhanced axial CT image (top) reveals a prominent, homogeneously enhancing left inguinal lymph node (white arrow). There was avid FDG uptake by the enlarged left inguinal lymph node on PET/CT (bottom). Biopsy of the lymph node was used to confirm the diagnosis.
lacrimal and salivary gland enlargement. Orbital inflammatory pseudotumour (Fig 11), pituitary infundibulohypophysitis, and hypertrophic pachymeningitis (Fig 12) have also been reported as extrapancreatic manifestations of IgG4-related disease.21 Hypothyroidism is fairly common in patients with autoimmune pancreatitis. It is now acknowledged that Riedel’s thyroiditis, and probably a fibrosing variant of Hashimoto’s thyroiditis fall within the spectrum of IgG4related disease.22,23 IgG4-related thyroiditis demonstrates a higher degree of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration as compared to non-IgG4-related thyroiditis, although both forms manifest similarly as a diffusely hypoechoic and vascular thyroid gland on ultrasound.24
Retroperitoneal fibrosis and vascular disease There have been several reports of IgG4-related retroperitoneal fibrosis, periarteritis, and periaortitis in the reviewed published literature.25e27 The characteristic radiological findings include abnormal soft-tissue thickening and fat stranding confined to the retroperitoneum, which is usually of low to intermediate T1-weighted and variable T2-weighted signal intensity on MRI, depending on the degree of active inflammation. Enhancement on contrast-enhanced images also varies with the degree of
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Figure 10 A 42-year-old man with Mikulicz’s disease. Contrast-enhanced coronal (left, centre) and axial (right) CT images show diffuse enlargement of the homogeneously enhancing lacrimal (black arrows), parotid, and submandibular glands, respectively (black asterisks). The same patient had biopsy-proven IgG4-related sclerosing cholangitis.
maturity of fibrous tissue. The abnormal soft tissue often surrounds the abdominal aorta and its branches, which in turn show arterial wall thickening in association with luminal stenosis or dilatation (Fig 13). Histological analysis of the arterial lesions has revealed diffuse lymphoplasmacytic infiltration with numerous
Figure 11 IgG4-related orbital inflammatory pseudotumour. Contrast-enhanced axial T1-weighted MRI image in a 37-year-old man (top) demonstrates enhancing intraconal soft tissue surrounding the right optic nerve (white arrow) and extending towards the orbital apex. Biopsy of a left lower eyelid mass (not shown) and elevated serum levels of IgG4 were used to establish the diagnosis. Contrastenhanced axial T1-weighted MRI image in a 61-year-old woman (bottom) reveals enhancing periorbital and intra-orbital, extraconal soft tissue masses (black arrows). Enhancing intraconal soft tissue was noted in the left orbit as well (black asterisk). Histopathological diagnosis of IgG4-related disease was made following biopsy of the periorbital masses.
Figure 12 A 37-year-old man with IgG4-related pituitary infundibulo-hypophysitis and hypertrophic pachymeningitis (same patient as in the top image of Fig 11). Contrast-enhanced axial T1weighted MRI images reveal (top) enlargement of the enhancing pituitary stalk (white arrow) and (bottom) focal dural thickening within the floor of the middle cranial fossa on the left side (white arrow).
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Figure 13 A 54-year-old man with IgG4-related retroperitoneal fibrosis. Axial contrast-enhanced T1-weighted MRI image demonstrates a sliver of enhancing soft tissue (white arrows) partially encasing the abdominal aorta (Ao) and inferior vena cava (IVC).
IgG4-positive plasma cells predominantly involving the adventitia, with attenuation or disruption of the media. Lymphoplasmacytic infiltrates and fibroblast proliferation have also been observed in and around the walls of veins draining the pancreas, resulting in an obliterative phlebitis in patients with autoimmune pancreatitis.
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Figure 15 Contrast-enhanced axial CT image from a 52-year-old man with right internal iliac periarteritis secondary to histopathologically proven IgG4-related disease. The thick cuff of perivascular soft tissue (black arrow) enhances almost to the same degree as the encased right internal iliac artery, the intima of which is partially outlined by a sliver of atherosclerotic calcification.
Although IgG4-related disease involving the aorta and its large branches is relatively common (Figs 14 and 15), coronary artery involvement (Fig 16) is rare, with only a handful of published case reports available in the reviewed literature to the authors’ knowledge.28e30 Mass-like softtissue lesions surrounding the right or left coronary arteries were found in these cases involving individuals over 60 years of age. There were also associated findings of mural thrombi, aneurysmal dilatation, and stenosis.
Paravertebral masses Paravertebral masses can occur in cases of extrapancreatic IgG4-related disease (Fig 17), but usually do not affect the adjacent spine.8 The differential diagnoses include lymphoma, granulomatosis with polyangiitis, extramedullary myeloma or haematopoiesis, and metastasis. Histological correlation is usually necessary for exclusion of malignancy.
Pulmonary disease
Figure 14 Contrast-enhanced axial T1-weighted MRI image (top) from a 56-year-old man with periarteritis secondary to IgG4-related disease shows a thin perivascular cuff of enhancing soft tissue partially encasing the superior mesenteric artery (white arrow). Corresponding MRI image following steroid therapy (bottom) shows interval reduction in the perivascular soft tissue, which was one of the criteria used for diagnosis.
The reported incidence of IgG4-related pulmonary disease in patients with autoimmune pancreatitis is approximately 13%. Pulmonary lesions may be the only extrapancreatic site of involvement, although extrapulmonary lesions often precede pulmonary lesions.31 Pulmonary involvement in IgG4-related disease may manifest as a myriad of imaging findings, which include solid parenchymal nodules (Fig 18) or mass-like lesions; multiple foci of round ground-glass opacities, which mimic bronchioloalveolar carcinoma; a bronchovascular pattern showing thickening of bronchovascular bundles (Fig 18) and interlobular septa, which may appear similar to a lymphoproliferative disorder or sarcoidosis; an alveolar interstitial type associated with bronchiectasis, honeycombing, and areas of diffuse ground-glass opacification, which may resemble non-specific interstitial pneumonia; as well as air-space consolidation.32 Mediastinal or hilar
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Figure 17 Paravertebral mass and periaortitis in a 55-year-old man. Contrast-enhanced axial CT image (top) reveals paravertebral softtissue thickening (white arrow) associated with a periaortic softtissue cuff (open white arrow) partially encasing the thoracic aorta (Ao). FDG PET/CT image (bottom) shows avid uptake by both the paravertebral (white arrow) and periaortic (open white arrow) soft tissue. Note normal FDG uptake by the myocardium (Myo). Histopathological diagnosis of IgG4-related disease was made following imaging guided biopsy of the paravertebral soft tissue.
lymphadenopathy is also a common a feature in patients with IgG4-related pulmonary disease. Parenchymal nodules seen in IgG4-related disease often have spiculated margins, are often confined to one lobe, and mimic the appearance of malignancy. The alveolar interstitial and bronchovascular patterns of disease involvement usually involve all lung zones. Histologically, these pulmonary lesions are characterized by diffuse infiltration with IgG4-positive plasma cells. Figure 16 A 52-year-old man with coronary artery involvement in IgG4-related disease (same patient as in Fig 15). CT coronary angiogram images (a) demonstrate conglomerate soft-tissue masses (black asterisk) surrounding the right coronary artery (RCA) in association with coronary arterial aneurysmal dilatation (black arrow) and luminal stenosis (white arrow). Similar soft-tissue masses were seen surrounding the left coronary artery. CT coronary angiogram images (b) prior (top) and following (bottom) steroid therapy revealed interval reduction in size of the soft-tissue masses surrounding the RCA and left coronary artery (LCA), which was one of the criteria used for diagnosis.
Sclerosing mesenteritis and inflammatory bowel disease Sclerosing mesenteritis is a rare condition characterized by inflammation of the root of the small bowel mesentery. An association with IgG4-related disease has been suggested, with Akram et al. finding marked infiltration with IgG4-positive plasma cells in four out of 12 patients (33%) with sclerosing mesenteritis who had undergone immunohistochemical studies.33 Sclerosing mesenteritis usually
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Figure 18 Axial CT image (lung window; top) demonstrates discrete subcentimetre pulmonary nodules within the right lung base in a 42year-old man with biopsy proven IgG4-related sclerosing cholangitis (white arrows). Peribronchial soft-tissue thickening in the lower lobes of both lungs (white arrows) as well as subcarinal lymphadenopathy (black arrow) are seen in this contrast-enhanced axial CT image (soft-tissue window; bottom) of a 73-year-old woman with IgG4-related autoimmune pancreatitis.
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Figure 19 An 18-year-old man with IgG4-related autoimmune pancreatitis. Contrast-enhanced axial (top) and coronal (bottom) CT images demonstrate diffuse mild colonic wall thickening (white arrows). Colonoscopy confirmed the presence of a pancolitis.
Conclusion appears as mass-like soft-tissue thickening encasing the mesenteric vessels on cross-sectional imaging, usually in the root of the small bowel mesentery. Inflammatory bowel disease (Fig 19) has also been found to be more frequently associated with IDCP (type II autoimmune pancreatitis) as compared to LPSP (type I autoimmune pancreatitis).34
Other organ involvement Although gastritis and gastric ulcers can be associated with IgG4-related disease and autoimmune pancreatitis, rare cases of extrapancreatic IgG4-related disease manifesting as a focal gastric mass have also been reported.35 There are also a few histologically confirmed cases of extrapancreatic IgG4-related disease involving the omentum, ureters, prostate, seminal vesicles, testicles, and breast in the published literature.35e41 Histopathological findings in these cases are similar to those of other organs affected by IgG4-related disease and typically show partial or total parenchymal replacement with dense stromal fibrosis and IgG4-positive plasma cells.
Autoimmune pancreatitis is the most common manifestation of IgG4-related disease and typical imaging findings have been extensively described in the published literature. However, it is important for the reporting radiologist to also recognize the myriad of extrapancreatic manifestations of this multisystem disorder. This will allow for an accurate and timely diagnosis to be made, avoiding unnecessary invasive procedures, and ensuring that early effective corticosteroid therapy is commenced.
References 1. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982e4. 2. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the international association of pancreatology. Pancreas 2011;40:352e8. 3. Procter RD, Rofe CJ, Bryant TJC, et al. Autoimmune pancreatitis: an illustrated guide to diagnosis. Clin Radiol 2013;68:422e32. 4. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539e51. 5. Vlachou PA, Khalili K, Jang HJ, et al. IgG4-related sclerosing disease: autoimmune pancreatitis and extrapancreatic manifestations. RadioGraphics 2011;31:1379e402.
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6. Nakatani K, Nakamoto Y, Togashi K. Utility of FDG PET/CT in IgG4-related systemic disease. Clin Radiol 2012;67:297e305. 7. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010e6. 8. Horger M, Lamprecht H-G, Bares R, et al. Systemic IgG4-related sclerosing disease: spectrum of imaging findings and differential diagnosis. AJR Am J Roentgenol 2012;199:276e82. 9. Kawamoto S, Siegelman SS, Hruban RH, et al. Lymphoplasmacytic sclerosing pancreatitis (autoimmune pancreatitis): evaluation with multidetector CT. RadioGraphics 2008;28:157e70. 10. Bodily KD, Takahashi N, Fletcher J, et al. Autoimmune pancreatitis: pancreatic and extrapancreatic imaging findings. AJR Am J Roentgenol 2009;192:431e7. 11. Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroenterol 2008;14:3948e55. 12. Takahashi N, Fletcher JG, Fidler JL, et al. Dual-phase CT of autoimmune pancreatitis: a multireader study. AJR Am J Roentgenol 2008;190:280e6. 13. Kamisawa T, Tu Y, Nakajima H, et al. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J Gastroenterol 2006;12:3736e9. 14. Khalili K, Doyle DJ, Chawla TP, et al. Renal cortical lesions in patients with autoimmune pancreatitis: a clue to differentiation from pancreatic malignancy. Eur J Radiol 2008;67:329e35. 15. Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology 2007;242:791e801. 16. Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol 2010;76:228e38. 17. Fujita A, Sakai O, Chapman MN, et al. IgG4-related disease of the head and neck: CT and MR imaging manifestations. RadioGraphics 2012;32:1945e58. 18. Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell € ttner’s tuinfiltration characterizes chronic sclerosing sialadenitis (Ku mor). Am J Surg Pathol 2005;29:783e91. 19. Kamisawa T, Takuma K, Kuruma S, et al. Lacrimal gland function in autoimmune pancreatitis. Intern Med 2009;48:939e43. 20. Yamada K, Kawano M, Inoue R, et al. Clonal relationship between infiltrating immunoglobulin G4 (IgG4)-positive plasma cells in lacrimal glands and circulating IgG4-positive lymphocytes in Mikulicz’s disease. Clin Exp Immunol 2008;152:432e9. 21. Toyoda K, Oba H, Kutomi K, et al. MR imaging of IgG4-related disease in the head and neck and brain. AJNR Am J Neuroradiol 2012;33:2136e9. 22. Dahlgren M, Khosroshahi A, Nielsen GP, et al. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res 2010;62:1312e8. 23. Deshpande V, Huck A, Ooi E, et al. Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease. J Clin Pathol 2012;65:725e8. 24. Li Y, Nishihara E, Hirokawa M, et al. Distinct clinical, serological, and sonographic characteristics of Hashimoto’s thyroiditis based with and
25.
26.
27. 28.
29.
30.
31. 32. 33.
34. 35.
36.
37.
38.
39. 40.
41.
without IgG4-positive plasma cells. J Clin Endocrinol Metab 2010;95:1309e17. Fukukura Y, Fujiyoshi F, Nakamura F, et al. Autoimmune pancreatitis associated with idiopathic retroperitoneal fibrosis. AJR Am J Roentgenol 2003;181:993e5. Kasashima S, Zen Y, Kawashima A, et al. Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis. Am J Surg Pathol 2008;32:197e204. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related periaortitis and periarteritis: CT findings in 17 patients. Radiology 2011;261:625e33. Matsumoto Y, Kasashima S, Kawashima A, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol 2008;39:975e80. Ikutomi M, Matsumura T, Iwata H, et al. Giant tumorous lesions surrounding the right coronary artery associated with immunoglobulinG4-related systemic disease. Cardiology 2011;120:22e6. Kusumoto S, Kawano H, Takeno M, et al. Mass lesions surrounding coronary artery associated with immunoglobulin G4-related disease. J Cardiol Cases 2012;5:e150e4. Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 2009;33:1886e93. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology 2009;251:260e70. Akram S, Pardi DS, Schaffner JA, et al. Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients. Clin Gastroenterol Hepatol 2007;5:589e96. Park DH, Kim MH, Chari ST. Recent advances in autoimmune pancreatitis. Gut 2009;58:1680e9. Kim JH, Byun JH, Lee SS, et al. Atypical manifestations of IgG4-related sclerosing disease in the abdomen: imaging findings and pathologic correlations. AJR Am J Roentgenol 2013;200:102e12. Kim SA, Lee SR, Huh J, et al. IgG4-associated inflammatory pseudotumour of ureter: clinicopathologic and immunohistochemical study of 3 cases. Hum Pathol 2011;42:1178e84. Uehara T, Hamano H, Kawakami M, et al. Autoimmune pancreatitisassociated prostatitis: distinct clinicopathological entity. Pathol Int 2008;58:118e25. Taniguchi T, Kobayashi H, Fukui S, et al. A case of multifocal fibrosclerosis involving posterior mediastinal fibrosis, retroperitoneal fibrosis and a left seminal vesicle with elevated serum IgG4. Hum Pathol 2006;37:1237e9. € smu € ller H, von Weyhern CH, Adam P, et al. Paratesticular fibrous pseuBo dotumor d an IgG4-related disorder? Virchows Arch 2011;458:109e13. Zen Y, Kasahara Y, Horita K, 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;29:275e8. Cheuk W, Chan ALC, Lam WL, et al. IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases. Am J Surg Pathol 2009;33:1058e64.