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IgG4-Related Disease in the Abdomen: A Great Mimicker
Author's Accepted Manuscript
IgG4-related Disease in the Abdomen: A Great Mimicker Hassan Al Zahrani MD, Tae Kyoung Kim MD, Korosh Khalili MD, Paraskevi Vlachou MD, Hojun Yu MD, Hyun-Jung Jang MD
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S0887-2171(13)00147-9 http://dx.doi.org/10.1053/j.sult.2013.12.002 YSULT570
To appear in: Semin Ultrasound CT MRI
Cite this article as: Hassan Al Zahrani MD, Tae Kyoung Kim MD, Korosh Khalili MD, Paraskevi Vlachou MD, Hojun Yu MD, Hyun-Jung Jang MD, IgG4-related Disease in the Abdomen: A Great Mimicker, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2013.12.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
IgG4-related Disease in the Abdomen: A Great Mimicker
Hassan Al Zahrani, MD,1 Tae Kyoung Kim, MD, 1 Korosh Khalili, MD, 1 Paraskevi Vlachou, MD, 1 Hojun Yu, MD, 2 Hyun-Jung Jang, MD1
1
Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
2
Department of Medical Imaging, QE2 hospital, Grande Prairie, Alberta, Canada
Address reprint requests to Tae Kyoung Kim, MD Department of Medical Imaging, Toronto General Hospital 585 University Avenue Toronto, Ontario, Canada M5G 2N2 Tel: 416-340-3372 E-mail: [email protected]
Abstract
IgG4-related disease is a systemic disorder that can involve various abdominal organs. Abdominal manifestations include autoimmune pancreatitis, sclerosing cholangitis, gallbladder pseudotumours, multifocal renal abnormalities, retroperitoneal fibrosis, and sclerosing mesenteritis. Radiological appearances of the IgG4-related disease often resemble malignant tumors and other inflammatory processes, potentially leading to unnecessary invasive procedures. Moreover, a timely diagnosis of IgG4-related disease leads to an effective treatment by steroid. Therefore, it is important to understand the spectrum of imaging manifestations of IgG4-related disease and their differentiating features from other diagnoses.
Introduction
IgG4-related disease is a broad spectrum systemic disease characterized by an extensive IgG4positive plasma cells and lymphocyte infiltration of various organs and a good response to steroid therapy. Most instances of IgG4-related sclerosing disease are eventually found to be associated with autoimmune pancreatitis (AIP), but cases without pancreatic involvement are occasionally encountered 1. The recent increase in the number of the cases might be related to the awareness of the disease. Variable imaging features of IgG4-related disease and the overlap with other differential diagnoses often pose a diagnostic challenge as it frequently mimics malignant tumors or other inflammatory diseases in the abdomen. The recognition of the suggestive imaging findings and multi-organ involvements is often critical to reach the diagnosis.
Autoimmune Pancreatitis
The diagnosis of AIP is made based on a combination of imaging, serological and histological findings as well as other organ involvement and response to steroids. While there have been some differences among the sets of diagnostic criteria for AIP from different geographic regions, international consensus diagnostic criteria for AIP have recently been proposed. The consensus criteria classified AIP into type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic duct-centric pancreatitis) and described the diagnostic criteria and algorithms for each type. Type 2 AIP is relatively rare and affects younger patients without sex predilection whereas type 1 AIP is more commonly seen in elderly men. Most cases of AIP in Asia belong to type 1. Imaging and response to steroids cannot distinguish type 1 from type 2 but serum IgG4 elevation
and other organ involvement are seen only in type 1. Therefore the definitive diagnosis of type 2 AIP requires pancreatic histology 2.
The imaging patterns of AIP can be diffuse, focal, or multifocal 1. Diffuse pancreatic involvement is most common and typically manifests as a sausage-like enlargement of the pancreas with loss of lobulation (Fig. 1), narrowing adjacent vessels and intrapancreatic portion of the common bile duct 3. The main pancreatic duct demonstrates a diffuse narrowing with or without mild and irregular dilatation. A thin hypoattenuating/hypointense rim (halo sign) surrounding the enlarged pancreas (Fig. 1) is helpful to differentiate AIP from neoplastic diseases such as lymphoma (Fig. 2). Minimal or absent peripancreatic stranding in AIP is useful to differentiate from usual acute pancreatitis. Pancreatic pseudocysts are uncommon in AIP, but their presence does not exclude the possibility of AIP 4 (Fig. 3). The involvement of pancreatic parenchyma in AIP is often non-uniform and heterogeneous even in the cases with diffuse pancreatic involvement. An irregular narrowing of the main pancreatic duct is seen in more severely involved areas while mild pancreatic ductal dilatation is seen in relatively spared areas.
The diagnosis of focal or multifocal diseases in AIP is more challenging than diffuse disease as it mimics pancreatic malignancy (Figs. 4, 5). The halo sign on CT is highly specific for AIP although it is not frequently seen in focal AIP (Figs. 3, 6). Multifocal strictures and irregularity on ERCP or MRCP are also suggestive findings of AIP. The dilatation of the main pancreatic duct tends to be milder (mostly < 5 mm in diameter) and the length of the main pancreatic duct narrowing tends to be longer in AIP (> 30 mm) than pancreatic cancer on MRCP 5. Upstream pancreatic atrophy is more commonly seen in pancreatic cancer, but is occasionally seen in AIP
especially in recurrent or chronic cases 6. Strong enhancement of the involved pancreas in the delayed phase CT or MRI is consistently seen in AIP because of extensive fibrosis whereas it is not commonly seen in pancreatic cancer 5,6 (Figs. 6, 7). Interestingly, AIP tends to show lower apparent diffusion coefficient (ADC) values than pancreatic cancer on diffusion-weighted MR imaging 6,7 (Fig. 7).
Follow-up imaging after steroid therapy usually shows a dramatic improvement of pancreatic abnormalities in AIP as early as a few weeks of steroids (Fig. 6). Moon 8 suggested that a 2-week steroid trial and subsequent imaging assessment of its response may be helpful in confirming the diagnosis of AIP without negative consequences for resectable pancreatic cancer. The pancreas frequently shows atrophy and the increased ADC values on MRI after steroid therapy 7. However, it is important to recognize that relapses either in the pancreas or bile ducts occur in more than 30% of patients during steroid taper or following withdrawal of steroids 9.
Laboratory test for serum IgG4 is needed when there are any suggestive findings of AIP. However, it is important to be aware that a mild elevation in serum IgG4 can be seen in other pancreatic diseases including pancreatic cancer. Tumor markers such as CA 19-9 are more commonly elevated in pancreatic cancer than AIP 5,10. Findings of adjacent extrapancreatic abnormalities in the bile ducts, kidneys, and retroperitoneum on imaging are often helpful to lead to the correct diagnosis of AIP (Fig. 4). Chari et al 11 reported that a pancreatic core biopsy, steroid trial, or surgery was required for diagnosis in approximately 30% of the patients of AIP in their experience of 48 patients with AIP and 100 patients with pancreatic cancer.
Bile Duct Involvement
IgG4-related sclerosing cholangitis is frequently associated with AIP. On cross-sectional imaging, involved bile ducts demonstrate thickened wall with substantial enhancement, luminal narrowing, and upstream biliary dilatation. Bile duct involvement can be confined to the intrapancreatic segment of the common bile duct or can involve proximal extrahepatic and/or intrahepatic bile ducts. Ghazale et al 12 reported in a retrospective cohort of 53 patients that 51% with IgG4-related sclerosing cholangitis had an involvement of intrapancreatic bile duct only, and in the other 49% the proximal extrahepatic/intrahepatic ducts were involved. Serum IgG4 was elevated in 74% and AIP was associated in 92%.
IgG4-related sclerosing disease confined to the intrapancreatic portion of distal common bile duct can mimic pancreatic cancer especially when there is a focal AIP involving the pancreatic head. Imaging appearances suggestive of AIP described earlier are the most important clue to the diagnosis and lead to the test for serum IgG4 levels. A careful evaluation for the involvement of other organs such as the kidneys or retroperitoneum is also helpful 13.
When IgG4-related sclerosing cholangitis involves the proximal extrahepatic/intrahepatic ducts, the imaging findings closely mimic the primary sclerosing cholangitis (PSC) (Figs. 8, 9). The differentiation is important because IgG4-related sclerosing cholangitis usually responds dramatically to steroid therapy, unlike PSC. Although difficult, there are a few clinical and radiological findings that often help the differentiation. Patients with IgG4-related sclerosing cholangitis are usually older and present more abruptly with obstructive jaundice, whereas
obstructive jaundice is uncommon in PSC patients 1. The patients with PSC frequently have a history of ulcerative colitis while IgG4-related sclerosing cholangitis is not related to inflammatory bowel disease. Many of the patients with IgG4-related sclerosing cholangitis have a prior history of AIP. On cholangiography, a beaded appearance and diverticulum-like lesions in the bile ducts are highly suggestive of PSC (Fig. 10) while IgG4-related sclerosing cholangitis frequently affects a longer segment of the bile ducts 14 (Figs. 11, 12). IgG4-related sclerosing cholangitis tends to show thicker bile ducts than PSC and occasionally shows a mass-like focal thickening mimicking cholangiocarcinoma 1 (Fig. 13). Finally, many patients with IgG4-related cholangitis may improve or remain stable many years after the initial presentation, whereas PSC tends to be a slowly progressive disease.
Gallbladder involvement
Gallbladder involvement of IgG4-related disease usually appears as diffuse or focal wall thickening resulting from IgG4-positive plasma cell infiltration and transmural fibrosis 1 (Fig. 11). A large focal gallbladder is a rare manifestation of IgG4-related cholecystitis (Fig. 14). AIP and other organ involvements are often the clue to the diagnosis; however, isolated IgG4-related cholecystitis has been reported 15,16. It might be extremely challenging or impossible to differentiate it from gallbladder cancer when there are no other organ involvements. We recently encountered a case of mass-forming IgG4-related cholecystitis without other organ involvements which was considered a gallbladder cancer preoperatively and the diagnosis of IgG4-related cholecystitis was made only after extensive surgery (Fig. 15).
Renal Involvement
Renal lesions in IgG4-related disease most commonly manifest as multiple wedge-shaped or nodular cortical lesions in unilateral or bilateral kidneys 17 (Figs. 8, 16), which represent areas of tubulointerstitial nephritis with dense lymphoplasmacytic infiltration and interstitial fibrosis 18. These lesions are hypoattenuating or hypointense in the early phase of post-contrast CT or MR images and become less distinct in the late phase of enhancement. The lesions are typically hypointense on T2-weighted MR images. Less common patterns include irregular patchy renal parenchymal lesions, renal pelvic wall thickening, and perirenal rim of soft tissue (Fig. 9) 19.
Bilateral renal cortical nodules in IgG4-related disease can mimic neoplasms such as lymphoma or metastases. Some renal cortical nodules may form a confluent mass with a band-like or geographic configuration (Fig. 14). Hypointensity on T2-weighted MR images and delayed enhancement on post-contrast images may be helpful for the diagnosis.
Renal lesions can mimic renal cell carcinoma or transitional cell carcinoma in uncommon cases of a single unilateral mass-like renal lesion or focal unilateral renal pelvic thickening. Wedgeshaped renal lesions can be also misdiagnosed as pyelonephritis (Fig. 17). The involvement of other organs such as the pancreas, bile ducts, or retroperitoneum is most helpful to reach the diagnosis. Kawano et al 18 reported that 39 of 41 patients (95.1%) with renal IgG4-related disease had other organ involvement. The coexistence of pancreatic and renal cortical lesions can be used as an important clue for the differentiation of IgG4-related disease from pancreatic or renal malignancy 20 (Figs. 9, 14).
Retroperitoneal and Mesenteric Involvement
Retroperitoneal fibrosis is characterized by the presence of a fibro-inflammatory tissue, which usually surrounds the abdominal aorta and extends into the retroperitoneum, often encasing the ureters causing hydronephrosis (Fig. 12). Since the establishment of the concepts of IgG4-related disease, many previously diagnosed cases of idiopathic retroperitoneal fibrosis are now considered IgG4-related disease, especially those that are steroid responsive 21. The lesion most frequently involves the paraaortic region or near the renal hilum 22. Typical imaging appearance is a thin or thick homogenous soft tissue mass surrounding the abdominal aorta and its branches (Figs. 4, 8, 9, 13). The lesion may appear as a bulky soft tissue mass, mimicking a malignancy 23. CT and MRI are most useful for the initial diagnosis and follow-up after steroid treatment. Other organ involvements such as AIP can help to reach the correct diagnosis (Figs. 4, 8, 9, 12). Retroperitoneal fibrosis is not uncommonly detected during the imaging work-up or follow-up for AIP (Fig. 4).
Sclerosing mesenteritis is a rare disorder that involves the small bowel mesentery with varying degrees of fibrosis, inflammation and fat necrosis. Some cases of tumefactive sclerosing mesenteritis have been suggested to be a member of the family of IgG4-related sclerosing disease 24. Akram et al 25 reported that abundant tissue infiltration of IgG4-positive plasma cells was noted in 4 of 12 cases with sclerosing mesenteritis where immunohistochemical studies of the pathologic specimen were available. On contrast-enhanced CT, sclerosing mesenteritis typically appears as a soft-tissue mass encasing and narrowing the mesenteric vessels (Fig. 17).
The mesenteric mass can be contiguous with lesions caused by AIP (Fig. 18). Differentiation from other mesenteric masses including lymphoma, fibromatosis, and neuroendocrine tumor can be challenging. The evaluation with serum IgG4 level and image-guided biopsy of the lesion can lead to the diagnosis, avoiding unnecessary major surgery.
Conclusion
IgG4-related disease is a unique and distinct systemic disease that is frequently misdiagnosed as neoplastic and other inflammatory processes. Focal or multifocal involvement of the pancreas mimics pancreatic malignancy. Bile duct involvement can be easily interpreted as primary sclerosing cholangitis or cholangiocarcinoma. Disease involvement of the gallbladder or kidneys can manifest as pseudotumors mimicking a malignancy. Retroperitoneal fibrosis and sclerosing mesenteritis are occasionally associated with IgG4-related disease. The most important diagnostic clue is often a multi-organ involvement (Fig. 19) and/or a prior history of AIP. The recognition of the typical imaging patterns in each abdominal organ can raise the suspicion of the disease, prompting a careful search for other organ involvement and a laboratory test for serum IgG4 levels. A combination of radiologic, serologic, and histologic findings can lead to the diagnosis, ensuring a timely and effective treatment with steroid.
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Figure Legends
Fig 1. IgG4-related disease in a 68-year-old man. A-B: Axial contrast-enhanced CT shows diffusely enlarged pancreas surrounded by slightly hypoattenuating rim (halo sign) (arrows).
Fig. 2. Lymphoma in a 66-year-old man. A: Axial T1-weighted contrast-enhanced MR image in the arterial phase show multifocal hypointense lesions in the pancreas (arrows). B: Axial T2weighted image shows diffuse swelling of the pancreas with mild hyperintensity and mild focal dilatation of the main pancreatic duct (arrow). C: MRCP in oblique coronal plane shows multifocal smooth narrowing of the main pancreatic duct with mild dilatation in the body and tail. Intrapancreatic portion of the common bile duct also shows a smooth narrowing. Percutaneous biopsy of the pancreatic lesion revealed B-cell lymphoma.
Fig. 3. IgG4-related disease in a 54-year-old man. A: Axial contrast-enhanced CT shows a welldefined hypoattenuating lesion (arrow) superior to the tail of pancreas, representing a pseudocyst. B: CT image at a lower level shows swelling of the pancreatic tail with peripancreatic hypoattenuating halo (arrows).
Fig. 4. IgG4-related disease in a 80-year-old man. A: Transverse ultrasound scan shows a heterogeneously hypoechoic mass in the body of the pancreas (arrows). B-C: Axial contrastenhanced CT scans in the pancreatic phase (B) and portal venous phase (C) show a hypoattenuating mass with progressive enhancement (arrow) associated with upstream pancreatic duct dilatation with parenchymal atrophy in the tail. D: Axial contrast-enhanced CT
scans in the portal venous phase at the level of the kidneys reveals cortical hypoattenuating mass (arrow) in the anterior aspect of the lower pole of the left kidney. E: Axial contrast-enhanced CT scans in the portal venous phase at a lower level demonstrates a rind of soft tissue thickening surrounding the infrarenal abdominal aorta and the proximal segment of the inferior mesenteric artery (arrow).
Fig. 5. IgG4-related disease in a 69-year-old man. A: Axial contrast-enhanced CT scans in the arterial phase (A) and portal venous phase (B) and coronal image in the portal venous phase (C) show an infiltrating mass with heterogeneous enhancement involving the pancreatic tail extending in to the splenic hilum.
Fig. 6. IgG4-related disease in a 56-year-old man. A-B: Axial contrast-enhanced CT scan in the pancreatic phase shows a hypoattenuating mass in the body of the pancreas (long arrow in A). There is abnormal enhancement of the tail of the pancreas and surrounded by thin hypoattenuating rim (arrows). The splenic vein (arrow in B) is attenuated posterior to the pancreatic tail lesion. C: Axial contrast-enhanced CT in the portal venous phase shows progressive enhancement of the pancreatic lesions (arrows). D: Axial contrast-enhanced CT 6 months later after steroid treatment shows complete resolution of the pancreatic lesions.
Fig. 7. IgG4-related disease in a 61-year-old man. A: Axial T1-weighted MR image demonstrates a hypointense mass in the tail of the pancreas (arrow). B-C: The pancreatic tail lesion (arrow) shows hypointensity in the arterial phase (B) of T1-weighted contrast-enhanced and progressive enhancement in the delayed phase (C). D: The pancreatic tail lesion (arrow) is
hyperintense on axial T2-weighted image. E-F: The lesion (arrow) is hyperintense on diffusionweighted image with the b-value of 600 s/mm2 (E) and hypointense on apparent diffusion coefficient map (F), demonstrating a restrictive diffusion.
Fig. 8. IgG4-related disease in an 85-year-old man. A: Coronal CT scan demonstrates marked thickening of the common bile duct (arrows). B: There are small cortical hypoattenuating lesions (arrows) in the right kidney with hydronephrosis. C: Axial T1-weighted contrast-enhanced MRI three months later demonstrates thin, concentric enhancing soft tissue lesion (arrows) surrounding the infrarenal aorta in keeping with retroperitoneal fibrosis. D: Coronal T1-weighted contrast-enhanced MRI six months later after steroid treatment revealed substantial improvement of the common bile duct thickening (arrows).
Fig. 9. IgG4-related disease in a 67-year-old man. A-D: Axial contrast-enhanced CT scans demonstrate diffuse thickening and enhancement of the intrahepatic and extrahepatic bile ducts (arrows in A and B). Intrahepatic bile duct thickening is seen as periportal hypoattenuation (arrows in A). There is mild dilatation of the main pancreatic duct (arrow in C). There are multiple ill-defined cortical hypoattenuating lesions in bilateral kidneys and mild perinephric hypoattenuating soft tissue thickening. Periaortic soft tissue thickening (arrow in D) due to retroperitoneal fibrosis is also seen. E: ERCP image shows irregular narrowing of the main pancreatic duct and the intrapancreatic segment of the common bile duct, which is typical for autoimmune pancreatitis.
Fig. 10. Primary sclerosing cholangitis in a 66-year-old woman. A: Coronal T2-weighted MR images show marked irregularity of the intra and extrahepatic biliary ducts with a beaded appearance and a diverticulum-like lesion (arrow) and mild dilatation of the peripheral intrahepatic bile ducts. B: Oblique coronal MRCP shows an irregularity and beaded appearance of the common bile duct and multifocal biliary strictures with mild dilatation of intrahepatic and extrahepatic biliary tree. There are tiny filling defects in the dilated peripheral intrahepatic bile ducts, in keeping with small calculi or sludge. Incidentally noted are pancreas divisum and a small lobulated cystic lesion in the pancreatic head representing a side-branch intraductal papillary mucinous neoplasm (arrow).
Fig. 11. IgG4-related disease in an 87-year-old man. A-B: Axial T1-weighted contrast-enhanced MR images in the arterial phase show atrophic pancreatic tail and focal thickening with substantial enhancement of the gallbladder neck (arrow in A) and fundus (arrow in B). C: Coronal T1-weighted contrast enhanced MR image in the delayed phase shows bile duct thickening and strong delayed enhancement in the hilar bile duct confluence and distal common bile duct (arrows). D: MRCP in oblique coronal plane shows moderate dilatation of intrahepatic biliary tree with multifocal strictures at the hilar bile duct confluence and intrapancreatic portion of the distal common bile duct. There is mild dilatation of the main pancreatic duct and side in the tail.
Fig. 12. IgG4-related disease in a 58-year-old man. A: Oblique ultrasound scan shows diffuse thickening of the extrahepatic bile duct (arrows) and dilated intrahepatic bile ducts. B: Transverse ultrasound scan at the level of aortic bifurcation shows hypoechoic soft tissue lesion
(arrows) encasing bilateral common iliac arteries. C: Axial T1-weighted contrast-enhanced MR image in the delayed phase shows right sided hydronephrosis. There is enhancing soft tissue thickening partially encasing the infrarenal aorta representing retroperitoneal fibrosis (arrow). D: MRCP shows dilated intrahepatic bile ducts and main pancreatic duct with multi-focal strictures. Gallbladder is distended.
Fig. 13. IgG4-related disease in a 73-year-old man. A-C: Axial T1-weighted contrast-enhanced MR images in the delayed phase demonstrate strong delayed enhancement of the central intrahepatic bile ducts near the hepatic hilum (arrows in A) and proximal extrahepatic bile duct (arrow in B) with mild dilatation of the peripheral intrahepatic ducts. There is periaortic circumferential enhancing soft tissue (arrow in C) representing retroperitoneal fibrosis.
Fig. 14. IgG4-related disease in a 48-year-old man. A: Axial contrast-enhanced CT scans show hypoattenuating masses in the upper pole of the bilateral kidneys (arrows in A). B: The pancreas is diffusely swollen and hypoattenuating with peripancreatic hypoattenuating halo (arrow). A stent is seen in the common bile duct. C-D: Axial contrast-enhanced follow up CT scans 4 years later demonstrate atrophic pancreas and marked interval resolution of bilateral renal masses causing renal capsular retraction. There is newly developed mass in the gallbladder extending to the adjacent liver parenchyma (arrow).
Fig. 15. IgG4-related disease in a 60-year-old man. A-D: Axial (A-C) and coronal (D) contrastenhanced CT scans in the portal venous phase show dilated intrahepatic bile ducts and a hypoattenuating mass replacing the gallbladder (arrows in B-D) with a stone. No abnormality is
seen in the pancreas. The patient underwent cholecystectomy with partial hepatectomy and the gallbladder mass was confirmed as IgG4-related disease.
Fig. 16. IgG4-related disease in a 42-year-old man. A-C: Axial contrast-enhanced CT scans show mild thickening with enhancement of the common bile duct (arrow in A). Bilateral kidneys are enlarged with ill-defined confluent hypoattenuating lesions. The pancreas is mildly atrophic. There are multiple enlarged peripancreatic, mesenteric and retroperitoneal lymph nodes (asterisks in A-C). D: Axial T1-weighted contrast-enhanced MR image 3 years later with steroid treatment reveals interval resolution of renal lesions and abdominal lymphadenopathy. Fig. 17. IgG4-related disease in a 73-year-old woman. A: Axial contrast-enhanced CT scan demonstrates focal dilatation of the main pancreatic duct (arrow) with loss of pancreatic contour lobulation. B: Axial contrast-enhanced CT at the level of kidneys reveal bilateral wedge-shaped cortical hypoattenuating lesions (arrows). C-D: Axial (C) and coronal (D) contrast-enhanced CT scans show a lobulated hypoattenuating mass in the ileocolic mesentery (arrow) encasing mesenteric vessels.
Fig. 18. IgG4-related disease in a 69-year-old man. A-C: Axial contrast-enhanced CT scans in the portal venous phase show diffuse hypoattenuation of the pancreatic body and tail (arrows in A) with mass effect. There is an ill-defined mass (arrows in B and C) involving the mesenteric route encasing and narrowing the lumen of the superior mesenteric artery and superior mesenteric vein. D: Axial contrast-enhanced CT scans in the portal venous phase 6 years later show an atrophic change of the pancreas and resolution of the retroperitoneal masses.
Fig 19. Diagram showing multi-organ involvement of IgG4-related disease.
IgG4-related Disease in the Abdomen: A Great Mimicker Hassan Al Zahrani MD, Tae Kyoung Kim MD, Korosh Khalili MD, Paraskevi Vlachou MD, Hojun Yu MD, Hyun-Jung Jang MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0887-2171(13)00147-9 http://dx.doi.org/10.1053/j.sult.2013.12.002 YSULT570
To appear in: Semin Ultrasound CT MRI
Cite this article as: Hassan Al Zahrani MD, Tae Kyoung Kim MD, Korosh Khalili MD, Paraskevi Vlachou MD, Hojun Yu MD, Hyun-Jung Jang MD, IgG4-related Disease in the Abdomen: A Great Mimicker, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2013.12.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
IgG4-related Disease in the Abdomen: A Great Mimicker
Hassan Al Zahrani, MD,1 Tae Kyoung Kim, MD, 1 Korosh Khalili, MD, 1 Paraskevi Vlachou, MD, 1 Hojun Yu, MD, 2 Hyun-Jung Jang, MD1
1
Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
2
Department of Medical Imaging, QE2 hospital, Grande Prairie, Alberta, Canada
Address reprint requests to Tae Kyoung Kim, MD Department of Medical Imaging, Toronto General Hospital 585 University Avenue Toronto, Ontario, Canada M5G 2N2 Tel: 416-340-3372 E-mail: [email protected]
Abstract
IgG4-related disease is a systemic disorder that can involve various abdominal organs. Abdominal manifestations include autoimmune pancreatitis, sclerosing cholangitis, gallbladder pseudotumours, multifocal renal abnormalities, retroperitoneal fibrosis, and sclerosing mesenteritis. Radiological appearances of the IgG4-related disease often resemble malignant tumors and other inflammatory processes, potentially leading to unnecessary invasive procedures. Moreover, a timely diagnosis of IgG4-related disease leads to an effective treatment by steroid. Therefore, it is important to understand the spectrum of imaging manifestations of IgG4-related disease and their differentiating features from other diagnoses.
Introduction
IgG4-related disease is a broad spectrum systemic disease characterized by an extensive IgG4positive plasma cells and lymphocyte infiltration of various organs and a good response to steroid therapy. Most instances of IgG4-related sclerosing disease are eventually found to be associated with autoimmune pancreatitis (AIP), but cases without pancreatic involvement are occasionally encountered 1. The recent increase in the number of the cases might be related to the awareness of the disease. Variable imaging features of IgG4-related disease and the overlap with other differential diagnoses often pose a diagnostic challenge as it frequently mimics malignant tumors or other inflammatory diseases in the abdomen. The recognition of the suggestive imaging findings and multi-organ involvements is often critical to reach the diagnosis.
Autoimmune Pancreatitis
The diagnosis of AIP is made based on a combination of imaging, serological and histological findings as well as other organ involvement and response to steroids. While there have been some differences among the sets of diagnostic criteria for AIP from different geographic regions, international consensus diagnostic criteria for AIP have recently been proposed. The consensus criteria classified AIP into type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic duct-centric pancreatitis) and described the diagnostic criteria and algorithms for each type. Type 2 AIP is relatively rare and affects younger patients without sex predilection whereas type 1 AIP is more commonly seen in elderly men. Most cases of AIP in Asia belong to type 1. Imaging and response to steroids cannot distinguish type 1 from type 2 but serum IgG4 elevation
and other organ involvement are seen only in type 1. Therefore the definitive diagnosis of type 2 AIP requires pancreatic histology 2.
The imaging patterns of AIP can be diffuse, focal, or multifocal 1. Diffuse pancreatic involvement is most common and typically manifests as a sausage-like enlargement of the pancreas with loss of lobulation (Fig. 1), narrowing adjacent vessels and intrapancreatic portion of the common bile duct 3. The main pancreatic duct demonstrates a diffuse narrowing with or without mild and irregular dilatation. A thin hypoattenuating/hypointense rim (halo sign) surrounding the enlarged pancreas (Fig. 1) is helpful to differentiate AIP from neoplastic diseases such as lymphoma (Fig. 2). Minimal or absent peripancreatic stranding in AIP is useful to differentiate from usual acute pancreatitis. Pancreatic pseudocysts are uncommon in AIP, but their presence does not exclude the possibility of AIP 4 (Fig. 3). The involvement of pancreatic parenchyma in AIP is often non-uniform and heterogeneous even in the cases with diffuse pancreatic involvement. An irregular narrowing of the main pancreatic duct is seen in more severely involved areas while mild pancreatic ductal dilatation is seen in relatively spared areas.
The diagnosis of focal or multifocal diseases in AIP is more challenging than diffuse disease as it mimics pancreatic malignancy (Figs. 4, 5). The halo sign on CT is highly specific for AIP although it is not frequently seen in focal AIP (Figs. 3, 6). Multifocal strictures and irregularity on ERCP or MRCP are also suggestive findings of AIP. The dilatation of the main pancreatic duct tends to be milder (mostly < 5 mm in diameter) and the length of the main pancreatic duct narrowing tends to be longer in AIP (> 30 mm) than pancreatic cancer on MRCP 5. Upstream pancreatic atrophy is more commonly seen in pancreatic cancer, but is occasionally seen in AIP
especially in recurrent or chronic cases 6. Strong enhancement of the involved pancreas in the delayed phase CT or MRI is consistently seen in AIP because of extensive fibrosis whereas it is not commonly seen in pancreatic cancer 5,6 (Figs. 6, 7). Interestingly, AIP tends to show lower apparent diffusion coefficient (ADC) values than pancreatic cancer on diffusion-weighted MR imaging 6,7 (Fig. 7).
Follow-up imaging after steroid therapy usually shows a dramatic improvement of pancreatic abnormalities in AIP as early as a few weeks of steroids (Fig. 6). Moon 8 suggested that a 2-week steroid trial and subsequent imaging assessment of its response may be helpful in confirming the diagnosis of AIP without negative consequences for resectable pancreatic cancer. The pancreas frequently shows atrophy and the increased ADC values on MRI after steroid therapy 7. However, it is important to recognize that relapses either in the pancreas or bile ducts occur in more than 30% of patients during steroid taper or following withdrawal of steroids 9.
Laboratory test for serum IgG4 is needed when there are any suggestive findings of AIP. However, it is important to be aware that a mild elevation in serum IgG4 can be seen in other pancreatic diseases including pancreatic cancer. Tumor markers such as CA 19-9 are more commonly elevated in pancreatic cancer than AIP 5,10. Findings of adjacent extrapancreatic abnormalities in the bile ducts, kidneys, and retroperitoneum on imaging are often helpful to lead to the correct diagnosis of AIP (Fig. 4). Chari et al 11 reported that a pancreatic core biopsy, steroid trial, or surgery was required for diagnosis in approximately 30% of the patients of AIP in their experience of 48 patients with AIP and 100 patients with pancreatic cancer.
Bile Duct Involvement
IgG4-related sclerosing cholangitis is frequently associated with AIP. On cross-sectional imaging, involved bile ducts demonstrate thickened wall with substantial enhancement, luminal narrowing, and upstream biliary dilatation. Bile duct involvement can be confined to the intrapancreatic segment of the common bile duct or can involve proximal extrahepatic and/or intrahepatic bile ducts. Ghazale et al 12 reported in a retrospective cohort of 53 patients that 51% with IgG4-related sclerosing cholangitis had an involvement of intrapancreatic bile duct only, and in the other 49% the proximal extrahepatic/intrahepatic ducts were involved. Serum IgG4 was elevated in 74% and AIP was associated in 92%.
IgG4-related sclerosing disease confined to the intrapancreatic portion of distal common bile duct can mimic pancreatic cancer especially when there is a focal AIP involving the pancreatic head. Imaging appearances suggestive of AIP described earlier are the most important clue to the diagnosis and lead to the test for serum IgG4 levels. A careful evaluation for the involvement of other organs such as the kidneys or retroperitoneum is also helpful 13.
When IgG4-related sclerosing cholangitis involves the proximal extrahepatic/intrahepatic ducts, the imaging findings closely mimic the primary sclerosing cholangitis (PSC) (Figs. 8, 9). The differentiation is important because IgG4-related sclerosing cholangitis usually responds dramatically to steroid therapy, unlike PSC. Although difficult, there are a few clinical and radiological findings that often help the differentiation. Patients with IgG4-related sclerosing cholangitis are usually older and present more abruptly with obstructive jaundice, whereas
obstructive jaundice is uncommon in PSC patients 1. The patients with PSC frequently have a history of ulcerative colitis while IgG4-related sclerosing cholangitis is not related to inflammatory bowel disease. Many of the patients with IgG4-related sclerosing cholangitis have a prior history of AIP. On cholangiography, a beaded appearance and diverticulum-like lesions in the bile ducts are highly suggestive of PSC (Fig. 10) while IgG4-related sclerosing cholangitis frequently affects a longer segment of the bile ducts 14 (Figs. 11, 12). IgG4-related sclerosing cholangitis tends to show thicker bile ducts than PSC and occasionally shows a mass-like focal thickening mimicking cholangiocarcinoma 1 (Fig. 13). Finally, many patients with IgG4-related cholangitis may improve or remain stable many years after the initial presentation, whereas PSC tends to be a slowly progressive disease.
Gallbladder involvement
Gallbladder involvement of IgG4-related disease usually appears as diffuse or focal wall thickening resulting from IgG4-positive plasma cell infiltration and transmural fibrosis 1 (Fig. 11). A large focal gallbladder is a rare manifestation of IgG4-related cholecystitis (Fig. 14). AIP and other organ involvements are often the clue to the diagnosis; however, isolated IgG4-related cholecystitis has been reported 15,16. It might be extremely challenging or impossible to differentiate it from gallbladder cancer when there are no other organ involvements. We recently encountered a case of mass-forming IgG4-related cholecystitis without other organ involvements which was considered a gallbladder cancer preoperatively and the diagnosis of IgG4-related cholecystitis was made only after extensive surgery (Fig. 15).
Renal Involvement
Renal lesions in IgG4-related disease most commonly manifest as multiple wedge-shaped or nodular cortical lesions in unilateral or bilateral kidneys 17 (Figs. 8, 16), which represent areas of tubulointerstitial nephritis with dense lymphoplasmacytic infiltration and interstitial fibrosis 18. These lesions are hypoattenuating or hypointense in the early phase of post-contrast CT or MR images and become less distinct in the late phase of enhancement. The lesions are typically hypointense on T2-weighted MR images. Less common patterns include irregular patchy renal parenchymal lesions, renal pelvic wall thickening, and perirenal rim of soft tissue (Fig. 9) 19.
Bilateral renal cortical nodules in IgG4-related disease can mimic neoplasms such as lymphoma or metastases. Some renal cortical nodules may form a confluent mass with a band-like or geographic configuration (Fig. 14). Hypointensity on T2-weighted MR images and delayed enhancement on post-contrast images may be helpful for the diagnosis.
Renal lesions can mimic renal cell carcinoma or transitional cell carcinoma in uncommon cases of a single unilateral mass-like renal lesion or focal unilateral renal pelvic thickening. Wedgeshaped renal lesions can be also misdiagnosed as pyelonephritis (Fig. 17). The involvement of other organs such as the pancreas, bile ducts, or retroperitoneum is most helpful to reach the diagnosis. Kawano et al 18 reported that 39 of 41 patients (95.1%) with renal IgG4-related disease had other organ involvement. The coexistence of pancreatic and renal cortical lesions can be used as an important clue for the differentiation of IgG4-related disease from pancreatic or renal malignancy 20 (Figs. 9, 14).
Retroperitoneal and Mesenteric Involvement
Retroperitoneal fibrosis is characterized by the presence of a fibro-inflammatory tissue, which usually surrounds the abdominal aorta and extends into the retroperitoneum, often encasing the ureters causing hydronephrosis (Fig. 12). Since the establishment of the concepts of IgG4-related disease, many previously diagnosed cases of idiopathic retroperitoneal fibrosis are now considered IgG4-related disease, especially those that are steroid responsive 21. The lesion most frequently involves the paraaortic region or near the renal hilum 22. Typical imaging appearance is a thin or thick homogenous soft tissue mass surrounding the abdominal aorta and its branches (Figs. 4, 8, 9, 13). The lesion may appear as a bulky soft tissue mass, mimicking a malignancy 23. CT and MRI are most useful for the initial diagnosis and follow-up after steroid treatment. Other organ involvements such as AIP can help to reach the correct diagnosis (Figs. 4, 8, 9, 12). Retroperitoneal fibrosis is not uncommonly detected during the imaging work-up or follow-up for AIP (Fig. 4).
Sclerosing mesenteritis is a rare disorder that involves the small bowel mesentery with varying degrees of fibrosis, inflammation and fat necrosis. Some cases of tumefactive sclerosing mesenteritis have been suggested to be a member of the family of IgG4-related sclerosing disease 24. Akram et al 25 reported that abundant tissue infiltration of IgG4-positive plasma cells was noted in 4 of 12 cases with sclerosing mesenteritis where immunohistochemical studies of the pathologic specimen were available. On contrast-enhanced CT, sclerosing mesenteritis typically appears as a soft-tissue mass encasing and narrowing the mesenteric vessels (Fig. 17).
The mesenteric mass can be contiguous with lesions caused by AIP (Fig. 18). Differentiation from other mesenteric masses including lymphoma, fibromatosis, and neuroendocrine tumor can be challenging. The evaluation with serum IgG4 level and image-guided biopsy of the lesion can lead to the diagnosis, avoiding unnecessary major surgery.
Conclusion
IgG4-related disease is a unique and distinct systemic disease that is frequently misdiagnosed as neoplastic and other inflammatory processes. Focal or multifocal involvement of the pancreas mimics pancreatic malignancy. Bile duct involvement can be easily interpreted as primary sclerosing cholangitis or cholangiocarcinoma. Disease involvement of the gallbladder or kidneys can manifest as pseudotumors mimicking a malignancy. Retroperitoneal fibrosis and sclerosing mesenteritis are occasionally associated with IgG4-related disease. The most important diagnostic clue is often a multi-organ involvement (Fig. 19) and/or a prior history of AIP. The recognition of the typical imaging patterns in each abdominal organ can raise the suspicion of the disease, prompting a careful search for other organ involvement and a laboratory test for serum IgG4 levels. A combination of radiologic, serologic, and histologic findings can lead to the diagnosis, ensuring a timely and effective treatment with steroid.
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Figure Legends
Fig 1. IgG4-related disease in a 68-year-old man. A-B: Axial contrast-enhanced CT shows diffusely enlarged pancreas surrounded by slightly hypoattenuating rim (halo sign) (arrows).
Fig. 2. Lymphoma in a 66-year-old man. A: Axial T1-weighted contrast-enhanced MR image in the arterial phase show multifocal hypointense lesions in the pancreas (arrows). B: Axial T2weighted image shows diffuse swelling of the pancreas with mild hyperintensity and mild focal dilatation of the main pancreatic duct (arrow). C: MRCP in oblique coronal plane shows multifocal smooth narrowing of the main pancreatic duct with mild dilatation in the body and tail. Intrapancreatic portion of the common bile duct also shows a smooth narrowing. Percutaneous biopsy of the pancreatic lesion revealed B-cell lymphoma.
Fig. 3. IgG4-related disease in a 54-year-old man. A: Axial contrast-enhanced CT shows a welldefined hypoattenuating lesion (arrow) superior to the tail of pancreas, representing a pseudocyst. B: CT image at a lower level shows swelling of the pancreatic tail with peripancreatic hypoattenuating halo (arrows).
Fig. 4. IgG4-related disease in a 80-year-old man. A: Transverse ultrasound scan shows a heterogeneously hypoechoic mass in the body of the pancreas (arrows). B-C: Axial contrastenhanced CT scans in the pancreatic phase (B) and portal venous phase (C) show a hypoattenuating mass with progressive enhancement (arrow) associated with upstream pancreatic duct dilatation with parenchymal atrophy in the tail. D: Axial contrast-enhanced CT
scans in the portal venous phase at the level of the kidneys reveals cortical hypoattenuating mass (arrow) in the anterior aspect of the lower pole of the left kidney. E: Axial contrast-enhanced CT scans in the portal venous phase at a lower level demonstrates a rind of soft tissue thickening surrounding the infrarenal abdominal aorta and the proximal segment of the inferior mesenteric artery (arrow).
Fig. 5. IgG4-related disease in a 69-year-old man. A: Axial contrast-enhanced CT scans in the arterial phase (A) and portal venous phase (B) and coronal image in the portal venous phase (C) show an infiltrating mass with heterogeneous enhancement involving the pancreatic tail extending in to the splenic hilum.
Fig. 6. IgG4-related disease in a 56-year-old man. A-B: Axial contrast-enhanced CT scan in the pancreatic phase shows a hypoattenuating mass in the body of the pancreas (long arrow in A). There is abnormal enhancement of the tail of the pancreas and surrounded by thin hypoattenuating rim (arrows). The splenic vein (arrow in B) is attenuated posterior to the pancreatic tail lesion. C: Axial contrast-enhanced CT in the portal venous phase shows progressive enhancement of the pancreatic lesions (arrows). D: Axial contrast-enhanced CT 6 months later after steroid treatment shows complete resolution of the pancreatic lesions.
Fig. 7. IgG4-related disease in a 61-year-old man. A: Axial T1-weighted MR image demonstrates a hypointense mass in the tail of the pancreas (arrow). B-C: The pancreatic tail lesion (arrow) shows hypointensity in the arterial phase (B) of T1-weighted contrast-enhanced and progressive enhancement in the delayed phase (C). D: The pancreatic tail lesion (arrow) is
hyperintense on axial T2-weighted image. E-F: The lesion (arrow) is hyperintense on diffusionweighted image with the b-value of 600 s/mm2 (E) and hypointense on apparent diffusion coefficient map (F), demonstrating a restrictive diffusion.
Fig. 8. IgG4-related disease in an 85-year-old man. A: Coronal CT scan demonstrates marked thickening of the common bile duct (arrows). B: There are small cortical hypoattenuating lesions (arrows) in the right kidney with hydronephrosis. C: Axial T1-weighted contrast-enhanced MRI three months later demonstrates thin, concentric enhancing soft tissue lesion (arrows) surrounding the infrarenal aorta in keeping with retroperitoneal fibrosis. D: Coronal T1-weighted contrast-enhanced MRI six months later after steroid treatment revealed substantial improvement of the common bile duct thickening (arrows).
Fig. 9. IgG4-related disease in a 67-year-old man. A-D: Axial contrast-enhanced CT scans demonstrate diffuse thickening and enhancement of the intrahepatic and extrahepatic bile ducts (arrows in A and B). Intrahepatic bile duct thickening is seen as periportal hypoattenuation (arrows in A). There is mild dilatation of the main pancreatic duct (arrow in C). There are multiple ill-defined cortical hypoattenuating lesions in bilateral kidneys and mild perinephric hypoattenuating soft tissue thickening. Periaortic soft tissue thickening (arrow in D) due to retroperitoneal fibrosis is also seen. E: ERCP image shows irregular narrowing of the main pancreatic duct and the intrapancreatic segment of the common bile duct, which is typical for autoimmune pancreatitis.
Fig. 10. Primary sclerosing cholangitis in a 66-year-old woman. A: Coronal T2-weighted MR images show marked irregularity of the intra and extrahepatic biliary ducts with a beaded appearance and a diverticulum-like lesion (arrow) and mild dilatation of the peripheral intrahepatic bile ducts. B: Oblique coronal MRCP shows an irregularity and beaded appearance of the common bile duct and multifocal biliary strictures with mild dilatation of intrahepatic and extrahepatic biliary tree. There are tiny filling defects in the dilated peripheral intrahepatic bile ducts, in keeping with small calculi or sludge. Incidentally noted are pancreas divisum and a small lobulated cystic lesion in the pancreatic head representing a side-branch intraductal papillary mucinous neoplasm (arrow).
Fig. 11. IgG4-related disease in an 87-year-old man. A-B: Axial T1-weighted contrast-enhanced MR images in the arterial phase show atrophic pancreatic tail and focal thickening with substantial enhancement of the gallbladder neck (arrow in A) and fundus (arrow in B). C: Coronal T1-weighted contrast enhanced MR image in the delayed phase shows bile duct thickening and strong delayed enhancement in the hilar bile duct confluence and distal common bile duct (arrows). D: MRCP in oblique coronal plane shows moderate dilatation of intrahepatic biliary tree with multifocal strictures at the hilar bile duct confluence and intrapancreatic portion of the distal common bile duct. There is mild dilatation of the main pancreatic duct and side in the tail.
Fig. 12. IgG4-related disease in a 58-year-old man. A: Oblique ultrasound scan shows diffuse thickening of the extrahepatic bile duct (arrows) and dilated intrahepatic bile ducts. B: Transverse ultrasound scan at the level of aortic bifurcation shows hypoechoic soft tissue lesion
(arrows) encasing bilateral common iliac arteries. C: Axial T1-weighted contrast-enhanced MR image in the delayed phase shows right sided hydronephrosis. There is enhancing soft tissue thickening partially encasing the infrarenal aorta representing retroperitoneal fibrosis (arrow). D: MRCP shows dilated intrahepatic bile ducts and main pancreatic duct with multi-focal strictures. Gallbladder is distended.
Fig. 13. IgG4-related disease in a 73-year-old man. A-C: Axial T1-weighted contrast-enhanced MR images in the delayed phase demonstrate strong delayed enhancement of the central intrahepatic bile ducts near the hepatic hilum (arrows in A) and proximal extrahepatic bile duct (arrow in B) with mild dilatation of the peripheral intrahepatic ducts. There is periaortic circumferential enhancing soft tissue (arrow in C) representing retroperitoneal fibrosis.
Fig. 14. IgG4-related disease in a 48-year-old man. A: Axial contrast-enhanced CT scans show hypoattenuating masses in the upper pole of the bilateral kidneys (arrows in A). B: The pancreas is diffusely swollen and hypoattenuating with peripancreatic hypoattenuating halo (arrow). A stent is seen in the common bile duct. C-D: Axial contrast-enhanced follow up CT scans 4 years later demonstrate atrophic pancreas and marked interval resolution of bilateral renal masses causing renal capsular retraction. There is newly developed mass in the gallbladder extending to the adjacent liver parenchyma (arrow).
Fig. 15. IgG4-related disease in a 60-year-old man. A-D: Axial (A-C) and coronal (D) contrastenhanced CT scans in the portal venous phase show dilated intrahepatic bile ducts and a hypoattenuating mass replacing the gallbladder (arrows in B-D) with a stone. No abnormality is
seen in the pancreas. The patient underwent cholecystectomy with partial hepatectomy and the gallbladder mass was confirmed as IgG4-related disease.
Fig. 16. IgG4-related disease in a 42-year-old man. A-C: Axial contrast-enhanced CT scans show mild thickening with enhancement of the common bile duct (arrow in A). Bilateral kidneys are enlarged with ill-defined confluent hypoattenuating lesions. The pancreas is mildly atrophic. There are multiple enlarged peripancreatic, mesenteric and retroperitoneal lymph nodes (asterisks in A-C). D: Axial T1-weighted contrast-enhanced MR image 3 years later with steroid treatment reveals interval resolution of renal lesions and abdominal lymphadenopathy. Fig. 17. IgG4-related disease in a 73-year-old woman. A: Axial contrast-enhanced CT scan demonstrates focal dilatation of the main pancreatic duct (arrow) with loss of pancreatic contour lobulation. B: Axial contrast-enhanced CT at the level of kidneys reveal bilateral wedge-shaped cortical hypoattenuating lesions (arrows). C-D: Axial (C) and coronal (D) contrast-enhanced CT scans show a lobulated hypoattenuating mass in the ileocolic mesentery (arrow) encasing mesenteric vessels.
Fig. 18. IgG4-related disease in a 69-year-old man. A-C: Axial contrast-enhanced CT scans in the portal venous phase show diffuse hypoattenuation of the pancreatic body and tail (arrows in A) with mass effect. There is an ill-defined mass (arrows in B and C) involving the mesenteric route encasing and narrowing the lumen of the superior mesenteric artery and superior mesenteric vein. D: Axial contrast-enhanced CT scans in the portal venous phase 6 years later show an atrophic change of the pancreas and resolution of the retroperitoneal masses.
Fig 19. Diagram showing multi-organ involvement of IgG4-related disease.