I. Overview
Cholangiocarcinoma usually refers to extrahepatic cholangiocarcinoma, including malignant tumors originating from the mucosal epithelium of the bile ducts in the lower segment of the left and right common hepatic ducts, excluding tumors in the abdomen of the papillary jug, and tumors originating from the small intrahepatic bile ducts belong to cholangiocarcinoma. Cholangiocarcinoma can occur in upper, middle and lower segments, among which the incidence of upper cholangiocarcinoma is the highest, accounting for 50-80%, and is also called hilar cholangiocarcinoma, or Klaskin’s tumor, because it is at the confluence of hepatic ducts.
The etiology of bile duct cancer is still unknown, and its risk factors include congenital disorders of the biliary tract (e.g. congenital common bile duct cyst), chronic biliary inflammation (e.g. primary sclerosing cholangitis), hepatobiliary stones (e.g. intrahepatic bile duct stones), parasitic infection (e.g. Toxoplasma gondii), cirrhosis, hepatitis C, etc. Cholangiocarcinoma is the second most common malignant tumor in the biliary system of the liver, and its incidence has been increasing worldwide in recent years. The radical surgical resection rate of early cholangiocarcinoma patients is about 30-40%, and the surgical mortality rate is 12%, but most cholangiocarcinoma patients have insidious onset, and most of them are already in advanced stage at the time of onset, and have lost the opportunity of radical treatment, so they mostly adopt palliative treatment. In recent years, with the development of endoscopic technology and imaging as well as the deepening of the understanding of bile duct cancer, the level of treatment for bile duct cancer patients has also increased. Currently, endoscopic bile duct drainage has been used as the first-line palliative treatment for patients with bile duct cancer that cannot be surgically resected.
For cholangiocarcinoma of the hilar region, French scholar Bismuth-Corette classified it into four types in 1975, namely, Bismuth type I, in which the tumor is located in the common hepatic duct and does not invade the confluence of the left and right hepatic ducts; Bismuth type II, in which the tumor invades the common hepatic duct and the confluence of the left and right hepatic ducts; and Bismuth type III, which is divided into IIIa and IIIb based on the invasion of the left and right hepatic ducts on the basis of type II. Bismuth type III, on the basis of type II, is divided into type IIIa and type IIIb according to the invasion of the right and left hepatic ducts, and type IIIb for the invasion of the left and right hepatic ducts. Bismuth staging of cholangiocarcinoma of the hilar region is now widely used. For patients with hilar tumors that cannot be resected radically, Bismuth staging can guide our endoscopic treatment.
Due to the different sites of cholangiocarcinoma, endoscopic bile duct drainage is further divided into endoscopic drainage of hilar cholangiocarcinoma and endoscopic drainage of distal common bile duct (middle and lower end).
II. Endoscopic treatment
2.1 Endoscopic treatment of distal choledochal tumor
For patients with cholangiocarcinoma of the distal common bile duct, endoscopic placement of a stent is usually sufficient to relieve obstructive jaundice. The results of a cost-effectiveness analysis randomized study have shown better efficacy of self-expanding metal stents (SEMS) due to their good patency, which reduces the need for repeated endoscopic reinterventions to relieve recurrent obstructive jaundice. in a prospective study by Davids PH et al. of 105 patients who could not In a prospective study by Davids et al, endoscopic stent placement was performed in 105 patients with distal cholangiocarcinoma that could not be surgically resected for palliative treatment; metal stents were placed in 49 cases and plastic stents were placed in 56 cases. The results showed that the mean time to patency was significantly higher with metal stents than with plastic stents (273:126, p=0.006).
2.2 Endoscopic treatment of hepatoportal bile duct cancer
1. Unilateral stenting versus bilateral stenting
In patients with Bismuth type I hilar cholangiocarcinoma, because the stenosis caused by the tumor does not affect the left and right hepatic duct confluence, the obstruction caused by this type of stenosis can be completely relieved by unilateral stenting, so as in distal cholangiocarcinoma, unilateral metal stents can be placed to relieve obstructive jaundice.
The most controversial issue is whether unilateral or bilateral stents are more effective in Bismuth type II, III and IV hilar cholangiocarcinoma. It is well known that drainage of 25-30% of the liver is sufficient to relieve the symptoms of obstruction. Therefore, if there is no disease in one lobe of the liver, then placement of a single stent to drain the liver is sufficient to relieve the obstruction and relieve jaundice. Some domestic and foreign scholars have conducted some clinical experimental studies comparing the drainage effect of unilateral and bilateral stent placement, but some less than scientific results were obtained due to the small sample size of the experiment itself, the retention of contrast agent, the absence of postoperative antibiotics, and the unreasonable design of the experiment. The only prospective study available is the clinical randomized trial designed by De Palma GD,et a comparing the efficacy of unilateral and bilateral stents, they used a willingness-to-treat analysis (ITT) to scientifically evaluate the efficacy of drainage in 157 patients with hilar cholangiocarcinoma. 157 patients were divided into group A (unilateral stent group) and group B (bilateral stent group), and the result of the ITT analysis was that the unilateral stent drainage group stent placement success rate (88.6%:76.9%, p<0.0.5) and successful drainage rate (81%:739%, p<0.05) were significantly higher than those of the bilateral stent drainage group, and early complications were lower than those of the bilateral stent group (18.9%:26.9%, p<0.026). However, the associated operative mortality, late complications, median survival and 30-day mortality rates were not statistically significant in both groups. The results of this prospective randomized study suggest that placement of unilateral stent drainage is sufficient to relieve obstructive symptoms in hilar cholangiocarcinoma. We have statistically analyzed 52 patients with cholangiocarcinoma treated endoscopically at our institution, and the results were consistent with those described above. However, a multicenter study is still needed to determine whether unilateral or bilateral stents should be placed.
2. Plastic stents and metal stents
The placement of plastic stents or metal stents for stenosis caused by cholangiocarcinoma in the hilar region is also controversial. One is that the lumen diameter of plastic stent is relatively small, so the patency is limited and the length of stent needed for intrahepatic bile duct is very long; the other is that it is very difficult to place plastic stent above 10F, and the plastic stent placed in the hilar region can easily shift and block the secondary intrahepatic bile duct (causing no mesh), which theoretically increases the risk of infection. Metal stents with mesh will not block the secondary intrahepatic bile ducts, and the larger diameter will keep them open for a long time, making re-intervention less likely. Also, the short length of the metal stent, when flared in the bile duct, prevents the reflux of duodenal contents into the biliary system, thus reducing the possibility of cholangitis. However, bilateral metal stents placed in the porta hepatis may lead to loss of biliary drainage on one side because the distal ends are not at the same level, and this makes it very difficult to intervene again endoscopically when the stent is blocked. de
Palma GD et al studied the efficacy of unilateral metal stenting in 61 cases of hilar cholangiocarcinoma and showed a successful drainage rate of 96.7%, a complete remission of jaundice of 86%, and an incidence of early cholangitis of 4.9%, suggesting that unilateral metal stenting is a safe and effective palliative treatment. We have conducted a related study on 52 patients with bile duct cancer, which is consistent with the above findings in terms of complications, blockage rate and stent replacement rate.
3. MRCP-guided ERCP stent placement
MRCP is superior to ERCP for cholangiopancreatic system imaging because it clearly shows the right and left hepatic ducts and bile duct branches at all levels, which avoids stent placement into atrophic liver segments during ERCP and reduces the need to inject contrast into multiple liver segments, thereby reducing cholangitis after ERCP. The endoscopist applies a manipulated guidewire to selectively insert the catheter into the target hepatic duct identified by MRCP, thereby minimizing contrast contamination.
MRCP is a non-invasive test that provides three-dimensional imaging, clearly demonstrates the proximal and distal biliary system at the site of biliary stricture, has no risk of infection, and is superior to ERCP in diagnosing biliary malignancy at a rate of 80-90%. Hintze RE et al applied MRCP-guided ERCP for unilateral stent placement in 51 patients with cholangiocarcinoma and showed a 100% success rate of stent placement, an 86% remission rate of jaundice, and a mean median survival of 11 months with low mortality and complications.
4. Photodynamic therapy
German scholar Raab discovered the photosensitizing effect in 1887 and applied it to clinical practice in the United States in the 20th century. In recent years, with the continuous progress of laser and photosensitization technology, photodynamic therapy (PDT) has developed rapidly and become a safe and effective method for the treatment of surface and internal cavity tumors. Photodynamic therapy involves MRCP to determine the extent of tumor dispersion and spread, ERC to determine bile duct patency and locate tumor margins (endoscopic ultrasound), and multiple tumor biopsies. Then, a non-toxic photosensitizer (hematoporphyrin or its derivatives) is injected into the patient’s body, and the laser is applied under ERCP to activate the photosensitizer and produce cytotoxic oxygen radicals, which cause local ischemia and induce apoptosis of tumor cells, resulting in cell death. The killing depth of photodynamic therapy is 4-4.5 cm, so it is not suitable for the radical treatment of tumors as deep as 7-9 cm.
In a prospective study of photodynamic therapy, Ortner ME et al found that biliary stenting combined with photodynamic therapy was associated with a significant increase in median survival, significant improvement in cholestasis and quality of life compared with stenting alone, and Berr F, et al concluded that photodynamic therapy was effective in blocking occlusion of the hepatoportal bile duct and improving patient survival. However, there are still not many clinical applications of PDT, but with further research on this treatment method, it is believed that it will be used more and more in clinical practice and become an important treatment method for patients with unresectable cholangiocarcinoma, together with endoscopic stent placement and drainage.
5. Intraductal brachytherapy
Intraluminal brachytherapy (ILBT) is an endoscopic or percutaneous procedure in which an endobiliary support tube containing a radioactive source I192 is delivered through a T-tube, U-tube, or ERCP or PTC into the biliary tract and through the stenosis, and the tumor proximal to the source can be irradiated at a high dose. Intraductal brachytherapy can prevent tumor invasion of the intrahepatic biliary branches and prolong the remission time of jaundice. The results of studies on intraductal brachytherapy are inconsistent, with some studies suggesting that it may prolong the survival of patients with inoperable cholangiocarcinoma, while others suggest that it has no significant benefit for patients with cholangiocarcinoma and increases complications such as cholangitis. Therefore, further studies are needed to determine whether ILBT has significant efficacy in patients with cholangiocarcinoma.
In conclusion, endoscopic treatment has become the palliative treatment of choice for patients with inoperable bile ducts, but for a long time to come, there will be a great deal of controversy regarding the placement of metal or plastic stents, and unilateral or bilateral stents. In any case, with the development of medical technology, endoscopic treatment will be further developed to better improve the symptoms and quality of life of patients with cholangiocarcinoma.