Autoimmune pancreatitis: An illustrated guide to diagnosis

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Clinical Radiology 68 (2013) 422e432

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Autoimmune pancreatitis: An illustrated guide todiagnosisR.D. Proctor a, C.J. Rofe b,*, T.J.C. Bryant b, C.N. Hacking b, B. Stedman b

aDepartment of Clinical Radiology, Royal Cornwall Hospitals NHS Trust, Truro, UKbDepartment of Clinical Radiology, Southampton University Hospitals NHS Trust, Southampton, UK

article information

Article history:Received 8 February 2012Accepted 21 August 2012

* Guarantor and correspondent: C.J. Rofe, Southtals NHS Trust, Tremona Road, Southampton SO7974205118; fax: þ44 (0) 2380 794720.

E-mail address: [email protected]

0009-9260/$ e see front matter � 2012 The Royal Cohttp://dx.doi.org/10.1016/j.crad.2012.08.016

Autoimmune pancreatitis (AIP) remains one of the rarer forms of pancreatitis but has becomeincreasingly well recognized and widely diagnosed as it is an important differential, particu-larly due to the dramatic response to appropriate therapy. It is now best considered as part ofa multisystem disease and the notion of “IgG4-related systemic sclerosing disease” has becomewidely recognized as the number of extra-pancreatic associations of AIP grows. More recentlyAIP has been classified into two subtypes: lymphoplasmacytic sclerosing pancreatitis (LPSP)and idiopathic duct-centric pancreatitis (IDCP) with distinct geographical, age and sex distri-butions for the two subtypes, in addition to different pathological characteristics. The role ofimaging is crucial in AIP and should be considered in conjunction with clinical, serological, andhistopathological findings to make the diagnosis. Radiologists are uniquely placed to raise thepossibility of AIP and aid the exclusion of significant differentials to allow the initiation ofappropriate management and avoidance of unnecessary intervention. Radiological investiga-tion may reveal a number of characteristic imaging findings in AIP but appearances can varyconsiderably and the focal form of AIP may appear as a pancreatic mass, imitating pancreaticcarcinoma. This review will illustrate typical and atypical appearances of AIP on all imagingmodes. Emphasis will be placed on the imaging features that are likely to prove useful indiscriminating AIP from other causes prior to histopathological confirmation. In addition,examples of relevant differential diagnoses are discussed and illustrated.

� 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction

The concept of an immune-mediated form of pancrea-titis is not new and Sarles et al.1 proposed an autoimmunemechanism for pancreatitis in 1961. Kawaguchi2 describedtwo cases of lymphoplasmacytic sclerosing pancreatitis(LPSP) in 1991 and, in 1995 Yoshida et al.3 proposed theconcept of “AIP” to define chronic pancreatitis that wasfound in conjunction with autoimmune manifestations

ampton University Hospi-16 6YD, UK. Tel.: þ44 (0)

(C.J. Rofe).

llege of Radiologists. Published by

seen on histological, serological, and clinicalinvestigations.

More recently AIP has become widely accepted asa systemic disease.6e11 There has been widespread interestdue to its distinctive clinical features and response totreatment, coupled with frequent difficulties in dis-tinguishing it from important differentials, includingpancreatic carcinoma.

Presentation

The clinical presentation is variable, featuresmay includejaundice, abdominal pain, back pain, weight loss, fatigue,diabetes mellitus, or the patient may be completely

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Table 1Asian consensus diagnostic criteria for AIP (Otsuki 200830).

� Pancreatic parenchymal imaging reveals diffuse/segmental/focalgland enlargement, occasionally with a mass and/or rim ofhypoattenuation.

� Pancreaticobiliary duct imaging reveals diffuse/segmental/focalduct narrowing, often with stenosis of the bile duct.

And either of the following� Elevated serum IgG or IgG4 concentration and detection ofautoantibodies

Or� Lymphoplasmacytic infiltration of pancreatic tissue with abundantIgG4-positive plasma cells.

Or (optional criterion)Response to steroid therapy: due to the dramatic positive response tosteroids in AIP an optional criterion was included. This stated thatdiagnostic trials of steroid therapy could be conducted in those patientsfulfilling criterion 1 alone and negative work-up for pancreaticobiliarycancer.

R.D. Proctor et al. / Clinical Radiology 68 (2013) 422e432 423

asymptomatic.7e10 Presentation with severe abdominalpain and/or acute pancreatitis is, however, uncommon andshould raise suspicions of an alternative diagnosis.

Pathogenesis, histopathological andserological findings

AIP has come to be seen in the context of a multisystemdisorder characterized by a fibro-inflammatory process thatresponds to steroid treatment and affects multipleorgans.4,5,11 A number of extra-pancreatic tissues have alsobeen shown to demonstrate the presence of IgG4-positiveplasma cells6,12 leading to the concept of “IgG4-relatedsystemic sclerosing disease”.

Although there is strong evidence to suggest an auto-immune component in the pathogenesis of AIP,13,14 theexact relationship remains unclear. A genetic association hasbeen establishedwithin the Japanese population,15 althoughthis correlation has yet to be recognized in any other group.A number of immunological abnormalities, including highserum IgG4 levels, hypergammaglobulinaemia and thepresence of autoantibodies against carbonic anhydrase andlactoferrin, have been documented as significant markers ofAIP9,16 although the role of each of these in the diseaseprocess remains unclear. For example, immunohistochem-istry in the majority of cases of AIP demonstrates that theplasma cells are predominantly IgG4-positive5,17,18 butinfiltration by IgG4-positive cells is also seen in chronicalcoholic pancreatitis and pancreatic carcinoma.5,19 IgG4may be elevated in 5% of healthy people and 10% of thosewith pancreatic carcinoma20; elevated levels of IgG4 couldsimply indicate a secondary response to an as yet uniden-tified initial trigger of the inflammatory process.

The key histopathological traits are inflammation,fibrosis, and vascular changes.6,17,21e23 Inflammationdemonstrates a periductal distribution, predominantlyaffecting 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 advanceddisease due to fibrotic replacement of tissue.6 Vascularchanges commonly involve veins of small and medium sizeand are termed “obliterative phlebitis”, manifesting asperivenular inflammation, destruction of the venular wall,and obliteration of the lumen.

Features such as pseudocyst formation25 and intraductalcalcification,26 which are commonly seen in other forms ofpancreatitis, are rare in AIP, but may occasionally occur.

Diagnostic criteria

A combination of findings is required tomake a diagnosisof AIP, including the imaging appearance and also addi-tional information from serological and histopathologicaltests. Diagnostic criteria have been proposed and withincreasing awareness of AIP, particularly in Japan and Korea,have evolved21,27e29 leading to agreement of the AsianDiagnostic Criteria in 200830 (Table 1). There is not yetconsensus, however, as other authors have suggested

alternative diagnostic criteria, such as the HISORt criteriafrom theMayo Clinic, which place an increased emphasis onhistological findings22,31 and serum IgG4-negative AIP hasalso been described.32 This remains a developing area andthere has been a recent proposal to sub-classify AIP into twosubtypes33e37, 44: LPSP and idiopathic duct-centric pancre-atitis (IDCP). Diagnostic criteria to date have focused onLPSP, which appears more prevalent in Far Eastern pop-ulations. IDCP, while pathologically distinct and morecommon in the West, is a much less well-known conditionwith relatively few case series described.34,38e40

Incidence and geography

Although it is recognized that compared with gallstoneand alcoholic pancreatitis, AIP is rare, the majority of studieshave been based on series of patients from tertiary referralcenters, and therefore, the exact prevalence of the conditionin wider populations remains unknown. That AIP isbecoming recognized as a heterogeneous entity withsubtypes that have different pathological characteristics anddifferent geographical distributions, further compounds theissue but the number of cases has been found to vary widelyin different studies,7e9, 41 accounting for between 1.8% and11% of cases of chronic pancreatitis. Nishimori42 founda prevalence rate of 0.82/100,000 in Japan, based on a studyof patients attending hospital who fulfilled the JapanPancreas Society criteria for AIP.

The LPSP subtype is thought to be at least twice ascommon in men as in women,42,43 whereas IDCP appears tohave a more even sex distribution.44 A wide age range atpresentation (14e77 years)7,38 has been reported witha peak age of onset in the seventh decade and 96% of patientspresenting after the age of 46 years,42 although patients withIDCP tend to present around a decade younger.44

Imaging findings

The role of imaging in the management of AIP is beingconstantly reassessed as understanding of the disease and itsmanymanifestations develops. The range of possible imaging

R.D. Proctor et al. / Clinical Radiology 68 (2013) 422e432424

features in AIP and the overlap in appearance with otherdifferentials means that diagnosis solely on the basis ofimaging is not possible. However, the radiological findingsremain extremely important and should be considered inconjunction with the clinical and pathological findings. Avariety of different imaging methods including computedtomography (CT), magnetic resonance imaging (MRI), endo-scopic retrograde cholangiopancreatography (ERCP), andultrasound, (transabdominal and endoscopic) are employedin 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 offibrosis and inflammatory infiltrate.49 Nevertheless, thecardinal features of AIP are of focal or diffuse pancreaticenlargement with distortion and/or loss of the lobulararchitecture often termed “sausage-shaped pancreas” (seenin 40e60% of cases).50 This is best seen on cross-sectionalimaging. In most centres CT (Fig 1) and MRI (Figs 2 and 3)

Figure 1 AIP: classical, diffuse enlargement of the pancreas on arte-rial (a) and portal venous-phase images (b) axial CT images showingmildly bulky pancreas with delayed enhancement. Also note thethickening of the pancreatic envelope and the paucity of peri-pancreatic stranding.

Figure 2 AIP: gadolinium-enhanced T1-weighted MRI image demon-strating diffuse enlargement of the pancreas in addition to enhancingmural thickening of the CBD (arrow).

are the most commonly used techniques due to theiravailability, non-invasive nature, established role in theevaluation of the pancreas, and ability to demonstrateimportant radiological features.

The enhancement pattern on CT may also be helpful. AIPclassically enhances less than normal pancreas in thepancreatic phase and then demonstrates delayedenhancement to show more enhancement in the hepaticphase than would be typical for carcinoma.51 A similarenhancement pattern is seen on MRI. Enhancementpatterns are useful in distinguishing AIP from the possibledifferentials: AIP shows persistent or delayed enhancementin over 90% of cases,52 lymphoma exhibits low levels ofenhancement in three quarters of cases,52 and so too do themajority of adenocarcinomas.53

Figure 3 AIP: gadolinium-enhanced T1-weighted MRI image demon-strating mildly bulky pancreas.

Figure 5 AIP: peri-pancreatic stranding (arrow) is not usuallya prominent feature of AIP but does sometimes occur. Note also


MRI gives better soft-tissue characterization than CT,which helps to differentiate AIP from other pancreaticlesions.52 The majority of cases of AIP demonstrate lowsignal on T2-weighted imaging, which can be similar toadenocarcinoma whereas most cases of pancreaticlymphoma are high signal.

Supplementary findings on both CT and MRI includea hypoattenuating or hypointense capsule-like peripheralrim or “envelope” seen in 12e40% of cases (Fig 4, alsothickening of the pancreatic envelope in Figs 1 and 2),which is believed to correlate with changes of the peri-pancreatic tissues related to the inflammatory process.54

Unlike many other causes of pancreatitis, peri-pancreaticstranding is usually minimal in AIP but can occur49,55

(Fig 5). Involution of the pancreatic tail and regionallymphadenopathy may also be seen.9,49

The other imaging hallmark of AIP is a diffusely nar-rowed or non-dilated main pancreatic duct (MPD) bestdemonstrated on pancreatography. Magnetic resonancecholangiopancreatography (MRCP) is the technique ofchoice56,57 other than in symptomatic biliary obstructionwhen ERCP would be appropriate (Fig 6). Other typical

Figure 4 (a) AIP: MRI image of the pancreas demonstrates the bulkyhead of the pancreas on the T1-weighted image (arrow). (b) Bulkypancreas with thickening of the pancreatic envelope on the T2-weighted image (arrow).

biliary dilatation and diffuse pancreatic enlargement with thickeningof the pancreatic envelope.

abnormalities of the pancreatic duct system includeabsence of the normal duct branching structure andminimal dilatation of the duct proximal to any stricture.58

Bile duct abnormalities are also recognized. Theseinclude smooth narrowing of the intrapancreatic portion ofthe common bile duct (CBD)55 (Fig 7), or irregularity andstricturing of the intra- and extrahepatic bile ducts withfeatures similar to those seen in primary sclerosing chol-angitis (PSC; Fig 8).59 Enhancing duct wall thickening is also

Figure 6 AIP: ERCP image of a smooth mid-duct stricture (arrow)with proximal biliary dilatation.

Figure 9 AIP: (a) T1-weighted, contrast-enhanced MRI image of thepancreas demonstrating the bulky head of pancreas (arrow). (b)Ductal enhancement (arrow).

Figure 7 AIP: CT coronal reformat image demonstrating CBD stricturewith diffuse enhancing mural thickening (arrow).


a recognized feature55 (Fig 9) and, less commonly, intra-hepatic bile duct dilatation may also be observed.

Peri-portal soft-tissue thickeningmay also occur and thiscan cause diagnostic confusion with cholangiocarcinoma(Figs 10 and 11). In this situation tissue-specific contrastagents such as supraparamagnetic iron oxide (SPIO) can beuseful in differentiation. Uptake indicates the presence offunctioning Kupffer cells suggesting peri-portal inflamma-tory change rather than cholangiocarcinoma (Fig 10b).

The most important atypical imaging finding in AIP isthat of a focal pancreatic mass seen in 30e40% of cases,

Figure 8 AIP: MRCP image exhibiting a hilar stricture (arrow) alsoinvolving second and third-order ducts.

commonly in the pancreatic head, as a result of localizedinvolvement (Fig 9).9

Ultrasound is often the first imaging investigation whena patient presents with symptoms due to AIP and mayraise the possibility of the diagnosis. It is simple, non-invasive, and allows for diagnosis and monitoring oftreatment response.60 The appearances of AIP on ultra-sound are non-specific but typical findings are of a hypo-echoic and diffusely enlarged pancreas (Fig 12).Ultrasound also allows assessment of gallbladder wallthickness and some assessment of the biliary ducts, whichmay be thickened (Fig 13). In addition, abdominal or morecommonly endoscopic ultrasound may be used to guidetissue biopsy.

Positron-emission tomography combined with CT (PET/CT)61e65 and diffusion-weighted MRI66,67 have also beenused and show some promise in further differentiationbetween AIP and pancreatic carcinoma, but are not yet inroutine use in most centres. PET/CT findings of a diffusepattern of uptake within the pancreas and extra-pancreaticuptake in the biliary system, retroperitoneal space, or sali-vary glands are suggestive of AIP whereas localized,homogenous nodular uptake is more in keeping withpancreatic carcinoma.68,69

Extra-pancreatic manifestations of AIP

Many extra-pancreatic sites of involvement have beendescribed in AIP,6,9,70 including the liver, extra-pancreatic

Figure 11 (a) and (b) AIP: MRI image using T1-weighted, contrast-enhanced volume-interpolated gradient echo (“VIBE”) indicating anenhancing soft-tissue mass, centred on the CBD with associatedintrahepatic duct dilatation.

Figure 12 AIP: ultrasound images showing hypoechoic and diffusely enlarged gland (arrows).

Figure 10 AIP: (a) marked peri-portal soft-tissue thickening ongadolinium-enhanced T1-weighted MRI image (arrow). (b) Uptake ofSPIO in this region indicates functioning Kupffer cells.


Figure 13 AIP: ultrasound images showing (a) duct dilation (arrow)and (b) thickening of the wall of the gallbladder (arrow).

Figure 14 AIP: enlarged salivary gland: an example of an extra-pancreatic manifestation.

Figure 15 Adenocarcinoma on axial CT: (a) a large mass in the head ofthe Pancreas (arrow), which was histologically confirmed as anadenocarcinoma. (b) Local involvement of superior mesenteric arteryby pancreatic adenocarcinoma (arrow).



biliary tree, gallbladder, ampulla, lymph nodes, salivaryglands, kidney, lungs, pituitary, aorta, and thyroid, andextra-pancreatic imaging findings can be a pointer to thediagnosis of AIP.71 Histologically proven renal abnormalitieshave been reported in up to 35% of patients, and these arecharacterized by rounded or wedge-shaped cortical lesionsdemonstrating reduced enhancement, appearing similar tolesions seen in renal lymphoma.72,73 Symptomatic salivarygland enlargement, similar to chronic sialadenitis may alsobe seen (Fig 14) and has been described in 15% of patients.74

Differential diagnosis

The most important consideration in the differentialdiagnosis of AIP, particularly the focal mass variant, ispancreatic carcinoma. Both diseases may appear radiologi-cally as focal masses of the pancreas (Figs 13 and 15)although there are a number of imaging characteristics thatcan help in distinguishing the two: prominent lymphade-nopathy, vascular occlusion, abrupt narrowing of thepancreatic duct, and marked atrophy of the pancreasproximal to themass, point toward a diagnosis of pancreaticcarcinoma rather than AIP (Fig 15). Histological confirma-tion, however, remains the reference standard for diagnosis,although rarely carcinoma may occur concurrently orduring follow-up for AIP, even after histological confirma-tion of the diagnosis.75,76

More diffuse AIP must be differentiated from other cau-ses of pancreatitis or diffuse pancreatic infiltration. Thepresence of clearly identifiable causative factors, such asgallstones, in addition to signs of acute inflammation, suchas peri-pancreatic stranding and fluid collections, reducethe likelihood of AIP (Fig 16, note the comparatively smallamount of peri-pancreatic stranding in Fig 3). Pseudocysts

Figure 16 Acute pancreatitis: gross inflammatory change surroundingthe pancreatic head with peri-pancreatic stranding to a much greaterdegree than would be typical in AIP.

are rarely a feature of AIP,25 but are often seen in alcohol-induced pancreatitis77 (Fig 17).

Widespread lymphadenopathy and diffuse pancreaticinfiltration would suggest lymphoma. The presence of ductstrictures should add cholangiocarcinoma and PSC to thedifferential (Figs 18 and 19).

Treatment

Recent evidence suggests that although AIP may remitspontaneously, treatment with corticosteroids speedsrecovery, reduces complications, and prolongs the periodbetween relapses.78e82 Most patients have been found toreport significant symptomatic improvement withina month of starting treatment, and this is usually accom-panied by radiological and serological resolution.46,83e85

However, the resolution of radiological features is depen-dent upon the degree of established fibrosis, with inflam-matory 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 pancreaticcalcification (arrow) and large pseudocyst. (b) Pancreatic duct dila-tation (arrow) and large pseudocyst.

Figure 18 Axial CT in (a) arterial and (b) portal venous phase, arrowindicating a cholangiocarcinoma.

Figure 20 (a) Axial CT image pre-treatment demonstrates intra-hepatic biliary dilatation with a bulky pancreas and low attenuationenvelope (arrow). (b) CT image post-treatment shows resolution ofbiliary dilation. The pancreas now appears normal.


appearance with treatment and extra-pancreatic manifes-tations may resolve at a different rate from the pancreaticfindings.86

Other immunosuppressants, including azathioprine80

and rituximab85,87 have been utilized in some cases,

Figure 19 (a) and (b) PSC demonstrated on MRCP: beading of the ducts and proximal biliary dilatation.


although their role in treatment of AIP remains uncertain.Recent research has begun to address the appropriate doseand duration of steroids, as well as possible pharmacolog-ical alternatives and the role of intervention.80,82,88e92

Conclusion

AIP is a multisystem disorder that is usually exquisitelysensitive to appropriate treatment. The nomenclature andexact diagnostic criteria continue to evolve. Although thediagnosis cannot bemade on the imaging appearance alone,radiologists are in a good position to raise the possibility ofAIP based on an awareness of the typical and atypicalimaging findings.

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Autoimmune pancreatitis: An illustrated guide to diagnosis