Isolated IgG4-related sclerosing cholangitis misdiagnosed as malignancy in an area with endemic cholangiocarcinoma: a case report

The most common cause of perihilar biliary obstruction is perihilar CCA (Klatskin tumors) [2], especially in Thailand, which has the highest prevalence of both intrahepatic and extrahepatic CCA worldwide due to parasitic infestation [1]. Surgical resection including major hepatic resection remains the mainstay of treatment for perihilar CCA [19]. According to the AJCC classification 7^th edition, the extrahepatic bile duct is divided into the perihilar (proximal common bile duct and hilar) and distal common bile duct [20]. The incidence of benign proximal biliary obstruction preoperatively diagnosed as hilar CCA in which the final histological examination of resection specimens shows benign stricture is approximately 8–17.3% [2‐13]. One type of benign perihilar stricture is IgG4-RD. IgG4-RD is an emerging systemic condition characterized by mass-forming sclerosing lesions, elevated serum IgG4 concentrations, and extensive tissue infiltration by IgG4-positive plasma cells. IgG4-RD can involve any organ, but the most common is the pancreas. IgG4-SC is the sixth most common type of organ involvement [14]. IgG4-SC is a characteristic type of sclerosing cholangitis with dense infiltration of IgG4-positive plasma cells and extensive fibrosis in the bile duct wall [17]. IgG4-SC concomitant with pancreatic involvement or AIP is the most common presentation, while isolated IgG4-SC is uncommon. The previously reported incidence of perihilar stricture due to IgG4-SC without pancreatic involvement represents 4.8–9.1% of benign biliary stricture [12]. Zen et al. reported the prevalence and incidence of proximal IgG4-SC to be 1.0 and 0.3 per 100,000 population, respectively [17].

The diagnosis of IgG4-SC is crucial. Because IgG4-SC lacks any highly specific diagnostic features, a high index of suspicion in all patients with unexplained biliary strictures can lead to the most accurate diagnosis. Some authors have proposed criteria for the diagnosis of IgG4-SC. Firstly, Ghazale et al. from the Mayo group proposed the worldwide acceptance of the HISORt criteria for IgG4-SC, adopted from previously reported criteria for AIP including histology of the bile duct, imaging of the bile duct, serology, other organ involvement and response to steroid therapy [15, 18]. Recently, Ohara et al. reported Japanese and Korean guidelines for the clinical diagnostic criteria of IgG4-related sclerosing cholangitis [21]. According to these guidelines, the current case was definitely diagnosed with IgG4-SC. The most important clue to diagnosis were three distinct histopathological findings including markedly dense fibrous tissue in the background with focal storiform pattern and densely infiltrating lymphocytes and plasma cells and obliterative phlebitis. The IgG4+/IgG+ plasma cell ratio was more than 40% and IgG4+ plasma cells density was 80cells/HPFs [18, 21].

Serum IgG4 level is an important part of the diagnosis of IgG4-SC. However, an increased serum IgG4 level alone should not be used to diagnose of IgG4-SC. Ghazale et al. report the sensitivity of serum IgG4 to be 74% [18]. Oseini et al. report that a cut-off level of serum IgG4 above 135 or 140 mg/dl shows higher sensitivity, while a serum IgG4 level 4-fold higher than normal is 100% specific for IgG4-SC [22]. Lytras et al. report the sensitivity and specificity of serum IgG4 level to be 50% and 75%, with the positive predictive value (PPV) and negative predictive value (NPV) of 75% and 50%, respectively. The accuracy of elevated serum IgG4 for the diagnosis of IgG4-SC reached 69% [13]. Ohara et al. report a large cohort study from Japan that increasing specificity for preoperative diagnosis by cytology of hilar involved IgG4-SC to 96.6% when a cut-off level of serum IgG4 level is 207 mg/dL [23].

Cross-sectional study, CT and MRI have proven difficult to use for differentiation from CCA [24‐27]. IgG4-SC can present with a focal/segmental or diffused biliary stricture [26, 27]. Patients with concomitant AIP and other organ involvement might demonstrate characteristics of organ involvement that raise suspicions of IgG4-SC. The absence of other organ involvement could make it more difficult for a physician to distinguish IgG4-SC from CCA. Some authors have described image findings for the diagnosis of IgG4-SC including multifocal biliary strictures, a markedly thickened bile duct wall (mean wall thickness, 4.9 mm), a smooth outer margin, a narrow but visible lumen, hyper-enhancement during the late arterial phase, homogeneous hyper-enhancement during the delayed phase, concurrent gallbladder wall thickening and an absence of vascular invasion [27‐29].

Recently, Chen L et al. have reported the accuracy rate, sensitivity, specificity, PPV and NPV of intraductal ultrasound (IDUS) with tissue sampling in proximal bile duct obstruction to be above 90% [30]. The characteristic IDUS findings for IgG4-SC are circular symmetrical wall thickness, a smooth outer margin, a smooth inner margin and a homogeneous internal echo in the stricture [31].

Isolated IgG4-SC without AIP is uncommon. Despite aggressive preoperative evaluation, especially in the center that have limitation of resource, it is very difficult to differentiate IgG4-SC without AIP from CCA. Preoperative histology in biliary stricture remains controversial. Davidson et al. concluded that there is currently no evidence to support routine histological examination for the diagnosis of CCA [32]. But his study does not employ the results of a number of studies that have demonstrated the value of histology, the role of additional studies such as fluorescence in situ hybridization (FISH). Recently, the incorporation of routine cytology and FISH for evaluation of endoscopic brushings would be an important role for diagnosis of pancreatobiliary tract malignancy [33]. Some reported cases of IgG4-SC in the absence of AIP have been misdiagnosed as cholangiocarcinoma and treated by surgical resection (Table 1). In this case, the misdiagnosis was partly because CCA is very common in Thailand. The clinical manifestation was similar to CCA. Surgical resection was recommended to these patients because of high suspicion of CCA that could not be distinguished from benign biliary stricture. According to current available guidelines, some authors recommend steroid treatment and waiting for response to therapy [18, 21].