Patients presenting with biliary strictures and obstructive jaundice remain a clinical challenge, especially since in many cases a clear diagnosis can not be made without surgery.
The major differential diagnosis include malignant tumors – primarily cholangiocarcinoma (CCA), and a variety of benign diseases, such as different types of sclerosing cholangitis. In 2003, Kanisawa et al added a new clinicopathologic entity, called Immunoglobulin G4 Associated Cholangitis (IAC), to the list of diseases to be considered.
Despite the fact that IAC is increasingly being recognized, its diagnosis and differentiation from CCA may not always be possible. Based on common clinical criteria (age, gender, onset of jaundice, fatigue, weight loss), even the use of advanced radiological (MRCP) and endoscopic techniques (ERCP, cholangioscopy) together with cytologic and histologic examination of brushings or biopsy, as well as tumor markers, and more recently developed serologic tests of autoimmune diseases - like serum IgG4 levels - have not significantly changed this dilemma.
Even in so-called high-volume centers with a long-standing experience, approximately 50 % of patients with suspicion of perihilar CCA undergo resection without confirmed tissue diagnosis. It is a fact that only a clearly tumor-positive cytology or histology would rule in patients with CCA whereas negative findings do not rule out CCA.
Thus, even the recent surgical literature suggests that approximately 15-24 % of patients undergoing resection for suspected bilary malignancy have a benign etiology, only identified by microscopical examination of the resected specimens. According to a review from 2015, up to a third of patients in current IAC cohorts had erroneous extensive surgery prior to diagnosis.
The question was raised whether serologic tests help to distinguish between CCA and IAC.
Serum CA 19-9 is a tumor marker which is elevated (>100 IU/ml) in 60-80 % of patients with CCA, but also in 18 % of IAC cases. In one series from 2007, 5/8 IAC patients (63 %) had high levels of CA 19-9. CA-125 is detectable in up to 65 % of patients with CCA, but often raised in parenchymal liver disease.
Measurement of serum IgG4 was first reported in 2001 in patients with sclerosing pancreatitis, and in 2007 in a review article about IAC. Although a serum IgG4 increase is characteristic of IAC, it may not be diagnostic, especially when only moderately elevated (< 4 ULN).
A study from 2011 showed elevated serum IgG4 levels in 78 % of IAC patients versus 13.5 % in CCA cases. On the other hand, 20-25 % of patients with IAC and autoimmune pancreatitis had normal IgG4 levels. In a publication from 2016, approximately 30 % of patients with IgG4-related pancreatitis (and/or cholangiopathy) had normal levels of serum IgG4 whereas elevated IgG4 levels can be seen in patients with primary sclerosing cholangitis or pancreatobiliary malignancy.
Interestingly, IgG4-positive plasma cell infiltrates - which are characteristic for ICA - were found in 12% of biopsies and 18 % of liver explants after transplantation, respectively, in patients with CCA.
According to various algorithms, recommendations, and guidelines published more recently, the diagnosis of IAC requires not only a high index of suspicion, but also a multidisciplinary approach, with assessment of clinical presentation, histologic and imaging findings, serum tests, organ manifestation pattern, and response to immunosuppressive/steroid therapy as summarized in the HISORt criteria.
If CCA is suspected, IAC should be excluded. Vice versa, CCA should be carefully ruled out in patients with suspected ICA whose serum IgG4 is only mildly elevated, particularly when they do not fully meet the HISORt criteria required to diagnose IAC. This distinction is important in view of the use of steroids to manage IAC, which may result in delays in administering appropriate treatment of CCA.
In conclusion, considering the difficulty in definitely diagnosing IAC - despite the pathway and criteria mentioned above, and because of the poor prognosis of patients with CCA, and the catastrophe to eventually miss this diagnosis, it is reasonable and still widely accepted in the surgical community rather to perform a possibly needless operation on a patient with benign disease and accept the surgical risk, than not to take the chance of a potentially curative operation on a patient with a malignant tumor and accept the fatal outcome.
Cholangiocarcinoma medical expert witness specialties include pathology, transplant surgery, hematology, gastroenterology, general surgery, surgical oncology, hepatobiliary surgery, hepatology, and radiology.