Rare and aggressive perihilar cholangiocarcinoma, which is also known as Klatskin tumor, starts in the bile ducts where the common hepatic duct is formed by the meeting of the right and left hepatic ducts. It accounts for roughly 10%–15% of all cases of cholangiocarcinoma. While the exact cause of perihilar cholangiocarcinoma remains uncertain, various risk factors have been identified, including primary sclerosing cholangitis (PSC), choledochal cysts, and persistent infections.

The implementation of resection and transplantation has had a profound effect on perihilar cholangiocarcinoma management, providing much optimism for patients who previously had restricted choices. Implementing these treatments has resulted in higher survival rates, greater quality of life, and a more positive perspective for patients suffering from this chronic condition. However, the lack of widespread availability of these medicinal interventions, the possibility of adverse effects, and the restricted supply of donor organs pose persistent challenges. Sustained research and advancements in surgical methods are crucial to surmount these obstacles and broaden the availability of these life-saving treatments for all qualified patients.

Patient Selection

It is common for patients waiting for surgery to experience malnutrition, repeated episodes of cholangitis, and neo-adjuvant therapy-related adverse events, explaining patients’ high vulnerability. Consequently, patient selection must follow rigorous evaluation criteria to ensure good outcomes. Patients who are not considered fit or who have poor nutritional status, even after a pre-rehabilitation program, should not be considered for surgery. Candidates for major liver resection (LR) should have sufficient liver function as well as enough future liver remnant (FLR). Resection should only be considered when the FLR is larger than 40% in cirrhotic patients, 30% in patients presenting significant steatosis or fibrosis, or 20% in the case of normal parenchyma [1].

Neo-adjuvant Therapy

A previous systematic review included seven studies that evaluated neo-adjuvant therapy before liver resection, with a pooled number of 87 patients [2]. Neo-adjuvant therapy has the potential benefit of increasing the R0 resection rate and the rate of complete pathological response. However, neo-adjuvant therapies are quite heterogeneous across studies, with a neo-adjuvant-to-surgery time interval ranging from 3 days to 6 months. The most used chemotherapies include gemcitabine, fluoropyrimidine- and platinum-based regimens with concurrent radiotherapy ranging from 10.5–60 cGy.

Surgical Techniques for Resection

Perihilar cholangiocarcinoma resection typically entails an intricate surgical protocol that requires specialist knowledge. Perihilar cholangiocarcinoma resection is the surgical excision of the tumor, along with a corresponding margin of healthy tissue. The degree of excision is contingent upon the site, dimensions, and proximity of the tumor to adjacent tissues. The technique used is determined by the tumor’s precise site and nature, as well as the patient’s overall well-being.

When the FLR is insufficient, strategies to increase the FLR such as portal vein embolization or associating liver partition and portal vein ligation for staged hepatectomy have to be considered [3,4]. Although there is no consensus on the best approach due to the lack of strong evidence, several reports indicate that a minimally invasive approach is nowadays feasible for perihilar cholangiocarcinoma resection and has become a valuable alternative to conventional open surgery [5]. Caudate lobe resection is mandatory to increase the likelihood of R0 resection. The Nagoya group in Japan was the first to recommend caudate lobe resection in the 1970s and 1980s [6]. The Gilbert meta-analysis reported that caudate lobe resection increased the odds of R0 resection (odds ratio=5.85) and survival (hazard ratio [HR]=0.65) without increasing postoperative morbidity [7]. Frozen section analysis should be considered during the hepatectomy to check for margin involvement. If the common bile duct margin is involved wider excision and eventually associated pancreaticoduodenectomy are necessary.

Right hepatectomy, which entails the excision of the liver’s right lobe, is the predominant surgical method. Under certain circumstances, a more comprehensive surgical procedure, such as a left hepatectomy or extended right hepatectomy, may be required. Tumors that invade either the right or left hepatic duct may require this procedure. The specific anatomical features, tumor properties, and overall health condition of the patient determine the surgical approach. Perihilar cholangiocarcinoma surgical removal is a high-risk operation associated with substantial morbidity and mortality. We must evaluate each case individually to determine the feasibility of resection, considering the potential advantages and disadvantages.

Postoperative Management

While it is possible to cure perihilar cholangiocarcinoma, surgical removal of the tumor carries a significant risk of complications, including postoperative hemorrhage, bile leakage, and wound infection. The primary objectives of postoperative care are to reduce complications, enhance recovery, and monitor for disease recurrence. Regular surveillance of vital signs, laboratory tests, and imaging investigations are critical to identifying and managing possible problems such as infections, bleeding, or bile leakage for monitoring for complications. We use pharmaceutical interventions and pain management techniques to regulate postoperative pain. Hospitalized patients may need nutritional support via intravenous fluids or feeding tubes until they can tolerate consuming food orally. Major hepatectomy carries risks for postoperative 30- and 90-day mortality of 5% and 9%, respectively. Meanwhile, the overall morbidity and severe morbidity rates were 57% and 40%, respectively [8]. The risk for liver failure was 11% for left-sided resection and 22% for left- and right-sided resection.

Regular follow-up appointments, which include imaging investigations and tumor markers, are crucial for monitoring the incidence of disease recurrence and ensuring the best possible long-term treatment.

Adjuvant Therapy

Adjuvant therapy, either using chemotherapy or chemo-radiotherapy, may be beneficial for patients with stage III–IV perihilar cholangiocarcinoma. In the case of compromised margins, radiotherapy should be performed [9]. Treatment decisions must be based on the patient’s tolerability. Another study suggests adjuvant chemo-radiotherapy with a radiation dosage of 45 cGy and oral 5-fluorouracil or adjuvant chemotherapy with gemcitabine monotherapy or a combination of gemcitabine/cisplatin [9]. A recent study suggests administering adjuvant therapy to all perihilar cholangiocarcinoma patients after liver resection. In a population-based study, the benefits of adjuvant therapy were significant, even in the case of node-positivity or a positive margin resection [10].

Prognosis and Outcomes

Many factors, including the disease stage, the degree of resection, the effectiveness of the surgical intervention, and the patient’s overall welfare, influence the outlook for patients diagnosed with perihilar cholangiocarcinoma after undergoing resection. A complete excision of a localized illness can result in a 5-year survival rate of up to 50%. In one study, 5-year overall survival (OS) rate was 43.7% after left-sided resection and 38.2% after right-sided resection, respectively [8]. Key recently published series reporting long-term outcomes after liver resection for perihilar cholangiocarcinoma are displayed in Table 1 [11-20]. However, these survival rates decrease dramatically for patients with advanced-stage disease. Curative excision of perihilar cholangiocarcinoma typically results in a lower 5-year survival rate compared to other forms of cancer. Nevertheless, recent breakthroughs in surgical procedures, chemotherapy, and radiation administration have enhanced the results for certain patients. Sustained monitoring for recurrence and effective management of any problems are crucial aspects of long-term follow-up.

Table 1 . Liver resection for perihilar cholangiocarcinoma.

Studies	Year	Study type	Numbers of patients	Recruitment period	Neo-adjuvant therapy	Overall survival
Nagino et al. [11]	2013	RSC	574	1977–2010	No	44.3% at 3 yrs
Govil et al. [12]	2016	RSC	36	2009–2015	No	32.5% at 5 yrs
Kawabata et al. [13]	2017	RSC	40	2010–2016	No	N/A
Kobayashi et al. [14]	2017	RSC	229	2001–2015	Chemotherapy and radiotherapy	85% at 5 yrs
Kimura et al. [15]	2017	RSC	105	1995–2014	No	46.7% at 3 yrs
Sumiyoshi et al. [16]	2018	RSC	15	2006–2016	Chemotherapy and radiotherapy	13% at 5 yrs
Tran et al. [17]	2019	RMC	257	2000–2014	6% underwent chemotherapy or radiotherapy	19% at 5 yrs
Jo et al. [18]	2020	RSC	83	2010–2017	No	39.4% at 5 yrs
Jeddou et al. [19]	2022	RSC	102	2012–2019	No	63% at 3 yrs
Olthof et al. [20]	2024	RMC	1,701	2000–2022	N/A	30% at 5 yrs

RSC, retrospective single-center; RMC, retrospective multicenter; N/A, not available..

Indications for Transplantation

Liver transplantation (LT) is a very efficient therapy for patients diagnosed with perihilar cholangiocarcinoma who are ineligible for surgical removal or who have progressed to an advanced stage of the illness. All candidates for LT should be medically fit and free of metastatic disease according to computed tomography (CT) scan and magnetic resonance imaging performed within 3 months before LT. Most cases of unresectable perihilar cholangiocarcinoma, where the tumor is considered inoperable due to its size, location, or intrusion into adjacent structures, indicate the need for transplantation.

LT has the potential to provide long-term survival in appropriately chosen patients. Individuals should decide whether to continue with transplantation, considering several factors like the patient’s illness stage, general condition, and specific risk factors. The main indications and contraindications for LT for perihilar cholangiocarcinoma are listed in Table 2 [21]. Additional criteria for transplantation include recurring cholangiocarcinoma following resection, tumors accompanied by severe liver disease, and compromised general health or comorbidities that prevent resection. Although LT provides the possibility of a full recovery, it is an intricate and high-risk operation that necessitates careful patient selection and thorough post-transplant care. Generally, any of the following should be used as exclusion criteria for LT: tumor size >3 cm; tumor below the cystic duct; presence of lymph node involvement and/or extrahepatic dissemination; realization of a transcutaneous or transperitoneal tumor biopsy; previous attempt of liver resection; metastatic disease found at surgery; or non-completion of chemo-radiation regimen; and medically unfitness or a history of other malignancies within the last 5 years. These criteria should be individually assessed [21-23]. In the context of LT, it is important to determine the etiology of the perihilar cholangiocarcinoma. Contrary to de novo perihilar cholangiocarcinoma, perihilar cholangiocarcinoma that has developed in an underlying PSC is often seen in the context of impaired liver function. Consequently, patients with perihilar cholangiocarcinoma and PSC will be more frequently oriented toward LT [24].

Table 2 . Indications and contraindications to liver transplantation to perihilar cholangiocarcinoma.

Indications	Contraindications
Confirmed diagnosis of perihilar cholangiocarcinomaa) Good performance status Age <70 yrs old Tumor size <3 cm Completion of neo-adjuvant therapy Unresectable tumor, advanced liver disease, or PSC Absence of other malignancy in the last 5 yrs (except skin and cervical tumors)	Previous attempt at liver hilum Dissection Previous biopsy of the tumor Metastatic diseases Lymph node involvement

Cited from the article of Andraus et al. (Hepatobiliary Pancreat Dis Int 2024;23:139-145) [21]..

PSC, primary sclerosing cholangitis; CA, carbohydrate antigen..

^a)Confirmed by intraluminal brush cytology and/or intraluminal biopsy and/or CA19-9 >100 U/mL, in the absence of cholangitis and with a radiologic image (CT or MRI) showing stricture of biliary tree or mass in the hepatic hilum..

Neo-adjuvant Therapy

Several authors have proposed neo-adjuvant treatment with chemo-radiation before LT [21,22]. Such a tri-modal approach (radiotherapy and chemotherapy followed by surgery) aims to increase the R0 resection rate and improve long-term survival [25]. Before considering neo-adjuvant chemotherapy, (internal) biliary drainage should be performed to alleviate symptoms, treat infection, enable chemotherapy, and most importantly eliminate the tumor burden [26]. The role of biliary drainage still needs to be further clarified. A Mayo Clinic team proposed a neo-adjuvant protocol with fractionated high-dose external beam and internal (iridium-192 brachytherapy) radiotherapy under chemo-sensitization using intravenous 5-fluorouracil and oral capecitabine [25,26]. A Toronto-based group developed a protocol with capecitabine with hyper-fractionated external beam radiotherapy and maintenance chemotherapy with gemcitabine and cisplatin. Loveday et al. [27] performed a retrospective analysis of patients with unresectable perihilar cholangiocarcinoma treated with this protocol: their patients were treated with conformal radiotherapy given concurrently with capecitabine; then, following surgical staging, patients received maintenance cisplatin and gemcitabine until transplantation. The authors concluded that their treatment protocol was feasible although completed in six of 43 patients only. The analysis of a European patient cohort, done by Hoogwater et al. [28], also revealed that neo-adjuvant chemo-radiotherapy resulted in a lower risk for recurrence but a greater risk of early liver vascular complications. Finally, Mantel et al. [29] evaluated the post-transplantation complications related to this protocol, observing that arterial and portal complications occurred in 21% and 22%, respectively, yielding an overall risk of 40% for developing vascular complications after LT in this tri-modal protocol.

Procedure

Several methods, chosen based on the specific requirements of the patient and the accessibility of donor organs, can be used to complete LT for perihilar cholangiocarcinoma. We can broadly classify LT methods into two basic types: deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). DDLT involves the complete replacement of a damaged liver with a healthy liver obtained from a deceased donor. This is the predominant form of LT. LDLT involves the transplantation of a liver segment from a living donor to the recipient. The living donor’s liver will undergo regeneration, resulting in a completely operational liver for both the recipient and the donor. The choice between DDLT and LDLT is contingent on several criteria, including the tumor size, the patient’s age, the patient’s general health, the accessibility of healthy donor organs, and the availability of a suitable donor.

Neo-adjuvant chemo-radiotherapy causes changes in the irradiated surgical field, and damage to the native hepatic artery and portal vein are especially feared. To reduce the risk of hepatic arterial thrombosis and stenosis induced by the changes of the native vessels, complex arterial reconstructions such as the use of free arterial interposition grafts to the infrarenal aorta (a technique that is more difficult to apply in the case of LDLT or alternative methods of arterialization to the graft, such as the use of the gastroepiploic artery) are advocated. The arterialization of the allograft needs to be closely monitored; in case hepatic artery thrombosis or stenosis is diagnosed, early re-intervention is warranted. The same holds for delayed portal vein stenosis. In recent years, endovascular therapies, such as balloon dilatation and/or endovascular stenting, have become an appealing and minimally invasive alternative for surgical reintervention in addressing vascular stenosis following LT. A staging laparoscopy is necessary before LT to exclude extra-hepatic disease. Routine sampling of lymph nodes along the common hepatic (8a and 8p stations) and the proper hepatic arteries, bile duct and portal vein (12a, 12b, and 12p stations) is necessary to exclude involvement [21]. Even though the risk for dissemination in the celiac trunk and along the superior mesenteric artery is lower, sampling nodes should also be completed at these stations [30]. In patients with perihilar cholangiocarcinoma arising from PSC, microscopic involvement of the common bile duct is common; therefore, frozen section analysis is mandatory during the hepatectomy to check for margin involvement. If a positive margin is identified, a re-excision or even combined pancreaticoduodenectomy must be performed [31].

Post-transplant Management

Vascular complications are of major concern due to neo-adjuvant radiotherapy. Hepatic artery thrombosis or stenosis, pseudoaneurysm, and eventual rupture, as well as portal vein, hepatic vein, and inferior vena cava stenosis or thrombosis, have all been reported [32]. In the world’s largest series from the Mayo Clinic, the incidence of early arterial complications was 5.4%, and the incidence of late arterial complications was 18.9%, while portal vein, hepatic vein, and inferior vena cava complications occurred in 37.8% and 1.4% of cases, respectively [32]. Short- and long-term outcomes of the primary recently published transplant series for perihilar cholangiocarcinoma are displayed in Table 3 [33].

Table 3 . Outcomes after liver transplantation for perihilar cholangiocarcinoma.

Studies	Year	Study type	Numbers of patients	Neo-adjuvant therapy	DFS (%)				OS (%)
					1-yr	3-yr	5-yr		1-yr	3-yr	5-yr
Loveday et al. [27]	2018	RSC	16	Yes	16	N/A	N/A		83.3	N/A	N/A
Ethun et al. [38]	2018	RMC	155	Yes	76	N/A	N/A		93	72	64
Dondorf et al. [33]	2019	RSC	22	Yes	78.2	32.1	24.1		89.2	36.0	28.8
Tan et al. [32]	2020	RSC	74	Yes	N/A	N/A	N/A		84.9	N/A	66.5
Azad et al. [34]	2020	RSC	84	Yes	91	67	55		92	78	68
Kitajima et al. [37]	2020	RMC	155	Yes	N/A	N/A	N/A		83.7	54.4	39.7
Vugts et al. [23]	2021	RMC	34	Yes	N/A	N/A	N/A		56	18	11
Breuer et al. [42]	2022	RMC	120	Yes	N/A	N/A	N/A		91	N/A	N/A

DFS, disease-free survival; OS, overall survival; RSC, retrospective single-center; RMC, retrospective multi-center; N/A, not available..

Following transplantation, the patient will require lifelong administration of immunosuppressant drugs to combat organ rejection. These pharmaceuticals inhibit the body’s immune system, thereby limiting its ability to target the newly formed liver. The administration of immunosuppressant medication is critical for the transplanted liver’s continued viability and the patient’s overall well-being. Rigorous surveillance of the patient’s well-being is required following transplantation, which includes routine blood tests to assess liver function, renal function, and susceptibility to infections. Furthermore, the patient will need frequent appointments with the transplant team to ensure continuous care and supervision. In conjunction with immunosuppressant treatment, the patient may need to implement lifestyle modifications, such as embracing a nutritious diet and engaging in regular physical activity, to enhance their well-being and avert potential problems. Prompt identification and adequate management of any possible adverse effects, such as infection or rejection, are essential to guarantee the sustained efficacy of the transplantation.

Recurrence

Regardless of the method of transplantation, the risk of perihilar cholangiocarcinoma recurrence remains a significant concern. A potential recurrence may manifest in the transplanted liver as well as in other organs such as lymph nodes or remote locations. At the Mayo Clinic, a report of LT experiences rates for perihilar cholangiocarcinoma, including 237 patients, documented 5- and 10-year OS rates that reached 68% and 60%, while the 5-year disease-free survival rate was 55% [34]. Variables such as the advanced stage of the disease during transplantation, the specific surgical procedure, and the patient’s general condition influence the recurrence rate.

Timely identification of recurrence is essential to deliver immediate therapy and enhance the likelihood of effective control. Systematic monitoring using imaging examinations and blood testing is crucial to detect any indications of recurrence.

Outcomes and Survival

LT for perihilar cholangiocarcinoma can facilitate a substantial improvement of both survival rates and quality of life for well-chosen individuals. Various factors, including the patient’s age, general health, and disease stage at the transplantation procedure, influence prognosis and survival rates after transplantation. Previous studies have shown that the 5-year survival rates for perihilar cholangiocarcinoma following LT 40%–60%, depending on the unique characteristics of the patient and the transplant facility.

Patients transplanted for PSC-associated perihilar cholangiocarcinoma had a higher long-term OS rate than patients transplanted for de novo perihilar cholangiocarcinoma (74% vs. 58% at 5 years; p=0.023). In the Toronto experience, using a different neo-adjuvant protocol, 1- and 2-year OS rates reached 83.3% and 55.6%, respectively [35]. Cambridge et al. [36] completed a meta-analysis, and the pooled 1-, 3-, and 5-year OS rates were 71.2%, 48.0%, and 31.6%, respectively, in the absence of neo-adjuvant therapy; these results improved to 82.8%, 65.5%, and 65.1% in the case of completed neo-adjuvant therapy. A North American multicenter study showed that OS was significantly associated with institutional experience (5-year: HR=1.81; p=0.026). In centers that had performed ≥6 LTs, the 1-, 3-, and 5-year OS rates were 91.8%, 56.9%, and 45.8%, compared to 65.6%, 48.8%, and 26.0%, respectively, in centers that had performed <6 LTs [37]. The presence of a residual tumor in the explant specimen has been identified as the most important prognostic factor [36]; 5- and 10-year OS rates reached only 45.1% and 36.1% for this patient population versus 44.7% and 27.9% in PSC and de novo perihilar cholangiocarcinoma patients, respectively [32]. When free margins were not achieved, the probability of 5-year OS was near 0% [38]. Elderly patients, patients with elevated preoperative serum carbohydrate antigen (CA)19-9 levels, and large tumors have also been shown to experience recurrence at greater rates [25,26]. Finally, patients with PSC-associated perihilar cholangiocarcinoma have significantly higher survival rates than those with de novo perihilar cholangiocarcinoma [32].

Postoperative Follow-up and Adjuvant Therapy

Patients should undergo a 3-month reevaluation using routine biochemistry, including tumor marker CA19-9 levels and CT imaging, to look for recurrences. Immunosuppressive agents should be supplied according to institutional protocols and the patient’s individual requirements [26,29]. Assessing the pro-oncogenic effect of the immunosuppressive regimen in minimizing the immunosuppressive load is advocated for to further assess the impact on the risk for recurrence [39]. Schmelzle et al. [40] previously compared LT alone to LT with adjuvant therapy with gemcitabine in a multicenter randomized trial; unfortunately, their study was prematurely terminated without conclusion due to slow enrollment. In the absence of clear benefits, the use of adjuvant therapy should be based on risk stratification. Patients with high preoperative CA19-9 levels and large tumors are more likely to experience recurrence and hence could be considered candidates for adjuvant therapy. Further studies are necessary to better evaluate the impact of such a strategy on outcomes after LT [21,26].

The choice between resection and transplantation is highly personalized and depends on a complicated interaction of variables, such as the patient’s general well-being, the characterization and severity of their liver disease, and the accessibility of appropriate donor organs. Moris et al. [41] compared LT to liver resection for perihilar cholangiocarcinoma in a meta-analysis that included five observational studies; however, due to the rarity, nature, and complexity of the condition, there was again significant clinical heterogeneity among studies. Still, despite the absence of a significant difference in postoperative mortality, the length of hospital stay was shorter in the LT group compared to the liver resection group, and the 3-year survival rate was better after LT (HR=0.61; 95% confidence interval: 0.40–0.93) [41]. A recent large multicenter study comparing a transplanted cohort to a matched LR Bismuth-Corlette IV perihilar cholangiocarcinoma cohort revealed a significant improvement in the 5-year disease-free survival rate after LT (50.2% vs. 17.4%) [42]; its authors demonstrated that, even in patients with potentially resectable lesions, the oncologic outcomes are better after LT compared to liver resection [42].

Liver resection may potentially cure localized liver tumors. Transplantation is typically limited to individuals with severe disease or many tumors that cannot be removed surgically. Resection is more suitable for patients who have good general health and a certain level of liver function. Individuals with debilitated health or significantly impaired liver function may be more suited for transplantation. The transplantation procedure depends on the presence of an appropriate donor liver, which can cause a temporal delay. However, this limitation does not apply to the resection procedure, making it a better choice. In addition, both treatments entail inherent dangers, although the level of complexity and related complications can differ. Physician and surgeons must be cognizant of these hazards and make well-informed choices depending on their unique circumstances.

Surgical resection and transplantation have revolutionized perihilar cholangiocarcinoma management. These interventions provide a means to achieve higher rates of survival, improved quality of life, and a more positive perspective for patients. Rigorous monitoring and continuous treatment are critical to detect any indications of recurrence and guarantee the procedure’s continued effectiveness. Nevertheless, ongoing research and clinical progress are necessary to overcome obstacles and maximize the implementation of these treatments.

By facilitating a multidisciplinary approach, encouraging research innovation, and guaranteeing fair access to therapy, we may further enhance the care for patients with perihilar cholangiocarcinoma and work toward a more promising future for patients affected by this complex and demanding disease.

This research was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2023R1A2C2005946). Korean NRF did not influence study design, data analysis, data interpretation, or drafting of the manuscript.

Jongman Kim is a chief editor of the journal but was not involved in the review process of this manuscript.