Shu-Sen Zheng , Zhe Yang , Yi-Chao Wu

a Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China

b National Clinical Research Center of Infectious Diseases, Hangzhou 310003, China

c Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Cholangiocarcinomas are categorized as intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA) [1] . iCCA and pCCA are the second most common primary hepatobiliary malignant neoplasms [1,2].Most patients with iCCA and pCCA have asymptomatic clinical course, highly aggressive nature and dismal prognosis [3] . Complete surgical resection offers the best possibility of long-term survival but only a minority of patients are amenable to R0 resection [4] . Tumor involvement of segmental bilateral intrahepatic bile duct, inadequate remnant liver volume or hepatic functional reserve due to underlying chronic liver disease, are key factors limiting the resectability of iCCA and pCCA. Liver transplantation(LT) provides an option for patients with unresectable iCCA and pCCA [4] .

Historically, the long-term survival of LT for iCCA or pCCA is discouraging. In order to achieve better outcomes, standardized patient selection and rigorous screening of patients suitable for transplantation is essential. A retrospective international multicenter study [5]first demonstrated that patients with a single iCCA＜2 cm (defined as “very early”iCCA) had a 5-year overall survival of 65% and a 5-year cumulative recurrence of 18%. Therefore, “very early”iCCA patients with liver cirrhosis who are not candidates for surgery might become candidates for LT. Another retrospective study [6] from Hong Kong, China enrolled nine LT patients with incidental iCCA and their 5-year overall survival was 77.8%, significantly better than those who received hepatectomy. Implementation of neoadjuvant chemoradiotherapy and adjuvant therapy have been reported in certain transplant centers to improve the efficacy of LT in patients with advanced iCCA [7-10] . In a retrospective analysis in UCLA, patients who received both neoadjuvant and adjuvant therapy had higher recurrence-free survival rates compared to patients with only adjuvant therapy or no adjunctive therapy [8] . A prospective case-series in USA, six patients with locally advanced iCCA were treated with neoadjuvant chemotherapy followed by LT, with 5-year overall and recurrence-free survival of 83.3% and 50%, respectively [9] . Wong et al. [10] conducted the first prospective study to show successful pretransplant downstaging of unresectable locally advanced iCCA and pCCA, which met the criteria of tumor size ≤3.5 cm for pCCA or ≤8 cm for iCCA,and regional lymphadenopathy but absence of distant metastasis.Neoadjuvant therapy followed by transplantation in highly selected patients could achieve acceptable short-term recurrence-free survival, with 1-year post-transplant survival of 80% [10] . In this regard, selected patients with “l(fā)ocally advanced”iCCA who can achieve successful downstaging and effective control of tumors on neoadjuvant systemic chemotherapy can benefit from LT.

Before the establishment of strict selection criteria or administration of neoadjuvant treatments for pCCA, the long-term outcome after LT was essentially poor, with 5-year survival rate of only 30% [11] . In 2004, Heimbach et al. [12] proposed Mayo Clinic multimodal neoadjuvant chemoradiotherapy protocol, which included introduction of external beam radiation therapy together with intravenous 5-fluorouracil, and then followed by intraluminal brachytherapy and finally oral capecitabine treatment while awaiting LT. The neoadjuvant chemoradiotherapy group reported excellent long-term recurrence-free survival by strict preoperative staging followed by LT. A recent systematic review and metaanalysis [13] compared the outcome between LT and resection for pCCA. There was a trend towards superior survival outcome after receiving neoadjuvant chemoradiotherapy and strict LT selection criteria in comparison with resection, with this advantage became obvious at 3 years after LT. Another focus point is whether the favorable outcome of pCCA after LT should be contributed to the successful downstage and neoadjuvant chemoradiotherapy or to the strict selection criteria. Mayo Clinic selection criteria of LT for pCCA was introduced, fulfilling tumor size＜3 cm, absence of distant metastases and negative regional lymph nodes metastases.Recently, the European Liver Transplant Registry (ELTR) retrospectively analyzed the long-term survival of patients who met the strict Mayo Clinic criteria, but had not received neoadjuvant chemoradiation therapy. The 5-year survival in patients fulfilling Mayo Clinic criteria was 59%, which is comparable to patients who had undergone pretransplant chemoradiation therapy [14] . In this regard, with strict recipient selection for pCCA, improved survival after transplantation can also be achieved.

Herein, we summarize the current research progresses in LT for iCCA and pCCA. For patients with unresectable proximal cholangiocarcinoma in the background of chronic liver disease, LT could provide acceptable long-term survival when fulfilling strict Mayo Clinic criteria, as well as after successful neoadjuvant chemoradiation therapy. The effort s evolved into multicenter clinical trials and establishment of standardized recipient selection criteria need further study. With the development of multi-omics technologies, an integrated approach to identify genomic features of cholangiocarcinoma and classify different molecular subtypes has important implications for the precise selection of transplant recipients [15] . On the other hand, frequent monitoring and follow-up should be paid more attention to pursue long-term overall survival after LT. Faced with recurrent tumor after LT, whole genome analysis could characterize the genomic landscape and potentially actionable molecular aberrations of cholangiocarcinoma. Therefore, surgical resection, interventional treatment, molecular targeted therapy or immunotherapy can be selected precisely. In the era of “Transplant Oncology”, therapy-guided selection criteria in combination with tumor morphological, pathological and molecular biological feature are also needed.

CRediT authorship contribution statement

Shu-Sen Zheng:Conceptualization, Writing - review & editing.Zhe Yang:Writing - original draft, Writing - review & editing.Yi-Chao Wu:Data curation, Writing - original draft.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.