Patients awaiting surgery are vulnerable to malnutrition, cholangitis recurrence, and neoadjuvant therapy-related adverse events. Therefore, appropriate evaluation and selection of patients based on specific criteria can improve outcomes. Patients deemed unfit, whose nutritional status is inadequate, and those undergoing a pre-rehabilitation program, should be excluded from surgical consideration. Candidates for large liver resection must possess adequate liver function and sufficient future liver remnant (FLR). Resection should be contemplated solely when the FLR exceeds 40% in cirrhotic patients, 30% in those with considerable steatosis or fibrosis, or 20% in instances of normal parenchyma [6].

A prior systematic analysis reviewed seven trials assessing neo-adjuvant treatment prior to liver resection, involving a total of 87 individuals [7]. Neo-adjuvant therapy may enhance the R0 resection rate and the rate of complete pathological response. Nonetheless, neo-adjuvant therapies exhibit considerable heterogeneity across trials, with the interval between neo-adjuvant treatment and surgery varying from 3 days to 6 months. The most frequently utilized chemotherapies comprise gemcitabine, fluoropyrimidine- and platinum-based regimens, administered alongside radiation doses ranging from 10.5 to 60 cGy [8-10].

Resection of perihilar cholangiocarcinoma generally involves a complex surgical procedure with specialized expertise. Perihilar cholangiocarcinoma resection involves the surgical removal of the tumor together with an adjacent margin of healthy tissue. The extent of excision depends on the location, size, and proximity of the tumor to surrounding tissues. The method employed is dictated by the tumor’s specific location and characteristics, in addition to the patient’s overall health status.

When the FLR is inadequate, interventions to enhance the FLR, such as portal vein embolization or associating liver partition and portal vein ligation for phased hepatectomy, should be considered [11,12]. Insufficient evidence has led to a lack of consensus on the optimal method, but several studies have shown that minimally invasive techniques can be applied to resect pericholangiocarcinoma of the common bile duct, serving as an alternative to traditional organ surgery [13]. Resection of the caudate lobe is essential to enhance the probability of achieving R0 resection. The Nagoya group in Japan was the first entity to advocate for caudate lobe excision during the 1970s and 1980s [14]. The Gilbert meta-analysis indicated that caudate lobe resection enhanced the likelihood of R0 resection (odds ratio, 5.85) and improved survival (hazard ratio [HR], 0.65) without elevating postoperative morbidity [15]. Frozen section analysis should be utilized during hepatectomy to assess margin involvement. Wider excision and potentially pancreaticoduodenectomy may be required if the common bile duct margin is compromised.

Right hepatectomy, which involves resection of the liver’s right lobe, is the primary surgical technique. In specific situations, a more extensive surgical intervention, such as a left hepatectomy or extended right hepatectomy, may be necessary. Tumors that infiltrate the right or left hepatic duct may necessitate this surgery. The surgical method is dictated by the patient’s anatomical characteristics, tumor attributes, and overall health status. The surgical excision of perihilar cholangiocarcinoma is a high-risk procedure linked to significant morbidity and fatality rates. Each case must be assessed individually to ascertain the feasibility of resection, taking into account the potential benefits and drawbacks.

In order to prevent complications like cholangitis and restore normal bile flow after tumor excision, the biliary tract has to be restored. Numerous conventional methods of reconstruction exist. Roux-en-Y configuration hepaticojejunostomy is a surgical operation that connects the remnant bile duct to a jejunal loop; it is the primary technique for rebuilding perihilar cholangiocarcinoma defects. The hepaticoduodenostomy procedure involves direct anastomosis of the remaining bile duct to the duodenum. Those with neoplasms adjacent to the duodenum may be appropriate candidates for this therapy. Choledochojejunostomy surgery involves linking the remaining bile duct to a jejunal loop; nevertheless, its use in perihilar cholangiocarcinoma is rather uncommon. Anatomical details and surgical concerns unique to each patient dictate the method of reconstruction.

Although perihilar cholangiocarcinoma can be treated, surgical excision of the tumor entails considerable risk of complications, such as postoperative hemorrhage, bile leakage, and wound infection. The principal aims of postoperative treatment are to minimize problems, facilitate recovery, and surveil for illness recurrence. Consistent monitoring of vital signs, laboratory analyses, and imaging studies is essential for detecting and addressing any issues such as infections, hemorrhaging, or bile leakage. Pharmacological therapies and analgesic approaches should be used to address postoperative pain. Hospitalized individuals may require nutritional support through intravenous fluids or feeding tubes until they can return to adequate oral intake. Major hepatectomy presents a 5% risk of postoperative death at 30 days and a 9% risk at 90 days, with total morbidity and severe morbidity rates of 57% and 40%, respectively [4]. The probability of liver failure is 11% for left-sided resection and 22% for bilateral resection.

Consistent follow-up sessions that incorporate imaging studies and tumor markers are essential to track disease recurrence and optimize long-term treatment outcomes.

Adjuvant therapy with either chemotherapy or chemoradiotherapy may be advantageous for patients with stage III-IV perihilar cholangiocarcinoma. Radiotherapy should be administered in instances of compromised margins [16]. Treatment decisions should be predicated on patient tolerability. Adjuvant chemoradiotherapy utilizing a radiation dose of 45 cGy alongside oral 5-fluorouracil (5-FU) or adjuvant chemotherapy employing gemcitabine monotherapy or a gemcitabine/cisplatin combination are typically recommended [16]. A recent study suggested that adjuvant therapy should be administered to all patients with perihilar cholangiocarcinoma following liver resection [16,17]. A population-based study indicated substantial benefits of adjuvant therapy, especially in instances of node-positivity or positive-margin resection [17].

The prognosis of individuals diagnosed with perihilar cholangiocarcinoma after resection is influenced by many factors, including disease stage, the extent of the resection, the effectiveness of the surgical procedure, and the patient’s overall health. The total removal of a localized disease can yield a 5-year overall survival (OS) rate as high as 50%, but curative excision still generally yields lower rates relative to other cancer type. In one study, the 5-year OS rate was 43.7% following left-sided resection and 38.2% following right-sided resection [4]. Table 1 presents recently published series detailing long-term results following liver resection for perihilar cholangiocarcinoma. Survival rates are significantly lower for patients with advanced-stage illness. Recent advancements in surgical techniques, chemotherapy, and radiation therapy have improved outcomes for specific patients. Continuous surveillance for recurrence and adequately treatment for any issues are essential components of long-term follow-up.

Liver transplantation (LT) is an effective treatment for patients with perihilar cholangiocarcinoma who are not candidates for surgical resection or who have significant advanced disease progression. All candidates for LT must be medically fit and devoid of metastatic illness, as determined by computed tomography (CT) and magnetic resonance imaging conducted within 3 months prior to LT. Transplantation is most often required for pericholangiocarcinoma that is unresectable because of the tumor’s size, location, or invasion into surrounding tissue.

LT has the potential to facilitate long-term survival in suitable patients. Whether to proceed with transplantation should be determined by evaluating disease stage, overall patient health, and particular risk factors. The primary indications and contraindications for LT in cases of perihilar cholangiocarcinoma are enumerated in Table 2. Supplementary criteria for transplantation encompass recurrent cholangiocarcinoma post-resection, tumors associated with significant liver disease, and poor overall health or comorbidities that hinder resection. LT offers the potential for full recovery, but requires careful patient selection and comprehensive post-transplant care. In general, exclusion criteria for liver transplantation should include tumor size greater than 3 cm, tumor located inferior to the cystic duct, lymph node involvement and/or extrahepatic spread, percutaneous or peritoneal tumor biopsy, previous attempted liver resection, incomplete chemotherapy and radiotherapy, medical unsuitability, or a history of other malignancies within the previous 5 years; each criterion should be evaluated separately [18-20]. In the context of LT, it is crucial to ascertain the etiology of perihilar cholangiocarcinoma. In contrast to de novo perihilar cholangiocarcinoma, perihilar cholangiocarcinoma arising in the context of underlying PSC is frequently associated with compromised liver function. As a result, individuals with perihilar cholangiocarcinoma and primary sclerosing cholangitis will more often be directed towards LT [21].

Numerous papers have suggested neoadjuvant therapy that includes chemoradiotherapy prior to LT [18,20]. This tri-modal strategy (radiotherapy and chemotherapy followed by surgery) seeks to enhance the R0 resection rate and augment long-term survival [8]. Prior to the administration of neo-adjuvant chemotherapy, internal biliary drainage should be conducted to alleviate symptoms, address infection, facilitate chemotherapy, most critically, and reduce tumor burden [22]. The role of biliary drainage requires additional elucidation.

Neoadjuvant radiation is typically conducted with the concomitant injection of 5-FU because of its chemosensitizing properties. A team from the Mayo Clinic suggested neo-adjuvant treatment utilizing fractionated high-dose external beam and internal (iridium-192 brachytherapy) radiation, combined with chemosensitization through intravenous 5-FU and oral capecitabine [8,22]. A Toronto-based organization established a treatment incorporating capecitabine, hyper-fractionated external beam radiation, and maintenance chemotherapy utilizing gemcitabine and cisplatin [23]. Loveday et al. [23], conducted a retrospective analysis of patients with unresectable perihilar cholangiocarcinoma who were treated according to the followingprotocol: 1) concurrent conformal radiotherapy and capecitabine and 2) surgical staging, followed by maintenance cisplatin and gemcitabine until transplantation. The authors determined that their therapy plan was feasible, although was completed by only 6 of 43 patients. Hoogwater et al. [9], examination of a European patient cohort indicated that neo-adjuvant chemoradiotherapy decreased the risk of recurrence but increased the likelihood of early liver vascular problems. Mantel et al. [24], assessed post-transplantation problems associated with this procedure, noting that arterial and portal issues manifested in 21% and 22% of cases, respectively, resulting in an overall risk of 40% for vascular complications following liver transplantation under this tri-modal protocol.

Nonetheless, 5-FU has consistently failed to demonstrate efficacy in managing disease development, and its application as a monotherapyor in conjunction with radiotherapy, is seen as highly problematic by numerous medical oncologists [8-10]. While the neoadjuvant regimen has potential efficacy, when the significant dropout rate from the transplant protocol is considered (15-28% in the Mayo Clinic experience [8]), patients unable to complete transplantation would be subjected to a suboptimal chemotherapy regimen and associated complications without deriving any benefit.

The current standard chemotherapy regimen for patients with unresectable cholangiocarcinoma is a combination of gemcitabine and cisplatin [8,25,26], with varied incorporation of immune checkpoint inhibitors. The TOPAZ-1 trial demonstrated substantial advantages from including durvalumab in chemotherapy, whereas favorable outcomes are anticipated from the alternate combinations with pembrolizumab [27-29]. Currently, radiation is excluded from contemporary guidelines for the management of perihilar cholangiocarcinoma [3,30].

Neoadjuvant therapy, while successful in cancer treatment, may lead to both short- and long-term medical and surgical concerns. The incidence of patient dropouts due to debilitation or illness progression is difficult to calculate, and is often overestimated or underreported. Aggressive neoadjuvant radiation may result in irreversible hepatic damage and vascular problems post-liver transplantation [8]. Furthermore, invasive procedures (e.g., pancreaticoduodenectomy) coupled with preoperative therapies result in a significant incidence of surgical problems and retransplantation [2]. The ongoing debate regarding the utility and structure of neoadjuvant therapy is fueled by the major risks faced by both transplant patients and those who discontinue treatment due to disease progression or complications. The primary question is the role that radiation plays in achieving favorable post-transplant outcomes, or if case selection should be regarded as the predominant determinant of positive results [31]. Thus, with further research, neoadjuvant radiation may be deemed superfluous and omitted [8,9,22-24].

Various techniques, which are selected according to the patient’s individual needs and the availability of donor organs, can be employed to perform liver transplantation for perihilar cholangiocarcinoma. LT procedures can be categorized into two primary types: deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). DDLT entails the whole substitution of a compromised liver with a viable liver sourced from a deceased donor. This constitutes the primary form of LT. LDLT is the transfer of a liver segment from a living donor to a recipient. The living donor’s liver will regenerate, yielding a fully functional liver for both the recipient and the donor. The decision between DDLT and LDLT depends on various factors, such as tumor size, patient age, overall health, availability of healthy donor organs, and the presence of an appropriate donor.

Neoadjuvant chemoradiotherapy induces alterations in the irradiated surgical area, with particular concern regarding injury to the native hepatic artery and portal vein. To mitigate the risk of hepatic arterial thrombosis and stenosis resulting from alterations in the native vessels, intricate arterial reconstructions, including the implementation of free arterial interposition grafts to the infrarenal aorta, are recommended. This technique is more challenging to execute in the context of LDLT or alternative arterialization methods for the graft, such as utilizing the gastroepiploic artery. Arterialization of the allograft requires vigilant monitoring; should hepatic artery thrombosis or stenosis be identified, prompt reintervention is necessary. The same applies to delayed portal vein stenosis. In recent years, endovascular therapies, including balloon dilation and/or endovascular stenting, have emerged as an attractive and minimally invasive option to surgical reintervention for treating arterial stenosis after liver transplantation. A staging laparoscopy is essential prior to liver transplantation to rule out extra-hepatic illness. Systematic sampling of lymph nodes adjacent to the common hepatic (stations 8a and 8p) and appropriate hepatic arteries, as well as the bile duct and portal vein (stations 12a, 12b, and 12p), is essential to rule out involvement [20]. Despite the reduced risk of spread in the celiac trunk and in the superior mesenteric artery, lymph node biopsy should still be conducted at these locations [32]. In individuals with perihilar cholangiocarcinoma secondary to primary sclerosing cholangitis, microscopic infiltration of the common bile duct is prevalent; thus, frozen section analysis is essential after hepatectomy to assess margin involvement. Should a positive margin be detected, re-excision or a combination pancreaticoduodenectomy is necessary [33].

Vascular problems are a major worry after neoadjuvant radiation. Hepatic artery thrombosis or stenosis, pseudoaneurysm, and subsequent rupture, together with portal vein, hepatic vein, and inferior vena cava stenosis or thrombosis, have all been documented [31]. While portal vein, hepatic vein, and inferior vena cava difficulties occurred in 37.8% and 1.4% of cases, respectively, the incidence of early arterial complications was 5.4% and the incidence of late arterial complications was 18.9% in the largest dataset [31]. The short- and long-term results of the recently published primary transplant series for perihilar cholangiocarcinoma are presented in Table 3.

Post-transplantation, patients will require continuous immunosuppressive medication administration to prevent organ rejection. These medications suppress the immune system, restricting its capacity to attack the newly developed liver, and are essential for the transplanted liver’s sustained viability and the patient’s general health. Meticulous monitoring of the patient’s health is vital post-transplantation, encompassing regular blood tests to evaluate hepatic function, renal function, and vulnerability to infections. Alongside immunosuppressant therapy, the patient should adopt lifestyle adjustments, including a nutritious diet and frequent exercise, to improve well-being and prevent potential complications. Timely recognition and effective management of any side effects, including infection or rejection, are crucial to ensure the continued success of transplantation.

Perihilar cholangiocarcinoma recurrence is an ongoing concern irrespective of the transplantation method employed. Recurrence can occur in several organs, including the transplanted liver, lymph nodes, or other locations. Research from the Mayo Clinic on liver transplantation outcomes for perihilar cholangiocarcinoma, involving 237 patients found 5- and 10-year OS rates of 68% and 60%, respectively, with a 5-year disease-free survival rate of 55% [34]. The recurrence rate is influenced by variables like disease stage at transplantation, precise surgical approach employed, and overall patient status.

Prompt detection of recurrence is crucial to timely treatment, which improves the probability of good outcomes. Systematic surveillance through imaging studies and blood analysis is essential for identifying any signs of recurrence.

LT for perihilar cholangiocarcinoma can significantly enhance survival rates and quality of life for selected patients. Patient ages, overall health, and illness stage at the time of transplantation are some of the variables that impact prognosis and likelihood of survival following treatment. Previous studies indicated that the 5-year survival rates for perihilar cholangiocarcinoma following liver transplantation ranged from 40% to 60%, contingent on the specific characteristics of the patient and the transplant facility [5,35].

Patients undergoing transplantation for PSC-associated perihilar cholangiocarcinoma exhibited superior long-term overall survival rates compared to those receiving transplants for de novo perihilar cholangiocarcinoma (74% vs. 58% at 5 years; p=0.023). In a Toronto study, employing an alternative neo-adjuvant protocol, the overall survival rates at 1 and 2 years were 83.3% and 55.6%, respectively [26]. Cambridge et al. [35], conducted a meta-analysis revealing pooled OS rates of 71.2%, 48.0%, and 31.6% at 1, 3, and 5 years, respectively, without neo-adjuvant therapy. In contrast, these rates increased to 82.8%, 65.5%, and 65.1% with completed neoadjuvant therapy [35]. A multicenter study in North America demonstrated a significant association between overall survival and institutional experience (5-year: HR, 1.81; p=0.026). In centers that conducted six or more LTs, the OS rates at 1, 3, and 5 years were 91.8%, 56.9%, and 45.8%, respectively. In contrast, centers that performed fewer than six LTs reported OS rates of 65.6%, 48.8%, and 26.0% for the same time intervals [36]. The presence of a residual tumor in the explant specimen was the most significant prognostic factor [35]. The 5- and 10-year overall survival rates for this patient population were 45.1% and 36.1%, compared to 44.7% and 27.9% for patients with PSC and de novo perihilar cholangiocarcinoma, respectively [31]. The probability of 5-year overall survival was approximately 0% when free margins were not attained [37]. Elderly patients, those with elevated preoperative serum carbohydrate antigen 19-9 (CA 19-9) levels, and individuals with large tumors demonstrate higher rates of recurrence [8,22]. Patients with PSC-associated perihilar cholangiocarcinoma exhibited significantly higher survival rates compared to those with de novo perihilar cholangiocarcinoma [31].

Regular biochemistry, including levels of the tumor marker CA 19-9 and CT imaging, should be repeated in 3 months to check for recurrence in patients. Immunosuppressive agents must be administered in accordance with institutional protocols and tailored to the specific needs of the patient [22,24]. The evaluation of the pro-oncogenic effects of the immunosuppressive regimen in reducing immunosuppressive load is recommended to further investigate its impact on recurrence risk [38]. Schmelzle et al. [25], conducted a multicenter randomized trial comparing LT alone to LT with adjuvant therapy using gemcitabine; however, the study was prematurely terminated due to slow enrollment, preventing any conclusive results. The implementation of adjuvant therapy should be guided by risk stratification in the absence of evident benefit. Patients exhibiting elevated preoperative CA 19-9 levels and larger tumors demonstrate a higher likelihood of recurrence, suggesting their potential candidacy for adjuvant therapy. Additional research is required to more accurately assess the effects of this strategy on outcomes following LT [20,22].

LT and resection can enhance quality of life, although outcomes may differ based on individual patient factors and treatment complexity. Following resection, patients experience a recovery phase characterized by pain, fatigue, and dietary limitations. The long-term quality of life for patients who undergo successful resection is typically excellent, with most individuals returning to their prior levels of activity and well-being [15,40].

Following transplantation, patients must undergo long-term immunosuppression to avert organ rejection. This may result in side effects including heightened vulnerability to infections, changes in immune response, and possible long-term complications. With careful monitoring and management, numerous transplant recipients achieve satisfactory quality of life. The emotional effects of transplantation must be acknowledged as patients manage the complexities of adapting to a new organ and the continuous medical care required.