Authors: Jia Mingru, Cao Fei, Yan Tao, Wang Junyan
Source: International Journal of Surgery, 2022, 49(8)
summary
hilar cholangiocarcinoma is the most common extrahepatic malignant tumor in clinical practice, accounting for 50%~60% of bile duct tumors. At present, radical R0 resection is the preferred treatment for early hilar cholangiocarcinoma, but there are no obvious clinical symptoms in the early stage, and most patients are already in the advanced stage when they present at the clinic, and the surgical resection rate is low, and the five-year survival rate is not more than 25%. For patients with intermediate and advanced hilar cholangiocarcinoma that cannot be resected by surgery, neoadjuvant therapy can be downdated and then undergoing surgical treatment, which can prolong the survival time of patients. At the same time, the recurrence rate after surgery can reach 50%~70%, and cancer is easy to invade microvessels, lymphovasculature, peripheral nerves and liver invasion, which is one of the most challenging problems in the field of biliary surgery. Therefore, the early diagnosis, perioperative management, preoperative and accurate staging assessment, standardized intraoperative resection, and postoperative adjuvant therapy of hilar cholangiocarcinoma are of great significance to improve the radical surgical resection rate and prolong the survival time of patients.
Hilar cholangiocarcinoma (HCCA) is a malignant tumor of the bile duct epithelial that occurs between the beginning of the left and right hepatic ducts and the common bile duct, with a low incidence, accounting for about 3% of all malignant tumors. At present, the cause of HCCA is not very clear, and liver fluke parasitic infection, primary sclerosing cholangitis (PSC), choledochal cyst, bile duct stones, and viral hepatitis are important risk factors. The onset of HCCA is relatively insidious, and there are no specific clinical symptoms in the early stage, mainly painless jaundice, skin itching, abdominal pain, etc., which is progressively worse, and most HCCA patients are already in the middle and advanced stages, resulting in a small chance of radical resection and low long-term survival rate, but radical surgical resection is still the most important strategy for long-term survival. Therefore, how to diagnose HCCA early, improve the surgical resection rate, and improve the treatment strategy are important challenges in the treatment of HCCA.
1 Diagnosis of hilar cholangiocarcinoma
1.1 Clinical manifestations
The incidence of HCCA is prevalent in middle-aged and older adults, with 90 percent of patients presenting with progressive jaundice as the first symptom, but at this time it is already in the advanced stage [1]. Non-specific symptoms such as epigastric discomfort, anorexia, fatigue, and itching may occur in the early stage, which can easily be misdiagnosed as gastric disease or other digestive diseases [2], which requires further laboratory examination and imaging examination by clinicians to make a clear diagnosis early and provide an opportunity for radical resection.
1.2 Blood test indicators
There are no specific biochemical indicators for the diagnosis of HCCA, but current studies have shown that CA19-9 and carcinoembryonic antigen combined with CA125 can be used as preoperative high-risk warnings, clinical treatment effects, and indicators to evaluate patients' prognosis [3]. Recent studies have shown that the levels of CA19-9 and carcinoembryonic antigen are positively correlated with the stage of HCCA. If the serum levels of tumor markers are significantly elevated preoperatively, the probability of surgical unresectable is significantly higher and the prognosis is poor [4].
1.3 Imaging tests
影像学技术的发展为HCCA的诊断和肿瘤分期提供了强有力的支持。 目前临床中主要的影像学检查包括超声、CT、MRI、磁共振胰胆管成像(Magnetic resonance cholangiopancreatography，MRCP)、经内镜逆行胰胆管造影术和经皮穿刺胆管造影等[5]。
As the preferred screening method for the clinical diagnosis of HCCA, ultrasonography showed that the intrahepatic bile duct was dilated and truncated at the hilum of the liver, the tumor formed a butterfly sign with the dilated bile duct, the uneven echo mass of the hilar part of the liver, the atrophy of the gallbladder and the non-dilation of the common bile duct, and the infiltration of the surrounding tissues made the bile duct wall unclear. Ultrasound cannot accurately show the extent of tumor involvement, so CT and MRI are needed for further clarification [6]. CT scan with contrast is the standard imaging modality for the preoperative evaluation of HCCA. It is not affected by obesity and gastrointestinal gas, and can accurately show the location of HCCA tumors, evaluate the relationship between tumors and blood vessels, bile duct dilation, and whether adjacent tissues are invaded and lymph node metastasis, so it can be used as an important diagnostic basis for preoperative staging evaluation and resectability of HCCA. MRI and MRCP are non-invasive, non-invasive, and non-radioactive imaging tests. MRI combined with MRCP technology has high application value in the diagnosis of HCCA and the evaluation of radical surgical resection. Compared with CT, MRCP can more clearly show the location and extent of the tumor, biliary obstruction, lymph node metastasis, and tumor invasion of adjacent tissues and blood vessels, so it can provide an important strategy for the diagnosis and surgical selection of HCCA [7]. Endoscopic retrograde cholangiopancreatography and percutaneous cholangiopancreatography can clearly show the location of tumor lesions, the expansion of tumors in the intrahepatic bile ducts, and the obstruction of bile ducts by tumors, but sometimes they cannot show the extent of tumor invasion in the bile ducts, and they are all invasive examinations, which are easy to cause a series of complications such as bleeding, biliary tract infection, and pancreatitis, so their clinical application has been gradually replaced by safer MRCP [8].
2 Perioperative management and preoperative evaluation
2.1 Preoperative yellowing
Most patients with HCCA are diagnosed in an advanced stage with varying degrees of jaundice, which is a serious risk factor for intraoperative and prognosis [9]. Therefore, lowering bilirubin levels before surgery can reduce the occurrence of postoperative liver failure and increase survival time. At present, most scholars believe that preoperative yellowing can benefit patients with (1) advanced age, long-lasting biliary obstruction, and significant malnutrition, (2) HCCA patients with acute cholangitis or hepatic insufficiency, and (3) HCCA patients with significantly elevated total bilirubin (total bilirubin >400 micromol/L) who have been evaluated and decided to undergo extensive hepatectomy (30 percent residual liver <volume after surgery) [10].
2.2 Preoperative portal vein embolization
Portal vein embolization is intended to avoid the occurrence of complications such as liver failure after radical resection, which increases the residual liver function and affects the long-term prognosis of patients [11]. Some scholars believe that the proportion of residual liver volume in the whole liver volume is less than 40% (the proportion of residual liver volume in patients with liver impairment and HCCA is less than 50%) is an indication for portal vein embolization, and abdominal CT is re-examined about 2 weeks after surgery to evaluate the residual liver volume and achieve index radical surgical resection, and the evaluation time should not be too long, otherwise the optimal timing of surgery and the prognosis of patients will be delayed [12].
2.3 Imaging evaluation
Preoperative imaging evaluation of HCCA tumor resectability and resection extent should meet the following three criteria: (1) complete resection and R0 margin, (2) sufficient residual liver volume and vascular and bile duct system that meet the conditions for reconstruction, and (3) HCCA patients can tolerate surgery. Imaging is the most commonly used method to assess resectability preoperatively [13,14].
Preoperative imaging evaluation provides great support for the early screening and diagnosis of HCCA, preoperative staging, selection of surgical methods and long-term prognosis of patients, and many important theoretical supports can be obtained from imaging: (1) HCCA classification to guide the selection of surgical plan, (2) local invasion of tumor and lymph node metastasis to evaluate the surgical stage, (3) transverse tumor to intrahepatic vein, portal vein, (4) show the structural relationship between the bile duct and hepatic artery and portal vein to reduce surgical injury, and (5) evaluate the residual liver volume or liver function volume according to the planned surgical protocol to evaluate whether HCCA can be radically resected and whether to increase residual liver volume by portal vein embolization [15,16,17].
3 Comprehensive treatment of hilar cholangiocarcinoma
3.1 Surgical treatment
At present, experts and scholars at home and abroad believe that surgery is the main means of treating HCCA, and the scope of radical resection is mainly determined by Bismuth-Corlette classification. Gallbladder and extrahepatic cholangioectomy and cholangiojejunal Roux-en-Y anastomosis in type I; gallbladder and extrahepatic cholangectomy combined with caudate lobectomy, biliary-intestinal anastomosis, and regional lymph node dissection in type II patients can improve the rate of R0 surgical resection and reduce postoperative recurrence. III.b and III.a) + lymph node dissection, type IV.a with extended hepatic resection with trilobar, revascularization of the invaded vascularization + lymph node dissection, and type IV.b with nonsurgical treatment or liver transplantation [18,19].
3.2 肝移植
Liver transplantation is undoubtedly the only treatment that can achieve radical cure for patients who cannot be removed due to tumor invasion of the left and right hepatic ducts to the intrahepatic bile duct, insufficient residual liver volume, and poor liver function to tolerate surgery, but liver transplantation should be carefully considered in the treatment of HCCA due to the shortage of liver sources, high recurrence rate after transplantation, and high mortality [20]. It has been suggested that liver transplantation may be considered if the tumor extends beyond the sagittal portion of the left portal vein and the right posterior and right anterior bifurcations of the portal vein without hepatic resection and without lymph node metastases or distant metastases [21]. Liver transplantation in combination with neoadjuvant chemoradiotherapy has been shown to be considered for unresectable HCCA to prolong survival and improve prognosis [22].
3.3 Chemotherapy
The chemotherapy drugs used for the early treatment of HCCA are mainly 5-fluorouracil and doxorubicin, but the treatment effect of tumors is relatively poor. At present, the new chemotherapy drug gemcitabine in combination with other chemotherapy agents in the treatment of advanced HCCA can significantly improve the survival of patients [23]. For patients with unresectable HCCA in advanced stages, guidelines issued by the National Comprehensive Cancer Network conclude that HCCA is moderately sensitive to gemcitabine chemotherapy drugs. Chemotherapy is usually available in the following situations: (1) chemotherapy as the only option when surgical resection is not possible, (2) preoperative liver transplantation, and (3) adjuvant therapy after surgical resection to prevent positive margins and preoperative or intraoperative lymph node metastasis [24].
3.4 Radiotherapy
Radiotherapy is mainly used for the treatment of unresectable locally advanced HCCA, but the effect of radiotherapy is not very certain. Adjuvant radiation therapy after surgical resection has been shown to be associated with no improvement in survival compared with palliative care when surgical resection is not possible [25]. However, recent studies have shown that adjuvant radiotherapy after surgical resection of HCCA can significantly improve patient outcomes. For the treatment of unresectable locally advanced HCCA, biliary drainage combined with adjuvant radiation therapy can reduce clinical symptoms, improve quality of life, and improve survival [26]. For patients with locally advanced HCCA, adjuvant radiation therapy after R0 resection can significantly improve the efficacy of HCCA [27]. At present, there is a lack of clinical data on neoadjuvant radiotherapy for HCCA, and a large number of prospective studies may be needed to clarify the efficacy of radiotherapy.
3.5 Photodynamic therapy
Photodynamic therapy (PDT) is a novel treatment that has been shown to be effective in a variety of malignancies. The therapeutic mechanism is the intravenous injection of photosensitizers that have an affinity for tumor cells, which can accumulate in malignant tumor tissues, and when the tumor tissues are irradiated with a light source of a specific wavelength, a series of photodynamic reactions are generated to destroy the tumor tissue, thereby killing the tumor [28]. At present, some studies have shown that when PDT combined with stent drainage in the treatment of HCCA, the rate of jaundice reduction is fast and the incidence of postoperative cholangitis is low. PDT in combination with chemotherapy can prolong survival in patients with advanced cholangiocarcinoma [29]. Adjuvant PDT during surgery may reduce the rate of recurrence after surgery, and adjuvant PDT after surgery may prolong survival [30]. There are few prospective randomized controlled trials related to PDT in the treatment of HCCA, and more high-quality clinical studies are needed to support these conclusions.
3.6 Targeted therapy
The mechanism of targeted therapy is to inhibit specific receptors that promote the growth of tumor cells, interfering with the signaling pathways of the corresponding receptors, so as to achieve the purpose of anti-tumor therapy. Pemilitinib, the first targeted drug for the treatment of cholangiocarcinoma, has been approved in the United States by inhibiting fibroblast growth factor receptors [31]. At present, the research on immunotherapy of novel programmed cell death protein 1 and programmed cell death ligand-1 has developed rapidly and has broad application prospects. Recent data have shown that 40 percent of patients have high expression of programmed cell death protein 1 and 15 percent of programmed cell death ligand-1 expression in cholangiocarcinoma [32]. Therefore, programmed cell death protein 1/programmed cell death ligand-1 inhibitors may be immunotargeted drugs for the treatment of HCCA patients.
4 Summary
In summary, HCCA is a challenging primary biliary malignancy. With the development of diagnostic technology, surgical technology and neoadjuvant treatment technology, the early diagnosis of HCCA, the resectability of tumors, and the long-term survival rate of patients after surgery have been continuously improved, which is the result of the cooperation of multiple disciplines such as radiology, digestive endoscopy, vascular intervention, general surgery, anesthesiology and intensive care medicine.
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