Journal of Clinical Medicine Review Cholangiocarcinoma as an Indication for Liver Transplantation in the Era of Transplant Oncology 1, 2, , 3 3 Enrico Gringeri y , Martina Gambato * y , Gonzalo Sapisochin , Tommy Ivanics , Erica Nicola Lynch 2, Claudia Mescoli 4, Patrizia Burra 2 , Umberto Cillo 1 and Francesco Paolo Russo 2 1 Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, 35100 Padua, Italy; [email protected] (E.G.); [email protected] (U.C.) 2 Multivisceral Transplant Unit and Gastroenterology, Padua University Hospital, 35100 Padua, Italy; [email protected] (E.N.L.); [email protected] (P.B.); [email protected] (F.P.R.) 3 Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, Department of Surgery, University of Toronto, Toronto, ON M5G 2N2, Canada; [email protected] (G.S.); [email protected] (T.I.) 4 Surgical Pathology & Cytopathology Unit, Department of Medicine, Padua University Hospital, 35100 Padua, Italy; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Received: 2 April 2020; Accepted: 24 April 2020; Published: 5 May 2020 Abstract: Cholangiocarcinoma (CCA) arises from the biliary tract epithelium and accounts for 10–15% of all hepatobiliary malignancies. Depending on anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). The best treatment option for pCCA is liver resection and when a radical oncological surgery is obtained, 5-year survival rate are around 20–40%. In unresectable patients, following a specific protocol, liver transplantation (LT) for pCCA showed excellent long-term disease-free survival rates. Fewer data are available for iCCA in LT setting. Nevertheless, patients with very early unresectable iCCA appear to achieve excellent outcomes after LT. This review aims to evaluate existing evidence to define the current role of LT in the management of patients with CCA. Keywords: liver transplantation; cholangiocarcinoma; surgery 1. Introduction Cholangiocarcinoma (CCA) is the second most common hepatic malignancy after hepatocellular carcinoma (HCC); its overall incidence has progressively increased worldwide over the past four decades [1–3]. CCA is a malignant tumor of the cholangiocytes (i.e., the epithelial cells lining the bile ducts), which can develop at any portion of the biliary tree, from the canals of Hering to the main bile duct [4,5]. Most CCAs are well, moderately or poorly differentiated adenocarcinomas; other histological subtypes are rarely encountered. Surgery is the preferred therapeutic option for all subtypes of CCA, although, involvement of the vascular structures and lymph nodes needs to be considered when evaluating the best approach. Refinements in CCA diagnosis and better understanding of genetic profiles may lead to an optimized surgical treatment. In addition, novel drugs, such as checkpoint inhibitors and molecular-targeted molecules, may represent future options for adjuvant and neoadjuvant therapy, alone or in combination with downstaging locoregional therapies [6]. This review aims to analyze the recent advances in the management of CCA, focusing on surgical treatments and highlighting the role of liver transplantation in the era of transplant oncology. J. Clin. Med. 2020, 9, 1353; doi:10.3390/jcm9051353 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 1353 2 of 19 2. Anatomo-Pathological Features of CCA CCAs represent an estimated 3% of all gastrointestinal system malignancies. They are classically divided into three groups, depending on the anatomic site of origin: intrahepatic CCAs (iCCAs), perihilar CCAs (pCCAs) and distal CCAs (dCCAs) [7]. iCCAs are defined as CCAs located proximally to the second-order bile ducts. iCCA can present three different patterns of growth: mass-forming (MF-iCCA), periductal infiltrating (PI-iCCA) and intraductal growing (IG-iCCA). Of these, the MF-iCCA is by far the most frequent type [8]. pCCAs can arise anywhere from the second-order bile ducts to the common bile duct above and at the site of cystic duct insertion. In contrast, dCCAs are confined to the area between the origin of the cystic duct and the ampulla of Vater [7]. pCCAs account for ~50–60% of all CCAs and dCCAs for 20–30% [9]. pCCA and dCCA have similar macroscopic features; they generally are flat or poorly defined nodular sclerosing tumors which diffusely infiltrate into adjacent structures in 80% of cases. Less frequently, pCCAs and dCCAs present as intraductal papillary tumors [10]. PI-iCCAs and flat/nodular sclerosing p/dCCAs often develop from preinvasive lesions, classified as biliary intraepithelial neoplasm (BilIN); likewise, papillary p/dCCAs and IG-iCCA arise from intraductal papillary neoplasms of the bile duct (IPNBs). No preinvasive lesions of the MF-type of iCCA have been identified [11]. Histologically, most pCCAs and dCCAs are mucin-producing adenocarcinomas or papillary tumors, into conventional and unconventional iCCAs. Conventional iCCAs are well to moderately differentiated adenocarcinomas made up of columnar to cuboidal epithelial cells, which bear a resemblance to biliary epithelial cells [12]. Varying degrees of desmoplasia and inflammation can be present. Mucin can be found in the lumen of tubular structures, in the apical side of tumor cells and in the cell cytoplasm. iCCAs cells can cause compression of the surrounding parenchyma or invade hepatocyte plates and sinusoids [10]. iCCAs can also be classified into two main histological subtypes depending on the anatomic site where they may arise [10]. The small bile duct type of iCCA may develop from small intrahepatic bile ducts, progenitor cells or hepatocytes. It presents as small-sized tubular or acinar adenocarcinoma with invasive mass-forming growth pattern and absent or minimal mucin production. It commonly has a peripheral location in the liver [10,13]. On the other hand, large bile duct iCCAs derive from large intrahepatic bile ducts [14] or from peri-biliary glands [15]. They are formed of mucin-producing columnar tumor cells arranged in a large-duct or papillary architecture. Most large bile duct iCCAs are PI-iCAAs and are centrally located in the liver [14,16]. 3. pCCA: Surgical Approach and LT Indications 3.1. Liver Resection When feasible, liver resection (LR) is the best treatment option for pCCA. Surgery can offer a 5-year survival rate of 20–40% after R0 resection (microscopic margins negative for tumor). When R0 is not feasible, the 5-year survival rate drops to 0% [17–21]. Unfortunately, only 20–25% of patients are appropriate candidates for curative resection. Due to its anatomic location—adjacent to the hepatic artery and portal vein—vascular involvement is common in pCCA and represents the main reason for the tumor to be deemed unresectable. Other criteria for unresectability are local progression, jaundice or presence of metastases. The main goal of surgery is to obtain an R0 resection; to achieve it, a complex surgical procedure is required, which involves performing a major hepatectomy with caudate lobe and en-bloc biliary resection, a hepaticojejunostomy and a lymphadenectomy (Figure1). Vascular resection and subsequent reconstruction can also be performed, when necessary. Mortality rates remain high even in experienced centers due to the complexity of the procedure. The 30-day mortality rate ranges from 5–15% [22–27], and the leading cause of death is postoperative liver failure. An accurate diagnosis is crucial to select patients for surgery correctly. Five to 20% of presumed pCCAs, which are resected, turn out to be negative on histopathological assessment [28] and finally showed benign biliary stricture due to chronic inflammation in the setting of IgG4-disease or primary sclerosis cholangitis (PSC). This means that some patients undergo a high-risk surgical procedure even if no J. Clin. Med. 2020, 9, 1353 3 of 19 tumor is to be found. Optimal care of patients with pCCA requires the involvement of liver-specific multidisciplinary teams, which should include interventional radiologists, oncologists, hepatologists, endoscopists and hepatobiliary surgeons, with surgical oncology, vascular and transplant skills [29]. Figure 1. Left hepatectomy with caudate lobe resection for perihilar cholangiocarcinoma (pCCA) (Bismuth IIIb). 3.1.1. Staging Although there is no universal definition of resectability, there are classifications that can help clinicians choose the best treatment for pCCA. The Bismuth classification was introduced in 1975 and, despite it being the oldest classification, it is still primarily used to define pCCAs according to the biliary segment affected by the tumor. A type IV tumor is characterized by a bilateral involvement of the second-order intrahepatic bile ducts and is generally considered unresectable. However, the Bismuth classification does not describe vascular involvement. In 2001, Blumgart introduced the clinical T staging system, which describes both vascular and parenchymal involvement but does not account for distant metastases or lymph node involvement. Recently, the American Joint Committee on Cancer (AJCC) published the 8th edition of the Cancer Staging Manual [30]. The staging system for pCAA included in the Manual is the most comprehensive, as it provides for the assessment of tumor progression, vascular involvement, lymph node and distant metastases. 3.1.2. Biliary Drainage and Future Liver Remnant Quantification Before LR Hyperbilirubinemia and low