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Cardinale et al. Hepatoma Res 2018;4:20  I  http://dx.doi.org/10.20517/2394-5079.2018.46                                      Page 9 of 16

               neoplastic transformation (i.e., CCA) . Further validation studies will be necessary to bring this important
                                              [135]
               scientific advance into the clinical approach of CCA differential diagnosis.


               NEW ADVANCES INTO CCA THERAPY
               Surgery with complete resection, including liver transplantation in highly selected cases, is the only curative
               therapy for CCA. In patients with unresectable tumours, several types of loco regional therapy or chemotherapy
               (such as trans arterial chemoembolization, trans arterial radio embolization or radiofrequency ablation) can
               be considered. In substance, CCAs must be managed by dedicated centres with multidisciplinary expertise in
               which personalized diagnostic work-up and management can be performed, as clearly stated by a European
               Consensus (see review by Banales et al. ).
                                                [3]
               Recently two important advances have been reached in therapy of iCCA. On one hand, the first clinical
               trial of adjuvant therapy has been concluded . In this clinical trial, 447 surgically resected patients
                                                       [136]
               were randomly assigned to capecitabine for 6 months or observation (> 80% of the patients were followed
               for at least 3 years). Interestingly, results showed a survival of 51 vs. 36 months in capecitabine arm vs.
               observation, and median time to cancer recurrence of 25 vs. 18 months, respectively. In 430 patients who
               received treatment per study protocol, capecitabine is associated with a 25% lower chance of death than
               observation . On the other, the first report of a molecular target therapy in chemotherapy-refractory CCA
                         [136]
               appeared. BGJ398 was a first-in-class FGFR kinase inhibitor with manageable toxicities showing meaningful
               clinical activity against chemotherapy-refractory CCA containing FGFR2 fusions. This promising antitumor
               activity supports continued development of BGJ398 in this highly selected patient population . Emerging
                                                                                              [137]
               therapeutic approaches based on the molecular targets are still in early phase of clinical study and have been
               recently reviewed by Rizvi and Gores .
                                               [117]


               PERSPECTIVES
               A unique feature of CCA is that it recognizes as origin tissues, the hepatic parenchyma or large bile ducts,
               which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands (PBGs),
               respectively .
                         [138]

               Stem cells have been identified as cells of origin of different cancer types, comprising primary liver cancers,
               both in experimental studies and in humans [139-147] . Based on the grade of maturation of the cells of origin
               within the two lineages of the liver (hHpSC-derived and hBTSC-derived lineages), we have proposed that
               CCAs could be classified as:
               • Primary liver parenchymal CCA: cholangiolo-carcinoma, small bile duct type (mixed) CCA. These tumors
               emerge within the liver parenchyma from canals of Hering, bile ductules and interlobular bile ducts and
               indeed  originate  from  hHpSCs,  immature  NCAM+  cholangiocytes,  or  mature  (NCAM-)  interlobular
               cholangiocytes. A rigourous study, based on an integrative genomic analysis of HCC-CCAs, demonstrated
               that cholangiolo-carcinoma represents a distinct biliary-derived entity compared with the mixed/combined
               HCC-CCA, which, on the other side, comprised the stem-cell type, with an aggressive nature and poor
               outcome, and the classical type, with common cell lineage for both the HCC and the iCCA component .
                                                                                                      [148]
               • Primary biliary CCA: dCCA, pCCA, and large bile duct (mucinous) type iCCA. These tumors emerge from
               extra-hepatic biliary tree and larger intra-hepatic bile ducts and originate from PBGs or surface epithelium
               of corresponding bile ducts.

               Thus, facing the origin of iCCA, a physiopathology concept should be considered, instead of the cell of origin,
               the lineage of origin [10,12,13,138] . An iCCA classification based on the cell-lineages-of origin is more coherent
               with current knowledge on the epidemiology and risk factors and may have important clinical implications
               for the definition of specific therapeutic targets. Moreover, it highlights a lineage dependency of the chronic
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