Cholangiocarcinoma (CCA) is a highly lethal neoplasia comprising approximately 15% of all primary liver tumors. Its incidence is increasing worldwide, and despite significant advancements in the knowledge of molecular mechanisms, diagnosis, management, and survival have not substantially improved in the past decade ^[1][2][1,2]. These cancers are heterogeneous and are best classified according to the primary anatomic origin as intrahepatic CCA (iCCA), when located proximally to the second-order bile ducts within the liver parenchyma, perihilar CCA (pCCA), arising between the second-order bile ducts and the insertion of the cystic duct into the common bile duct, and distal CCA (dCCA), located in the common bile duct below the cystic duct insertion [1].

Several risk factors have been linked to CCA, most of them associated with chronic inflammation of the biliary epithelium and bile stasis. Some recognized risk factors such as obesity, metabolic syndrome, or high alcohol consumption have increased globally over recent decades, which could be contributing to increasing CCA incidence. However, the majority of CCA cases do not present any identifiable risk factors.

In most cases, the diagnosis of CCA is established when the disease is already at advanced stages, which highly compromises access to effective treatment, resulting in a dismal outcome ^[3][4][3,4]. Therefore, prevention and early diagnosis remain the cornerstone for improving the survival of this devasting disease.

Surgical resection is the best therapy for CCA ^[5][6][5,6]. Unfortunately, complete resection is possible in less than 15–35% of cases ^[4][7][4,7], and even in those patients in whom complete tumor removal is achieved, the risk of recurrence is greater than 60% ^[8][9][8,9]. Another radical option is liver transplantation (LT), but its use in CCA is controversial due to the high risk of recurrence and the lower survival benefit compared to other LT indications as well as the limited number of donors [5]. In addition, locoregional therapies have been recently proposed as a reliable treatment alternative for those patients with liver-only, unresectable CCA, but the low level of evidence supporting their efficacy impedes making any robust recommendation [10]. Finally, systemic therapy has rapidly evolved in the last years, and the irruption of targeted therapies and immunotherapy has changed the treatment approach.

2. Liver Transplantation in Cholangiocarcinoma

Theoretically, LT is an excellent treatment option for primary liver tumors due to (1) its capacity to completely remove the tumor (and the undetected liver micrometastasis), particularly when major resection is needed due to tumor extension/location, (2) its ability to eliminate the underlying chronic liver disease, and (3) the possibility of maximizing the survival benefit compared to alternative therapies. Regrettably, the major problem for the wide application of LT is the shortage of donors, since the number of candidates largely exceeds the available livers to be implanted. Due to the scarce number of donors, it is the usual policy to exclude from transplantation any patients with an expected suboptimal post-transplant survival (with a cutoff arbitrarily established to be at least greater than 50–60% at 5 years) ^[11][12][11,12]. In addition, the LT allocation policy should be adjusted to guarantee real access to LT, preventing drop-out due to tumor progression and withdrawal from the waiting list in an excessive proportion of patients, but at the same time, requiring an observation period which would allow for identifying biologically aggressive tumors that would be associated with a higher risk of unacceptable recurrence.

2.1. Liver Transplantation in iCCA

iCCA was considered a contraindication for LT in most centers worldwide due to very poor initial results, i.e., a reported 2-year survival of around 30% ^[13][14][13,14]. These unacceptable outcomes were directly related to a high prevalence of microvascular invasion and poor tumor differentiation, particularly in patients with an unresectable or locally advanced tumor [15]. However, more recent retrospective studies have demonstrated encouraging results in terms of overall survival (OS) when a thorough selection of the population is performed. The relevance of selection based on tumor burden was demonstrated for the first time in an international multicenter study that included 48 patients who underwent LT and had been diagnosed with incidental iCCA in the explant. A total of 15 patients had “very early” iCCA (single tumor ≤ 2 cm) and 33 patients had “advanced” iCCA (single tumor > 2 cm or multifocal disease). After a median follow-up of 35 months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, 7%, 18%, and 18%, respectively, in the very early iCCA group vs. 30%, 47%, and 61% in the advanced iCCA group (p < 0.01). The 1-year, 3-year, and 5-year overall survival rates were 93%, 84%, and 65% in the very early iCCA group vs. 79%, 50%, and 45% in the advanced iCCA group (p < 0.02) [16]. Microvascular invasion and poor differentiation were associated with tumor recurrence in the multivariate analysis. Patients in the advanced iCCA group were divided into an intermediate stage (n = 6; single tumors 2.1–3 cm, not poorly differentiated) and an advanced stage (n = 27; all other tumors). The 1-year, 3-year, and 5-year overall survival rates were, 82%, 61%, and 61%, respectively, in the intermediate stage vs. 55%, 47%, and 42% in the advanced stage (p < 0.03) [16]. Ziogas et al. performed a meta-analysis of 18 studies, finding that the 5-year OS for very early iCCA was 71%, versus only 48% for advanced iCCA (single tumor > 2 cm or multiple tumors) [17]. Disappointingly, all these data come from retrospective studies, including mostly LT patients in whom iCCA was an incidental finding. Accordingly, prospective studies with well-defined inclusion and exclusion criteria and a predefined post-LT imaging follow-up are fervently needed. Furthermore, the outcome of LT should be analyzed according to the intention to treat the principle instead of only analyzing those patients finally transplanted. A multicenter, observational study (NCT02878473) aimed to prospectively evaluate the effectiveness of LT for very early iCCA is still ongoing.

2.2. Locally Advanced, Unresectable iCCA and Liver Transplantation: Role of Neoadjuvant Therapy

iCCA patients with a stable, liver-limited disease on neoadjuvant therapy may have a favorable disease biology, with long-term survival after LT. Disappointingly, the evidence is scarce, and most studies are single-center, retrospective, and include a low number of patients and heterogeneous population in terms of tumor stage and neoadjuvant approach. The most relevant study, which is also performed within a study protocol at MD Anderson in Texas, was recently published by McMillan et al. [18]. Patients with CCA liver-only with the absence of vascular or lymph node involvement were considered for LT. Neoadjuvant therapy consisted of the first-line use of gemcitabine plus cisplatin (GemCis), and disease stability was required by radiological evaluation for at least six months. The treatments performed prior to LT in addition to GemCis were heterogeneous, including various types of locoregional therapies, liver resection, and targeted therapies such as inhibitors of isocitrate dehydrogenase 1 (IDH-1), fibroblast growth factor receptor (FGFR), and poly ADP-ribose polymerase (PARP). Over 11 years, 65 patients were evaluated, of whom 28 were denied for listing. Five patients were excluded after being eligible for resection due to tumor regression after neoadjuvant therapy. At the end of the follow-up, 18 out of 32 patients underwent LT and 14 did not (7 were still on the waiting list and 7 were because of tumor progression or death while on the WL). The time range between diagnosis and inclusion in the WL was very wide (74–1054 days), which could implicitly suggest a selection of patients linked to tumor biology. Intent-to-treat (ITT) survival analysis at 1, 3, and 5 years was 90%, 61%, and 49%, respectively. The recurrence-free survival (RFS) at 3 years was 52%, and 7 out of 18 transplant patients (39%) developed tumor recurrence (4 during the first year post-LT). In another retrospective analysis recently published by Ito T. et al. [19], 30 patients who underwent neoadjuvant therapy were finally transplanted. In this series, the neoadjuvant protocol was less defined, and the 5-year overall survival was 49%. In conclusion, data on LT for unresectable iCCA are scarce and the level of evidence is low (Table 1). The response to neoadjuvant chemotherapy, especially in the context of new personalized target therapies, could identify patients with biologically less aggressive tumors in whom LT may offer long-term results. Prospective studies, with well-characterized and homogeneous populations in terms of baseline tumor burden, with clear-cut multimodal neoadjuvant protocols (locoregional and/or systemic treatment), and relevant outcomes (OS by ITT, RFS, and cancer-related survival), are mandatory to establish the role of LT in patients with locally advanced iCCA.

Abbreviations: GemCis, Gemcitabine and Cisplatin; iCCA, intrahepatic cholangiocarcinoma; IDH, isocitrate dehydrogenase; FGFR, fibroblast growth factor receptor; and TT, targeted therapy.

2.3. Perihiliar CCA (pCCA) and Liver Transplantation

The prognosis of pCCA is marked by frequent late diagnosis, which precludes the use of potentially curative treatments. The pCCA could develop in the context of primary sclerosing cholangitis (PSC) or de novo, in the absence of liver disease ^[1][4][1,4]. The indication of LT after neoadjuvant chemoradiation has been established as a therapeutic option with acceptable long-term OS results (>50% at 5 years) in carefully selected patients with early-stage unresectable pCCA and patients with pCCA associated with PSC [20]. Among different neoadjuvant chemoradiation strategies, the Mayo Clinic protocol based on strict criteria for diagnosis and patient selection, aggressive neoadjuvant chemoradiation, and surgical staging before transplantation, has been positioned as the best strategy. Tan et al. recently reported the Mayo Clinic results from 1993 to 2018. A total of 349 patients were initially assessed, but 277 (79%) underwent staging work-up, and in 60% (n = 211) LT was performed. According to ITT analysis (from the start of neoadjuvant therapy, including patients who did not undergo LT), the survival rates at 1, 5, and 10 years were 80%, 51%, and 46%, respectively, while the survival rates in those finally transplanted were 91%, 69%, and 62% [20]. The outcome in pCCA associated with PSC was significantly better than those arising within the healthy liver (5-year survival of 60% vs. 39%, respectively) ^[20][21][20,21], and the center experience positively impacts LT outcomes in patients with pCCA [22]. Other centers have reported poorer survival rates, inferior to 40% at 5 years ^{[23][24][25][26][27]}[23,24,25,26,27], partially explained by the lower proportion of PSC-related pCCA and the lesser center experience. The use of living donor liver transplantation (LDLT) has been postulated as an interesting option since it does not directly impact the principles of allocation justice related to cadaveric LT. Regrettably, robust data comparing both options are scarce, but LDLT for de novo pCCA seems to be associated with higher disease recurrence and slightly worse OS [20]. Patient selection and neoadjuvant chemoradiation protocol are critical, being the Mayo Clinic proposal the most frequently evaluated. The Mayo Clinic protocol requires having a lesion with a radial diameter (perpendicular to the duct) ≤3 cm and without extension below the cystic duct. Endoscopic ultrasound-guided aspiration of regional hepatic lymph nodes is routinely performed prior to neoadjuvant therapy, and the presence of lymph node metastases is an exclusion criterion. Diagnostic biopsies, whether transgastric endoscopic or percutaneous transhepatic, are usually dismissed given the potential risk of seeding metastases in the peritoneum ^[21][28][21,28]. Vascular encapsulation and tumor extension along the duct, although not considered contraindications for neoadjuvant treatment, are conditions of a worse prognosis in terms of response [29]. The neoadjuvant therapy includes external beam radiation plus concomitant 5-fluorouracil and brachytherapy, followed by maintenance capecitabine until LT. After completion of neoadjuvant chemoradiation, patients should undergo staging laparoscopy prior to LT, comprising a complete examination of the abdominal cavity, routine biopsy of the regional lymph nodes, and biopsy of any other suspicious lesions. The timing of the staging surgery is a subject of debate, especially in PSC patients with advanced liver disease and complications associated with the presence of portal hypertension. However, the drop-out probability in patients with pCCA-PSC is usually lower than in patients with de novo pCCA (15% vs. 28%) [30]. In addition, the treatment of clinical complications during the neoadjuvant protocol is the cornerstone for LT outcome. Sarcopenia is frequently present in pCCA patients. It has shown an impact on the post-LT outcome and should be actively treated with nutritional support, which in some cases may include nasogastric or nasojejunal tube insertion for feeding [31]. Recurrent cholangitis because of biliary obstruction, biliary stenting, radiation-induced ductal injury, and/or underlying PSC has led to the development of antimicrobial resistance which increases the risk of intra-abdominal infections after LT. Finally, radiotherapy during the neoadjuvant protocol increases the risk of hepatic artery thrombosis and radiation-induced fibrosis ^[32][33][32,33]. Finally, recent publications found that LT in patients who meet the criteria for liver resection had better survival than that observed after resection, even when sub-analysis stratified by PSC was performed ^[34][35][34,35]. However, the survival benefit decreases when analyzed according to the ITT principle, which clearly calls into question the possibility of using donor livers for resectable pCCA ^[20][36][20,36]. An ongoing randomized, ITT multi-center trial in France TRANSPHIL (NCT02232932) comparing neoadjuvant chemoradiation and LT vs. upfront surgical resection will clarify this controversial topic.