Epidemiology
Cholangiocarcinomas are a rare diverse group of tumors, yet its incidence is rising both globally and nationally, especially in its intrahepatic form. The highest incidence worldwide is found in Asian countries, ranging from 3.5 to 14.7 / 100,000 cases in Japan, Korea, and Thailand. In Europe too, the incidence is rising, especially in the United Kingdom (2.17 / 100,000), Austria (2.67 / 100,000) and Germany (3 / 100,000). As for Italy, the incidence is about 5,000 expected cases per year (or 1% of all new cancer cases). However, these incidence rates are globally steadily increasing by about 4.5% per year. It is estimated that by 2035 around 50% of deaths arising from primary liver tumors worldwide will be attributable to this neoplasm.
Cholangiocarcinoma and its symptoms
Tumors of the biliary tract or cholangiocarcinomas originate in the system of ducts responsible for transporting bile from the liver to the intestine. These are rare diseases that mainly affect older people between the ages of 50 and 80, though it can occur at any age.
Sometimes these tumors obstruct the drainage of bile, causing a series of typical symptoms, including the distinctive yellowing of the skin and whites of the eyes (jaundice), the presence of white-colored stools and dark urine, generalized itching, loss of appetite and weight, fever, and abdominal pain.
In many cases, these cancers are diagnosed at an advanced stage.
can develop from the biliary tract either within or outside the liver, resulting in intrahepatic and extrahepatic neoplasms, respectively.
Among the most frequent forms of extrahepatic cancer are gallbladder cancer and Klatskin's tumor, which develops at the junction of the right and left biliary tracts, which join to form the common hepatic duct.
The forms with intrahepatic development occur mainly in patients with biliary tract diseases, such as primary sclerosing cholangitis and gallstones.
Diagnosis
Technologies for diagnosing and evaluating biliary tract cancer include:
Ultrasound
Ultrasound is used as the initial abdominal imaging modality when biliary tract cancer is clinically suspected. This non-invasive investigation can specify the presence and extent of the dilation of the biliary tract and may sometimes pinpoint the area where the obstruction is present. Additionally, ultrasound can sometimes be used by the surgeon during surgery.
Magnetic Resonance (RM) and Cholangio-Resonance
After the ultrasound, MRI is the next step in identifying the cause of obstructive jaundice. When the patient is jaundiced (i.e., has yellowish sclera and skin due to high bilirubinemia levels in the blood), physicians resort to MRI. The sequences aimed at studying the biliary tract (Cholangiopancreatography-MRI or MRCP), in association with the evaluation of basic multiparametric and possibly after contrast, allow physicians to determine with certainty the nature, location, and cause of the obstruction. The method also finds application in the local staging of the disease.
Computed Tomography (CT)
The CT scan can specify the anatomy of the biliary tree and the location of the tumor, including any tumoral spread to adjacent structures. With the latest generation multilayer equipment, it is possible to acquire highly detailed scans of all abdominal organs, including vascular structures, which are then computationally reprocessed to obtain not only axial, but also coronal, sagittal, and three-dimensional images. The CT scan is also utilized to guide targeted biopsies on any mass responsible for the obstruction.
Staging and treatment
Once malignancy has been diagnosed, the staging process is carried out, describing the extent to which the disease has progressed and providing relevant information bearing upon the patient's prognosis. Obtained with the most sophisticated imaging techniques, staging is a fundamental process to determine the local and distant extensions of the tumor. Consequently, it provides one of the key elements for choosing and planning treatment. If the neoplasm is of an adequate size and suitable for resection, surgery may succeed as a curative intervention. If, on the other hand, the tumor is locally extended or spread to other sites beyond the liver, local treatment will not be sufficient. In such cases, it will be necessary to resort to systemic therapies, such as chemotherapy (based on platinum derivatives and gemcitabine) or targeted molecular therapies or immunotherapy. Normally, physicians aim for control of the disease, since in most cases a cure cannot be reasonably expected.
As with most solid tumors, the system used in cholangiocarcinoma is the TNM (Tumor, Lymph Nodes, Metastasis), which considers the size of the neoplasm, the number of lymph nodes affected, and the presence of metastases, respectively. Depending on these three parameters, the disease is classified in four different stages.
Risk Factors
In most cases, cholangiocarcinoma occurs suddenly, in the apparent absence of risk factors or precancerous conditions.
There are numerous established or probable risk factors associated with the development of biliary tract cancers (intrahepatic and extrahepatic cholangiocarcinomas and cholecystic tumors). Some risk factors are significant but extremely rare; others are less significant but sufficiently widespread to be responsible for a larger number of cases overall.
The significant but rare type of risk factors includes hepatolithiasis, Caroli syndrome, and primary sclerosing cholangitis (an inflammatory disease of the bile ducts, frequently associated with ulcerative rectocolitis). Cholangiocarcinoma develops in one out of six people exposed to these risk factors.
Other notable risk factors for the occurrence of cholangiocarcinoma are parasitic infections by Clonorchis Sinensis and Opistorchis Viverrini. These occur frequently in Asia, particularly in China, Taiwan, Thailand, Korea, Laos, and Vietnam, but are comparatively rare in the Americas, Western Europe and the Australasia.
Other risk factors include the entire range of chronic hepatopathies and cirrhosis, of viral, metabolic (such as hepatic steatosis), or alcoholic etiology.
Despite the known range of risk factors associated with this disease, in more than half the cases of cholangiocarcinoma occurring in countries in the Americas, Western Europe (including Italy) and the Australasia, we have not identified any known risk factor. However, two significant elements strongly indicate the existence of a widespread environmental factor implicated in cholangiocarcinoma: (i) a cause of disease always exists, and (ii) the epidemiological data show a substantial increase in the incidence of intrahepatic cholangiocarcinoma. Epidemiological and genomic research, conducted primarily by the Bologna group led by Professor Brandi (president of the G.I.Co. – Gruppo Italiano di Ricerca sul Colangiocarcinoma), has identified previous asbestos exposure (a widespread risk factor of significant causal relevance) as the potential factor responsible for the epidemiological surge in cases of intrahepatic cholangiocarcinoma.
Gene characteristics adn tumor mutations
Given the progress achieved in genome sequencing techniques, medical research has become increasingly focused in recent years on the study and identification of specific genetic mutations present in cholangiocarcinoma. Moreover, numerous research programs have emerged, aimed at understanding the role of targeted therapies in advanced or metastatic cholangiocarcinoma, particularly in tumors with intrahepatic origin.
Overall, approximately half of all cholangiocarcinomas have at least one or several mutations that are potentially treatable with targeted therapies. To say that mutations are potentially treatable is not to say that treatment is immediately available or even feasible at the present time. However, there are numerous controlled clinical trials underway in this area, in both first- and second-line therapy. To avoid the loss of potential therapeutic opportunities, people with cholangiocarcinomas from must refer from the time of diagnosis to clinical centers with extensive experience.
A possibility of treatment within clinical trials is already available for two translocations/mutations: FGRFr2 and IDH1.
FGFR-2 receptor translocations are present in about 10% of intrahepatic cholangiocarcinoma, and several international multicenter studies are evaluating in phase 3 the use of FGFR-2 inhibitors, after obtaining promising preliminary data.
Another possibility of treatment is presented by IDH1 mutations, which occur in about 20% of intrahepatic cholangiocarcinomas; these mutations seem to be mutually exclusive with respect to FGFR-2 and are almost absent in forms with extrahepatic genesis. The results of the phase 3 study are expected shortly. The study will define the treatment’s effectiveness or lack thereof.
Lastly, there is immunotherapy, whose role in cholangiocarcinoma is still debated. Numerous trials are underway to evaluate the efficacy and safety of therapy with inhibitors of the immune checkpoint PD-1 or PD-L1 in this neoplasm. In general, there are no definite markers of efficacy of immunotherapy, although the role of a genome change called microsatellite instability (MSI) is being evaluated. Specifically, mismatch repair deficiency prevents cancer cells from repairing their damaged DNA, resulting in high rates of mutations in DNA microsatellites throughout the tumor genome. It is estimated that approximately 2% to 5% of cholangiocarcinoma cases have a mismatch repair deficit, which can be detected by microsatellite stability testing.