As the international classification of cholangiocarcinoma does not distinguish between perihepatic and distal cholangiocarcinoma [4], estimating the true incidence of pCCA is difficult. In the West, age standardized incidence rates range between 0.5 and 2 per 100,000 individuals, whereas in eastern Asia, incidence is higher due to endemic liver flukes (Opisthorchis viverrini and Clonorchis sinensis) infection as well as a higher incidence of hepatolithiasis. Worldwide, the incidence of pCCA has increased in recent years, which has been linked to the increased incidence of metabolic syndrome, especially in countries with historically low incidence rates [2].

Perihilar CCA is an aggressive disease. A large study from the Netherlands on 2031 patients showed an overall median survival of 5.2 months [58]. Patients undergoing palliative systemic treatment, loco-regional treatment or best supportive care had a median survival of 12.2, 14.5 and 2.9 months, respectively. Notably, only 15% of patients underwent curative resection, which was associated with a median survival of 29.6 months [58].

The outcome of patients suffering from pCCA is primarily determined by the possibility to undergo curative resection. However, only a minority of patients are eligible for surgical resection due to several factors. Early diagnosis is infrequent in pCCA because most patients with early disease are asymptomatic or symptoms are poorly specific (dyspepsia, abdominal discomfort, fatigue, weight loss) [3]. Furthermore, pCCA are desmoplastic and paucicellular tumors, which complicates obtaining histological confirmation once the clinical diagnosis becomes more evident [59]. At this stage, most patients will present with jaundice and/or cholangitis and will frequently require preoperative biliary drainage (PBD). In patients undergoing surgery for pCCA, preoperative cholangitis is associated with increased mortality, overall morbidity, incidence of liver failure, and sepsis, and it is an absolute indication for PBD [60]. In patients with jaundice but not cholangitis, PBD is still frequently indicated due to the concerns for impaired liver regeneration capability, as pCCA patients are frequently candidate for major liver resections. However, PBD has been associated with higher overall morbidity, perioperative transfusion, cholangitis, infection and bile leakage [61,62], suggesting that it could be reasonably avoided in patients with sufficient future liver remnant (≥50%). It is significant that regardless of the technique used for PBD (endoscopic versus percutaneous transhepatic biliary drainage), about 15% of patients will fail to proceed to surgery because of PBD complications and progressive deterioration [63]. Another factor complicating the surgical approach is the necessity to perform an oncologically adequate (R0) surgery, which frequently involves an extended hepatectomy associated with the resection of the biliary confluence and the reconstruction by an hepaticojejunostomy while preserving a sufficient portion of liver parenchyma. Portal vein embolization has traditionally been used to induce future liver remnant hypertrophy. Associating liver partition and portal vein ligation for stage hepatectomy (ALPPS) represents an alternative approach [64]. However, ALPPS is still debated in the setting of pCCA [65,66]. In patients who do not develop sufficient liver hypertrophy after portal vein embolization alone, associating hepatic vein embolization (so-called liver venous deprivation) could contribute to enhancing the growth of future liver remnants and improve access to curative resection [67].

Patients who can access resection with curative intent are exposed to an overall major morbidity rate of 43–65%, whereas postoperative mortality rates as high as 17% have been reported [68,69]. In a study evaluating outcomes of pCCA resection in 708 low-risk patients at 24 high-volume centers, the benchmark values (i.e., the 75% or 25% percentiles of the medians of each center) for Clavien–Dindo ≥ 3 complications rate and in-hospital mortality were ≤70% and ≤8%, respectively [70].

About 80% of patients will experience recurrence after resection, in most cases within 2 years from surgery [71,72]. Overall 5-year survival is 11–44% and appears to be strongly influenced by the radicality of surgical resection, being ~60% in patients undergoing R0 resection versus <10% after R1 resection [69]. Interestingly, benchmark value for R1 resection has been set at ≤43% [70].

Overall, surgery with curative intent appears to be an option only in a minority of patients suffering from pCCA, and it is burdened by a complicated preoperative management, high postoperative morbidity and mortality, and high recurrence rates, which highlights the urgent need for alternative strategies to improve the outcome in these patients.

In theory, LT is an interesting option for patients with pCCA because it allows for the radical excision of the tumor while avoiding the issue of residual hepatic functional reserve. Unfortunately, early results of LT performed in patients with pCCA were burdened by high recurrence rates, leading to pCCA being considered a contraindication for LT. [73,74]. However, observations that long-term survival could be achieved in patients with limited tumor burden, negative resection margins and no lymph node involvement opened to reconsider pCCA as a possible indication for LT in selected patients [75]. As aforementioned, the early experiences from the Mayo Clinic (Rochester, MN, USA) team showed that by stringent patient selection and by applying a neoadjuvant protocol of external beam radiotherapy, brachytherapy and 5-FU, excellent results could be achieved [11,76,77]. Table 1 summarizes the results of LT for pCCA [11,12,76,78,79,80,81,82,83,84,85,86,87,88,89,90].

In the absence of a neoadjuvant protocol, LT has been associated with 5-year overall survival rates ranging from 20% to 36%, whereas using a pre-transplant chemoradiation protocol has resulted in 5-year survival rates ranging from 52% to 82%. These positive outcomes have come at the expense of strict patient selection and the morbidity of the neoadjuvant treatment itself. Indeed, 25–42% of patients initially candidate to LT after chemoradiation will not be transplanted due to inability to tolerate the treatment, complications, or tumor progression. Furthermore, LT can be technically complicated due to the effects of radiotherapy on the hepatic hilum. Since the early reports [11], an increased incidence of hepatic artery and portal vein thrombosis has been reported, leading to the frequent choice of utilizing an interposition graft anastomosed to infrarenal aorta for arterial vascularization. Early postoperative outcomes have been marked by a higher rate of complications, sometimes directly related to preoperative radiation therapy. Another element of difficulty may be represented by the presence of adhesions. Indeed, a staging laparotomy is indicated to rule out peritoneal disease or extrahepatic lymphnodes involvement before the patient can be considered eligible for LT. In the setting of deceased donor LT, considerable time can separate the staging laparotomy from LT operation, further complicating an already difficult dissection. An alternative option, which has been adopted by some centers, is performing the staging laparotomy simultaneously with LT, to avoid a repeat operation and peritoneal adhesions. While this is a viable option in living donor liver transplantation, in deceased donor LT, it necessitates the availability of a back-up recipient and has the disadvantage of significantly prolonging preservation time, which may have a negative impact on postoperative graft function.

In summary, although excellent outcomes have been reported, LT for pCCA has not gained widespread adoption. This is likely explained by the limited number of eligible patients, the difficulties in preoperative management and the technical and logistical difficulties linked to the neoadjuvant chemoradiation protocol.