Author contributions: Twohig P performed a majority of the writing, prepared the figures and tables; Peeraphatdit TB assisted in writing the manuscript, preparing figures and tables, and reviewing the manuscript; Mukherjee S designed the outline of the manuscript, provided input into writing and reviewing the manuscript; all authors approved of the final manuscript.
Corresponding author: Sandeep Mukherjee, FRCP (C), MD, Full Professor, Department of Internal Medicine, Division of Gastroenterology, Creighton University, Suite 401, Education Building, 7710 Mercy Road, Omaha, NE 68124, United States. gro.tnegela@eejrehkum.peednas
Received 2021 Apr 7; Revised 2022 Jul 12; Accepted 2021 Dec 28. Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.
Keywords: Intrahepatic cholangiocarcinoma, Perihilar cholangiocarcinoma, Liver transplantation, Immunotherapy, Chemotherapy, Transplant
Core Tip: Perihilar cholangiocarcinoma (pCCA) is an accepted indication for liver transplantation (LT) using a strict selection process and standardized neoadjuvant treatment protocol with pre-operative disease staging. Intrahepatic cholangiocarcinoma (iCCA) has historically been a contraindication for LT due to poor reported outcomes. With improved tumor detection, patient selection, and neoadjuvant treatment, recent studies have reported improved survival in iCCA patients with LT. No standardized protocol exists for the treatment of iCCA using LT. Our review analyzes the history and current literature on the treatment of pCCA and iCCA, along with gaps in knowledge and future perspectives.
Cholangiocarcinoma (CCA) is a malignant tumor that arises from the bile duct epithelium[1]. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA) with the Whipple procedure the treatment of choice for dCCA[2]. In the past 20 years, liver transplantation (LT) has evolved to become the treatment of choice for carefully selected patients with unresectable pCCA[1]. Since 2009, a standard model for end-stage liver disease (MELD) exception point is available for patients listed for LT for pCCA[3]. In addition, a clinical trial is currently studying if LT is superior to surgical resection for “resectable” pCCA[4]. For iCCA, a recent prospective study incorporating neoadjuvant chemotherapy vs chemoradiation for selected patients with locally advanced iCCA followed by LT reported 5-year survival of 83%[5]. This has increased interest in LT for iCCA and further studies are ongoing. The aim of this article is to review the current role of LT in the management of CCA, specifically pCCA and iCCA.
Surgical resection is the mainstay of CCA treatment. Predictors of poor outcomes are size, positive margins, multiple lesions, and nodal metastasis[1]. However, resection is not always possible due to either large size or underlying cirrhosis and recurrence is common leaving LT as a possible option.
CCA is diagnosed with a dominant stricture on cholangiography and one or more of the following criteria positive cytology by endoscopic brushing or biopsy, fluorescence in situ hybridization polysomy, or elevated carbohydrate antigen 19-9 > 100 U/mL in the absence of cholangitis[1,6,7]. iCCA is commonly diagnosed with magnetic resonance imaging or computed tomography which demonstrates peripheral rim arterial phase enhancement followed by centripetal hyperenhancement on venous/delayed phase[2,8]. However, controversy exists surrounding the diagnosis of CCA given the frequency of incidentally found CCA that was suspected to be hepatocellular carcinoma (HCC) pre-operatively[8]. Biopsy may be required to differentiate CCA from HCC, but this carries a risk of tumor seeding.
The treatment and prognosis of CCA is dependent on its location along the biliary tree and likelihood of being completely resected with negative margins[9-11]. Surgical resection has been well-established as the standard treatment of CCA. Advances in surgical technique have improved outcomes in CCA patients over the past 20 years due to: (1) Extending the tumor resection to the hepatic parenchyma including caudate lobe, extended R-sided resection; (2) Extending tumor resection to the pancreatic head; (3) Performing vascular resections; (4) Performing lymphadenectomy to remove lymphatic pathways that may disseminate disease; and (5) Preoperative biliary drainage[1]. With complete resection and negative margins, 5-year survival rates are approximately 40%[1]. However, up to 70% of patients with hilar CCA are inoperable because of the extent of disease at presentation, therefore have a 5-year survival of 0%[2].
Historically, pCCA was a contraindication to LT. In the 1980s and early 1990s, LT was performed for pCCA in both Europe and the United States, but 5-year survival was 25%-30% with recurrence occurring in up to 60%[12]. The Mayo Protocol for pCCA was subsequently developed in 1993 and is outlined in Figure Figure1. 1 . With a 55% 5-year survival with LT, this has become the standard of care for LT in pCCA[13]. Downsides of this protocol were radiation-related injury which could affect surgery and the higher rates of vascular complications resulting in a greater need for vascular grafts[1]. Despite these difficulties, refining surgical and neoadjuvant protocol techniques have led to better long-term outcomes with survival increasing to 65% at 5 years and 59% at 10 years[14-16]. Since the development of the Mayo protocol in 1993, multicenter studies have validated this protocol and reported 5-year survival of 53%[16]. In 2002, Sudan et al[17] reported their experience with a neoadjuvant treatment protocol — using brachytherapy and 5-fluorouracil prior to LT for pCCA, this single center study reported a 45% survival over a median follow-up of 7.5 years[17]. Figure Figure2 2 illustrates the history of LT for pCCA. Subsequent studies have highlighted the improved overall survival (OS) of patients undergoing LT vs surgical resection, with age and comorbidity-matched patients having better outcomes with LT (3 and 5-year survival 72% vs 33% and 64% vs 18%, respectively)[18,19].
Mayo clinic protocol for neoadjuvant chemoradiation and staging laparoscopy prior to liver transplantation. Gy: Gray units of ionizing radiation; 5-FU: 5-Fluorouracil.
