Biomarkers can play a primary role in how physicians diagnose cholangiocarcinoma and determine its prognosis. 

Cholangiocarcinoma is a malignant tumor on the biliary tree, accounting for around 15% of primary hepatobiliary cancers. It is usually diagnosed only during later stages of the disease because its presentation is often insidious and nonspecific. In addition, most healthcare facilities do not have an optimized surveillance program for high-risk individuals. 

This matters because a late diagnosis usually means the cancer has advanced, limiting treatment options.

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From an epidemiological perspective, cholangiocarcinoma has been historically underreported, and misclassification of its subtypes commonly occurs, resulting in unreliable data collection. 

Cholangiocarcinomas are classified according to their relative anatomical location: intrahepatic, perihilar, and distal extrahepatic. An alternative way of classifying cholangiocarcinomas is to refer to data on their tumor growth pattern and cell of origin, which provide more useful information regarding tumor behavior. 

A well-characterized hypothesis in oncology circles regarding cancer growth is the adenoma-dysplasia-carcinoma sequence. This sequence of cancer growth has been validated in many cancers, but it has not been fully characterized in cholangiocarcinoma. This is primarily because many cells of origin—such as cholangiocytes, hepatic progenitor cells, or the peribiliary glands—can result in cholangiocarcinoma. 

Diagnostic Biomarkers 

A high number of risk factors for cholangiocarcinoma has been described. Briefly, these include cholestatic liver diseases such as primary sclerosing cholangitis, infections such as hepatitis B and C, toxins such as alcohol and tobacco, and metabolic conditions such as diabetes and obesity. 

“Although most cases of cholangiocarcinomas in Western countries are considered sporadic, there are a number of well-described risk factors,” Labib and colleagues wrote in BMC Cancer. “It is proposed that many of these risk factors cause chronic inflammation and cholestasis, resulting in a cycle of reactive cell proliferation, genetic and epigenetic mutations and eventual cholangiocarcinogenesis.” 

Read more about cholangiocarcinoma etiology 

However, knowledge of these risk factors does not necessarily translate into better cancer surveillance. This is because many of the risk factors described are also risk factors for other types of cancers. However, recurrent liver disease should prompt a closer monitoring of hepatic health.

For the diagnosis of cholangiocarcinoma, 2 molecular tissue biomarkers are routinely used in clinical practice: cytokeratin 7 and 19. However, these biomarkers are nonspecific; they can be expressed in some hepatocellular carcinomas, as well as other adenocarcinomas. The differential diagnosis of hepatocellular carcinoma is complicated if it is poorly differentiated. 

“In this case, a wider [immunohistochemistry] panel is recommended, which should include markers of hepatocyte  differentiation, such as hepatocyte paraffin 1 (HepPar–1), arginase–1, alpha–fetoprotein, CD10 and polyclonal  carcinoembryonic antigen or markers of malignant hepatocytes as glutamine synthetase, glypican 3 or heat shock protein 70,” Macias and colleagues wrote in Gut.

One of the most important things to distinguish during diagnosis is whether the cancer has metastasized. This is especially difficult in intrahepatic cholangiocarcinomas because metastatic adenocarcinomas from the gallbladder, extrahepatic bile ducts, and the pancreas can be indistinguishable from intrahepatic cholangiocarcinoma both histologically and via immunohistochemistry. The main method to overcome this impasse is to conduct routine multiomic analysis. 

Prognostic Biomarkers 

The correct diagnosis of cancers, including their relative stage of growth, is incredibly important for therapeutic purposes. A careful analysis of diagnostic data means physicians rarely get this wrong. In the case of intrahepatic cholangiocarcinomas, it is imperative that they be distinguished from metastatic pancreatic adenocarcinomas, since the prognosis between the 3 diverges significantly. 

The prognosis of a cancer is something that patients and their caregivers are usually most anxious about. Decades of cancer research mean physicians can usually provide an estimate of survival rates based on the stage of cancer upon diagnosis. 

Read more about cholangiocarcinoma prognosis 

However, going a step further, physicians can conduct routine histology to get more information that can further help them in risk stratification. For example, compared to small duct cancers, large duct-type intrahepatic cholangiocarcinoma has a poorer overall survival rate. In addition, large duct-type intrahepatic cholangiocarcinomas tend to have higher CA 19-9 levels and a higher pathological tumor stage. 

Scientists have discovered that the invasion of tumor cells through the perineurium holds prognostic value in resected distal cholangiocarcinoma. In addition, it is also an independent risk factor for recurrence and poor survival in perihilar cholangiocarcinoma and intrahepatic cholangiocarcinoma. 

Studies have also indicated that patients with intrahepatic cholangiocarcinoma demonstrating genetic alterations on the Kristen ras oncogene homolog (KRAS) and tumor protein P53 (TP53) genes have a considerably poorer prognosis and higher risk of tumor recurrence compared to those who do not. 

“Although liver transplantation is already considered a potentially feasible option for highly selected patients with [perihilar cholangiocarcinoma] and [intrahepatic cholangiocarcinoma], it is to be hoped that ongoing trials will help  determine if tissue biomarkers are also associated with prognosis after transplantation,” Macias and colleagues wrote. 

Biomarkers that aid in cancer diagnosis and prognosis play an important role in cancer care: diagnostic biomarkers help physicians determine the type and stage of cancer, and prognostic biomarkers help physicians determine the type of treatment regime best suited for the patient (such as palliative care for advanced tumors). Hence, research into tumor biomarkers in cholangiocarcinoma and other cancers should continue. 


Macias RIR, Cardinale V, Kendall TJ, et al. Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directionsGut. 2022;71(8):1669-1683. doi:10.1136/gutjnl-2022-327099

Labib PL, Goodchild G, Pereira SP. Molecular pathogenesis of cholangiocarcinomaBMC Cancer. 2019;19(1):185. doi:10.1186/s12885-019-5391-0