For example, at Mayo Clinic Rochester, approximately 10 cases of IAC are diagnosed per BMN 673 concentration year, of whom about

five cases (50% of 10, using the results from the test cohort) would have an sIgG4 greater than two times the upper limit of normal. Each year, in part because of the large CCA referral practice, approximately 250 cases of CCA are diagnosed per year, of whom eight cases (3.2% of 250) would have an sIgG4 greater than two times the upper limit of normal. Therefore, a patient presenting with a biliary stricture and elevated sIgG4 greater than two times the upper limit of normal at our institution has a greater than 50% chance (8/(5+8) = 8/13 = 62%) of having CCA as the final diagnosis. Although the exact proportions will be different at different institutions, this example illustrates the critical importance of our findings for the appropriate evaluation of patients presenting with biliary

GDC-0068 strictures and an elevated sIgG4. Among the subjects studied, the specificity for IAC (versus CCA) is 100% at ≥450 mg/dL for the test cohort and >620 mg/dL for the validation cohort. Increasing the cutoff for diagnosis of IAC to a high specificity cutoff of four times the upper limit of normal (560 mg/dL) would allow more confidence in the diagnosis of IAC (versus CCA) with specificities of 100% and 99% for the test and validation cohorts, but at the cost of a significantly decreased test sensitivity of 26% for the test cohort and 17% for the validation cohort. Interestingly, a higher percentage (22.6% and 19.6%) of the subset of CCA patients with associated PSC (CCA+PSC) had an elevated sIgG4 than of the subset of CCA patients without PSC (CCA-PSC) (10.5% and 9.1%). With a cutpoint of twice the upper limit of normal, 2/31 (6.5%) and 4/51 (7.8%) of CCA+PSC patients had IgG4 elevations above that level. There is therefore a trend toward a higher sIgG4 concentration

in patients with CCA and concomitant PSC (CCA+PSC). In fact, the percentages of CCA+PSC patients with high sIgG4 levels (i.e., >140 mg/dL) in both our cohorts is higher than those reported for pancreatic (10%) and non-CCA-associated PSC (9%).19, 22 In addition, CCA+PSC patients MCE were more likely to have a positive tissue IgG4 by immunohistochemistry. This potential association of PSC with high serum and tissue IgG4 in CCA patients suggests that PSC patients with high IgG4 may be at increased risk of developing CCA. Considered together with the finding that PSC patients with elevated sIgG4 tend to have more severe liver disease and a shorter time to liver transplantation, our study suggests the possibility that IgG4 immunoreactivity may be one of the driving forces behind the malignant transformation from PSC to CCA or perhaps to other neoplastic processes such as non-Hodgkin lymphoma.