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Autoimmune pancreatitis: An illustrated guide to diagnosis
Clinical Radiology 68 (2013) 422e432
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Pictorial Review
Autoimmune pancreatitis: An illustrated guide to diagnosis R.D. Proctor a, C.J. Rofe b, *, T.J.C. Bryant b, C.N. Hacking b, B. Stedman b a b
Department of Clinical Radiology, Royal Cornwall Hospitals NHS Trust, Truro, UK Department of Clinical Radiology, Southampton University Hospitals NHS Trust, Southampton, UK
article in formation Article history: Received 8 February 2012 Accepted 21 August 2012
Autoimmune pancreatitis (AIP) remains one of the rarer forms of pancreatitis but has become increasingly well recognized and widely diagnosed as it is an important differential, particularly due to the dramatic response to appropriate therapy. It is now best considered as part of a multisystem disease and the notion of “IgG4-related systemic sclerosing disease” has become widely recognized as the number of extra-pancreatic associations of AIP grows. More recently AIP has been classified into two subtypes: lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP) with distinct geographical, age and sex distributions for the two subtypes, in addition to different pathological characteristics. The role of imaging is crucial in AIP and should be considered in conjunction with clinical, serological, and histopathological findings to make the diagnosis. Radiologists are uniquely placed to raise the possibility of AIP and aid the exclusion of significant differentials to allow the initiation of appropriate management and avoidance of unnecessary intervention. Radiological investigation may reveal a number of characteristic imaging findings in AIP but appearances can vary considerably and the focal form of AIP may appear as a pancreatic mass, imitating pancreatic carcinoma. This review will illustrate typical and atypical appearances of AIP on all imaging modes. Emphasis will be placed on the imaging features that are likely to prove useful in discriminating AIP from other causes prior to histopathological confirmation. In addition, examples of relevant differential diagnoses are discussed and illustrated. Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The concept of an immune-mediated form of pancreatitis is not new and Sarles et al.1 proposed an autoimmune mechanism for pancreatitis in 1961. Kawaguchi2 described two cases of lymphoplasmacytic sclerosing pancreatitis (LPSP) in 1991 and, in 1995 Yoshida et al.3 proposed the concept of “AIP” to define chronic pancreatitis that was found in conjunction with autoimmune manifestations * Guarantor and correspondent: C.J. Rofe, Southampton University Hospitals NHS Trust, Tremona Road, Southampton SO16 6YD, UK. Tel.: þ44 (0) 7974205118; fax: þ44 (0) 2380 794720. E-mail address: [email protected] (C.J. Rofe).
seen on histological, serological, and clinical investigations. More recently AIP has become widely accepted as a systemic disease.6e11 There has been widespread interest due to its distinctive clinical features and response to treatment, coupled with frequent difficulties in distinguishing it from important differentials, including pancreatic carcinoma.
Presentation The clinical presentation is variable, features may include jaundice, abdominal pain, back pain, weight loss, fatigue, diabetes mellitus, or the patient may be completely
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asymptomatic.7e10 Presentation with severe abdominal pain and/or acute pancreatitis is, however, uncommon and should raise suspicions of an alternative diagnosis.
Pathogenesis, histopathological and serological findings AIP has come to be seen in the context of a multisystem disorder characterized by a fibro-inflammatory process that responds to steroid treatment and affects multiple organs.4,5,11 A number of extra-pancreatic tissues have also been shown to demonstrate the presence of IgG4-positive plasma cells6,12 leading to the concept of “IgG4-related systemic sclerosing disease”. Although there is strong evidence to suggest an autoimmune component in the pathogenesis of AIP,13,14 the exact relationship remains unclear. A genetic association has been established within the Japanese population,15 although this correlation has yet to be recognized in any other group. A number of immunological abnormalities, including high serum IgG4 levels, hypergammaglobulinaemia and the presence of autoantibodies against carbonic anhydrase and lactoferrin, have been documented as significant markers of AIP9,16 although the role of each of these in the disease process remains unclear. For example, immunohistochemistry in the majority of cases of AIP demonstrates that the plasma cells are predominantly IgG4-positive5,17,18 but infiltration by IgG4-positive cells is also seen in chronic alcoholic pancreatitis and pancreatic carcinoma.5,19 IgG4 may be elevated in 5% of healthy people and 10% of those with pancreatic carcinoma20; elevated levels of IgG4 could simply indicate a secondary response to an as yet unidentified initial trigger of the inflammatory process. The key histopathological traits are inflammation, fibrosis, and vascular changes.6,17,21e23 Inflammation demonstrates a periductal distribution, predominantly affecting the large and medium-sized interlobular ducts,24 and the extent is dependent upon the stage of the disease. Loss of exocrine pancreatic function can occur in advanced disease due to fibrotic replacement of tissue.6 Vascular changes commonly involve veins of small and medium size and are termed “obliterative phlebitis”, manifesting as perivenular inflammation, destruction of the venular wall, and obliteration of the lumen. Features such as pseudocyst formation25 and intraductal calcification,26 which are commonly seen in other forms of pancreatitis, are rare in AIP, but may occasionally occur.
Diagnostic criteria A combination of findings is required to make a diagnosis of AIP, including the imaging appearance and also additional information from serological and histopathological tests. Diagnostic criteria have been proposed and with increasing awareness of AIP, particularly in Japan and Korea, have evolved21,27e29 leading to agreement of the Asian Diagnostic Criteria in 200830 (Table 1). There is not yet consensus, however, as other authors have suggested
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Table 1 Asian consensus diagnostic criteria for AIP (Otsuki 200830). Pancreatic parenchymal imaging reveals diffuse/segmental/focal gland enlargement, occasionally with a mass and/or rim of hypoattenuation. Pancreaticobiliary duct imaging reveals diffuse/segmental/focal duct narrowing, often with stenosis of the bile duct. And either of the following Elevated serum IgG or IgG4 concentration and detection of autoantibodies Or Lymphoplasmacytic infiltration of pancreatic tissue with abundant IgG4-positive plasma cells. Or (optional criterion) Response to steroid therapy: due to the dramatic positive response to steroids in AIP an optional criterion was included. This stated that diagnostic trials of steroid therapy could be conducted in those patients fulfilling criterion 1 alone and negative work-up for pancreaticobiliary cancer.
alternative diagnostic criteria, such as the HISORt criteria from the Mayo Clinic, which place an increased emphasis on histological findings22,31 and serum IgG4-negative AIP has also been described.32 This remains a developing area and there has been a recent proposal to sub-classify AIP into two subtypes33e37, 44: LPSP and idiopathic duct-centric pancreatitis (IDCP). Diagnostic criteria to date have focused on LPSP, which appears more prevalent in Far Eastern populations. IDCP, while pathologically distinct and more common in the West, is a much less well-known condition with relatively few case series described.34,38e40
Incidence and geography Although it is recognized that compared with gallstone and alcoholic pancreatitis, AIP is rare, the majority of studies have been based on series of patients from tertiary referral centers, and therefore, the exact prevalence of the condition in wider populations remains unknown. That AIP is becoming recognized as a heterogeneous entity with subtypes that have different pathological characteristics and different geographical distributions, further compounds the issue but the number of cases has been found to vary widely in different studies,7e9, 41 accounting for between 1.8% and 11% of cases of chronic pancreatitis. Nishimori42 found a prevalence rate of 0.82/100,000 in Japan, based on a study of patients attending hospital who fulfilled the Japan Pancreas Society criteria for AIP. The LPSP subtype is thought to be at least twice as common in men as in women,42,43 whereas IDCP appears to have a more even sex distribution.44 A wide age range at presentation (14e77 years)7,38 has been reported with a peak age of onset in the seventh decade and 96% of patients presenting after the age of 46 years,42 although patients with IDCP tend to present around a decade younger.44
Imaging findings The role of imaging in the management of AIP is being constantly reassessed as understanding of the disease and its many manifestations develops. The range of possible imaging
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features in AIP and the overlap in appearance with other differentials means that diagnosis solely on the basis of imaging is not possible. However, the radiological findings remain extremely important and should be considered in conjunction with the clinical and pathological findings. A variety of different imaging methods including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), and ultrasound, (transabdominal and endoscopic) are employed in the investigation and long-term surveillance of AIP.9,45e48 The imaging appearances of AIP can vary markedly, dependent on multiple factors including the degree of fibrosis and inflammatory infiltrate.49 Nevertheless, the cardinal features of AIP are of focal or diffuse pancreatic enlargement with distortion and/or loss of the lobular architecture often termed “sausage-shaped pancreas” (seen in 40e60% of cases).50 This is best seen on cross-sectional imaging. In most centres CT (Fig 1) and MRI (Figs 2 and 3)
Figure 2 AIP: gadolinium-enhanced T1-weighted MRI image demonstrating diffuse enlargement of the pancreas in addition to enhancing mural thickening of the CBD (arrow).
are the most commonly used techniques due to their availability, non-invasive nature, established role in the evaluation of the pancreas, and ability to demonstrate important radiological features. The enhancement pattern on CT may also be helpful. AIP classically enhances less than normal pancreas in the pancreatic phase and then demonstrates delayed enhancement to show more enhancement in the hepatic phase than would be typical for carcinoma.51 A similar enhancement pattern is seen on MRI. Enhancement patterns are useful in distinguishing AIP from the possible differentials: AIP shows persistent or delayed enhancement in over 90% of cases,52 lymphoma exhibits low levels of enhancement in three quarters of cases,52 and so too do the majority of adenocarcinomas.53
Figure 1 AIP: classical, diffuse enlargement of the pancreas on arterial (a) and portal venous-phase images (b) axial CT images showing mildly bulky pancreas with delayed enhancement. Also note the thickening of the pancreatic envelope and the paucity of peripancreatic stranding.
Figure 3 AIP: gadolinium-enhanced T1-weighted MRI image demonstrating mildly bulky pancreas.
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MRI gives better soft-tissue characterization than CT, which helps to differentiate AIP from other pancreatic lesions.52 The majority of cases of AIP demonstrate low signal on T2-weighted imaging, which can be similar to adenocarcinoma whereas most cases of pancreatic lymphoma are high signal. Supplementary findings on both CT and MRI include a hypoattenuating or hypointense capsule-like peripheral rim or “envelope” seen in 12e40% of cases (Fig 4, also thickening of the pancreatic envelope in Figs 1 and 2), which is believed to correlate with changes of the peripancreatic tissues related to the inflammatory process.54 Unlike many other causes of pancreatitis, peri-pancreatic stranding is usually minimal in AIP but can occur49,55 (Fig 5). Involution of the pancreatic tail and regional lymphadenopathy may also be seen.9,49 The other imaging hallmark of AIP is a diffusely narrowed or non-dilated main pancreatic duct (MPD) best demonstrated on pancreatography. Magnetic resonance cholangiopancreatography (MRCP) is the technique of choice56,57 other than in symptomatic biliary obstruction when ERCP would be appropriate (Fig 6). Other typical
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Figure 5 AIP: peri-pancreatic stranding (arrow) is not usually a prominent feature of AIP but does sometimes occur. Note also biliary dilatation and diffuse pancreatic enlargement with thickening of the pancreatic envelope.
abnormalities of the pancreatic duct system include absence of the normal duct branching structure and minimal dilatation of the duct proximal to any stricture.58 Bile duct abnormalities are also recognized. These include smooth narrowing of the intrapancreatic portion of the common bile duct (CBD)55 (Fig 7), or irregularity and stricturing of the intra- and extrahepatic bile ducts with features similar to those seen in primary sclerosing cholangitis (PSC; Fig 8).59 Enhancing duct wall thickening is also
Figure 4 (a) AIP: MRI image of the pancreas demonstrates the bulky head of the pancreas on the T1-weighted image (arrow). (b) Bulky pancreas with thickening of the pancreatic envelope on the T2weighted image (arrow).
Figure 6 AIP: ERCP image of a smooth mid-duct stricture (arrow) with proximal biliary dilatation.
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Figure 7 AIP: CT coronal reformat image demonstrating CBD stricture with diffuse enhancing mural thickening (arrow).
a recognized feature55 (Fig 9) and, less commonly, intrahepatic bile duct dilatation may also be observed. Peri-portal soft-tissue thickening may also occur and this can cause diagnostic confusion with cholangiocarcinoma (Figs 10 and 11). In this situation tissue-specific contrast agents such as supraparamagnetic iron oxide (SPIO) can be useful in differentiation. Uptake indicates the presence of functioning Kupffer cells suggesting peri-portal inflammatory change rather than cholangiocarcinoma (Fig 10b). The most important atypical imaging finding in AIP is that of a focal pancreatic mass seen in 30e40% of cases,
Figure 9 AIP: (a) T1-weighted, contrast-enhanced MRI image of the pancreas demonstrating the bulky head of pancreas (arrow). (b) Ductal enhancement (arrow).
commonly in the pancreatic head, as a result of localized involvement (Fig 9).9 Ultrasound is often the first imaging investigation when a patient presents with symptoms due to AIP and may raise the possibility of the diagnosis. It is simple, noninvasive, and allows for diagnosis and monitoring of treatment response.60 The appearances of AIP on ultrasound are non-specific but typical findings are of a hypoechoic and diffusely enlarged pancreas (Fig 12). Ultrasound also allows assessment of gallbladder wall thickness and some assessment of the biliary ducts, which may be thickened (Fig 13). In addition, abdominal or more commonly endoscopic ultrasound may be used to guide tissue biopsy. Positron-emission tomography combined with CT (PET/ CT)61e65 and diffusion-weighted MRI66,67 have also been used and show some promise in further differentiation between AIP and pancreatic carcinoma, but are not yet in routine use in most centres. PET/CT findings of a diffuse pattern of uptake within the pancreas and extra-pancreatic uptake in the biliary system, retroperitoneal space, or salivary glands are suggestive of AIP whereas localized, homogenous nodular uptake is more in keeping with pancreatic carcinoma.68,69
Extra-pancreatic manifestations of AIP Figure 8 AIP: MRCP image exhibiting a hilar stricture (arrow) also involving second and third-order ducts.
Many extra-pancreatic sites of involvement have been described in AIP,6,9,70 including the liver, extra-pancreatic
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Figure 10 AIP: (a) marked peri-portal soft-tissue thickening on gadolinium-enhanced T1-weighted MRI image (arrow). (b) Uptake of SPIO in this region indicates functioning Kupffer cells. Figure 11 (a) and (b) AIP: MRI image using T1-weighted, contrastenhanced volume-interpolated gradient echo (“VIBE”) indicating an enhancing soft-tissue mass, centred on the CBD with associated intrahepatic duct dilatation.
Figure 12 AIP: ultrasound images showing hypoechoic and diffusely enlarged gland (arrows).
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Figure 13 AIP: ultrasound images showing (a) duct dilation (arrow) and (b) thickening of the wall of the gallbladder (arrow).
Figure 15 Adenocarcinoma on axial CT: (a) a large mass in the head of the Pancreas (arrow), which was histologically confirmed as an adenocarcinoma. (b) Local involvement of superior mesenteric artery by pancreatic adenocarcinoma (arrow).
Figure 14 AIP: enlarged salivary gland: an example of an extra-pancreatic manifestation.
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biliary tree, gallbladder, ampulla, lymph nodes, salivary glands, kidney, lungs, pituitary, aorta, and thyroid, and extra-pancreatic imaging findings can be a pointer to the diagnosis of AIP.71 Histologically proven renal abnormalities have been reported in up to 35% of patients, and these are characterized by rounded or wedge-shaped cortical lesions demonstrating reduced enhancement, appearing similar to lesions seen in renal lymphoma.72,73 Symptomatic salivary gland enlargement, similar to chronic sialadenitis may also be seen (Fig 14) and has been described in 15% of patients.74
Differential diagnosis The most important consideration in the differential diagnosis of AIP, particularly the focal mass variant, is pancreatic carcinoma. Both diseases may appear radiologically as focal masses of the pancreas (Figs 13 and 15) although there are a number of imaging characteristics that can help in distinguishing the two: prominent lymphadenopathy, vascular occlusion, abrupt narrowing of the pancreatic duct, and marked atrophy of the pancreas proximal to the mass, point toward a diagnosis of pancreatic carcinoma rather than AIP (Fig 15). Histological confirmation, however, remains the reference standard for diagnosis, although rarely carcinoma may occur concurrently or during follow-up for AIP, even after histological confirmation of the diagnosis.75,76 More diffuse AIP must be differentiated from other causes of pancreatitis or diffuse pancreatic infiltration. The presence of clearly identifiable causative factors, such as gallstones, in addition to signs of acute inflammation, such as peri-pancreatic stranding and fluid collections, reduce the likelihood of AIP (Fig 16, note the comparatively small amount of peri-pancreatic stranding in Fig 3). Pseudocysts
Figure 16 Acute pancreatitis: gross inflammatory change surrounding the pancreatic head with peri-pancreatic stranding to a much greater degree than would be typical in AIP.
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are rarely a feature of AIP,25 but are often seen in alcoholinduced pancreatitis77 (Fig 17). Widespread lymphadenopathy and diffuse pancreatic infiltration would suggest lymphoma. The presence of duct strictures should add cholangiocarcinoma and PSC to the differential (Figs 18 and 19).
Treatment Recent evidence suggests that although AIP may remit spontaneously, treatment with corticosteroids speeds recovery, reduces complications, and prolongs the period between relapses.78e82 Most patients have been found to report significant symptomatic improvement within a month of starting treatment, and this is usually accompanied by radiological and serological resolution.46,83e85 However, the resolution of radiological features is dependent upon the degree of established fibrosis, with inflammatory changes being far more likely to resolve quickly (Fig 20). Long-standing fibrotic disease may not change
Figure 17 (a) Acute-on-chronic alcoholic pancreatitis with pancreatic calcification (arrow) and large pseudocyst. (b) Pancreatic duct dilatation (arrow) and large pseudocyst.
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Figure 18 Axial CT in (a) arterial and (b) portal venous phase, arrow indicating a cholangiocarcinoma.
appearance with treatment and extra-pancreatic manifestations may resolve at a different rate from the pancreatic findings.86 Other immunosuppressants, including azathioprine80 and rituximab85,87 have been utilized in some cases,
Figure 20 (a) Axial CT image pre-treatment demonstrates intrahepatic biliary dilatation with a bulky pancreas and low attenuation envelope (arrow). (b) CT image post-treatment shows resolution of biliary dilation. The pancreas now appears normal.
Figure 19 (a) and (b) PSC demonstrated on MRCP: beading of the ducts and proximal biliary dilatation.
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although their role in treatment of AIP remains uncertain. Recent research has begun to address the appropriate dose and duration of steroids, as well as possible pharmacological alternatives and the role of intervention.80,82,88e92
Conclusion AIP is a multisystem disorder that is usually exquisitely sensitive to appropriate treatment. The nomenclature and exact diagnostic criteria continue to evolve. Although the diagnosis cannot be made on the imaging appearance alone, radiologists are in a good position to raise the possibility of AIP based on an awareness of the typical and atypical imaging findings.
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69. Lee TY, Kim M-H, Park DH, et al. Utility of 18F-FDG PET/CT for differentiation of autoimmune pancreatitis with atypical pancreatic imaging findings from pancreatic cancer. AJR Am J Roentgenol 2009;193:343e8. 70. Bodily KD, Takahashi N, Fletcher JG, et al. Autoimmune pancreatitis: pancreatic and extrapancreatic imaging findings. AJR Am J Roentgenol 2009;192:431. 71. Heffernan E, Weiss A, Harris A. Autoimmune pancreatitis with multiple extrapancreatic manifestations. Eur J Radiol Extra 2008;68:17e20. 72. Takahashi N. Renal involvement in patients with autoimmune pancreatitis. CT and MR imaging findings. Radiology 2007;242:791e801. 73. 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. 74. Kamisawa T, Tu Y, Egawa N, et al. Salivary gland involvement in chronic pancreatitis of various etiologies. Am J Gastroenterol 2003;98:323e6. 75. Loos M, Esposito I, Hedderich DM, et al. Autoimmune pancreatitis complicated by carcinoma of the pancreatobiliary system. Pancreas 2011;40:151e4. 76. Takuma K, Kamisawa T, Tabata T, et al. Short-term and long-term outcomes of autoimmune pancreatitis. Eur J Gastroenterol Hepatol 2011;23:146e52. vy P, Ruszniewski P, et al. Predictive factors in the outcome 77. Gouyon B, Le of pseudocysts complicating alcoholic chronic pancreatitis. Gut 1997;41:821e5. 78. Ghazale A. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102:1646e53. 79. Yadav D, Notahara K, Smyrk TC, et al. Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and natural history after resection. Clin Gastroenterol Hepatol 2003;1:129e35. 80. Lara LP, Chari ST. Autoimmune pancreatitis. Curr Gastroenterol Rep 2005;7:101e6. 81. Chari ST. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010e6. 82. Hirano K, Tada M, Isayama H, et al. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut 2007;56:1719e24. 83. Church NI, Pereira SP, Deheragoda MG, et al. Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series. Am J Gastroenterol 2007;102:2417e25. 84. Ghazale A. Immunoglobulin G4-associated cholangitis: clinical profile and response to steroids. Gastroenterology 2008;134:706e15. 85. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum 2010;62:1755e62. 86. Sohn J-H, Byun JH, Yoon SE, et al. Abdominal extrapancreatic lesions associated with autoimmune pancreatitis: radiological findings and changes after therapy. Eur J Radiol 2008;67:497e507. 87. Rueda JC, Duarte-Rey C, Casas N. Successful treatment of relapsing € gren’s syndrome with Rituxautoimmune pancreatitis in primary Sjo imab: report of a case and review of the literature. Rheumatol Int 2009;29:1481e5. 88. Tomiyama T, Uchida K, Matsushita M, et al. Comparison of steroid pulse therapy and conventional oral steroid therapy as initial treatment for autoimmune pancreatitis. J Gastroenterol 2011;46(5):696e704. 89. Pannala R, Chari ST. Corticosteroid treatment for autoimmune pancreatitis. Gut 2009;58:1438e9. 90. Working members of Research Committee for Intractable Pancreatic Disease and Japan Pancreas SocietyKamisawa T, Okazaki K, et al. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol 2010;45:471e7. 91. Kalaitzakis E, Webster GJM. Review article: autoimmune pancreatitisdmanagement of an emerging disease. Aliment Pharmacol Ther 2011;33:291e303. 92. Kim HM, Chung MJ, Chung JB. Remission and relapse of autoimmune pancreatitis: focusing on corticosteroid treatment. Pancreas 2010;39: 555e60.
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Pictorial Review
Autoimmune pancreatitis: An illustrated guide to diagnosis R.D. Proctor a, C.J. Rofe b, *, T.J.C. Bryant b, C.N. Hacking b, B. Stedman b a b
Department of Clinical Radiology, Royal Cornwall Hospitals NHS Trust, Truro, UK Department of Clinical Radiology, Southampton University Hospitals NHS Trust, Southampton, UK
article in formation Article history: Received 8 February 2012 Accepted 21 August 2012
Autoimmune pancreatitis (AIP) remains one of the rarer forms of pancreatitis but has become increasingly well recognized and widely diagnosed as it is an important differential, particularly due to the dramatic response to appropriate therapy. It is now best considered as part of a multisystem disease and the notion of “IgG4-related systemic sclerosing disease” has become widely recognized as the number of extra-pancreatic associations of AIP grows. More recently AIP has been classified into two subtypes: lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP) with distinct geographical, age and sex distributions for the two subtypes, in addition to different pathological characteristics. The role of imaging is crucial in AIP and should be considered in conjunction with clinical, serological, and histopathological findings to make the diagnosis. Radiologists are uniquely placed to raise the possibility of AIP and aid the exclusion of significant differentials to allow the initiation of appropriate management and avoidance of unnecessary intervention. Radiological investigation may reveal a number of characteristic imaging findings in AIP but appearances can vary considerably and the focal form of AIP may appear as a pancreatic mass, imitating pancreatic carcinoma. This review will illustrate typical and atypical appearances of AIP on all imaging modes. Emphasis will be placed on the imaging features that are likely to prove useful in discriminating AIP from other causes prior to histopathological confirmation. In addition, examples of relevant differential diagnoses are discussed and illustrated. Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The concept of an immune-mediated form of pancreatitis is not new and Sarles et al.1 proposed an autoimmune mechanism for pancreatitis in 1961. Kawaguchi2 described two cases of lymphoplasmacytic sclerosing pancreatitis (LPSP) in 1991 and, in 1995 Yoshida et al.3 proposed the concept of “AIP” to define chronic pancreatitis that was found in conjunction with autoimmune manifestations * Guarantor and correspondent: C.J. Rofe, Southampton University Hospitals NHS Trust, Tremona Road, Southampton SO16 6YD, UK. Tel.: þ44 (0) 7974205118; fax: þ44 (0) 2380 794720. E-mail address: [email protected] (C.J. Rofe).
seen on histological, serological, and clinical investigations. More recently AIP has become widely accepted as a systemic disease.6e11 There has been widespread interest due to its distinctive clinical features and response to treatment, coupled with frequent difficulties in distinguishing it from important differentials, including pancreatic carcinoma.
Presentation The clinical presentation is variable, features may include jaundice, abdominal pain, back pain, weight loss, fatigue, diabetes mellitus, or the patient may be completely
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asymptomatic.7e10 Presentation with severe abdominal pain and/or acute pancreatitis is, however, uncommon and should raise suspicions of an alternative diagnosis.
Pathogenesis, histopathological and serological findings AIP has come to be seen in the context of a multisystem disorder characterized by a fibro-inflammatory process that responds to steroid treatment and affects multiple organs.4,5,11 A number of extra-pancreatic tissues have also been shown to demonstrate the presence of IgG4-positive plasma cells6,12 leading to the concept of “IgG4-related systemic sclerosing disease”. Although there is strong evidence to suggest an autoimmune component in the pathogenesis of AIP,13,14 the exact relationship remains unclear. A genetic association has been established within the Japanese population,15 although this correlation has yet to be recognized in any other group. A number of immunological abnormalities, including high serum IgG4 levels, hypergammaglobulinaemia and the presence of autoantibodies against carbonic anhydrase and lactoferrin, have been documented as significant markers of AIP9,16 although the role of each of these in the disease process remains unclear. For example, immunohistochemistry in the majority of cases of AIP demonstrates that the plasma cells are predominantly IgG4-positive5,17,18 but infiltration by IgG4-positive cells is also seen in chronic alcoholic pancreatitis and pancreatic carcinoma.5,19 IgG4 may be elevated in 5% of healthy people and 10% of those with pancreatic carcinoma20; elevated levels of IgG4 could simply indicate a secondary response to an as yet unidentified initial trigger of the inflammatory process. The key histopathological traits are inflammation, fibrosis, and vascular changes.6,17,21e23 Inflammation demonstrates a periductal distribution, predominantly affecting the large and medium-sized interlobular ducts,24 and the extent is dependent upon the stage of the disease. Loss of exocrine pancreatic function can occur in advanced disease due to fibrotic replacement of tissue.6 Vascular changes commonly involve veins of small and medium size and are termed “obliterative phlebitis”, manifesting as perivenular inflammation, destruction of the venular wall, and obliteration of the lumen. Features such as pseudocyst formation25 and intraductal calcification,26 which are commonly seen in other forms of pancreatitis, are rare in AIP, but may occasionally occur.
Diagnostic criteria A combination of findings is required to make a diagnosis of AIP, including the imaging appearance and also additional information from serological and histopathological tests. Diagnostic criteria have been proposed and with increasing awareness of AIP, particularly in Japan and Korea, have evolved21,27e29 leading to agreement of the Asian Diagnostic Criteria in 200830 (Table 1). There is not yet consensus, however, as other authors have suggested
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Table 1 Asian consensus diagnostic criteria for AIP (Otsuki 200830). Pancreatic parenchymal imaging reveals diffuse/segmental/focal gland enlargement, occasionally with a mass and/or rim of hypoattenuation. Pancreaticobiliary duct imaging reveals diffuse/segmental/focal duct narrowing, often with stenosis of the bile duct. And either of the following Elevated serum IgG or IgG4 concentration and detection of autoantibodies Or Lymphoplasmacytic infiltration of pancreatic tissue with abundant IgG4-positive plasma cells. Or (optional criterion) Response to steroid therapy: due to the dramatic positive response to steroids in AIP an optional criterion was included. This stated that diagnostic trials of steroid therapy could be conducted in those patients fulfilling criterion 1 alone and negative work-up for pancreaticobiliary cancer.
alternative diagnostic criteria, such as the HISORt criteria from the Mayo Clinic, which place an increased emphasis on histological findings22,31 and serum IgG4-negative AIP has also been described.32 This remains a developing area and there has been a recent proposal to sub-classify AIP into two subtypes33e37, 44: LPSP and idiopathic duct-centric pancreatitis (IDCP). Diagnostic criteria to date have focused on LPSP, which appears more prevalent in Far Eastern populations. IDCP, while pathologically distinct and more common in the West, is a much less well-known condition with relatively few case series described.34,38e40
Incidence and geography Although it is recognized that compared with gallstone and alcoholic pancreatitis, AIP is rare, the majority of studies have been based on series of patients from tertiary referral centers, and therefore, the exact prevalence of the condition in wider populations remains unknown. That AIP is becoming recognized as a heterogeneous entity with subtypes that have different pathological characteristics and different geographical distributions, further compounds the issue but the number of cases has been found to vary widely in different studies,7e9, 41 accounting for between 1.8% and 11% of cases of chronic pancreatitis. Nishimori42 found a prevalence rate of 0.82/100,000 in Japan, based on a study of patients attending hospital who fulfilled the Japan Pancreas Society criteria for AIP. The LPSP subtype is thought to be at least twice as common in men as in women,42,43 whereas IDCP appears to have a more even sex distribution.44 A wide age range at presentation (14e77 years)7,38 has been reported with a peak age of onset in the seventh decade and 96% of patients presenting after the age of 46 years,42 although patients with IDCP tend to present around a decade younger.44
Imaging findings The role of imaging in the management of AIP is being constantly reassessed as understanding of the disease and its many manifestations develops. The range of possible imaging
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features in AIP and the overlap in appearance with other differentials means that diagnosis solely on the basis of imaging is not possible. However, the radiological findings remain extremely important and should be considered in conjunction with the clinical and pathological findings. A variety of different imaging methods including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), and ultrasound, (transabdominal and endoscopic) are employed in the investigation and long-term surveillance of AIP.9,45e48 The imaging appearances of AIP can vary markedly, dependent on multiple factors including the degree of fibrosis and inflammatory infiltrate.49 Nevertheless, the cardinal features of AIP are of focal or diffuse pancreatic enlargement with distortion and/or loss of the lobular architecture often termed “sausage-shaped pancreas” (seen in 40e60% of cases).50 This is best seen on cross-sectional imaging. In most centres CT (Fig 1) and MRI (Figs 2 and 3)
Figure 2 AIP: gadolinium-enhanced T1-weighted MRI image demonstrating diffuse enlargement of the pancreas in addition to enhancing mural thickening of the CBD (arrow).
are the most commonly used techniques due to their availability, non-invasive nature, established role in the evaluation of the pancreas, and ability to demonstrate important radiological features. The enhancement pattern on CT may also be helpful. AIP classically enhances less than normal pancreas in the pancreatic phase and then demonstrates delayed enhancement to show more enhancement in the hepatic phase than would be typical for carcinoma.51 A similar enhancement pattern is seen on MRI. Enhancement patterns are useful in distinguishing AIP from the possible differentials: AIP shows persistent or delayed enhancement in over 90% of cases,52 lymphoma exhibits low levels of enhancement in three quarters of cases,52 and so too do the majority of adenocarcinomas.53
Figure 1 AIP: classical, diffuse enlargement of the pancreas on arterial (a) and portal venous-phase images (b) axial CT images showing mildly bulky pancreas with delayed enhancement. Also note the thickening of the pancreatic envelope and the paucity of peripancreatic stranding.
Figure 3 AIP: gadolinium-enhanced T1-weighted MRI image demonstrating mildly bulky pancreas.
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MRI gives better soft-tissue characterization than CT, which helps to differentiate AIP from other pancreatic lesions.52 The majority of cases of AIP demonstrate low signal on T2-weighted imaging, which can be similar to adenocarcinoma whereas most cases of pancreatic lymphoma are high signal. Supplementary findings on both CT and MRI include a hypoattenuating or hypointense capsule-like peripheral rim or “envelope” seen in 12e40% of cases (Fig 4, also thickening of the pancreatic envelope in Figs 1 and 2), which is believed to correlate with changes of the peripancreatic tissues related to the inflammatory process.54 Unlike many other causes of pancreatitis, peri-pancreatic stranding is usually minimal in AIP but can occur49,55 (Fig 5). Involution of the pancreatic tail and regional lymphadenopathy may also be seen.9,49 The other imaging hallmark of AIP is a diffusely narrowed or non-dilated main pancreatic duct (MPD) best demonstrated on pancreatography. Magnetic resonance cholangiopancreatography (MRCP) is the technique of choice56,57 other than in symptomatic biliary obstruction when ERCP would be appropriate (Fig 6). Other typical
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Figure 5 AIP: peri-pancreatic stranding (arrow) is not usually a prominent feature of AIP but does sometimes occur. Note also biliary dilatation and diffuse pancreatic enlargement with thickening of the pancreatic envelope.
abnormalities of the pancreatic duct system include absence of the normal duct branching structure and minimal dilatation of the duct proximal to any stricture.58 Bile duct abnormalities are also recognized. These include smooth narrowing of the intrapancreatic portion of the common bile duct (CBD)55 (Fig 7), or irregularity and stricturing of the intra- and extrahepatic bile ducts with features similar to those seen in primary sclerosing cholangitis (PSC; Fig 8).59 Enhancing duct wall thickening is also
Figure 4 (a) AIP: MRI image of the pancreas demonstrates the bulky head of the pancreas on the T1-weighted image (arrow). (b) Bulky pancreas with thickening of the pancreatic envelope on the T2weighted image (arrow).
Figure 6 AIP: ERCP image of a smooth mid-duct stricture (arrow) with proximal biliary dilatation.
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Figure 7 AIP: CT coronal reformat image demonstrating CBD stricture with diffuse enhancing mural thickening (arrow).
a recognized feature55 (Fig 9) and, less commonly, intrahepatic bile duct dilatation may also be observed. Peri-portal soft-tissue thickening may also occur and this can cause diagnostic confusion with cholangiocarcinoma (Figs 10 and 11). In this situation tissue-specific contrast agents such as supraparamagnetic iron oxide (SPIO) can be useful in differentiation. Uptake indicates the presence of functioning Kupffer cells suggesting peri-portal inflammatory change rather than cholangiocarcinoma (Fig 10b). The most important atypical imaging finding in AIP is that of a focal pancreatic mass seen in 30e40% of cases,
Figure 9 AIP: (a) T1-weighted, contrast-enhanced MRI image of the pancreas demonstrating the bulky head of pancreas (arrow). (b) Ductal enhancement (arrow).
commonly in the pancreatic head, as a result of localized involvement (Fig 9).9 Ultrasound is often the first imaging investigation when a patient presents with symptoms due to AIP and may raise the possibility of the diagnosis. It is simple, noninvasive, and allows for diagnosis and monitoring of treatment response.60 The appearances of AIP on ultrasound are non-specific but typical findings are of a hypoechoic and diffusely enlarged pancreas (Fig 12). Ultrasound also allows assessment of gallbladder wall thickness and some assessment of the biliary ducts, which may be thickened (Fig 13). In addition, abdominal or more commonly endoscopic ultrasound may be used to guide tissue biopsy. Positron-emission tomography combined with CT (PET/ CT)61e65 and diffusion-weighted MRI66,67 have also been used and show some promise in further differentiation between AIP and pancreatic carcinoma, but are not yet in routine use in most centres. PET/CT findings of a diffuse pattern of uptake within the pancreas and extra-pancreatic uptake in the biliary system, retroperitoneal space, or salivary glands are suggestive of AIP whereas localized, homogenous nodular uptake is more in keeping with pancreatic carcinoma.68,69
Extra-pancreatic manifestations of AIP Figure 8 AIP: MRCP image exhibiting a hilar stricture (arrow) also involving second and third-order ducts.
Many extra-pancreatic sites of involvement have been described in AIP,6,9,70 including the liver, extra-pancreatic
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Figure 10 AIP: (a) marked peri-portal soft-tissue thickening on gadolinium-enhanced T1-weighted MRI image (arrow). (b) Uptake of SPIO in this region indicates functioning Kupffer cells. Figure 11 (a) and (b) AIP: MRI image using T1-weighted, contrastenhanced volume-interpolated gradient echo (“VIBE”) indicating an enhancing soft-tissue mass, centred on the CBD with associated intrahepatic duct dilatation.
Figure 12 AIP: ultrasound images showing hypoechoic and diffusely enlarged gland (arrows).
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Figure 13 AIP: ultrasound images showing (a) duct dilation (arrow) and (b) thickening of the wall of the gallbladder (arrow).
Figure 15 Adenocarcinoma on axial CT: (a) a large mass in the head of the Pancreas (arrow), which was histologically confirmed as an adenocarcinoma. (b) Local involvement of superior mesenteric artery by pancreatic adenocarcinoma (arrow).
Figure 14 AIP: enlarged salivary gland: an example of an extra-pancreatic manifestation.
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biliary tree, gallbladder, ampulla, lymph nodes, salivary glands, kidney, lungs, pituitary, aorta, and thyroid, and extra-pancreatic imaging findings can be a pointer to the diagnosis of AIP.71 Histologically proven renal abnormalities have been reported in up to 35% of patients, and these are characterized by rounded or wedge-shaped cortical lesions demonstrating reduced enhancement, appearing similar to lesions seen in renal lymphoma.72,73 Symptomatic salivary gland enlargement, similar to chronic sialadenitis may also be seen (Fig 14) and has been described in 15% of patients.74
Differential diagnosis The most important consideration in the differential diagnosis of AIP, particularly the focal mass variant, is pancreatic carcinoma. Both diseases may appear radiologically as focal masses of the pancreas (Figs 13 and 15) although there are a number of imaging characteristics that can help in distinguishing the two: prominent lymphadenopathy, vascular occlusion, abrupt narrowing of the pancreatic duct, and marked atrophy of the pancreas proximal to the mass, point toward a diagnosis of pancreatic carcinoma rather than AIP (Fig 15). Histological confirmation, however, remains the reference standard for diagnosis, although rarely carcinoma may occur concurrently or during follow-up for AIP, even after histological confirmation of the diagnosis.75,76 More diffuse AIP must be differentiated from other causes of pancreatitis or diffuse pancreatic infiltration. The presence of clearly identifiable causative factors, such as gallstones, in addition to signs of acute inflammation, such as peri-pancreatic stranding and fluid collections, reduce the likelihood of AIP (Fig 16, note the comparatively small amount of peri-pancreatic stranding in Fig 3). Pseudocysts
Figure 16 Acute pancreatitis: gross inflammatory change surrounding the pancreatic head with peri-pancreatic stranding to a much greater degree than would be typical in AIP.
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are rarely a feature of AIP,25 but are often seen in alcoholinduced pancreatitis77 (Fig 17). Widespread lymphadenopathy and diffuse pancreatic infiltration would suggest lymphoma. The presence of duct strictures should add cholangiocarcinoma and PSC to the differential (Figs 18 and 19).
Treatment Recent evidence suggests that although AIP may remit spontaneously, treatment with corticosteroids speeds recovery, reduces complications, and prolongs the period between relapses.78e82 Most patients have been found to report significant symptomatic improvement within a month of starting treatment, and this is usually accompanied by radiological and serological resolution.46,83e85 However, the resolution of radiological features is dependent upon the degree of established fibrosis, with inflammatory changes being far more likely to resolve quickly (Fig 20). Long-standing fibrotic disease may not change
Figure 17 (a) Acute-on-chronic alcoholic pancreatitis with pancreatic calcification (arrow) and large pseudocyst. (b) Pancreatic duct dilatation (arrow) and large pseudocyst.
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Figure 18 Axial CT in (a) arterial and (b) portal venous phase, arrow indicating a cholangiocarcinoma.
appearance with treatment and extra-pancreatic manifestations may resolve at a different rate from the pancreatic findings.86 Other immunosuppressants, including azathioprine80 and rituximab85,87 have been utilized in some cases,
Figure 20 (a) Axial CT image pre-treatment demonstrates intrahepatic biliary dilatation with a bulky pancreas and low attenuation envelope (arrow). (b) CT image post-treatment shows resolution of biliary dilation. The pancreas now appears normal.
Figure 19 (a) and (b) PSC demonstrated on MRCP: beading of the ducts and proximal biliary dilatation.
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although their role in treatment of AIP remains uncertain. Recent research has begun to address the appropriate dose and duration of steroids, as well as possible pharmacological alternatives and the role of intervention.80,82,88e92
Conclusion AIP is a multisystem disorder that is usually exquisitely sensitive to appropriate treatment. The nomenclature and exact diagnostic criteria continue to evolve. Although the diagnosis cannot be made on the imaging appearance alone, radiologists are in a good position to raise the possibility of AIP based on an awareness of the typical and atypical imaging findings.
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