Key words : Biliary malignancy, Hepatic neoplasm, Liver tumor

Introduction

Cholangiocarcinoma (CCA) is the second most common primary hepatic neoplasm, accounting for 10% to 20% of primary liver tumors and 3% of all gastrointestinal neoplasms.^1,2 The disease is believed to originate from malignant transformation of cholangiocytes and/or possibly biliary stem cells and hepatocytes.³ The 3 anatomic types (intrahepatic, perihilar, and distal [iCCA, pCCA, and dCCA, respectively]) have distinct epidemiology, etiopatho-genesis, and clinical outcomes. However, pCCA and dCCA are shown as extrahepatic dCC despite their distinct clinical behavior.¹ Mixed hepatocellular-cholangiocellular carcinoma (HCC-CCA), which represents <1% of liver tumors, is the newly recognized phenotype of CCA. This phenotype expresses markers of hepatocellular and biliary differentiations and portends aggressive disease and poorer outcomes.

Considerable variations have been shown in age-standardized incidence of CCA, with the highest in Eastern regions; incidence varies from 85 per 100 000 in northeastern Thailand (the highest globally) to 0.4 per 100 000 in Canada.¹ The incidence of iCCA in Asian people is twice that shown in White and African American people.² These variations in incidence probably reflect potential genetic variations and differences in local risk factors such as liver flukes. Cirrhosis is the major risk factor for iCCA, with a combined odds ratio of 22.92.4 Primary sclerosing cholangitis (PSC) is the major risk factor for pCCA, with patients having 5% to 10% lifetime risk of developing CCA; the cumulative incidence of CCA is ~25% over 20 years for men and 15% for women.⁵ There is a trend toward increasing incidence, which may partly be attributed to increasing prevalence of risk factors, including increased alcohol consumption, smoking, infections with hepatotropic viruses, and obesity, leading to metabolic syndrome and nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. From 1973 to 2012, the incidence of iCCA has increased from 0.44 to 1.18 cases per 100 000 person-years, which represents a 2.3% annual percent change, whereas the incidence of extrahepatic CCA has increased from 0.96 to 1.02 per 100 000 person-years, which represents a 0.14% annual percent change.⁴

Mortality from CCA has also increased globally from 1973 to 2014.^1,2 Mortality is higher in men than in women and in Asian regions than in the West. Despite advances in awareness, earlier diagnosis, and trials of many treatment modalities, prognosis has not improved substantially in the past decade, with 5-year survival of 7% to 20%.¹ Survival may be attributed to the notorious difficulty for accurate diagnosis due to inaccessible locations for histology or cytology, a lack of clear diagnostic imaging criteria, and inaccurate noninvasive tumor biomarkers.⁶

Early and confirmed diagnosis is still a challenge with presentation at advanced stages, beyond possibility of cure with the current modalities. Diagnostic criteria set forth by the United Network for Organ Sharing for patients with pCCA require either tissue biopsy or cytology showing adenocarcinoma, aneuploidy on fluorescence in situ hybridization (FISH), or the presence of a malignant-appearing stricture with an elevated CA 19-9 of ≥100 U/mL.⁴ Transperitoneal, percutaneous, or endoscopic ultrasonograph-guided biopsy of the tumor are contraindications to liver transplant (LT) for pCCA, due to breaching of tumor planes and seeding. In addition, obtaining a tissue diagnosis can be difficult due to the paucicellular, fibrous nature of pCCA. Brush cytology has a sensitivity of 30%, which may be improved with use of FISH (sensitivity of 60%) or single-operator cholangioscopy (80% sensitivity).⁴

Landscape Is Not Uniform

The varied etiopathogenesis, myriad morphologies, and underlying different mutations mean that CCA subtypes will have different outcomes. Most pCCA and dCCA are conventional mucin-producing adenocarcinomas or papillary tumors.⁷ However, iCCA shows several histological variants (conventional CCA and rare variants).⁸ The different pathogenesis and cells of origin may be ascribed to the myriad histological types and accompanied molecular heterogeneity. Both CCA and the small duct variety of iCCA are believed to originate from hepatic progenitor stem cells and develop on a background of chronic liver disease (such as chronic viral hepatitis and cirrhosis) characterized by hepatic progenitor stem cell activation.^1,9,10 However, columnar mucous cholangiocytes or peribiliary glands are implicated in the origin of large bile duct iCCA, pCCA, and dCCA. These varieties mostly develop in chronically inflamed bile ducts such as in PSC or liver fluke infections. This chronic inflammation also produces a “field change” with propensity to develop malignant changes at multiple sites in the biliary tree.^10,11 Furthermore, iCCA has been subtyped as inflammation (38%) and proli-feration (62%) subtypes according to transcriptomic profiling; patients with the proliferation subtype of iCCA have median overall survival (OS) of 24.3 months versus 47.2 months for those with the inflammation subtype (P = .048).¹²

Nakamura and colleagues have emphasized differences in anatomic location of the tumor, highlighting IDH, EPHA2, and BAP1 mutations and FGFR2 fusions in iCCA, whereas extrahepatic tumors specifically show the PRKACA and PRKACB fusions and mutations in ELF3 (similar to tumors in the ampulla of Vater) and ARID1B. On the basis of these fundamental causal alterations, tumors in distinct anatomic sites should probably be treated differently.¹³ The RAS-MAPK pathway activation due to KRAS-activating mutations is found in all CCAs without distinction, whereas the BRAF mutations are more prevalent in iCCA.^1,14

In this review, we have focused on the role of LT as a treatment option for patients with CCA. Because most patients with dCCA are treated with Whipple pancreaticoduodenectomy when discovered early enough, liver resection and LT are not commonly considered treatment options. Thus, we will focus mainly on pCCA and iCCA.

Effects of Current Nontransplant Treatment Modalities on Survival

Cholangiocarcinomas are asymptomatic in early cases, and jaundice is the most common presenting feature in pCCA and dCCA. Unfortunately, jaundice is a late feature in iCCA; up to 25% are discovered at late stages when imaging is performed for some other reason.

A biopsy is not needed to confirm the diagnosis for a surgically resectable tumor in patients with characteristic iCCA imaging, elevated serum levels of CA19-9, and normal immunoglobulin G4 (IgG4) levels or after exclusion of other primary tumors (ie, colorectal, gastric, breast). However, histopathological or cytological analysis is mandatory to confirm the diagnosis in cases where palliative chemotherapy is to be planned.¹⁵ Only 30% of patients are diagnosed early enough to be offered the potentially curative treatment in the form of surgical resection.^1,16 Current accepted standard treat modalities are depicted in Figure 1.

Surgery Is the Only Option of Cure But Not Always Successful

Surgery plus adjuvant chemotherapy is the only modality to offer a possibility of cure at present (Figure 1). Unfortunately, most patients with iCCA present late with median tumor size of 6 cm, mostly spread to hilar lymph nodes, and only 15% of these present with jaundice because of tumor growth toward the hilum.¹ Recommended treatment is R0 resection with adequate lymphadenectomy to provide at least 6 lymph nodes for adequate staging.¹ Guidelines recommend staging laparoscopy in cases of high CA 19-9 levels or when there is evidence of vascular invasion on imaging.¹⁷ Long-term outcomes after resection in patients with iCCA showed median OS of 43.2 months with a solitary iCCA versus 21.2 months in those with 2 tumors and 15.3 months in those with ≥3 tumors. Five-year survival with 1, 2, and 3 lesions was 43.3%, 28.0%, and 8.6%, respectively.¹⁸

On the other hand, patients with pCCA mostly present with obstructive jaundice and 15% present with peritoneal metastatic disease. Thus, staging laparoscopy is recommended in patients with pCCA before laparotomy.¹⁹ High preoperative bilirubin level is a major risk factor for postoperative morbidity and mortality, with a cutoff value of 2.5 mg/dL and 6.2 mg/dL for morbidity and mortality, respectively.²⁰ Liver volume modulation to increase size of future liver remnant (FLR) may also be needed. In a propensity score-matched analysis, lower incidences of liver failure, biliary leakage, abscess formation, and 90-day mortality were shown in patients treated with portal vein embolization before major liver resection (LR) for pCCA.²¹ The usual surgical treatment for pCCA includes biliary drainage of FLR (via percutaneous transhepatic biliary drainage or endoscopic biliary drainage to improve liver function and prevent posthepatectomy liver failure), followed by extended hepatectomy with caudate lobectomy and en bloc resection of the extrahepatic bile duct and regional lymph nodes. Surgery can offer a 5-year survival rate of 20% to 40% after R0 resection, which decreases to 0% with R1 resection.⁷

As experience with liver transplant is increasing, the acquired expertise of vascular reconstruction is finding its way into extensive hepatectomies, where portal vein and hepatic artery resections and reconstruction to achieve R0 resection in pCCA is increasingly employed, especially in Bismuth type IV tumors.²² Increased morbidity, mortality associated with vascular resections, and risk of posthepatectomy liver failure remain the Achilles heel of surgical treatment of pCCA. Five to 20% of resected, presumed pCCAs, turn out to be negative on histopathological assessment and turn out to be benign biliary strictures due to chronic inflammation in the setting of IgG4 disease or PSC.^7,23

Intrahepatic Cholangiocarcinoma

Approximately 2% to 5% of all intrahepatic neoplasms in the presence of parenchymal liver disease may be CCA or mixed HCC-CCA.²⁴ Currently, iCCA is a contraindication for LT, and surgical resection remains the mainstay of treatment. Given larger sizes at presentation, major hepatectomy is required to achieve negative margins in 70-80% patients.⁷ Diffuse bilobar involvement, underlying parenchymal liver disease, and inadequate FLR preclude resection in liver-restricted iCCA, although this presentation may in the future become an accepted indication for LT. Adjunct modalities for liver volume manipulation, including portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), make some patients resectable in event of inadequate FLR. Survival rates are better with anatomic resection than with nonanatomic resection (nonanatomic resection was associated with worse disease-free survival and OS than anatomic resection [hazard ratio (HR) 1.461 and 1.488]) and with lymphadenectomy even in clinically node-negative patients.^25,26 Indeed, adequate lympha-denectomy with at least 6 lymph nodes excised is now recommended by the National Comprehensive Cancer Network, the International Liver Cancer Association, and the eighth edition of the American Joint Committee on Cancer staging manual.⁷

In the historic series of LR for iCCA published in 2001, the overall resectability rate for preoperatively deemed resectable tumors was 62%, median survival after LR was 34 months, 3-year survival was 55%, and recurrence rate was 61% at median of 12.4 months.27 Remnant liver was the most common site of recurrence followed by retroperitoneal or hilar nodes, lung, and bone. Resection of iCCA with major venous structures, including inferior vena cava and portal vein branches, was not associated with inferior survival (median recurrence-free survival of 14.0 vs 14.7 months; median OS of 33.4 vs 40.2 months) compared with resection without vascular involvement.²⁸ However, transplant may result in improved recurrence rates by eliminating the local seeding and removing the field change.

Le Roy and colleagues showed that locally advanced iCCA can be resected after downstaging with neoadjuvant chemotherapy (mostly gemcitabine-based) with results comparable to upfront surgery for initially resectable disease (median survival with neo-adjuvant chemotherapy and surgery was 24.1 months vs 25.7 months for upfront surgery).²⁹ Survival after LR in pCCA was lower, with OS of ~50 months.¹ As evidence emerges for most solid-organ malignancies, neoadjuvant chemotherapy is the way forward toward achieving better outcomes.

Paving the Way for Liver Transplant for CCA

The long learning curve for improved survival
Even surgical resection, the only option with curative intent, has a dismal OS of ~50 months, with 60% recurrence rate.1 In a 34-year review of hepatectomies for pCCA, Nagino and colleagues reported excellent survival (67.1% at 5 y in their latest group, as experience grew) for completely excised pCCA without pathologically positive lymph nodes.30 Overall disease-free survival was 32.5% at year 5 and 19.9% at year 10. Survival in pN1 patients was 21.1%. However, these excellent results from Japan have not been consistently reproduced in Western countries. This and other studies highlighted improved survival of patients as experience of teams has grown over 3 decades, which can have repercussions for setting up new centers.^23,30

Poor locoregional control translates to high recurrence rates
Recurrence after curative intent resection of iCCA has been reported as high as 74% (23.8% recurred only intrahepatically, 35.6% of patients had locore-gional recurrence, and 40.6% of patients had distant metastasis).³¹ Periductal-infiltrating growth pattern, tumor size >5cm, lymph node involvement, and vascular invasion were independent risk factors for recurrence after liver resection. Similarly, for pCCA, locoregional recurrence is the commonest variety.¹ Kobayashi and colleagues reported a recurrence rate of 53% after R0 resection for pCCA; 10% were locoregional recurrences, but 43% were distant metastases.³²

Adjuvant Chemotherapy: An Attempt to Improve Survival

Frequent postresection relapse mandates enquiry into the efficacy of neoadjuvant or adjuvant chemotherapy. Three phase III randomized clinical studies have been reported; in all of the studies, patients with resected biliary tract cancer (CCA and gallbladder cancer) were randomly assigned to observation alone or chemotherapy.^33-35 The chemotherapy arm was gemcitabine in the BCAT study, gemcitabine and oxaliplatin in the PRODIGE-12 study, and capecitabine in the BILCAP study. In total, 896 patients were randomly assigned in these studies. Although the BCAT and the PRODIGE-12 study did not show a benefit from gemcitabine-based chemotherapy, the BILCAP study showed a benefit from adjuvant capecitabine compared with observation alone, in terms of OS (HR = 0.71); however, the intention-to-treat OS analysis showed no difference. The BILCAP study did show a benefit in favor of capecitabine in terms of relapse-free survival (HR = 0.75). On the basis of the partial benefits reported in the BILCAP trial, international guidelines currently recommend adjuvant capeci-tabine for 6 months following curative resection of CCA as the current standard of care.³⁶ The role of adjuvant chemoradiotherapy remains unclear and might be of benefit in patients with pCCA or dCCA with microscopic positive surgical margins (R1). Ongoing studies are evaluating the role of combination chemotherapy such as cisplatin and gemcitabine (ACTICCA-1 trial; ClinicalTrials.gov identifier NCT02170090) in the adjuvant setting.

Current Evidence of Improved Survival With Liver Transplant

The high rate of locoregional recurrence even after R0 resection may be because of local microscopic seeding, field change, or microscopic intrahepatic spread. Liver transplant, which aims to remove the field change and avoid local seeding during resection, may allow attainment of negative margins, thus becoming the logical next step. Liver transplant can solve several surgery-related issues (positive margins, inadequate FLR) and can also treat any underlying PSC. Despite the sound rationale , initial results of LT for CCA have not been encouraging.

Perihilar Cholangiocarcinoma

In the United States, 207 patients underwent LT for CCA between 1968 to 1997. The data from the Cincinnati Transplant Tumor Registry showed a 5-year survival rate of 23% with a tumor recurrence rate of 51% (84% within the first 2 years). Forty-seven percent of recurrences occurred in the allograft and 30% in the lungs. Survival after recurrence was <1 year, and no advantage in survival was detected in patients with CCA and PSC, in patients with incidental tumors, or in patients receiving adjuvant chemotherapy.³⁷ European centers have reported recurrence rates of ~50% and 3-year survival rate of ~30%.^38,39 However, most patients with pCCA in the Spanish study were surgically unresectable which have no 5 year survival with any other treatment.³⁸ Even CCA incidentally found in liver explants portended a similar prognosis, with 3-year survival of 30%, and 26 months median time to recurrence in a multicenter Canadian study.⁴⁰

A breakthrough treatment was reported in 2004 when superior results (82% 5-year survival for 28 patients) were shown with LT for unresectable pCCA following pretransplant chemoradiotherapy per the Mayo protocol.^41,42 The Mayo protocol (Figure 1), developed in 1993, was based on the University of Nebraska-pioneered strategy of high-dose neoadju-vant brachytherapy and 5-fluorouracil followed by LT. After selection per criteria, patients underwent neoadjuvant therapy comprising external-beam radiotherapy (EBRT; 30 fractions twice daily for 3 weeks for a total dose of 4500 cGy) with a continuous infusion of 5-fluorouracil administered for the duration of the EBRT. Patients are given high-dose brachytherapy administered intraductally through transcatheter iridium-192 seeds inserted during ERCP. Patients then take oral capecitabine (2000 mg/m² of body surface area) until transplant. Near the time of transplant, patients receive hand-assisted laparoscopic staging operation with a biopsy of any suspicious lesions and periportal lymph nodes to exclude metastasis.⁵

In an update to initial results, overall 5-year survival posttransplant was 73% (79% for patients with underlying PSC and 63% for those with de novo CCA); 18% of patients developed recurrence at a mean interval of 25 months posttransplant.⁴¹ Factors identified for poor outcomes were older patient age, prior cholecystectomy, CA-19.9 >100 mg/mL at the time of transplant, visible mass on cross-sectional imaging, long wait time, residual cancer >2 cm in explant, high tumor grade, and perineural invasion.⁴¹ These promising results were followed by a multicenter retrospective study in 216 patients with early-stage, unresectable pCCA treated with neoadjuvant chemoradiotherapy followed by LT in 12 centers in the USA with encouraging 5-year disease-free survival of 65%. In the study, there was an 11.5% dropout rate at 3 months for patients awaiting LT. The OS after LT at 1, 3, and 5 years was 91%, 81%, and 74%, respectively, intent-to-treat 5-year survival rate was 53% at 5 years, and recurrence-free survival rates were 78% and 65%, respectively, at 2 and 5 years.⁴³ Furthermore, patients with PSC had a higher 5-year survival rate than patients with de novo pCCA (80% vs 64%). Recurrence occurred in 17% of patients, and patients with de novo pCCA showed lower survival after LT (63%) than those with background of PSC (79%). Thus, differences in survival between resection and neoadjuvant therapy and transplant are less marked in de novo CCA than in those with underlying PSC, which may be attributed to early detection of CCA in patients of PSC due to close monitoring.

Following the Mayo protocol, a team in Dublin reported on their 27 pCCA patients, 20 of whom were transplanted. Although the perioperative mortality was high at 20%, the 1-year and 4-year survival rates were 94% and 61% among those who survived the peritransplant  period.⁴⁴ Interestingly, the team performed pancreatoduodenectomy in 30% of their patients (half of whom died in the perioperative period). Three patients needed a retransplant for vascular complications.

A recent report of Mayo clinic experience of LT for pCCA showed a dropout rate of 14%, which was same for de novo pCCA and that on background of PSC.⁵ However, 26% of patients with de novo pCCA could not have a transplant procedure because of advanced disease at surgical staging, compared with 14% with PSC-related pCCA. Among the 237 transplants in patients with pCCA, the intention-to-treat analysis revealed a 5-year survival rate of 68% ± 3% and survival rate of 60% at 10 years. Recurrence rate was 22% in the PSC group versus 45% in the de novo group, indicating poor survival outcomes in the de novo group. Average time to recurrence was 26 months from transplant. Patient survival in the de novo group at 5 and 10 years was 58% ± 6% and 47% ± 6% compared with 74% ± 4% and 67% ± 4% in the PSC group.⁵

In a retrospective analysis that compared resection versus LT in patients with pCCA,⁴⁶ 1 of 5 of patients deemed resectable could only achieve R2 resection and one-third of patients enrolled for LT dropped out. Compared with curative intent resection, LT recipients had improved OS (72% vs 33% at 3 years and 64% vs 18% at 5 years).Transplant remained associated with improved survival on intention-to-treat analysis, even after accounting for tumor size, lymph node status, and PSC. Of note, transplant recipients were younger (52 vs 65 years), more frequently had PSC (61% vs 2%), and received chemotherapy and/or radiation (98% vs 57%). However, this was only a retrospective study comparing resected patients with transplanted (ie, unresectable) patients. Also to date, there are no randomized controlled trials comparing LR to LT.

Factors associated with recurrence after LT in pCCA are tumor size >3 cm, portal vein encasement, transperitoneal biopsy of tumor, and absence of oral capecitabine therapy before transplant.⁵ Presence of residual tumor on explant pathology is also associated with higher rate of recurrence.⁴⁵ Histological grade of differentiation of residual tumor is not associated with recurrence risk, but perineural invasion is.⁴⁵ Further analysis showed similar risk of disease recurrence for PSC and non-PSC patients when controlled for risk factors such as size of the tumor, CA 19-9 level, portal vein encasement, and amount of residual tumor in the explant. Thus better survival in the PSC-related group is a result of earlier diagnosis in the PSC group as a result of active surveillance programs.

Liver Transplant for Intrahepatic Cholangiocar-cinoma

Given the poor long-term outcomes after LR even after neoadjuvant chemotherapy in iCCA, LT becomes the next logical frontier to explore. However, data remain rudimentary, and initial results have been quite disappointing, with 2-year survival of just 40%.7 Recent studies that addressed outcomes of transplant recipients who were incidentally found to have iCCA on explant histology are more encouraging, with 1-, 3-, and 5-year actuarial survival rates of 100%, 73%, and 73%, respectively, in those with tumors ≤2 cm.^46,47 A study on incidentally found iCCA and HCC-CCA in explants found survival similar to controls, if iCCA was uninodular with size <2 cm but worse than controls in cases of multinodular tumors or when tumor size was >2 cm.⁴⁷ This was clearly not the regular population of iCCA, where mean tumor diameter at diagnosis is 6 cm. Living donor LT (LDLT) for HCC, where explant showed iCCA or HCC-CCA, resulted in 1-, 5-, and 10-year OS and disease-free survival rates for patients with HCC-CCA of 87.5%, 72.9%, and 48.6% and 85.7%, 85.7%, and 85.7%, respectively, which were not statistically different from those with HCC within Milan criteria.⁴⁸

Living donor LT is an acceptable alternative to deceased donor LT for HCC. The largest report for iCCA and hCCA included 11 patients and reported a 3-year recurrence-free survival (RFS) of 46.7%.⁴⁹ A similar study from Pakistan on LDLT for iCCA or HCC on 13 patients showed 46.1% had recurrence in the follow-up period, with bone and the graft as the most common sites of recurrence. The overall 3-year RFS was 47% but 64% for well- to moderately differentiated tumors.⁵⁰

Of note, earlier series did not select patients on the basis of response to chemotherapy and disease trajectory. Indeed, there is growing acceptance that most malignancies have shed some tumor cells in the periphery by the time of diagnosis and some form of chemotherapy is essential for sustained tumor-free survival. Encouraged by positive results of LT for properly selected patients of pCCA, a potential efficacy was shown with LT in patients with biologically responsive iCCA who have had sustained tumor stability or regression with neoadjuvant therapy.⁵¹ Neoadjuvant chemotherapy for iCCA followed by LT showed improved survival with neoadjuvant chemotherapy followed by LT versus either LR or LT without neoadjuvant therapy.⁵² Encouraging results were shown in small case series of 6 patients with iCCA in noncirrhotic livers who under went LT following platinum- and gemcitabine-based chemotherapy.51 Patients were initially unresectable and were offered LT after 6 months of radiologically stable disease on platinum-based chemotherapy. Overall survival was 100% at 1 year, 83% at 3 years, and 83% at 5 years; 50% of patients developed recurrent disease at a median of 7.6 months (interquartile range, 5.8-8.6 mo) posttransplant, with 50% recurrence-free survival at 1, 3, and 5 years. Similar encouraging results were reported by Wong and colleagues.⁵³ These studies allude that disease stability after neoadjuvant therapy can select patients with favorable biology who will benefit from LT.

More recent reports have shown favorable outcomes of LT for iCCA in patients with tumor diameters exceeding 2 cm. In a French multicenter retrospective study from 2020, patients undergoing LT or resection for iCCA and mixed iCCA-HCC were compared, with a secondary objective to evaluate outcomes of patients with tumors diameters >2 cm and <5 cm.54 Among 49 patients who had LT for end-stage liver disease or HCC versus 25 patients undergoing resection, explant pathology after transplant showed iCCA in 24 patients (49%) and mixed iCCA-HCC in 25 patients (51%). Thirty-three patients (63%) had pretransplant locoregional therapy, which was most commonly transarterial chemoembolization. Among patients who had resection, none had neoadjuvant treatment, but 2 had adjuvant chemotherapy. Results showed OS at 1, 3, and 5 years of 90%, 76%, and 67% for transplant patients compared with 92%, 59%, and 40% for patients who had liver resection (P=.165). At 1, 3, and 5 years, RFS was 87%, 79%, and 75% for transplant patients and 69%, 45%, and 36% for patients who had liver resection (P=.004). In the subgroup analysis of transplant patients with tumor size between 2 and 5 cm versus patients with tumor diameter≤2 cm, comparable 5-year OS rates were shown (65% and 69%; P = .4) between groups, respectively, with statistically similar RFS for groups (P = .43).55 The factor most prognostic of recurrence or death on multivariate analysis was tumor differentiation (HR = 3.47 and 3.23; P = .001).

Although a lot of enthusiasm is building around these findings, they do not represent real-life situations where most iCCA are large tumors. A multicenter prospective trial (NCT02878473), started in 2018, aims to recruit 30 participants and to look at survival post-LT in very early-stage(<3 cm) iCCA in cirrhotic patients. The early results are projected to be available in 2026.⁵⁶ Although again not the common real-world situation, the study hopes to shed light on feasibility of LT for iCCA.

Several challenges exist for more widespread adoption of LT for iCCA. Difficulty in obtaining grafts for these patients primarily stems from nonacceptance of iCCA as an indication for LT. Furthermore, patients with iCCA often have a low laboratory Model for End-Stage Liver Disease (MELD) score and are not awarded exception points for iCCA. Validation of positive outcomes of LT will justify policies to facilitate deceased donor LT for iCCA. Living donor LT may be appropriate for patients with iCCA who have a positive response to neoadjuvant chemotherapy. As seen for pCCA, neoadjuvant chemotherapy followed by LT improved overall and RFS quite significantly. Given the poor survival after LR and good results in unresectable tumors with downstaging by neoadjuvant chemotherapy followed by LT, it may be time to consider LT for resectable iCCA after neoadjuvant chemotherapy. The rarity of donor livers may mean that this option is more viable in countries where LT is from living donors, reducing waiting times and possibly improving survival.

Decision of Resectable Versus Unresectable Tumor

One of the biggest challenges facing physicians attempting to transplant any oncology patient is the decreased immunosurveillance from the use of required immunosuppression post-LT, leading to high rates of recurrence. This made selecting the right patient even more difficult in an era where little information was available on tumor markers and biology. Changing patterns of disease, especially effective treatment for HCV, have resulted in decreased predictive value of current allocation scoring systems. Analysis of predictive value of MELD and MELD-Na to predict 90-day waitlist mortality has shown that MELD score concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015.⁵⁷ Milan criteria has been used for 26 years to assess transplant candidacy for patients with HCC and is used in ~95% of transplant centers worldwide. Despite this, there is a growing interest in its modification as new insights into tumor biology and utility of bridging therapies are made.⁵⁸ The same is true for CCA. The growing body of knowledge with development of chemoradiotherapy protocols need an update of our policies to consider candidacy for LT for CCA patients. In fact, selection represents the only variable that acts as an independent predictor of outcome and is modifiable at the same time. By adjusting selection alone, 5-year recurrence-free survival can be maximized.

As seen above, survival among LT recipients for pCCA is similar to that for other malignant neop-lasms. Studies showed 1-year and 5-year recipient survival rates after LT for malignant conditions between 2008 and 2015 of 91% and 69%, respectively (same duration survival in UK is 92% and 72%).⁵⁹ Given the proven superiority of transplant following neoadjuvant chemoradiation in improving survival in unresectable pCCA and high recurrence rate after resection in resectable disease, the argument opens for transplant of patients with resectable disease. The extremely limited supply of liver allografts and the need for life-long immunosuppression are important obstacles to this strategy.

Pitfalls in diagnosis remain the major argument against LT for pCCA. It is known that ~15% of patients who undergo LR for suspected pCCA have a benign biliary stricture rather than pCCA.⁶⁰ It remains a query of whether there no tumor in first place or it disappeared because of excellent response to chemoradiotherapy. There is indeed marked differences in 5-year survival (66% with a pathological diagnosis versus a 92% in the unconfirmed pathology subgroup).⁴³ Poor diagnostic accuracy is the main criticism of the Mayo protocol. Since transperitoneal biopsies exclude from LT candidacy, diagnosis rests on ERCP/spy glass brushings, cytology, and FISH. If these tests are negative but radiological findings support CCA diagnosis, patients are candidates for LT. In half of patients, a pathological diagnosis is not made before neoadjuvant therapy and half of the explanted livers do not have residual CCA at pathological evaluation after LT. Among patients who undergo LR for suspected pCCA, 15% to 20% are diagnosed with a benign biliary stricture. Unpublished results from the Mayo Clinic have shown that approximately half of the patients transplanted for CCA did not have pathologic confirmation of disease before administration of neoadjuvant therapy. Over 40% had residual CCA in the explanted liver compared with 60% residual disease in those patients with pathologically confirmed disease. Most importantly, the CCA recurrence rates were the same for patients with and without pathological confirmation before the start of therapy. Thus, the absence of a pathological diagnosis in some patients does not indicate that inclusion of patients with a misdiagnosis of CCA leads to an artificial improvement in survival.⁴¹

The Mayo Clinic has also reported that survival after LT in patients with unresectable CCA or CCA arising in the setting of PSC exceeded survival in patients who underwent resection.⁴¹ Transplantation affords a more radical extirpation of CCA than resection, and the procedure is technically feasible despite aggressive neoadjuvant therapy. Neoadjuvant therapy and LT for unresectable CCA achieve results similar to transplant for other chronic liver diseases (ie, hepatitis C virus infection, PSC) and HCC. Thus, it would seem appropriate that patients with CCA be considered appropriate recipients of the scarce deceased and living donor livers. As these patients are not candidates for resection (either because of being unresectable or having underlying PSC), LT is their only opportunity for prolonged survival. Given survival benefits achieved in unresectable tumors and the high recurrence in pCCA after R0 resection, it may be time now to extend LT as a curative treatment option to patients with resectable pCCA, especially in a background of PSC or chronic liver disease.

Because LT for hCCA has shown consistent favorable outcomes in selected patients with unresectable disease, some have considered expanding LT to patients with resectable disease. In a multicenter report from 2018, outcomes of successfully resected patients who otherwise met criteria for LT (<3 cm tumors with node-negative disease) were compared with unresectable patients who underwent LT. The group undergoing LT had superior OS compared with resection (5-year OS of 64% vs 18%; P < .001).55 A multicenter randomized trial of resection versus neoadjuvant chemoradiation followed by LT is now underway to ascertain which treatment modality is superior among resectable patients (ClinicalTrials.gov no. NCT02232932).⁴

Allocation of Exception Points to Cholangiocar-cinoma

Agreeing to transplant pCCA patients then asks for award of exception points to organ allocation scoring systems to offset their apparent improved survival due to good residual liver function, which leads to long wait list times. Most current allocation systems use MELD or a variant thereof to prioritize candidates for LT. These continuous scoring systems quite accurately predict likelihood of mortality from liver failure itself in the short term. However, in malignancy, mortality from intrinsic liver disease is relatively low; rather, the malignancy itself poses a higher risk of death. The dropout rate for HCC patients was 11.0%, 57.4%, and 68.7% at 6, 12, and 18 months for patients meeting Milan Criteria. They were thus assigned a priority score of 22, meant to equate the drop out risk for HCC patients to the risk of dying from progressive liver disease defined by MELD score of 22.⁶¹ The aim was to  maintain equity in access to deceased donor livers for both HCC and non-HCC liver transplant patients while maintai-ning respectable outcomes for all recipients.

In the United States, the Organ Procurement and Transplantation Network (OPTN) allows MELD exception for unresectable pCCA, with neoadjuvant therapy protocol, and requires operative staging after completion of neoadjuvant therapy and before liver transplant. Candidates meeting the above criteria are assigned a MELD score of 3 points below median MELD at transplant. This is the same as awarded to those with HCC requiring second extension on the wait list.

With adoption of strict Mayo criteria, 10% of all patients of pCCA presenting were eligible to be included in the protocol. Overall, the 12-month dropout rate for pCCA patients from wait lists according to the Mayo protocol is 46%.²⁴ An 11.5% dropout rate after 3.5 months of therapy indicates the appropriateness of the MELD exception.⁴³ The standard MELD score exception that was designated for patients with pCCA was set to mirror that of HCC, since the actual wait list dropout risk was unknown. Most patients drop out because of tumor progression. With the incomplete understanding of tumor biology, the effect of earlier access to transplant remains unknown. Earlier access to transplant may allow transplant for some patients with adverse tumor biology who may have higher recurrence rates. A small number of patients who may die from complications of therapy such as cholangitis and liver failure, on the other hand, will be saved by a rapid access to liver transplant.⁴³

Based on evidence in 2006, the MELD Exception Study Group recommended enrolment of patients in clinical trials of liver transplantation provided the following: (1) transplant centers submit formal patient care protocols to the UNOS Liver and Intestinal Committee; (2) candidates satisfy accepted diagnostic criteria for CCA and be considered unresectable on the basis of technical considerations or underlying liver disease (eg, PSC); (3) tumor mass, when visible on cross-sectional imaging studies, be less than 3 cm in diameter; (4) imaging studies to assess patients for intra- and extrahepatic metastases be repeated before the interval score increases; (5) regional hepatic lymph node involvement and the peritoneal cavity be assessed by operative staging after completion of neoadjuvant therapy and prior to transplantation; and (6) transperitoneal aspiration or biopsy of the primary tumor be avoided because of the high risk of tumor seeding associated with these procedures.

In 2009, the UNOS Board of Directors implemen-ted these recommendations and adopted the Mayo Clinic criteria for a MELD score exception points adjustment for pCCA and on allowing adjustments every 3 months.⁴¹

In the current organ allocation system, patients with HCC and pCCA are treated in an identical fashion in terms of receiving MELD exception points. However, a recent study focused on wait list dropout and posttransplant graft survival rates for both HCC and pCCA based on the Scientific Registry of Transplant Recipients (SRTR). When matched for the OPTN region and listing date, patients with pCCA had a significantly higher wait list dropout rate (6- and 12-month dropout rates of 13.2% and 23.9%, respectively) than patients with HCC (6- and 12-month drop-out rates of 7.3% and 12.7%, respectively).⁶² Furthermore, transplants for pCCA were associated with lower rates of graft survival than with HCC (60.7% vs 81.6% at 3 years, respectively).⁶²

The picture is not uniform globally. A recent analysis from the Netherlands reported on retros-pective cohort of pCCA patients and concluded only about 5% of patients presenting with pCCA in a tertiary European setting would be eligible for the Mayo LT protocol; however, treatment had potential to increase the expected survival from less than 1 year to 5-year OS of 53%.⁶³ Within the Eurotransplant region, awarding of exception points for CCA is country specific, with the Netherlands and Belgium awarding no points but Croatia, Germany, and Austria awarding exception points. In the United Kingdom, in the era of transplant benefit score, the allocation policy may undergo some radical changes. A rethink is needed to improve access of patients with pCCA to deceased donor LT, and an increase in MELD exception points compared with patients HCC may be needed. With the uncertainty of receiving a deceased donor LT offer, patients may be best served by a LDLT.

Option of Living Related Transplant

In a Mayo clinic report on LDLT for pCCA according to the Mayo protocol, LDLT for pCCA comprised 30% of total LDLT procedures. Presentation of early hepatic artery thromboses was similar to other indications (5.4% vs 7.6%); however, late hepatic artery (18.9% vs 4.1%) and portal vein (37.8% vs 8.7%) complications were more common in the pCCA group. Recurrence rate was 12.3%, and OS rates at 1, 5, and 10 years were 84.9%, 66.5%, and 55.6%, respectively.⁶⁴

Transplanting for Cholangiocarcinoma: The Technicalities

Transplanting patients using the Mayo protocol has its operative challenges. Dissection is difficult in the irradiated porta and can endanger vascular anastomoses. Transacting vessels and bile duct lower down, near the duodenum, avoids the most heavily irradiated part of hilum and at same time may minimize risk of tumor seeding. Radiation injury is usually progressive over time, and patients transplanted for hCCA have a higher rate of late hepatic artery thrombosis and portal vein complica-tions compared with patients without hCCA. Liver transplant after extensive chemoradiotherapy per the Mayo protocol is associated with high rates of vascular complications (18.9% vs 4.1%; P < .001, and 37.8% vs 8.7%; P < .001, respectively).⁶⁴ Operative strategies to mitigate postradiation complications may include the use of vascular conduits and Roux-en-Y biliary reconstruction to avoid using irradiated structures in the porta.

Vision of the Future

Cholangiocarcinomas are highly heterogeneous at both the intertumoral and intratumoral levels and have a poor prognosis. The high heterogeneity and chemoresistance of CCAs represent a limitation for common therapeutic strategies, but offers a unique opportunity for personalized, targeted therapies. As we gain knowledge of iCCA subgroups and molecular therapeutics, the decision to pursue LT for patients will be informed by a more precise understanding of tumor biology.⁴ Liver transplant has become an accepted indication of pCCA, and reducing the dropout rate and preventing recurrence remain the major areas needing improvement. A more individualized approach to neoadjuvant therapy, such as higher radiotherapy dose for patients with de novo pCCA (where native tissue may better tolerate more radiotherapy, as it is not injured by chronic inflammation of PSC), may improve outcomes and reduce dropout rates at staging. A better understanding of tumor biology with advancement in diagnostic modalities for presence of occult metastasis, such as detection of circulating cell-free DNA analysis by next-generation sequencing or cell-free DNA methylation assays, may help identify those  at higher risk of recurrence. Further strategies are needed to accurately identify and predict the biologic behavior, response, and sensitivity to neoadjuvant chemoradiation and the true extent of pCCA. Clearly, for patients with perihilar disease, we need better neoadjuvant therapies. Molecular analysis of tumors combined with precision or targeted therapies may allow more effective neoadjuvant therapy and improve outcomes and expand the group of patients who may benefit from LT for pCCA. For patients with iCCA, a better understanding of effectiveness of local regional therapy and its effect on outcomes after LT is needed.

Conclusions

We emphasize that the decision to resect or transplant is critical and must be made before any therapy is pursued, because the initiation of one approach excludes the other. Patients who have undergone a resection attempt with dissection of the hilum of the liver cannot be considered for LT, as the tumor plane has been violated, leading to a high chance of seeding. Similarly, patients who have undergone chemoradiation treatment in anticipation of LT cannot undergo resection due to the degree of inflammation and damage sustained by the perihilar area. In summary, the diagnosis, staging, and management of pCCA require thoug-htful multidisciplinary approaches consisting of expert hepatologists, advanced endoscopists, pathologists, and hepatobiliary/transplant surgeons. Liver transplant is a promising treatment modality with excellent outcomes in properly selected individuals and should be pursued; more research is needed for better selection of the patients who will benefit the most.

Figure 1. Flow chart of the Presentation, Management, and Outcome of Patients With Cholangiocarcinoma, According to Current Evidence and Guidelines

Table 1. Mayo Clinic Protocol for Transplanting Perihilar Cholangiocarcinoma

References:

1. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. doi:10.1038/s41575-020-0310-z
   CrossRef - PubMed
2. Razumilava N LK, Gores GJ. Chapter 47: Cholangiocarcinoma. In: Zakim and Boyer’s Hepatology. Elsevier; 2018:693-707.e4.
   CrossRef - PubMed
   
3. Fan B, Malato Y, Calvisi DF, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122(8):2911-2915. doi:10.1172/JCI63212
   CrossRef - PubMed
   
4. McMillan RR, Saharia A, Abdelrahim M, Ghobrial RM. New breakthroughs for liver transplantation of cholangiocarcinoma. Current Transplantation Reports. 2021;8:21-27.
   CrossRef - PubMed
   
5. Azad AI, Rosen CB, Taner T, Heimbach JK, Gores GJ. Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefit from liver transplantation. Cancers (Basel). 2020;12(11):3157. doi:10.3390/cancers12113157
   CrossRef - PubMed
   
6. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95-111. doi:10.1038/nrclinonc.2017.157
   CrossRef - PubMed
   
7. Gringeri E, Gambato M, Sapisochin G, et al. Cholangiocarcinoma as an indication for liver transplantation in the era of transplant oncology. J Clin Med. 2020;9(5):1353. doi:10.3390/jcm9051353
   CrossRef - PubMed
   
8. Kendall T, Verheij J, Gaudio E, et al. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int. 2019;39 Suppl 1:7-18. doi:10.1111/liv.14093
   CrossRef - PubMed
   
9. Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol. 2010;2(12):419-427. doi:10.4254/wjh.v2.i12.419
   CrossRef - PubMed
   
10. Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM. Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol. 2014;27(8):1163-1173. doi:10.1038/modpathol.2013.241
    CrossRef - PubMed
    
11. Carpino G, Cardinale V, Folseraas T, et al. Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis. Hepatology. 2019;69(2):622-638. doi:10.1002/hep.30210
    CrossRef - PubMed
    
12. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144(4):829-840. doi:10.1053/j.gastro.2013.01.001
    CrossRef - PubMed
    
13. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-1010. doi:10.1038/ng.3375
    CrossRef - PubMed
    
14. Moeini A, Sia D, Zhang Z, et al. Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity. J Hepatol. 2017;66(5):952-961. doi:10.1016/j.jhep.2017.01.010
    CrossRef - PubMed
    
15. Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280. doi:10.1038/nrgastro.2016.51
    CrossRef - PubMed
    
16. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvise M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019;39 Suppl 1:98-107. doi:10.1111/liv.14086
    CrossRef - PubMed
    
17. Sirica AE, Gores GJ, Groopman JD, et al. Intrahepatic Cholangiocarcinoma: continuing challenges and translational advances. Hepatology. 2019;69(4):1803-1815. doi:10.1002/hep.30289
    CrossRef - PubMed
    
18. Buettner S, Ten Cate DWG, Bagante F, et al. Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma. J Gastrointest Surg. 2019;23(11):2239-2246. doi:10.1007/s11605-019-04184-2
    CrossRef - PubMed
    
19. Bird N, Elmasry M, Jones R, et al. Role of staging laparoscopy in the stratification of patients with perihilar cholangiocarcinoma. Br J Surg. 2017;104(4):418-425. doi:10.1002/bjs.10399
    CrossRef - PubMed
    
20. Wronka KM, Grat M, Stypulkowski J, et al. Relevance of preoperative hyperbilirubinemia in patients undergoing hepatobiliary resection for hilar cholangiocarcinoma. J Clin Med. 2019;8(4):458. doi:10.3390/jcm8040458
    CrossRef - PubMed
    
21. Olthof PB, Aldrighetti L, Alikhanov R, et al. Correction to: portal vein embolization is associated with reduced liver failure and mortality in high-risk resections for perihilar cholangiocarcinoma. Ann Surg Oncol. 2020;27(Suppl 3):968. doi:10.1245/s10434-020-08353-5
    CrossRef - PubMed
    
22. Abbas S, Sandroussi C. Systematic review and meta-analysis of the role of vascular resection in the treatment of hilar cholangiocarcinoma. HPB (Oxford). 2013;15(7):492-503. doi:10.1111/j.1477-2574.2012.00616.x
    CrossRef - PubMed
    
23. van Gulik TM, Kloek JJ, Ruys AT, et al. Multidisciplinary management of hilar cholangiocarcinoma (Klatskin tumor): extended resection is associated with improved survival. Eur J Surg Oncol. 2011;37(1):65-71. doi:10.1016/j.ejso.2010.11.008
    CrossRef - PubMed
    
24. Gores GJ. Liver transplantation for cholangiocarcinoma. Liver Transpl. 2015;21 Suppl 1:S32-S33. doi:10.1002/lt.24219
    CrossRef - PubMed
    
25. Si A, Li J, Yang Z, et al. Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2019;26(6):1841-1850. doi:10.1245/s10434-019-07260-8
    CrossRef - PubMed
    
26. Yoh T, Cauchy F, Le Roy B, et al. Prognostic value of lymphadenectomy for long-term outcomes in node-negative intrahepatic cholangiocarcinoma: a multicenter study. Surgery. 2019;166(6):975-982. doi:10.1016/j.surg.2019.06.025
    CrossRef - PubMed
    
27. Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg. 2001;193(4):384-391. doi:10.1016/s1072-7515(01)01016-x
    CrossRef - PubMed
    
28. Reames BN, Ejaz A, Koerkamp BG, et al. Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis. J Surg Oncol. 2017;116(2):133-139. doi:10.1002/jso.24633
    CrossRef - PubMed
    
29. Le Roy B, Gelli M, Pittau G, et al. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018;105(7):839-847. doi:10.1002/bjs.10641
    CrossRef - PubMed
    
30. Nagino M, Ebata T, Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013;258(1):129-140. doi:10.1097/SLA.0b013e3182708b57
    CrossRef - PubMed
    
31. Chan KM, Tsai CY, Yeh CN, et al. Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence. BMC Gastroenterol. 2018;18(1):180. doi:10.1186/s12876-018-0912-x
    CrossRef - PubMed
    
32. Kobayashi A, Miwa S, Nakata T, Miyagawa S. Disease recurrence patterns after R0 resection of hilar cholangiocarcinoma. Br J Surg. 2010;97(1):56-64. doi:10.1002/bjs.6788
    CrossRef - PubMed
    
33. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019;37(8):658-667. doi:10.1200/JCO.18.00050
    CrossRef - PubMed
    
34. Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105(3):192-202. doi:10.1002/bjs.10776
    CrossRef - PubMed
    
35. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663-673. doi:10.1016/S1470-2045(18)30915-X
    CrossRef - PubMed
    
36. Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO Clinical Practice Guideline. J Clin Oncol. 2019;37(12):1015-1027. doi:10.1200/JCO.18.02178
    CrossRef - PubMed
    
37. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69(8):1633-1637. doi:10.1097/00007890-200004270-00019
    CrossRef - PubMed
    
38. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg. 2004;239(2):265-271. doi:10.1097/01.sla.0000108702.45715.81
    CrossRef - PubMed
    
39. Seehofer D, Thelen A, Neumann UP, et al. Extended bile duct resection and [corrected] liver and transplantation in patients with hilar cholangiocarcinoma: long-term results. Liver Transpl. 2009;15(11):1499-1507. doi:10.1002/lt.21887
    CrossRef - PubMed
    
40. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl. 2005;11(11):1412-1416. doi:10.1002/lt.20512
    CrossRef - PubMed
    
41. Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int. 2010;23(7):692-697. doi:10.1111/j.1432-2277.2010.01108.x
    CrossRef - PubMed
    
42. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004;24(2):201-207. doi:10.1055/s-2004-828896
    CrossRef - PubMed
    
43. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143(1):88-98 e3; quiz e14. doi:10.1053/j.gastro.2012.04.008
    CrossRef - PubMed
    
44. Duignan S, Maguire D, Ravichand CS, et al. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience. HPB (Oxford). 2014;16(1):91-98. doi:10.1111/hpb.12082
    CrossRef - PubMed
    
45. Lehrke HD, Heimbach JK, Wu TT, et al. Prognostic significance of the histologic response of perihilar cholangiocarcinoma to preoperative neoadjuvant chemoradiation in liver explants. Am J Surg Pathol. 2016;40(4):510-518. doi:10.1097/PAS.0000000000000588
    CrossRef - PubMed
    
46. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016;64(4):1178-1188. doi:10.1002/hep.28744
    CrossRef - PubMed
    
47. Sapisochin G, de Lope CR, Gastaca M, et al. Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study. Ann Surg. 2014;259(5):944-952. doi:10.1097/SLA.0000000000000494
    CrossRef - PubMed
    
48. Itoh S, Ikegami T, Yoshizumi T, et al. Long-term outcome of living-donor liver transplantation for combined hepatocellular-cholangiocarcinoma. Anticancer Res. 2015;35(4):2475-2476.
    CrossRef - PubMed
    
49. Chang CC, Chen YJ, Huang TH, et al. Living donor liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma: experience of a single center. Ann Transplant. 2017;22:115-120. doi:10.12659/aot.900779
    CrossRef - PubMed
    
50. Hafeez Bhatti AB, Tahir R, Qureshi NR, Mamoon N, Khan NY, Zia HH. Living donor liver transplantation for intra hepatic cholangiocarcinoma. Ann Med Surg (Lond). 2020;57:82-84. doi:10.1016/j.amsu.2020.07.028
    CrossRef - PubMed
    
51. Lunsford KE, Javle M, Heyne K, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol. 2018;3(5):337-348. doi:10.1016/S2468-1253(18)30045-1
    CrossRef - PubMed
    
52. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg. 2011;146(6):683-689. doi:10.1001/archsurg.2011.116
    CrossRef - PubMed
    
53. Wong M, Kim J, George B, et al. Downstaging locally advanced cholangiocarcinoma pre-liver transplantation: a prospective pilot study. J Surg Res. 2019;242:23-30. doi:10.1016/j.jss.2019.04.023
    CrossRef - PubMed
    
54. De Martin E, Rayar M, Golse N, et al. Analysis of liver resection versus liver transplantation on outcome of small intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma in the setting of cirrhosis. Liver Transpl. 2020;26(6):785-798. doi:10.1002/lt.25737
    CrossRef - PubMed
    
55. Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018;267(5):797-805. doi:10.1097/SLA.0000000000002574
    CrossRef - PubMed
    
56. Liver Transplantation for Early Intrahepatic Cholangiocarcinoma. Accessed April 3, 2021. https://clinicaltrials.gov/ct2/show/NCT02878473
    CrossRef - PubMed
    
57. Godfrey EL, Malik TH, Lai JC, et al. The decreasing predictive power of MELD in an era of changing etiology of liver disease. Am J Transplant. 2019;19(12):3299-3307. doi:10.1111/ajt.15559
    CrossRef - PubMed
    
58. McVey JC, Sasaki K, Firl DJ. Risk assessment criteria in liver transplantation for hepatocellular carcinoma: proposal to improve transplant oncology. Hepat Oncol. 2020;7(3):HEP26. doi:10.2217/hep-2020-0003
    CrossRef - PubMed
    
59. National Data - OPTN. Accessed April 4, 2021. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#
    CrossRef - PubMed
    
60. Kloek JJ, van Delden OM, Erdogan D, et al. Differentiation of malignant and benign proximal bile duct strictures: the diagnostic dilemma. World J Gastroenterol. 2008;14(32):5032-5038. doi:10.3748/wjg.14.5032
    CrossRef - PubMed
    
61. Washburn K, Edwards E, Harper A, Freeman R. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant. 2010;10(7):1643-1648. doi:10.1111/j.1600-6143.2010.03127.x
    CrossRef - PubMed
    
62. Ziogas IA, Hickman LA, Matsuoka LK, et al. Comparison of wait-list mortality between cholangiocarcinoma and hepatocellular carcinoma liver transplant candidates. Liver Transpl. 2020;26(9):1112-1120. doi:10.1002/lt.25807
    CrossRef - PubMed
    
63. Vugts JJA, Gaspersz MP, Roos E, et al. Eligibility for liver transplantation in patients with perihilar cholangiocarcinoma. Ann Surg Oncol. 2021;28(3):1483-1492. doi:10.1245/s10434-020-09001-8
    CrossRef - PubMed
    
64. Tan EK, Rosen CB, Heimbach JK, Gores GJ, Zamora-Valdes D, Taner T. Living donor liver transplantation for perihilar cholangiocarcinoma: outcomes and complications. J Am Coll Surg. 2020;231(1):98-110. doi:10.1016/j.jamcollsurg.2019.12.037
    CrossRef - PubMed