Cholangiocarcinoma

Cholangiocarcinoma (CC) is the second most common hepatobiliary cancer. It is often detected late and at an unresectable stage. Prognosis is poor and life expectancy does not exceed 6-12 months (Demols et al., 2007). Surgery at an early tumor stage is the only curative treatment option which, however, requires early diagnosis. The main predisposing factor for the development of cholangiocarcinoma in Western countries is primary sclerosing cholangitis (PSC), a chronic liver disease.

In the last decade, invasive methods such as endoscopic retrograde cholangiopancreaticography with or without cholangioscopy, intraductal ultrasound, brush cytology or forceps biopsies have found their way into clinical practice without having demonstrated a significant impact on the differentiation between malignant and benign biliary lesions (Weismüller et al., 2008). Moreover, the differentiation of malignant bile duct strictures solely through imaging studies is difficult and not feasible [Weismüller & Lankisch, 2011; Weismüller et al., 2008]. Tumor markers like CA 19-9 demonstrated a low sensitivity and specificity in different studies and are therefore not useful to detect CC at an early stage or for surveillance of patients with risk factors for CC (Sinakos et al., 2011).

A straightforward approach for the early detection of CC is the identification of markers in bile, as the development of carcinoma takes place at the biliary epithelium and tumour-related proteins are secreted or shed into the bile. Bile proteome analysis (BPA) was successfully performed by our group together with the gastroenterology department of the Hannover Medical School (Germany) leading to 84% sensitivity and 78% specificity in discriminating CC from PSC in a validation cohort of 25 CC and 18 PSC patients (Lankisch et al., 2011).

Bile analysis is limited to some extent due to its dependence on endoscopy, an invasive and potentially life-threatening procedure. Furthermore, access to bile becomes difficult if patients received a bilio-digestive anastomosis or other surgical procedures. Thus, CC diagnosis by use of a non-invasive source of body fluid is of great benefit since patients with risk factors for cancer can then be closer monitored.

In a recent study, we were successful in establishing a peptide marker model based on urinary peptides that mirror systemic effects of CC tumour progression (Metzger et al., 2013). Urine proteome analysis (UPA) was proven to be of equal diagnostic precision as that in bile. Based on UPA, we were able to detect CC in 35 of 42 patients (83% sensitivity) and to exclude it in 64 of 81 patients (79% specificity in cross-sectional validation. In fact, the urine peptide marker model identified CC in all patients with CC on top of PSC included in this clinical study, indicating its potential as diagnostic test for PSC surveillance.

In order to further improve sensitivity of CC diagnosis in patients with bile duct strictures the feasibility of a logistic regression modeling approach was tested by combining BPA and UPA. Applied to a prospective study cohort consisting of 16 patients with CC (including 6 with CC on-top-of PSC) and 29 patients with benign bile disorders, mainly PSC, the BPA/UPA logistic regression model was superior in its sensitivity (94%) and specificity (76%) over single BPA (63% sensitivity, 69% specificity) and UPA (81% sensitivity, 72% specificity) (Voigtländer et al., accepted for publication in Journal of United European Gastroenterol).

This gain in sensitivity by combined BPA and UPA analysis is required for reliable diagnosis of CC in patients with unclear biliary strictures. Furthermore, surveillance of patients with PSC during their time on the waiting list for liver transplantation with the highly sensitive CC BPA/UPA test may be of considerable diagnostic value, since it may allow periodical screening for signs of CC with the non-invasive UPA test. In case of a positive test result a follow-up with an ERCP including brush cytology, forceps biopsy and bile aspiration for BPA analysis may be performed leading potentially to an earlier diagnosis.

 

References
Demols A, Marechal R, Deviere J, Van Laethem JL. The multidisciplinary management of gastrointestinal cancer. Biliary tract cancers: from pathogenesis to endoscopic treatment. Best Pract Res Clin Gastroenterol 2007;21:1015-1029.
Lankisch TO, Metzger J, Negm AA, et al. Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology 2011;53:875-84.
Metzger J, Negm AA, Plentz RR, et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut 2013;62:122-30.
Sinakos E, Saenger AK, Keach J, et al. Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma. Clin Gastroenterol Hepatol 2011;9:434-9.
Weismüller TJ, Lankisch TO. Medical and endoscopic therapy of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2011;25:741-752.
Weismüller TJ, Wedemeyer J, Kubicka S, et al. The challenges in primary sclerosing cholangitis--aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 2008;48:S38-57.