Endoscopic retrograde pancreatography demonstrates a diffuse irregular narrowing of the main pancreatic duct in autoimmune pancreatitis
Endoscopic retrograde pancreatography demonstrates a focal narrowing of the main pancreatic duct (arrow) at the pancreatic head in autoimmune pancreatitis. The upstream dilatation of the main pancreatic duct is mild (<5 mm)
There has been substantial disparity between the Asian and the HISORt criteria in the use of ERP to diagnose AIP [7, 8]. The former mandates the use of an ERP to diagnose AIP, whereas the latter does not. According to a recent study, in which patients with AIP were divided into two subgroups according to CT features (typical vs. atypical), little incremental benefit was obtained from additional ERP in patients with typical CT features for AIP (diffuse pancreatic enlargement ± rim with homogeneous enhancement) . On the other hand, in patients with atypical CT features (segmental/focal enlargement, marked dilatation/cutoff of the main pancreatic duct, or pancreatic mass), additional ERP could increase the sensitivity and specificity in distinguishing AIP from pancreatic cancer. In the clinical setting of suspected AIP, therefore, the use of ERP may be tailored depending on CT features. Actually, when initial CT features are typical for AIP, the ICDC do not use ERP at all for differentiating AIP from pancreatic cancer. According to the ICDC, ERP is not usually used in cases with typical CT features and is only recommended in patients with atypical CT features or when there is no collateral evidence to support the diagnosis .
Many western endoscopists do not use ERP in patients with obstructive jaundice for fear of post-ERCP pancreatitis . In the previous studies, however, there was no post-ERCP pancreatitis in patients with AIP [4, 5, 9]. One plausible explanation is that AIP is a unique form of chronic pancreatitis and that post-ERCP pancreatitis is rare in patients with chronic pancreatitis . This may reflect a protective effect of chronic pancreatitis against post-ERCP pancreatitis due to fibrosis and decreased enzymatic activity.
Endoscopic Retrograde Cholangiography
AIP frequently accompanies the common bile duct (CBD) and the proximal bile duct involvement [11–13]. Biliary involvement of AIP or IgG4-related systemic disease is referred to as IgG4-SC and presents radiographically as bile duct strictures with ductal wall thickening [14, 15]. ERCP can reveal strictures of the biliary tree as well as the pancreatic duct. The most common feature of endoscopic retrograde cholangiography (ERC) is intrapancreatic CBD stricture, but proximal (hilar/intrahepatic) bile duct strictures may also be observed [11, 13]. IgG4-SC should be differentiated from primary sclerosing cholangitis (PSC), cholangiocarcinoma, and pancreatic cancer. Differential diagnosis depends on the location and characteristics of the biliary stricture. In cases with isolated intrapancreatic CBD strictures, differential diagnosis includes distal CBD cancer and pancreatic cancer [11, 16]. On the other hand, hilar cholangiocarcinoma and PSC should be differentiated in cases with intrahepatic/hilar bile duct strictures. Intrahepatic/hilar bile duct strictures can be an important clue for distinguishing AIP from pancreatic cancer [15, 17–19]. An international multicenter study reported that proximal bile duct strictures were detected in 20–79 % of AIP patients, whereas pancreatic cancer did not accompany proximal bile duct strictures .
Characteristic features of ERC may allow discrimination of IgG4-SC from PSC. Typical cholangiographic features for PSC include short annular or band-like strictures, diverticulum-like outpouching, and beaded or pruned-tree appearance, whereas these features are rarely observed in IgG4-SC [19, 21]. On the other hand, IgG4-SC has longer stricture and more prestenotic dilatation .
Characteristic cholangiographic features of IgG4-SC being useful in differential diagnosis from hilar cholangiocarcinoma are the following: symmetric (concentric) wall thickening, thickening of the bile duct wall (>1 mm) in a nonstenotic bile duct on ERC, smooth luminal surface and preservation of wall layer structure, multifocal strictures (skipped lesions), and mild proximal duct dilatation despite a long stricture . Several clinical and radiological features other than cholangiography can also be helpful in differential diagnosis [11, 19]. The coexistence of pancreatic lesions (e.g., pancreatic enlargement) and OOI (e.g., salivary gland, kidney, or retroperitoneum) can further support the diagnosis of IgG4-SC .
Endobiliary biopsy for bile duct stricture may be helpful to exclude malignancy . Endobiliary biopsy can be performed easily during endoscopic biliary drainage for obstructive jaundice . Although the biopsy specimen is usually too small to observe the full spectrum of lymphoplasmacytic sclerosing histology, IgG4 immunostaining may provide further histologic support for the diagnosis of AIP/IgG4-SC. The sensitivity and specificity for IgG4 immunostaining of endobiliary biopsy specimens in the differential diagnosis between AIP/IgG4-SC and malignancy were 18–88 % and 9–100 %, respectively [11, 19, 24, 25]. Endobiliary biopsy for diagnosing AIP/IgG4-SC is included in the ICDC .
Duodenal Papillary Biopsy for IgG4 Immunostaining
Anatomically, the major duodenal papilla corresponds to the junction of the common bile duct and the main pancreatic duct and is often involved in AIP . Kamisawa et al. first reported that positive IgG4 immunostaining in papillary biopsies was specific for AIP . The sensitivity and specificity of positive IgG4 immunostaining of the major duodenal papilla were 52–80 % and 89–100 %, respectively [24, 27–29]. Significant adverse events such as bleeding or pancreatitis have not been reported during/after endoscopic biopsy of the major duodenal papilla. Positive IgG4 immunostaining of the major duodenal papilla occurs regardless of serum IgG4 level [29, 30]. Duodenal papillary biopsy with IgG4 immunostaining may, therefore, be attractive especially when AIP is clinically suspected, whereas serum IgG4 levels are normal or pancreatic core biopsy is not available .
The ICDC also recommend endoscopic biopsy of the major duodenal papilla at the time of ERCP . In the ICDC, the presence of marked lymphoplasmacytic infiltrate and abundant IgG4-positive cells seen in duodenal papillary biopsy specimen is currently classified as level 2 OOI in diagnosing type 1 AIP.
EUS is used to verify the presence or absence of a pancreatic mass. EUS is superior to multidetector CT for the diagnosis of small pancreatic neoplasms . The negative predictive value of a normal EUS exam for pancreatic tumor detection is nearly 100 % . EUS examination and EUS-FNA is highly recommended for patients who have atypical features of AIP because (1) EUS has excellent negative predictive value and can detect a small pancreatic cancer not visible on CT, and (2) EUS-FNA is the most reliable tool for excluding pancreatic cancer and avoiding unnecessary pancreatic surgery [22, 32]. For the diagnosis of pancreatic cancer, EUS-guided trucut biopsy (EUS-TCB) may not offer advantages over EUS-FNA; however, EUS-TCB should be considered when details of tissue architecture and immunostaining are required to establish a specific diagnosis . EUS elastography and contrast-enhanced harmonic EUS may provide information complementary to conventional EUS imaging .
Conventional EUS Imaging
Although the role of EUS in the diagnosis of pancreatic cancer is well established, there is lack of evidence in the definite diagnosis of AIP. It is unclear if EUS imaging alone can reliably suggest definite diagnosis of AIP and differentiating between AIP and pancreatic cancer, since there are no pathognomonic findings suggestive of AIP on EUS. The lack of pathognomonic features and diverse spectrum of EUS imaging features limits the utility of EUS imaging alone . The reported EUS finding for AIP is diffuse hypoechoic pancreatic enlargement, sometimes with coarse hyperechoic inclusions, and a mass lesion mimicking pancreatic cancer may be observed [16, 34, 35]. In AIP, on EUS, ductal wall thickening commonly spreads continuously from intrapancreatic CBD to the suprapancreatic middle bile duct (Fig. 12.3). In contrast, on EUS finding of patients with pancreatic head cancer, bile duct wall thickening is observed only at the intrapancreatic area. Hoki et al. reported that the findings of diffuse hypoechoic areas, diffuse enlargement, bile duct wall thickening, and peripancreatic hypoechoic margins are more frequent in AIP than in pancreatic cancer . On the other hand, a focal hypoechoic area and focal enlargement are significantly more common in pancreatic cancer.
EUS demonstrates an enlargement of pancreas head (arrowhead) and a wall thickening of dilated bile duct (arrow) in autoimmune pancreatitis
EUS-FNA and Core Biopsy
Real-time EUS can guide cytology/biopsy, allowing distinction of benign from malignant lesions for the pancreatic mass . The EUS-guided fine-needle aspiration (FNA) provides sensitivity of about 80–90 %, specificity of about 95–100 %, and accuracy of about 90–95 % in the differential diagnosis between benign pancreatic disease and pancreatic cancer [34, 37, 38]. Although diagnostic sensitivity of EUS-FNA for pancreatic cancer is very high, some of the difficulty may exist in cases with well-differentiated carcinoma, those with extensive necrosis, and those with a background of chronic pancreatitis [39–41]. We should remember that a negative result of cytology/biopsy is not a guarantee of benign disease; hence repeat EUS-FNA or short-term follow-up imaging to assess steroids responsiveness is necessary [8, 23]. Actually, AIP is much less common than pancreatobiliary malignancies such as pancreatic cancer or cholangiocarcinoma. It should be emphasized that repeat EUS-FNA is warranted in patients with high suspicion of pancreatobiliary malignancies despite negative results at initial EUS-FNA . If the steroid responsiveness is negative or equivocal, a definitive diagnosis always should be pursued by surgical exploration or resection. In the ICDC, negative work-up for pancreatobiliary malignancies is a prerequisite for a steroids trial .
For the histological diagnosis of AIP, EUS-guided trucut biopsy (TCB) is necessary. The primary role of EUS-FNA in a diagnosis of AIP may be to exclude malignancy rather than to provide definitive histological evidence for AIP . While EUS-FNA with a small caliber (22/25 gauge) provides only cytological samples, a TCB needle (19 gauge) can acquire larger tissue specimen preserving tissue architecture and can permit a nonsurgical diagnosis of AIP [34, 43, 44]. For establishing a diagnosis of pancreatic cancer, EUS-TCB does not offer advantage over EUS-FNA; however, EUS-TCB should be considered when details of tissue architecture and immunostaining are required to establish a specific diagnosis [5, 34, 43]. EUS-TCB is particularly useful for diagnosing type 2 AIP patients who are seronegative and lack of OOI . Until now, EUS-TCB is only available in a few specialized tertiary-care centers and is often not technically feasible according to a location of mass/enlargement in the pancreas [1, 34, 45]. However, EUS-TCB is expected to become more widespread with the availability of newly developed core biopsy needles with enhanced flexibility and improved tissue acquisition . Newly developed core biopsy needles can access all areas in the pancreas. This may attain two goals of histologic examination in one sitting with the use of the same needle: exclusion of pancreatic cancer and histological diagnosis of AIP.
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EUS Elastography/Contrast-Enhanced Harmonic EUS
To overcome the limitations related to conventional EUS imaging, endosonographers have used several techniques including the characterization of tumor vascularization and estimation of elasticity distribution in normal and pathologic areas in the pancreas . These imaging techniques can make EUS less operator dependent and improve the diagnostic yield of EUS-guided tissue sampling by selecting the most suspicious area of a tumor.
Elastography noninvasively gather informations about the relative hardness of the examined lesions compared with the surrounding tissues [47–49]. The premise is that malignant tumors are of harder consistency than benign ones. In a study by Dietrich et al., elastographic imaging of pancreatic cancer showed a markedly firmer area confined to the site of the low-echoic mass area, while in AIP cases, the hard area was not restricted to the mass lesion (Fig. 12.4).
(a) EUS elastography demonstrates the very hard area (blue) with soft spots (yellow) inside the tumor, which proved to be irregularly dilated cancer ducts surrounded cancerous fibrous tissue in pancreatic cancer. (b) EUS elastography in autoimmune pancreatitis demonstrates the random color signals apparently different from those of pancreatic cancer
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