The incidence of hepatoportal cholangiocarcinoma, which is located above the opening of the cystic duct and at the bifurcation of the left and right hepatic ducts, accounts for 50-60% of cholangiocarcinoma and has a tendency to increase. The disease has an insidious onset and is usually in a progressive stage at the time of presentation, making early diagnosis difficult. Surgery remains the primary treatment modality for hilar cholangiocarcinoma and is the treatment option for patients with potential long-term survival. Currently, the misdiagnosis rate of hilar cholangiocarcinoma is 5-15%. To investigate the treatment of hilar cholangiocarcinoma by hilar jejunostomy, we performed resection (including partial resection) and hilar jejunostomy in 36 consecutive patients without distant metastases before surgery (Figure 1), and the patients had good quality of life after surgery. Postoperative pathology confirmed benign lesions in three cases, two of which were preoperatively misdiagnosed as Bismuth type IV hilar cholangiocarcinoma (one case with preoperative ENBD, Figure 2). Therefore, for patients whose surgical treatment can improve the quality of life and prolong survival time, surgical exploration should be actively performed. According to the characteristics of this disease combined with our experience, we will talk about the diagnosis and surgical treatment of hilar cholangiocarcinoma.
1. Etiology and pathology
1.1 Etiology
The etiology of hepatoportal cholangiocarcinoma is not clear. However, it is found that the incidence of bile duct cancer is increased in patients with sclerosing cholangitis, bile duct stones and ulcerative colitis. It is related to congenital bile duct cyst, Caroli disease, bile duct adenoma, multiple bile duct papillomatosis and contrast agent thorotrast. The incidence of cholangiocarcinoma is high in patients with Hepatobia sinensis infection, and some studies have shown an association between cholangiocarcinoma and smoking. However, many patients with cholangiocarcinoma do not have these risk factors. Genes such as K-ras, c-myc, c-neu, c-erb-b2, c-met , MUC-1, MUC-3, and Sialyl-Tn have been found to be possibly associated with hepatoportal bile ducts, however, variants or altered expression of these genes are also found in other tissues and non-tumor lesions, thus lacking specificity.
1.2 Histological features
Hilar cholangiocarcinoma, like most GI cancers, is mainly adenocarcinoma, papillary carcinoma, and mucinous carcinoma, with differentiation from highly differentiated to undifferentiated. In addition, there are squamous carcinoma, small cell carcinoma, mesenchymal tumor, Kaposi’s tumor and lymphoma that occur in the bile ducts of AIDS patients, which account for less than 5% of hilar cholangiocarcinoma. Hepatoportal cholangiocarcinoma tissue is generally hard and contains more fibrous tissue. Histologically, it is sometimes difficult to distinguish cholangitis, bile duct stones and tissue inflammatory reaction after biliary stent placement from highly differentiated cholangiocarcinoma. Immunohistochemical staining such as cytokeratin, CEA and mucin can help in the differential diagnosis.
1.3 Staging
1.3.1 Gross morphology
There are generally three types: nodular, sclerotic (Figure 3) and papillary. The nodular and sclerotic types account for most of the cases, and the papillary type (Figure 4) accounts for about 10%. Sometimes the nodular and sclerosing types are difficult to distinguish and are collectively referred to as the nodular sclerosing type. Papillary cholangiocarcinoma is sometimes seen as an obstruction of the bile duct by tumor tissue. Some patients are more difficult to classify according to this classification. Japanese scholars classify it as mass, infiltrative and papillary. According to our data, the Japanese scholars’ classification may cover a wider range.
1.3.2 Clinical staging
Clinical staging is generally based on the site of tumor involvement in the bile ducts to guide clinical diagnosis and treatment. Currently, there are many clinical staging types, and the most common one is Bismuth-Corlette staging method. Type I: The tumor is located in the common hepatic duct and does not involve the left and right hepatic duct bifurcations. Type II: The tumor is located in the common hepatic duct and involves the bifurcation of the hepatic duct, but does not invade the secondary hepatic ducts in the liver. Type IIIa: The tumor is located in the common hepatic duct, invades the right hepatic duct branch, and invades the secondary hepatic duct. Type IIIb: The tumor is located in the common hepatic duct and invades the left secondary hepatic duct. Type IV: The tumor is located in the common hepatic duct and invades the right and left secondary hepatic ducts. The increase in surgical resection rate may make the original staging incomplete for all clinical cases, or pathomorphologic types may be discovered that were not originally identified. Some clinical cases are difficult to be staged. This typing still has limitations, both in terms of gross morphology and clinical diagnosis and treatment.
1.4 Staging
Generally, with reference to TNM staging criteria, bile duct cancer is divided into stages 0-IV: stage 0, carcinoma in situ, without lymph nodes or distant metastasis. Stage I, tumor invades mucosa or muscle layer, without lymph node or distant metastasis. Stage II, the tumor invades the connective tissue around the muscle layer, without lymph nodes or distant metastasis. Stage III, with lymph node metastasis in the above cases. Stage IVa, tumor invades adjacent tissues such as liver, pancreas, duodenum, gallbladder, stomach and colon with or without lymph node metastasis and without distant metastasis. Stage IVb, regardless of tumor size, with or without lymph node metastasis, with distant metastasis.
1.5 Metastasis
Metastasis mainly includes direct spread (infiltration), lymphatic metastasis, hematogenous metastasis and abdominal implant metastasis. Direct spread and lymphatic metastasis are mainly for cholangiocarcinoma of the hilar region. Cholangiocarcinoma can spread under the mucosa, and the incidence of nerve infiltration is high. About half of the patients with hilar cholangiocarcinoma invading the surrounding tissues have lymph node metastasis, mainly through hepatoduodenal ligament and along the hepatic artery to the lymph nodes at the superior margin of pancreas.
2.Diagnosis
Most of the patients visit the clinic with jaundice as the first symptom or because of abnormal liver function test. It is difficult to be detected by general examination, so early diagnosis is difficult, and it is mostly in the progressive stage at the time of consultation. Sometimes small hepatocellular carcinoma immediately adjacent to the hilar region infiltrates the bile ducts of the hilar region causing jaundice, which is easily misdiagnosed as cholangiocarcinoma of the hilar region, and we have encountered two cases. However, such patients usually have a history of cirrhosis or hepatitis, and the combination of MRI may help to differentiate them.
2.1 Clinical presentation
Progressive worsening jaundice with hepatomegaly and generally non-palpable gallbladder. Jaundice is usually fast progressing and may fluctuate in patients with papillary carcinoma. Patients with longer disease duration may have clinical manifestations of biliary cirrhosis and portal hypertension, as well as symptoms and signs such as persistent chest and back pain, nausea, vomiting and ascites.
2.2 Laboratory tests
The bilirubin is usually significantly elevated, mainly direct bilirubin. akp and r-gt are significantly elevated. ca19-9 is meaningful in the absence of biliary ductitis, but lacks specificity. Cholangiocarcinoma related antigen CCRA is a new antigen found in recent years from human bile duct cancer tissue, which is significantly elevated in patients with bile duct cancer.
2.3 Imaging examination
Imaging examination can provide a reliable basis for the diagnosis of cholangiocarcinoma in the hilar region, determine the location of the lesion, understand the extent of infiltration of the lesion and formulate the treatment plan. There are mainly the following examinations:
2.3.1 B-ultrasound
B ultrasound is the first choice for diagnosing cholangiocarcinoma of the hilar region. Its advantages are: (1) it can show the dilated intrahepatic bile ducts and empty extrahepatic bile ducts and gallbladder; (2) the lumen distal to the dilated bile ducts is suddenly truncated and occluded, and moderate or hypoechoic masses can be detected; (3) the location and infiltration range of the tumor, the relationship between the tumor and hepatic artery and portal vein, and the presence of cancer thrombus in the portal vein can be clarified; (4) the presence of intrahepatic metastasis and extrahepatic lymph node metastasis can be understood. ⑤ Preliminary understanding of the atrophy of the right and left liver lobes.
2.3.2 CT
CT scan has clearer images, and enhanced scan can make the tissue structure clearer.CT can objectively show the location and size of tumor, the relationship with surrounding tissues, the morphological changes of liver lobes (hyperplasia or atrophy), and the relationship between tumor and caudate lobe. It can provide accurate obstruction level and signs of intrahepatic bile duct dilatation. The combination of the special image acquisition method of spiral CT and intravenous contrast allows the processed images to show vascular images more clearly. Therefore, spiral CT can basically replace angiography to show the structure of the portal venous system and understand the invasion of the portal venous system.
2.3.3 Magnetic resonance imaging (MRI) and magnetic resonance choledochopancreaticography (MRCP)
MRI can show the soft tissue shadows and changes of liver parenchyma in the hilar region, which can significantly improve the diagnosis rate of hilar cholangiocarcinoma in combination with CT, and can show the vascular involvement in different directions. It can show the site, size and infiltration range of cholangiocarcinoma in the hilar region and the bile ducts at the upper and lower ends of the obstruction at the same time.
2.3.4 Percutaneous transhepatic percutaneous cholangiography or drainage (PTBD), endoscopic nasobiliary ductography or drainage (ENBD)
It is mainly used for perioperative management and has greater value for diagnosis in a subset of patients. PTBD is more frequently used, but is currently controversial. We generally apply it to patients with blood bilirubin higher than 400 mg/L and in poor condition. According to our clinical observation, there is no significant increase in postoperative infection. The decision of whether to apply PTBD or ENBD preoperatively depends mainly on the patient’s tolerance, the size of the surgical trauma, and whether preserving liver tissue can meet the patient’s postoperative recovery needs. Therefore, all the surgeon can do is to perform the surgery delicately and minimize the surgical trauma. PTCD can show the morphology of intrahepatic bile ducts in detail, directly display and clarify the location of tumor, the extent of tumor involvement in hepatic ducts, and the relationship between tumor and hepatic duct confluence.
ENBD can show the lower boundary of the tumor and the bile ducts below the obstruction. If PTC and ERCP are performed at the same time, they can complement each other and completely show the upper and lower margins of the tumor, which is important for judging the size and scope of the tumor and deciding the surgical plan. However, it obviously increases the patient’s pain and cost.
2.3.5 Portal vein embolization and angiography
CT angiography, combined with MRI and ultrasound can clarify the infiltration of blood vessels. Selective arteriography and percutaneous and transhepatic portal vein angiography can more accurately show the situation of the vessels entering the liver in the hilar region and their relationship with the tumor. Since the blood supply of cholangiocarcinoma in the hilar region is less abundant, angiography generally cannot diagnose the nature and extent of the tumor, but can understand the presence of intrahepatic metastasis and show whether the blood vessels in the hilar region are invaded. Some reports suggest that portal vein embolization improves the surgical resection rate of hilar cholangiocarcinoma. There is a lack of effective comparison of the treatment effect and medical cost of patients who underwent further surgical treatment after portal vein embolization with other treatments for the same patients.
3. Surgery
3.1 Excision
3.1.1 Excisional method
Because bile duct cancer can spread under the mucosa, it is difficult to determine whether radical resection has been performed without pathological results. Sometimes, for highly differentiated cholangiocarcinoma of the hilar region, it is necessary to determine whether there is cancer at the incisional margin according to the conventional pathological diagnosis. According to the presence or absence of cancer at the surgical margin, the surgical procedures were classified as follows: R0 resection: no cancer at the margin; R1 resection: no cancer at the margin but cancer is visible microscopically; R2 resection: cancer at the margin is visible to the naked eye. The study showed that the postoperative survival rate of R0 resection group was significantly higher than that of R1 and R2 resection groups; while the survival rate and median survival period of R1 resection group were significantly higher than that of biliary drainage group.
3.1.2 Radical resection
The principles of radical resection (R0) are: no cancer residue at the cut edge, no metastasis in the liver, and no lymph node metastasis. The surgery includes resection of extrahepatic bile ducts, pulsation of ducts in hepatoduodenal ligament, and when the tumor invades the portal vessels of liver, the portal vein is mostly resected and repaired with partial portal vein flow blockage of the anterior wall (Figure 5), and if necessary, vascular graft can be used. If the hepatic artery is completely encircled by the tumor, it can be resected together if the portal vein is well supplied with blood. If necessary, one side of the liver lobe and caudate lobe can be resected (Figure 6). Sometimes pancreaticoduodenectomy can be performed in combination. Portal vein embolization is used to atrophy the embolized side of the liver lobe and stimulate regeneration of the contralateral lobe so that the remaining liver tissue can meet the patient’s metabolic needs.
3.1.3 Radical high level resection
In a subset of patients, where lobectomy is not required, hilar high resection is able to achieve R0 resection. Generally, after completing hepatoduodenal skeletonization and cholecystectomy from the upper edge of the duodenum, and then resecting the liver tissue within 1-2 cm above the anterior part of the cancer, we usually complete it with a common electric knife, turn up the power of electrocoagulation, cut the liver tissue, and tie it with sutures. It is easy to operate with 1/2 arc suture stitch. Care should be taken to protect the main trunk and major branches of the left and right portal vein branches. As we perform hepatic hilar jejunostomy, the bile duct branches should be cut with scissors to prevent postoperative bile duct opening stenosis caused by electrocoagulation. To prevent narrowing of the bile duct opening, for thicker bile ducts (0.5 cm or more), they were sutured to the surrounding tissue to enlarge the opening. When caudate lobe liver tissue is removed, attention should be paid to the posterior inferior vena cava. There is usually at least one caudate lobe vein that needs to be sutured, and if bleeding is difficult to control, it can be temporarily compressed to stop the bleeding. In patients with high resection, we routinely perform rapid intraoperative pathological examination and, if necessary, intermediate lobar and ipsilateral caudate lobe resection of the liver.
3.1.4 Palliative resection
Radical and palliative resection of cholangiocarcinoma of the porta hepatis depends on the type and extent of infiltration of the cholangiocarcinoma itself as well as the experience and skill of the surgeon. Palliative resection is used in cases of local metastasis, lymph node metastasis outside the hepatoduodenal ligament, and vascular invasion, and the literature reports that even palliative resection is more effective than internal or external drainage alone. We performed surgical resection and hepatic hilar-jejunostomy in 36 consecutive patients, with some patients undergoing palliative resection (partial resection). The patients had a good postoperative quality of life, which was better than that of patients with external drainage.
3.2 Reconstruction and anastomosis of the biliary tract
3.2.1 Biliary-intestinal anastomosis
Traditionally, the bile duct is reconstructed by integrating the bile duct in the resected section and then anastomosing it with the jejunal collaterals that are elevated from the posterior transverse colon, which is usually 30-70 cm in length. It is controversial whether to build a stent tube into the bile duct. A built-in stent tube may allow the bile-intestinal anastomosis to reduce bile immersion and allow for a significant reduction in jejunal collateral tension that may be caused by gas in the intestine. We routinely place stent tubes. The suture material and sutures used depend on the surgical approach and the operator’s habits. Interrupted or continuous sutures can be used. Silk sutures or synthetic sutures can be used. For hepatic hilar-jejunostomy continuous sutures are very difficult and the application of synthetic sutures is more expensive, we usually apply silk sutures and no significant difference is found.
3.2.2 Hepatic hilar jejunostomy
3.2.2.1 The main differences between hepatic hilar jejunostomy and hepatic hilar jejunostomy for hepatoportal cholangiocarcinoma and Kasai surgery
Hepatic hilar jejunostomy was first applied by Kasai in 1974 for pediatric congenital biliary atresia and achieved good results. It has been used in the treatment of hilar cholangiocarcinoma and high-grade bile duct injury. The length of the biliary branch intestinal collaterals for Roux-en-Y anastomosis of the hepatic hilar jejunum is generally 40-50 cm, and too short may easily cause upstream infection. The anastomosis should encompass all bile ducts. We applied the hepatic hilar jejunostomy to the surgery of hilar cholangiocarcinoma based on learning from Prof. S. Kimura who was involved in Kasai’s surgery back then. We experienced the following.
3.2.2.1.1 Hepatic hilar plate
Kasai surgery is easy to preserve the hepatic hilar plate, easy to remove the liver tissue behind the lesion, and easy to suture the hepatic hilar plate to the jejunum (posterior wall anastomosis). In patients with cholangiocarcinoma of the hilar region, it is difficult to remove the hepatic hilar plate, skeletonize the hilar, remove the liver tissue behind the lesion in the caudate lobe, and suture the liver tissue to the jejunum (posterior wall anastomosis).
3.2.2.1.2 Peribiliary tissues
In Kasai surgery, the outer membrane of the left and right hilar vessels and surrounding connective tissue are preserved as much as possible, and the perivascular tissues are easily excised and sutured when anastomosed with the jejunum. In patients with cholangiocarcinoma of the hilar region, the perivascular tissues should be removed as much as possible. It is difficult to excise and difficult to suture when anastomosing with the jejunum, and bleeding is easy.
3.2.2.1.3 Resected liver tissue
In Kasai surgery, after revealing the major bile ducts, the liver tissues around the bile ducts should be preserved as much as possible, the liver tissues around the bile ducts are not inflamed, and the liver tissues are easy to remove and easy to suture. In patients with hilar bile duct cancer, the surrounding liver tissues should be removed as much as possible. Sometimes the bile ducts are obstructed, co-infected, and the surrounding liver tissues are inflamed, which makes resection and suturing difficult.
Patients with hilar cholangiocarcinoma should have high hepatic square lobe cutting edge and some caudate lobe liver tissues should be removed (Figure 7). When resecting caudate lobe liver tissue, attention should be paid to the posterior inferior vena cava. There is usually at least one caudate lobe vein that needs to be sutured, and if bleeding is difficult to control, it can be temporarily compressed to stop bleeding.
3.2.2.2 Hepatic portal jejunostomy (Figures 1 and 8)
3.2.2.2.1 jejunal collaterals
As in the general Roux-en-Y anastomosis, about 40 cm of jejunal collaterals are elevated from the posterior aspect of the transverse colon. The jejunal stump is closed, and the lateral wall of the free edge of the jejunum is incised and anastomosed with the hepatic portal.
3.2.2.2.2 Anastomosis
The anastomosis should include all bile duct openings. When lobectomy is performed, the anastomosis should be as large as possible. In the absence of lobectomy, the anastomosis should be tension-free, usually with a full orifice anastomosis with the hepatic resection margin envelope. Because of the large hepatic hilar-jejunostomy anastomosis, local tension may sometimes be encountered and narrowing the anastomosis may be the ideal approach. We encountered a case where there was tension in the anterior wall of the anastomosis right in the middle and it was difficult to reanastomosis, the greater omentum was covered here and fixed with sutures.
3.2.2.2.3 Posterior wall anastomosis
Posterior wall anastomosis is one of the difficult aspects of the entire procedure and is relatively easy in patients with lobectomized liver. In other patients, suturing is difficult due to partial resection of caudate lobe liver tissue, deep anastomosis location, and little suturable tissue between portal vein and left and right trunks and inferior vena cava. It is difficult to repair a single stitch of tear when suturing and knotting, and it bleeds easily. The suture of liver tissue should not be too deep to avoid injuring the inferior vena cava, and the suture margin of intestinal wall tissue should not be too large, and it is very important to suture with 1/2 arc suture, in situ knotting, and moderate tension (Figure 1).
3.2.2.2.4 Suture at the left and right lobe of the liver vessels into the liver
Sutures are placed around the vessels with fibrous connective tissue and liver tissue, which are relatively less likely to tear when sutured and knotted. Generally, one suture is placed above, medially and below each vessel, which may reduce the occurrence of fistula.
3.2.2.2.5 Treatment of bile ducts and stent tubes
For larger bile ducts, several sutures may be placed with the surrounding tissue to widen the bile duct opening and may be able to prevent narrowing of the bile duct opening due to excessive healing of the bile duct. Adjacent bile ducts can be integrated together. We generally use three bile ducts with built-in stent ducts that are sutured to the bile duct wall with absorbable thread. One is an internal stent duct and the other two are drained outside the body via jejunal collaterals.
3.2.2.2.6 Anterior wall suture and pressure testing
The anterior wall suture is relatively easy, and the jejunal wall is sutured to the hepatic cut edge or peritoneum (Figure 8). After completion of the anastomosis, air or saline is injected through the stent tube to test the anastomosis for leakage. The test pressure should not be too high.
3.2.2.2.7 Drainage tubes
Two drains are usually built into the abdominal cavity, one placed behind the hepatic hilar-jejunal anastomosis (small omental orifice) and the other placed under the diaphragm.
The stent tubes are usually clamped in all patients 5 days postoperatively and removed after two weeks postoperative imaging (Figure 9). If fever develops after imaging, the stent tube is drained and removed after temperature normalization. For palliative or partially resected patients, the stent tube we kept for a maximum of 3 months.
3.2.3 Complication management
The most common postoperative complication is post-imaging fever, which occurs in some patients for varying lengths of time after imaging. Most patients improved after symptomatic treatment. For patients with longer duration, application of hormone has better effect.
3.3 Drainage surgery
The main purpose of internal drainage surgery is to reduce yellow drainage in order to relieve the liver damage caused by obstructive jaundice and the systemic effects of jaundice, thus improving the patient’s quality of life and providing the opportunity to receive other adjuvant treatments. Bile-intestinal anastomosis, built-in stent, left hepatic duct jejunostomy and U-tube are more commonly used. Due to the high obstruction level of cholangiocarcinoma in the hilar region, it is more difficult to perform bile-intestinal drainage, so intrahepatic bile duct jejunostomy can be performed, and the left bile duct branch is usually chosen. Internal drainage may be more advantageous in terms of improving the patient’s quality of life. External drainage alone often causes inconvenience and psychological burden to the patient and is mainly used for patients in advanced stages.
3.4 Liver transplantation
Liver transplantation is an effective treatment for patients with hepatoportal cholangiocarcinoma, and the indications need to be further explored. The transplantation procedure is the same as general liver transplantation, and regional lymph node dissection during resection of the diseased liver can help prevent recurrence after surgery. Roux-en-Y anastomosis between the donor common bile duct and the recipient jejunum can maximize the resection of the patient’s distal common bile duct.
In conclusion, hepatoportal cholangiocarcinoma remains a challenging topic for surgeons. In today’s rapidly advancing medicine, new diagnostic and therapeutic measures are constantly emerging. How to improve the early diagnosis and confirmation rate of hilar cholangiocarcinoma, improve patient’s quality of life, prolong patient’s survival time, and control medical costs, individualized diagnosis and treatment under the guidance of principles may be the ideal choice. Providing an ideal individualized treatment plan requires up-to-date medical knowledge, excellent surgical skills and a thorough understanding of the patient’s family, social and economic background.