G a s t r o i n t e s t i n a l I m a g i n g • R ev i ew Khandelwal et al. Advances in Autoimmune Pancreatitis

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Gastrointestinal Imaging Review

Recent Advances in the Diagnosis and Management of Autoimmune Pancreatitis Ashish Khandelwal1 Alampady Krishna Shanbhogue2 Naoki Takahashi 3 Kumaresan Sandrasegaran 4 Srinivasa R. Prasad5

OBJECTIVE. Autoimmune pancreatitis (AIP) is a rare chronic relapsing steroid-responsive fibroinflammatory disorder of the pancreas that is likely caused by immune dysregulation. It is now thought that AIP consists of two distinct clinicopathologic syndromes currently designated as types 1 and 2. CONCLUSION. A current update on etiopathogenesis, pathology, and clinical and imaging findings of AIP is provided with an emphasis on diagnosis and management.

Khandelwal A, Shanbhogue AK, Takahashi  N, Sandrasegaran K, Prasad SR


Keywords: autoimmune pancreatitis, International Consensus Diagnostic Criteria, pancreas, pancreatitis, type 1 autoimmune pancreatitis, type 2 autoimmune pancreatitis DOI:10.2214/AJR.13.11247 Received April 9, 2013; accepted after revision September 2, 2013. 1 Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. 2 Department of Radiology, Beth Israel Medical Center, 16th St and 1st Ave, New York, NY 10003. Address correspondence to A. K. Shanbhogue ([email protected]). 3

Department of Radiology, Mayo Clinic, Rochester, MN.

4 Department of Radiology, Indiana University School of Medicine, Indianapolis, IN. 5 Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

This article is available for credit. AJR 2014; 202:1007–1021 0361–803X/14/2025–1007 © American Roentgen Ray Society

utoimmune pancreatitis (AIP) is an immune-mediated tumefactive fibroinflammatory disorder that primarily affects the pancreas [1–3]. Although Sarles et al. [4] described the first cases of the entity in 1961, Yoshida et al. [5] are credited with coining of the term as well as providing the first detailed description of the steroid-responsive mass-forming pancreatitis syndrome with elevated autoantibody titers in 1995. In 1997, Ectors et al. [6] described a distinctive duct-destructive nonalcoholic pancreatitis syndrome. Several landmark studies in patients with AIP documented increased serum levels of IgG4 as well as tissue deposition of IgG4-synthesizing plasma cells [7–9]. In 2004, Zamboni et al. [10] described granulocytic epithelial lesion, the histologic hallmark of type 2 AIP. AIP is now thought to comprise two distinct clinicopathologic syndromes, currently designated as types 1 and 2. Type 1 AIP is now thought to be a prototype of IgG4-related systemic disease with predominant pancreatic involvement. Most patients with type 1 AIP have painless obstructive jaundice with frequent involvement of extrapancreatic organs, high tissue and serum levels of IgG4, and disease that often relapses in the pancreas and the biliary system. Type 2 AIP exclusively affects the pancreas; patients with type 2 AIP have a seronegative painful chronic pancreatitis syndrome that rarely recurs after steroid therapy [11, 12]. Recent advances in pathology have enabled improved understanding of the etiopathogenesis, natural history, and pathologic and imaging manifesta-

tions of AIP. Here, we provide a current update of this enigmatic entity, including current guidelines for diagnosis and management. Epidemiology of Autoimmune Pancreatitis The true incidence and prevalence of AIP are still unclear. The prevalence of patients with AIP in Japan was estimated to be 0.82 per 100,000 general population. AIP accounted for 5–6% of all patients with chronic pancreatitis [13]. AIP was seen in an estimated 6–8% of pancreatic resections performed for presumed pancreatic cancer in Japan [13–15]. A Mayo Clinic series of 245 pancreatic resections performed for benign indications reported the frequency of AIP to be 11% [16]. Type 1 AIP is more prevalent than type 2 AIP; it is the exclusive subtype of AIP seen in Japan and Korea and accounts for over 80% of cases of AIP seen in the United States [12, 17, 18]. Type 2 AIP is reported to be more common in North America and Europe, accounting for up to 33% of cases of resected AIP in a Mayo Clinic series (based on retrospective review) and up to 40% of cases of resected AIP in Europe [10, 19]. The exact incidence and prevalence are difficult to estimate because most cases are underdiagnosed [12]. Etiopathogenesis of Autoimmune Pancreatitis Despite considerable progress in our understanding of AIP, the exact etiopathogenesis of the two syndromes is still not clear. The autoimmune nature of the disease is inferred

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Khandelwal et al. by elevated antibody titers, parenchymal deposition of immune cells, and dramatic response to steroid therapy. AIP is now recognized as a multifactorial disease with genetic and immunologic factors playing major roles in pathogenesis. A Japanese study found increased frequencies of DRB1*0405 and DQB1*0401 human leukocyte antigen haplotypes in patients with type 1 AIP [20]. Substitution of aspartic acid to nonaspartic acid at DQβ1 57 was reported in Korean patients with type 1 AIP showing high relapse rates [21]. AIP is also found in association with genetic polymorphisms of cytotoxic T lymphocyte–associated protein 4 and Fc receptor–like gene 3 [22, 23]. In addition to a wide array of nonspecific autoantibodies, such as antinuclear antibody and rheumatoid factor, pancreas-specific antibodies directed at ductal antigens (e.g., carbonic anhydrase [CA]–II and lactoferrin) and enzymes produced by acinar cells (e.g., trypsinogen and pancreatic secretory trypsin inhibitor) have been found in patients with AIP [24, 25]. It is unknown, however, whether autoantibodies play a primary role in pathogenesis of the disease or are formed secondarily in response to parenchymal injury. The seminal role of cellular immunity in the etiopathogenesis of AIP has also been extensively described. Parenchymal infiltration by CD4+ CD25+ forkhead box protein 3 T regulatory cells is seen in patients with AIP and is considered one of the biomarkers for IgG4-related diseases [26]. It is thought that T helper (Th) 1 cytokines induce AIP and that Th2 cytokines contribute to disease progression. In the early stages, the aberrant immune response to self-antigens (e.g., lactoferrin, CA-II, CA-IV, pancreatic secretory trypsin inhibitor, and α-fodrin) and molecular mimicry (such as to Helicobacter pylori antigen) are thought to play a major role by inducing Th1 cells to release proinflammatory cytokines (e.g., interferon-γ, interleukin-1β, interleukin-2, and tumor necrosis factor–α). In the chronic stage, increased memory regulatory T cells and Th2 immune responses maintain active chronic inflammation [27]. About half of patients with AIP have allergic manifestations with elevated serum IgE levels and peripheral eosinophil counts, suggesting that underlying allergic mechanisms may also be involved in the pathogenesis of AIP [28]. In summary, the pathogenesis of AIP involves an initial immune response to self-antigens induced by a decrease in levels of naive regulatory T cells and Th1 cytokines in genetically susceptible individuals. The dis-


ease progression is mediated by memory regulatory T cells and Th2 immune response, which results in increased production of IgG4 and activation of a classic complement pathway, resulting in tissue damage and fibrosis. The etiopathogenesis of AIP is summarized in Figure 1. Histopathologic Findings of Autoimmune Pancreatitis Two distinct histologic patterns of AIP have been described, which are currently labeled as type 1 and type 2 AIP [17]. The

consensus statement on the pathologic profile of IgG4-related disease recognizes three major histopathologic features of type 1 AIP, or lymphoplasmacytic sclerosing pancreatitis: dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, “storiform” or swirling pattern of fibrosis, and obliterative endophlebitis [29] (Fig. 2). A ratio of IgG4to-IgG plasma cells of greater than 40% on tissue stains is suggested as a cutoff value for the diagnosis [29]. The histologic pattern in type 2 AIP is characterized as idiopathic duct-centric pan-

Exposure to lactoferrin, CA−II and PSTI antigens

Genetic predisposition

H. Pylori mimicry T regulatory cell

Th1 Cellular reaction

Initiation of AIP

Th2 Humoral reaction

1. Substitution of aspartic acid at position 57 of DQß1 2. HLA DRB1*0405−DQB1*0401 haplotype 3. CTLA4 polymorphism 4. FCRL3 polymorphism

Progression of AIP

Increased eosinophils and lgG4 with complement activation by classical pathway

Tissue damage

Fig. 1—Flowchart shows etiopathogenetic mechanism involved in autoimmune pancreatitis (AIP). CA-II = carbonic anhydrase II, CTLA4 = cytotoxic T lymphocyte–associated protein 4, FCRL3 = Fc receptor–like gene 3, HLA = human leukocyte antigen, H. pylori = Helicobacter pylori, PSTI = pancreatic secretory trypsin inhibitor, Th = T helper.



Fig. 2—62-year-old man with classic histopathologic findings of type 1 autoimmune pancreatitis. A, Photomicrograph (H and E, ×2) from pancreatic biopsy shows characteristic storiform (swirling pattern) fibrosis, lymphoplasmacytic infiltration around medial and large interlobular ducts, and obliterative phlebitis. B, Photomicrograph of immunostaining shows diffuse IgG4 positivity, consistent with diagnosis.

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Advances in Autoimmune Pancreatitis creatitis, the hallmarks of which are granulocytic epithelial lesions [30]. Type 2 AIP is characterized by ductal epithelial granulocytic infiltration leading to ductal damage and obliteration, a feature not seen in type 1 AIP. Ductal lesions show neutrophilic microabscesses and ulceration. Obliterative phlebitis is uncommon in type 2 AIP, and the tissue does not generally stain for IgG4-positive cells [30–33] (Fig. 3). Clinical Manifestations of Autoimmune Pancreatitis The clinical manifestations of two subtypes of AIP are distinct. The major differences are summarized in Table 1. Type 1 AIP typically presents in older men (> 50 years old in 70% cases) and is thought to be a part of a systemic fibroinflammatory disease called IgG4-related disease [34, 35]. The male-to-female ratio is 4–7.5:1 [13]. The classic clinical presentation of type 1 AIP is that of an elderly man presenting with painless obstructive jaundice (up to 75% cases) [17], symptoms that are remarkably similar to those of pancreatic cancer. Presentation with acute pancreatitis is increasingly recognized often in younger age groups, with an incidence of up to 35% in a recently published series [36]. Other clinical features include chronic or recurrent abdominal pain, weight loss, and steatorrhea [37]. Abnormalities of the pancreatic exocrine function are seen in up to 85% of patients with AIP. Diabetes mellitus may occur simultaneously with the onset of AIP (52% of cases) or may be present before the onset of AIP (33% of cases) [38]. Type 2 AIP is an uncommon entity that affects younger patients (mean age, 43 years), without a sex predilection (affects women in up to 38% cases), and often has a low prevalence of elevated serum IgG4 levels [11, 17]. As in type 1 AIP, type 2 AIP commonly presents with obstructive jaundice. Type 2 AIP is not associated with systemic manifestations, except for inflammatory bowel disease in about 30% of patients [39]. Diagnosis of Autoimmune Pancreatitis: The International Consensus Diagnostic Criteria Given its multifactorial causes and varied clinical manifestations, the diagnosis of AIP is often challenging. Several diagnostic criteria were proposed in the last decade, incorporating the clinical, pathologic, serologic, and imaging manifestations. These include

Fig. 3—22-year-old man with classic histopathologic findings of type 2 autoimmune pancreatitis. Photomicrograph (H and E, ×2) from pancreatic biopsy shows neutrophilic infiltration within epithelium and lumen of main or interlobular ducts (granulocytic epithelial lesion). Interlobular stroma is relatively acellular with only few lymphocytes and plasma cells, but obliterative phlebitis and IgG4-positive plasma cells are rare.

the Japan Pancreas Society criteria (2002 and 2006), Mayo Clinic and HISORt (histology, imaging, serology, other organ involvement, and response to therapy) criteria (2006 and 2009), Korean criteria (2007), Asian criteria (2008), Mannheim criteria (2009), and Italian criteria (2003 and 2009), as outlined elsewhere [40]. There was wide heteroge-

neity among the multiple proposed criteria, likely influenced by the regional and ethnic differences in the pathologic and clinical manifestations of AIP. Subsequently, in an attempt to formulate uniform criteria that can be used as a reference standard, an international panel of experts convened during the Fourteenth Congress of the International Association of Pancreatology developed the International Consensus Diagnostic Criteria (ICDC) for AIP after reviewing several existing criteria. The ICDC emphasizes five cardinal features of AIP: the imaging appearance of pancreatic parenchyma and the pancreatic duct, serum IgG4 level, other organ involvement with IgG4-related disease, pancreatic histology (from core biopsy or resection), and response to steroid therapy. The first four features are categorized as level 1 and 2 findings, depending on the diagnostic reliability. Two distinct subtypes are recognized in the ICDC classification. The diagnosis of type 1 and type 2 AIP can be described as either definitive or probable. In patients with type 1 AIP with typical CT findings for AIP, if there is supporting evidence from serology (elevation of serum IgG4 level) or other organ involvement, a definitive diagnosis of type 1 AIP can be made without the need for ERCP. According to the ICDC, the perfor-

TABLE 1: Differences Between Two Major Subtypes of Autoimmune Pancreatitis (AIP) Category

Type 1

Type 2


Lymphoplasmacytic sclerosing pancreatitis regarded as pancreatic manifestation of IgG4 sclerosing disease.

Idiopathic duct-centric chronic pancreatitis, AIP with granulocytic epithelial lesion.


Elderly (average, 62–64 y)

Younger (average, 43 y)


Male-to-female ratio, 4–7.5:1

Male-to-female ratio is equal

Clinical features

Obstructive jaundice most common (30–75% of cases)

Obstructive jaundice relatively less common; abdominal pain relatively more common

Acute pancreatitis

Acute pancreatitis in ≈ 15% of cases

Acute pancreatitis in ≈ 33% of cases

Extrapancreatic disease

Biliary tract, retroperitoneal, renal, and salivary disease involvement common

Inflammatory bowel disease (ulcerative colitis in 30% of cases)

Serum IgG4 level

Elevated (typically > 140 mg/dL)



Dense lymphoplasmacytic infiltrates involving pancreatic lobules and ducts, fibrosis, and obliterative phlebitis.

Inflammatory infiltrates are denser in the lobules than in the septa, transmural-mixed inflammatory infiltration of ducts, destruction of ductal epithelium, and absence of phlebitis


Exhibits frequent relapse (up to 40%)

Relapse is exceedingly rare

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Khandelwal et al. mance of diagnostic ERCP is not mandatory, and ERCP findings may provide collateral evidence. The ICDC limits the evidence of other organ involvement only to proximal bile duct, retroperitoneal fibrosis, enlarged salivary glands, and renal involvement because of the more consistent appearance of these organs in type 1 AIP. However, if the distinction between the subtypes is not possible, then it can be categorized as AIP, not otherwise specified. The salient features of ICDC classification are summarized in Tables 2, 3, and 4. Imaging: Pancreatic Manifestations Ultrasound Transabdominal ultrasound is of limited value in diagnosing AIP. However, the presence of a diffusely enlarged hypoechoic pancreas could suggest the diagnosis in the appropriate clinical scenario [41] (Fig. 4A). Typical imaging features described in endoscopic ultrasound include diffusely enlarged hypoechoic pancreas with echogenic interlobular septa and narrowing of the main pancreatic duct (Fig. 4B). Intraductal ultrasound of the common bile duct in AIP shows concentric bile duct–wall thickening with smooth configuration of the outermost layer and a smooth luminal surface. In contrast, cholangiocarcinoma shows eccentric wall thickening with an irregular luminal surface, disruption of the layered structure of the bile duct wall, and a hypoechoic mass with irregular margins. Thickening of the bile duct wall (exceeding 1 mm) in a bile duct that is dilated or nonstenotic on endoscopic ultrasound is 100% specific and 85% sensitive for a diagnosis of cholangiocarcinoma [42]. An additional advantage of endoscopic ultrasound is the feasibility of obtaining an ultrasound-guided biopsy for definitive histologic diagnosis. CT and MRI Three distinct morphologic patterns of involvement have been described: diffuse, focal, and multifocal forms. The classic imaging appearance of the diffuse pattern of involvement includes diffuse “sausageshaped” pancreatic enlargement with a smooth outline, the absence of normal pancreatic clefts (“featureless pancreas”), and a peripheral hypoattenuating or hypoenhancing halo [43–45] (Fig. 5). The pattern of enhancement is variable, depending on the degree of inflammatory infiltrate and fibrosis of the involved pancreas. Delayed enhancement of the parenchyma indicative of underlying fibrosis is typical. A capsule or rind 1010

TABLE 2: Level 1 and Level 2 Criteria for Type 1 Autoimmune Pancreatitis (AIP) Using International Consensus Diagnostic Criteria [40] Abbreviation


Level 1

Level 2


Parenchymal imaging

Diffuse enlargement with delayed enhancement

Indeterminate and atypical findings such as segmental or focal enlargement with delayed enhancement


Ductal imaging (ERCP)

Long and multiple strictures without marked upstream dilatation

Segmental or focal narrowing without marked upstream dilatation (duct size < 5 mm)



IgG4 level > 2 times upper limit IgG4 level 1–2 times upper of normal value limit of normal value

Other organ involvement

Either typical histology or radiology


a or b

a. Histology of extrapancreatic a. Histology of extrapancreorgans atic organs including endoscopic biopsies of bile duct Any three of the following:

Both of the following:

(1) Marked lymphoplasmacytic 1) Marked lymphoplasmainfiltration with fibrosis and cytic infiltration without without granulocytic infiltration granulocytic infiltration (2) Storiform fibrosis

(2) Abundant (> 10 cells/HPF) IgG4-positive cells

(3) Obliterative phlebitis

b. Physical or radiologic evidence

(4) Abundant (> 10 cells/HPF) IgG4-positive cells

At least one of the following:

b. Typical radiologic evidence

(1) Symmetrically enlarged salivary or lachrymal glands

At least one of the following:

(2) Radiologic evidence of renal involvement described in association with AIP

(1) Segmental or multiple proximal (hilar or intrahepatic) or proximal and distal bile duct stricture (2) Retroperitoneal fibrosis H

Histology of the pancreas LPSP (core biopsy or resection)

LPSP (core biopsy)

At least 3 of the following:

Any 2 of the following:

(1) Periductal lymphoplasmacytic infiltrate without

(1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration

granulocytic infiltration

(2) Obliterative phlebitis

(2) Obliterative phlebitis

(3) Storiform fibrosis

(3) Storiform fibrosis

(4) Abundant (> 10 cells/hpf) IgG4-positive cells

(4) Abundant (> 10 cells/hpf) IgG4-positive cells Rt

Response to steroid

Diagnostic steroid trial; rapid (≤ 2 weeks) radiologically demonstrable resolution or marked improvement in pancreatic or extrapancreatic manifestations

Note—hpf = high-power field, LPSP = lymphoplasmacytic sclerosing pancreatitis.

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Advances in Autoimmune Pancreatitis TABLE 3: Level 1 and Level 2 Criteria for Type 2 Autoimmune Pancreatitis (AIP) Using International Consensus Diagnostic Criteria [40]

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Level 1

Level 2


Parenchymal imaging

Typical: Diffuse enlargement with delayed enhancement

Indeterminate and atypical findings such as segmental or focal enlargement with delayed enhancement


Ductal imaging (ERCP)

Long and multiple strictures without marked upstream dilatation

Segmental or focal narrowing without marked upstream dilatation (duct size, < 5 mm)


Other organ involvement


Clinically diagnosed inflammatory bowel disease

Histology of the IDCP: Both of the following: Both of the following: pancreas (core (1) Granulocytic infiltration of (1) Granulocytic and lymphoplasbiopsy or reduct wall with or without granu- macytic acinar infiltrate section) locytic acinar inflammation (2) Absent or scant (0–10 cells/ hpf) IgG4-positive cells



(2) Absent or scant (0–10 cells/ hpf) IgG4-positive cells

Diagnostic steroid trial; rapid (≤ 2 weeks) radiologically demonstrable resolution or marked improvement in manifestations

Note—hpf = high-power field, IDCP = idiopathic duct-centric pancreatitis.

TABLE 4: Diagnosis of Definitive and Probable Type 1 and Type 2 Autoimmune Pancreatitis (AIP) Using International Consensus Diagnostic Criteria [40] Diagnosis, Primary Basis for Diagnosis

Imaging Evidence

Collateral Evidence

Definitive type 1 AIP Histology

Typical or indeterminate

Histologically confirmed LPSP (level 1 H)


Typical Indeterminate

Any non-D level 1 or level 2


Level 1 S or OOI + Rt or level 1 D + level 2 S or OOI or H + Rt

Probable type 1 AIP


Level 2 S or OOI or H + Rt

Definitive type 2 AIP

Typical or indeterminate

Histologically confirmed IDCP (level 1 H) or clinical inflammatory bowel disease + level 2 H + Rt

Probable type 2 AIP

Typical or indeterminate

Level 2 H or clinical inflammatory bowel disease + Rt

Response to steroid

Two or more from level 1 (+ level 2 D)a

Note—D = ductal imaging, H = histology of the pancreas, IDCP = idiopathic duct-centric pancreatitis, OOI = other organ involvement, Rt = response to steroid, S = serology. aLevel 2 D is counted as level 1 in this setting.

of hypoattenuation or hypoenhancement is thought to be secondary to fluid, phlegmon, or fibrous tissue and may appear hypointense on T2-weighted images [46–50]. Diffusionweighted imaging may show restricted diffusion [51] (Fig. 6). The focal form of AIP often involves the head or uncinate process of pancreas and is seen as localized enlargement or a masslike appearance of the pancreas with delayed enhancement after administration of contrast agent [52] (Fig. 7).

Although peripancreatic stranding and pseudocysts are relatively uncommon, vascular complications (compression, encasement, or thrombosis of splenic or mesenteric vessels) are reported in 23–57% of patients with AIP [37, 43]. Periportal, peripancreatic, and celiac lymphadenopathy can be seen up to 21% of patients as a manifestation of systemic IgG4-related disease [53, 54]. The lymph nodes may exhibit a perinodal halo similar to the peripancreatic halo typical of AIP.

B Fig. 4—Ultrasound findings of autoimmune pancreatitis in two different patients. A, 45-year-old man. Transabdominal ultrasound shows diffusely enlarged hypoechoic pancreas (arrow). B, 54-year-old man. Endoscopic ultrasound image shows typical features of parenchymal lobularity, and hyperechoic strands (arrow) are visible in enlarged gland.

Both type 1 and type 2 AIP appear similar on imaging; however, type 2 AIP tends to be more focal (in up to 85% cases) [12]. In addition, ductal injury in type 2 AIP results in pancreatic atrophy, which may preferentially affect the pancreatic tail, resulting in distal shortening of the pancreas, or “pancreatic cutoff sign” [55] (Fig. 8). This sign has been reported in up to 40% cases of type 2 AIP. Typical demographic features (i.e., younger age and no sex predilection) and an association with inflammatory bowel disease also help in differentiating the two subtypes of AIP. Ductal Imaging With MRCP and ERCP Both MRCP and ERCP can be used to assess ductal morphologic changes in AIP. Typically, AIP shows long-segment stricture of the main pancreatic duct (involving more

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Khandelwal et al. Fig. 5—50-year-old woman with diffuse form of autoimmune pancreatitis. A and B, Contrast-enhanced arterial (A) and venous (B) phase CT images show diffuse enlargement of pancreas (arrows) and loss of lobular architecture, giving featureless “sausage-shaped” appearance to pancreas. There is capsule or rind that shows persistent enhancement.






Fig. 6—41-year-old woman with diffuse autoimmune pancreatitis (AIP). A, Contrast-enhanced T1-weighted MRI shows typical featureless sausage-shaped diffuse form of AIP (arrow) with heterogeneous enhancement of pancreatic parenchyma. B, Diffusion-weighted MRI shows diffusely swollen high-intensity area (arrow) (b value = 800 s/mm2). C, Apparent diffusion coefficient (ADC) map shows low-signal-intensity region (arrow) with ADC value of 1.042 × 10 −3 mm2 /s.



than one third of the length), multiple strictures, lack of upstream dilatation from the stricture (< 5 mm), and side branches arising from the stricture segment (Figs. 9 and 10). The presence of all four features on ERCP is highly specific (91%) but only moderately sensitive (52%) for the diagnosis of AIP [56]. A positive duct-penetrating sign of the common bile duct (CBD)—that is, visualization of the CBD as it courses through the pancreas—with delayed wall enhancement can also

be seen in AIP [57, 58]. Abrupt cutoff of the intrapancreatic CBD and focal stenosing lesions are more common in pancreatic cancer and warrant tissue diagnosis [59]. The reported accuracy of MRCP for depicting ductal changes in the main pancreatic duct is low because it tends to overestimate the ductal narrowing (65%) [57]. MRCP is, however, a noninvasive risk-free technique useful for imaging surveillance of AIP and assessment of response to steroid therapy [50].


Fig. 7—60-year-old man with focal form of autoimmune pancreatitis (AIP). A, Axial T1-weighted fat-suppressed contrastenhanced MRI in parenchymal phase shows focal ill-defined mass (arrow) that is hypointense to normal pancreas. B, Axial T1-weighted fat-suppressed contrastenhanced MRI in delayed phase shows delayed enhancement of mass (arrow) without significant upstream pancreatic duct dilatation, features that help in differentiating AIP from adenocarcinoma.

Normalization of duct caliber on follow-up is an early imaging finding of response to steroid therapy. Fluorine-18-FDG PET Fluorine-18-FDG uptake by the pancreas is described in 83–100% of patients with AIP, as opposed to 13% with other forms of chronic pancreatitis [60, 61]. Extrapancreatic uptake into the salivary gland, kidney lymph nodes, and retroperitoneum, when

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Advances in Autoimmune Pancreatitis Fig. 8—25-year-old woman with history of ulcerative colitis and abdominal pain. Axial contrastenhanced CT image shows mild diffuse enlargement of pancreas with abrupt cutoff in pancreatic tail region, also called “pancreatic tail truncation.” This was biopsy-proven chronic pancreatitis with focal active inflammation, suggestive of type 2 autoimmune pancreatitis. Granulocyte epithelial lesions and IgG4 negativity were seen on histopathologic examination.

seen, aids in the diagnosis of AIP. Decreased FDG uptake has been described after corticosteroid therapy [62]. Role of Fine-Needle Aspiration or Biopsy in the Diagnosis of Autoimmune Pancreatitis The tissue diagnosis of AIP may be performed with imaging-guided biopsies or fineneedle aspiration via endoscopic ultrasound guidance. Endoscopic ultrasound–guided fine-needle aspiration has been shown to have poor sensitivity (up to 37.5%) and specificity [63]. However, with the recent advent of spring-loaded biopsy needles with quick motion, adequate tissue samples were obtained in 80% of cases [64]. The accuracy of endoscopic ultrasound–guided Tru-Cut needle (Cardinal Health) biopsy is reported to be as high as 85%. A sequential sampling strategy involving endoscopic ultrasound– guided fine-needle aspiration first, followed by endoscopic ultrasound–guided Tru-Cut needle biopsy when the initial cytologic examination is negative for pancreatic cancer in cases of suspected AIP, has been recommended as a diagnostic algorithm [65]. However, endoscopic ultrasound–guided Tru-Cut needle biopsy is technically more challenging and requires more expertise than does fine-needle aspiration [66]. Serology Type 1 AIP is associated with serologic abnormalities, including elevated titers of γ-globulin (≥ 2.0 g/dL), IgG (≥ 1800 mg/dL) and its subset IgG4 (≥ 140 mg/dL), and rheumatoid factor [2]. Serum IgG4 is the most commonly used biomarker, and a value higher than 140 mg/dL is reported to be

Fig. 9—66-year-old woman with diffuse form of autoimmune pancreatitis. ERCP image with pancreatic injection shows irregular main pancreatic duct with multifocal areas of narrowing (arrows).

up to 86% sensitive, 96% specific, and 91% accurate for the diagnosis of AIP [67, 68]. However, serum IgG4 may be elevated in up to 5% of healthy people and 10% of patients with pancreatic carcinoma [69], and up to 20% of patients with AIP can be seronegative [12]. Overall, the positive rates of serum markers in AIP are reported to be 50–60% for γ-globulin, 60–80% for IgG, 68–92% for IgG4, and 20–30% for rheumatoid factor [24]. In addition, titers of anti CA-II (55%), antilactoferrin (75%), and antinuclear antibody (60%) are also variably increased in AIP [70]. Recently, an antibody homologous with an amino acid sequence of plasminogen-binding protein of Helicobacter pylori and ubiquitin-protein ligase E3 component n-recognin 2, has also been described in association with AIP [71]. Extrapancreatic Manifestations of Autoimmune Pancreatitis Extrapancreatic manifestations are the hallmark of type 1 AIP, with nearly 60% of patients with type 1 AIP presenting with other organ involvement [12]. Major clinical manifestations are apparent in the organs affected with fibrosis and obstructive phlebitis, the most common being the bile ducts, kidneys, retroperitoneum, orbits, lymph nodes, and salivary glands [54, 72–85]. Figure 11 summarizes extrapancreatic manifestations of AIP. Biliary tract involvement is reported to occur in over 90% cases of AIP [86–88] and typically is seen as a smooth stricture of distal extrapancreatic CBD with mild dilatation proximally (Fig. 12A). A pattern of dilatation resembling primary sclerosing cholangitis (PSC) has also been described

Fig. 10—65-year-old man with diffuse autoimmune pancreatitis. ERCP image shows diffuse narrowing of main pancreatic duct (black arrow) and intrapancreatic segment of common bile duct (white arrow).

[89]. ERCP is, however, able to differentiate between IgG4-related sclerosing cholangitis and PSC with high reported sensitivity (93–96%) and specificity (96–100%) [42]. In their discriminant analysis to differentiate PSC from IgG4-related cholangitis, Nakazawa et al. [89] concluded that age, pruned-tree appearance, bandlike stricture, and long-segment distal CBD stricture are the major differentiating points between the two entities. For instance, for each additional year of age, the odds of receiving a diagnosis of

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Khandelwal et al. as 47% of patients with AIP and is seen as bilateral painless swelling of the glands and diffuse heterogeneity on ultrasound [39, 73]. Focal mass lesions can also be seen. Other manifestations include inflammatory pseudotumor of liver, paratesticular pseudotumor, aortitis, and autoimmune prostatitis [78, 94]. In addition, AIP has been found to be associated with other autoimmune diseases, such as Sjögren syndrome, myelodysplastic syndrome, and systemic lupus erythematosus [95, 96]. Several features of IgG4-related diseases are shown in Figure 14.

hilar, and cervical lymphadenopathy can occur in 33–78% of cases of AIP [54, 73]. IgG4-related lung disease is seen up to 54% of patients with AIP and is categorized into four major subtypes: solid nodular, round-shaped ground-glass opacity, alveolar interstitial, and bronchovascular [73, 75, 83]. Involvement of the salivary glands and lacrimal gland has been reported in as many

Natural History, Treatment, and Prognosis of Autoimmune Pancreatitis The natural history and prognosis of AIP depend on several factors, including the subtype (type 1 vs type 2 AIP), the pattern of organ involvement, and the genetic susceptibility. Although type 1 AIP has a high 3-year relapse rate of up to 60%, type 2 AIP relapses much less often (< 5%). The relapse rate for type 1 AIP has been described to range from 15% to 60%, with most cases (90%) occurring in the first 3 years [97]. Proximal bile duct involvement (IgG4-related cholangitis) and diffuse swelling of the pancreas are independent predictors of symptomatic disease relapse in type 1 AIP [12, 97]. The higher immune complex level (> 10 µg/dL) and the presence of susceptible human leukocyte antigen and cytotoxic T lymphocyte– associated protein 4 polymorphisms are useful predictors for AIP recurrence [98]. Corticosteroids are the mainstay of initial therapy for AIP, with high rates of ini-



Fig. 11—Summary of extrapancreatic manifestations of autoimmune pancreatitis. (Drawing by Houle B)

PSC instead of IgG4-related cholangitis decreased by a factor of 9%. Pruned-tree appearance and bandlike stricture are typical of PSC, and long-segment distal CBD stricture is typical of IgG4-related sclerosing cholangitis [89]. On contrast-enhanced CT and MRI, the affected segments of the biliary tree show wall thickening, stricture formation, wall irregularity, and abnormal contrast enhancement [89] (Fig. 12B). Renal involvement (Fig. 13) is present in up to 35% of patients with AIP [72] and can be seen as parenchymal lesions (round or wedge-shaped cortical nodules, peripheral cortical lesions, or masslike lesions), diffuse renal enlargement, perirenal soft-tissue rind, or urothelial thickening of the renal pelvis [90]. Retroperitoneal fibrosis, which is seen in 10–20% of patients with AIP, is characterized by a thick soft-tissue mass encasing the abdominal aorta and its branches, with or without encasement of the ureters [39, 54]. Focal infiltration of the gastric, duodenal, or colonic wall can be detected endoscopically or by imaging [54, 79, 91, 92]. Inflammatory bowel disease is seen in about 2–6% of patients with type 1 AIP and in 16–30% of patients with type 2 AIP [11, 12, 93]. Abdominal (retroperitoneal, peripancreatic, mesenteric, peripancreatic, and paraaortic), mediastinal,


Fig. 12—Biliary involvement in two patients with type 1 autoimmune pancreatitis (AIP). A, 70-year-old man. Coronal MRCP image shows smooth stricture of distal common bile duct. B, 54-year-old man. Axial contrast-enhanced CT image shows circumferential wall thickening and enhancement of common bile duct (arrow). Note typical imaging appearance of pancreas consistent with AIP.

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Advances in Autoimmune Pancreatitis because, if untreated, the pancreatic and biliary disease can progress to irreversible pancreatic insufficiency and secondary biliary cirrhosis. Steroids also hasten recovery and decrease the relapse rate [16, 89, 102]. Pancreatic cancer associated with AIP has been rarely reported in literature, with a preponderance in the body and tail regions of the pancreas [98]. In a large series of over 1000 patients, only five cases of pancreatic cancer were reported [97, 99]. Pancreatic duct stone formation is seen in up to 7% of cases and occurs more often in relapsing or recurrent disease [103]. Neither form of AIP significantly affects 5-year survival [11].





Fig. 13—Imaging spectrum of renal involvement in four different patients with type 1 autoimmune pancreatitis. A, 38-year-old man. Coronal contrast-enhanced CT image shows multiple well-defined hypodense rounded renal cortical lesions (arrows). B, 53-year-old man. Axial contrast-enhanced CT image shows multiple poorly enhancing hypodense masslike lesions (arrow) almost entirely replacing parenchyma. C, 67-year-old man. Axial contrast-enhanced CT image shows perinephric rind (arrow) of soft-tissue density. Reprinted with permission from [72]. D, 48-year-old man. Axial contrast-enhanced CT image shows urothelial thickening of renal pelvis (arrow).

tial remission seen in type 1 and type 2 AIP. The diagnosis of AIP should be reconsidered in patients who do not respond to steroids [97]. The most common indications for steroid therapy in AIP are jaundice, abdominal pain, or abnormal pancreatic imaging suggestive of AIP. In addition, endoscopic biliary drainage performed for jaundice, and glycemic control is necessary in patients with diabetes [97]. Immunomodulators (most commonly azathioprine or mycophenolate mofetil) are

used in patients with relapse or steroid-resistant disease. It is unclear whether long-term maintenance therapy alters the natural history of disease [97, 99]. Most authors recommend monitoring of liver enzymes to detect early biliary relapse and prompt steroid treatment of any relapse, rather than universal use of maintenance steroid therapy for relapse prevention [12]. Spontaneous disease remission is seen in 24–55% of patients treated conservatively [97, 100, 101]. In spite of this, early steroid therapy is recommended

Role of Imaging in Surveillance MDCT and MRI play significant roles in the assessment of treatment response in AIP. Imaging features, such as diffuse swelling and a peripancreatic halo, reflect an early inflammatory phase and are good predictors of treatment response to steroids, whereas features such as ductal strictures and focal masslike swelling are predictive of a suboptimal response indicative of late-stage disease with predominance of fibrosis [104]. Morphologic changes of reversal of imaging findings can occur as early as 1–2 weeks after the initiation of steroid therapy [45]. There is normalization or atrophy of parenchymal thickness, normalization of enhancement pattern (Fig. 15), and reversal of pancreatic duct narrowing in posttreatment follow-up imaging in most patients [105]. Pancreatic atrophy is indicative of the late burnt-out phase of disease. Parenchymal atrophy and calcifications are uncommonly seen in treated AIP. The focal form of AIP typically responds with resolution of the mass, pancreatic atrophy, and resolution of extrapancreatic manifestations (Fig. 16). MRI has been shown to detect recurrence of disease in up to 22% of patients who are clinically and biochemically asymptomatic [50]. Autoimmune Pancreatitis Versus Pancreatic Cancer One of the major differential diagnoses of AIP is pancreatic cancer. Both AIP and pancreatic cancer have common epidemiologic and clinical manifestations, such as preponderance in elderly men, presentation with painless jaundice, and elevated levels of serum tumor markers, making it difficult to distinguish the two entities. Although the diffuse form of AIP usually can be distinguished

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Khandelwal et al.










Fig. 14—Spectrum of extrapancreatic manifestations of IgG4-related disease in eight different patients. A, 36-year-old man with diabetes insipidus. Axial T2-weighted MR image (arrow) at level of orbits shows expanded T2-isointense pituitary gland. Subsequent resection of pituitary gland revealed lymphocytic hypophysitis with IgG4 positivity (arrow). B, 64-year-old man. Axial contrast-enhanced CT image at level of parotid glands shows homogeneously enhancing mass (arrow) that proved to be inflammatory pseudotumor with lymphoplasmacytic infiltrates and IgG4-positive cells. C, 65-year-old man. Ultrasound image of left submandibular salivary gland shows mildly enlarged gland (arrow) with heterogeneous hypoechoic appearance due to related sialadenitis. D, 36-year-old man. Axial contrast-enhanced CT image with oral contrast agent shows nonspecific gastric wall thickening (arrow), subsequently confirmed via endoscopic biopsy to be infiltrated with IgG4 inflammatory cells. E, 46-year-old man with focal mass forming autoimmune pancreatitis. Focal poorly enhancing hypodense lesion in right lobe of liver (arrow) was confirmed to be inflammatory hepatic pseudotumor. F, 77-year-old man. Axial CT image in lung window shows focal consolidative opacities in right upper lobe (arrow), suggesting pulmonary involvement with infiltrative IgG4related lung disease. G, 45-year-old man with dysuria and mildly elevated prostate-specific antigen levels (3 ng/mL). Transrectal ultrasound shows heterogeneous echotexture of prostate (arrows). Biopsy confirmed it to be autoimmune prostatitis. H, 64-year-old man. Contrast-enhanced axial T1-weighted MRI shows thickening and enhancement of aortic wall (arrow), suggesting aortitis or periaortitis associated with autoimmune pancreatitis. I, 54-year-old man. Axial contrast-enhanced CT image shows thick soft-tissue mass (arrow) surrounding abdominal aorta suggesting retroperitoneal fibrosis.


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Fig. 15—39-year-old woman with diffuse form of autoimmune pancreatitis and interstitial nephritis. A and B, Axial contrast-enhanced CT images obtained before (A) and after (B) steroid therapy reveal interval atrophy of gland (arrows) with resolution of peripancreatic hypodense rind after steroid therapy (B). Also seen is marginal interval improvement in hypodensities in bilateral kidneys.



Fig. 16—57-year-man with focal autoimmune pancreatitis. A, Axial contrast-enhanced CT image obtained at time of initial presentation with acute pancreatitis shows focal mass in body of pancreas (arrow) with peripancreatic lymph node (arrowhead). Hypodense rind of soft tissue is seen surrounding lymph node. B, Three months after steroid therapy, axial contrast-enhanced CT image reveals nearly total resolution of mass (arrow), atrophy of pancreas, and resolution of peripancreatic lymph node (arrowhead).

from pancreatic adenocarcinoma on imaging, differentiating focal AIP from pancreatic malignancy is challenging. Currently, the features that have been found to be helpful differentiating the two entities include serum IgG4 levels, serum tumor markers (cancer antigen [CA] 19-9 levels), imaging manifestations, and responsiveness to steroid therapy. Patients with AIP show higher levels of serum IgG4 (a more than twofold elevation or a value > 280 mg/dL is 99% specific for AIP) compared with patients with pancreatic adenocarcinoma. Hamano et al. [86] found that an IgG4 level greater than 135 mg/dL is 97% specific and 95% sensitive for differentiating AIP from pancreatic ductal adenocarcinoma. An estimated 7–10% of patients with pancreatic adenocarcinoma and 10% of patients with cholangiocarcinoma

may also have elevated IgG4 levels, but to a lesser extent [68, 106, 107]. On histologic analysis, up to 15% of patients with pancreatic cancer have been found to have IgG4-positive plasma cells. On the contrary, CA 19-9 is considered a standard biomarker for pancreatic cancer. Reported pooled sensitivity and specificity of CA 19-9 for the diagnosis of pancreatic cancer are 79–81% and 82–90%, respectively. CA 19-9 is, however, more useful in determining prognosis and recurrence than in establishing the diagnosis of pancreatic cancer because of its high false-positive and false-negative rates. On imaging, both focal AIP and pancreatic adenocarcinoma can be hypovascular on early phase contrast-enhanced imaging, but delayed persistent enhancement favors focal AIP. Furthermore, a markedly speckled pat-

tern of enhancement on the pancreatic phase of dynamic contrast-enhanced MRI is suggestive of focal AIP, as opposed to the target enhancement pattern observed more frequently in pancreatic cancer [52]. Peripancreatic halo, truncation of the pancreatic tail, and associated typical extrapancreatic involvement can further help in pinpointing the diagnosis of focal AIP. Diffusion-weighted imaging is also found to be useful in this differentiation because focal AIP tends to show less restricted diffusion, with an apparent diffusion coefficient value of less than 1.075 × 10−3 mm2/s 92.5% sensitive and 76.9%% specific in differentiating focal AIP from pancreatic adenocarcinoma [51]. On ductal imaging, AIP typically is seen with long strictures (> 3 cm) involving more than one third of the pancreatic duct length, strictures without an upstream dilatation of the duct (< 5 mm), multiple strictures, or strictures with intact side branches [59, 108]. The presence of single or multiple pancreatic duct strictures without upstream dilatation (< 5 mm) is highly specific for AIP (> 90%). In contrast, pancreatic adenocarcinoma presents with abrupt tapering of the main pancreatic duct with upstream ductal dilatation and without intact side branches from the stricture segment. On FDG PET, although diffuse AIP can be distinguished from adenocarcinoma by the diffusely heterogeneous increased pancreatic uptake, no differences in maximum standardized uptake value have been described between the focal form of AIP and adenocarcinoma. However, an abnormal extrapancreatic uptake in a pattern favoring IgG4-related sclerosing disease (e.g., renal, salivary gland, or retroperitoneal uptake) favors the diagnosis of AIP rather than pancreatic cancer [60]. Advances in ultrasound, such as contrast-enhanced ultrasound and ultrasound elastography, have also been reported to be helpful. Focal hypoechoic lesions showing a netlike hypervascularization pattern are seen in focal AIP, as opposed to hypovascular lesions in pancreatic cancer [109]. In addition to these, it has been found that patients with AIP present with fluctuating obstructive jaundice rather than the progressive painless jaundice seen in pancreatic adenocarcinoma. The major distinguishing features between AIP and pancreatic adenocarcinoma are summarized in Table 5. Conclusion AIP is a distinct treatable form of chronic nonalcoholic pancreatitis that shows exqui-

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Khandelwal et al. site response to corticosteroid therapy. AIP clinicopathologically consists of two subtypes: types 1 and 2. Type 1 AIP is now considered under the rubric of systemic IgG4related disease with predominant pancreatic involvement. Type 2 AIP, which is characterized by a seronegative painful pancreatitis syndrome, shows pathognomic granulocytic epithelial lesions that cause ductal obstruction. Type 1 AIP differs from type 2 AIP by IgG4 seropositivity, high tissue and serum levels of IgG4, frequent involvement of extrapancreatic organs, and a disease that typically recurs in the pancreas and the biliary system. Clinical, laboratory, and cross-sectional imaging modalities allow a noninvasive diagnosis of type 1 AIP in up to 70% of patients. MDCT and MRI play an integral role in the diagnosis, surveillance, and management of patients with AIP.

TABLE 5: Differences Between Autoimmune Pancreatitis and Pancreatic Cancer Differences


Pancreatic Cancer

Not useful


Elevated serum IgG4 level (> 140 mg/ Elevated serum cancer antigen 19-9 dL) (86% sensitive, 96% specific, level 91% accurate)

Not useful

Imaging MDCT or MRI

Capsulelike low-density rim, delayed Low-density mass, abrupt pancreenhancement of the pancreas, and atic duct cutoff, distal pancreatic no atrophy of the body and tail of atrophy, regional spread, and methe pancreas tastases


Long segmental MPD stricture, no Short-segment stricture of MPD with upstream ductal dilatation, multiple upstream ductal dilatation, no side MPD strictures, side branches branches from the strictured segarising from the strictured segment, abrupt narrowing of the distal ment, and strictures of intrahepatic common bile duct, and no intrahebile duct patic biliary strictures

Endoscopic ultrasound

Duct-penetrating sign

Duct cutoff with upstream dilatation


Storiform fibrosis, lymphoplasmacytic infiltrates, and obliterative phlebitis

Malignant cells

Extrapancreatic disease distribution

Biliary, renal, retroperitoneal, and salivary gland lesions



Steroid therapy

Surgery versus palliative chemoradiotherapy

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Recent advances in the diagnosis and management of autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a rare chronic relapsing steroid-responsive fibroinflammatory disorder of the pancreas that is likely caused by immun...
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