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Page 8 of 16                                       Cardinale et al. Hepatoma Res 2018;4:20  I  http://dx.doi.org/10.20517/2394-5079.2018.46

               (mucinous) type iCCAs [22,119] . The last iCCA subtype displays IHC, gene expression and clinic-pathological
               profile that can be superimposed on pCCA [4,120-122] . Small bile ducts or mixed-CCAs usually showed a peripheral
               localization and a mass forming growing pattern. Differently, the large bile duct (mucinous) type usually
               showed a peri-ductal infiltrating and/or mass forming growth pattern . Importantly, these separate entities
                                                                          [4]
               displayed different prognosis (being worst the one of the mucin-producing iCCAs) and different associated
               diseases [4,10,82,123] . Indeed, parenchymal liver diseases, including chronic viral and non-viral liver diseases and
               liver cirrhosis, characterize the clinical-pathologic background for mixed-iCCAs [4,10,82,123] . In contrast, chronic
               biliary diseases or pathologies and conditions affecting the intrahepatic medium-large and extrahepatic bile
               ducts characterize the clinical-pathologic background for mucin-producing iCCAs and pCCAs [4,10,82,123] .


               As far as the mixed type-mass-forming iCCA is concerned, the clinical presentation is similar to other
               intrahepatic liver malignancies, but different from that of pCCA [4,10,82,123] . iCCAs are usually asymptomatic
               in early stages (20%-25% of cases are incidental finding). Malaise, cachexia, abdominal pain, night sweats,
               fatigue and/or jaundice, associated or not with systemic manifestations, represent the clinical onset of
               symptomatic iCCA [4,10,82,123] . In contrast, a typically painless jaundice is the most frequent clinical onset in
               pCCA  [4,10,82,123] . Regarding patients with PSC, CCA may present as the development of a rapid deterioration
               of clinical conditions or a dominant stricture during follow-up . In general, the MF type represents the
                                                                      [3]
               most frequent macroscopic presentation of iCCA (> 90%) appearing, at imaging, as a nodule [3,123] . In the
               context of cirrhotic liver, the first diagnostic challenge is the differential diagnosis of iCCA vs. HCC. In the
               cirrhotic liver it was demonstrated that by contrast, enhanced MRI iCCAs showed constantly a lack of HCC
               hallmarks; however, by CT, this occurs only in large nodules (> 3 cm) [124-126] . Although, the HCC diagnosis
               belong from the demonstration of the typical contrast agent uptake, the identification of HCC with stem
               cell features (CK19+-HCC), combined HCC-CCA, cholangiolocellular carcinoma and bile duct mixed type
               iCCA, by imaging procedures, still remains an unsolved challenge [3,4,10,123,127,128] . Biopsy is, therefore, necessary
               after excluding HCC in cirrhosis, or in the context of a nodule in non-cirrhotic liver [3,129] . From a histological
               point of view, differential diagnosis of iCCA vs. HCC or metastasis represents an unsolved problem [2,3,129,130] ,
               also due to the lack of validation of specific markers.


               Radiologically, iCCA may appear as a dominant stricture in the context of PSC or in patients without a
               documented specific hepato-biliary disease. This is a typical presentation of the pCCA. When a dominant
               stricture of the intrahepatic biliary tree is suspected, the MRI + MRCP represents the imaging procedure with
               the highest diagnostic accuracy for localizing and sizing the stricture ; the challenge being the definitive
                                                                           [3]
               demonstration of malignancy . In this respect, ERCP enables a number of procedures in order to obtain
                                         [3]
               a microscopic confirmation, comprising, cytology, brushing, FISH-polisomy, biopsy, or further innovative
               techniques . However, all these techniques show an unsatisfactory sensitivity [54,130-133] , and even, the FISH-
                        [3]
               polisomy in detecting CCA in PSC patients demonstrated a low sensitivity in a meta-analysis .
                                                                                              [133]
               In substance, diagnosis of CCA still requires a combination of clinical, radiologic and non-specific histologic/
               biochemical markers (see review by Banales et al. ).
                                                         [3]
               As already mentioned, no specific serum, urine, biliary or histological biomarkers are currently available for
               the diagnosis of CCA and a proposal by our group which has been recently refreshed by new confirmation,
               identifies biliary IGF1 as specific markers of CCA. However, the very promising role of biliary IGF1 has
               been confirmed only in CCA without PSC. Recently, Arbelaiz et al.  evaluated the serum concentration
                                                                         [134]
               of extracellular vesicles (EVs) and performed a careful analysis of the protein content in patients with CCA,
               PSC, and HCC. Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential
               usefulness as diagnostic tools. As noted previously, the EV cargo in the two distinct EV populations (i.e.,
               basolateral and apical) is evidently different as a large difference exists between the protein content of EVs
               released by normal cholangiocytes and cholangiocytes involved in chronic inflammation (i.e., PSC) or
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