Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis – The promise of DNA methylation and molecular biomarkers

Abstract

Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.

Review of incidence and outcomes of treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis

“…In order to better characterise and manage CCA, it is commonly classified into three subtypes according to its anatomical location: (1) Intrahepatic (IHCCA), which is located proximally to the second order branches of the left or right hepatic duct; (2) Perihilar (PHCCA) or Klatskin tumour, which is located between the second order branches of the left or right hepatic duct and the CD confluence; and (3) Distal (DCCA), which is located between the CD confluence and the ampulla of Vater[ 4 , 117 ]. PHCCA is the most common type (50%), followed by DCCA (40%) and IHCCA (10%)[ 10 ]. According to its pattern of growth and macroscopic appearance, CCA may present in three different types: Mass-forming (which presents with a mass), periductal-infiltrating (growing along the wall of the bile duct) and intraductal-growing (with intraluminal growth)[ 117 , 118 ].…”

“…PSC-associated CCA is not diagnosed until intended OLT or at autopsy, in up to 40% of patients[ 10 ]. Surgery is the only potentially curative treatment for all anatomical subtypes of CCA, either in the form or resection or OLT with or without neoadjuvant or adjuvant therapy, which is mainly offered in highly selected patients with early stage PHCCA[ 10 , 11 , 98 , 117 , 148 ].…”

“…PSC-associated CCA is not diagnosed until intended OLT or at autopsy, in up to 40% of patients[ 10 ]. Surgery is the only potentially curative treatment for all anatomical subtypes of CCA, either in the form or resection or OLT with or without neoadjuvant or adjuvant therapy, which is mainly offered in highly selected patients with early stage PHCCA[ 10 , 11 , 98 , 117 , 148 ]. Overall, the prognosis of CCA is dismal, with an overall survival of 12-16 mo, without surgical treatment[ 10 , 149 ], while long-term survival is rare with medical therapy alone, owing to the paucity of effective medical and locoregional therapies[ 12 , 150 ].…”

“…Surgery is the only potentially curative treatment for all anatomical subtypes of CCA, either in the form or resection or OLT with or without neoadjuvant or adjuvant therapy, which is mainly offered in highly selected patients with early stage PHCCA[ 10 , 11 , 98 , 117 , 148 ]. Overall, the prognosis of CCA is dismal, with an overall survival of 12-16 mo, without surgical treatment[ 10 , 149 ], while long-term survival is rare with medical therapy alone, owing to the paucity of effective medical and locoregional therapies[ 12 , 150 ]. In the setting of PSC, historically and in the pre-transplant era, most patients succumbed to complications of cirrhosis, while most recently CCA appears to be the leading cause of deaths for the general PSC population (58%)[ 22 , 151 ], as well as for those on a transplant waiting list[ 22 ].…”

Diagnosis and treatment of biliary malignancies: biopsy, cytology, cholangioscopy and stenting

“…The role of CA 19-9 in patients with PSC is particularly helpful and can help with the diagnosis of CCA, especially if there is a sudden increase in the level [18] . Studies on CA 19-9 have shown wide variations in sensitivity (46%-90%) and specificity (54%-98%) [19][20][21] . It can be elevated in benign conditions like cholangitis, biliary obstruction due to other reasons, liver cirrhosis and other malignancies like pancreatic cancer.…”