Page 57 - Read Online

Calderon Novoa et al. Hepatoma Res 2023;9:33 https://dx.doi.org/10.20517/2394-5079.2023.36 Page 3 of 11

Brushing samples obtained from endoscopic retrograde cholangiopancreatography (ERCP) has been
described for the diagnosis of malignant biliary strictures. However, results in CCA are overall poor, with
sensitivity below 60% in several reports [30-32] . This is most likely due to the desmoplasic characteristics of
[32]
CCA . Given the difficulties in the early detection of iCCA, it is no surprise that surgical results remain
poor. With perioperative mortality ranging from 1%-9% [33-35] , and five-year survival ranging between 20% to
45% at best [35-38] , LR still lacks effectiveness, albeit being considered the gold standard for iCCA. The most
frequent cause of death for resected patients is local recurrence in the liver, as shown by the low rates of
disease-free survival (DFS) at 5 years, ranging from 2.1%-30% [33-38] . Most patients will die after a year of
recurrence, in spite of locoregional treatment for the recurrence .
[30]

In the context of unfavorable results for LR in iCCA, LT has been proposed as a possible alternative.
Theoretical benefits of LT for treatment of iCCA include the complete removal of the tumor and resolution
of the underlying disease in cirrhotic patients. However, initial reports of LT for iCCA have been
discouraging, with 5-year survival under 40% [39,40] . These numbers fall short of the expected 50%-60% LT
survival defined as benchmark results. There have been several retrospective studies regarding LT and
iCCA [41-47] . More recent studies from the last decade by Sapisochin et al. have shown extremely encouraging
results for "Very early" stage iCCA, which have rekindled the attention and efforts towards iCCA and
LT [48,49] . In spite of these efforts, high-yield evidence is lacking regarding the indication, patient selection and
bridging therapies or adjuvant treatment for LT in iCCA. This article aims to review the road so far
regarding LT for iCCA: Its initial poor results and contraindication for LT, followed by interesting findings
regarding accidental iCCA in explant specimens from LT, and the encouraging results published regarding
neoadjuvant therapies for LT in iCCA as well as future perspectives.

LIVER TRANSPLANT FOR INTRAHEPATIC CHOLANGIOCARCINOMA
Historical results for LT in Intrahepatic cholangiocarcinoma
Due to poor outcomes related to LR and the great advances in the field of transplant oncology, particularly
regarding another primary liver tumor such as hepatocellular carcinoma (HCC), the last decade has seen a
significant increase in the interest in LT in iCCA. Because of its rarity and non-specific imaging findings,
most of the data regarding iCCA and LT is incidental. Initial publications regarding iCCA on explant
specimens of LT date back to as early as the late 1980s, where outcomes were very poor [41,50] . O’Grady
reported a total of 26 cholangiocarcinomas (13 “peripheral” and 13 “central”), with dismal 1-year OS results
between 30%-38% for both groups, and almost 100% of recurrence for those patients who survived 1 year.
Studies that followed the next 20 years also proved quite disappointing [39,40,42-44,51] . In light of these
discouraging results, iCCA has been considered a relative and even absolute contraindication for LT in most
centers for the last decades. The recent flare-up and increase in interest for LT in iCCA may be related to
different factors: On one hand, it could be linked to the encouraging results observed in HCC using the
[52]
BCLC staging system and in perihilar cholangiocarcinoma and transplantation following the Mayo Clinic
protocol ; On the other hand, it might be influenced by the work of Sapisochin et al. [48,49] . In 2014, a
[53]
retrospective study analyzing outcomes of LT with specimen findings of an iCCA in 16 Spanish centers was
published. Most centers enlisted patients according to Milan criteria. In a 10-year period, over 7000 patients
were transplanted for end-stage liver disease (ESLD), of which 1% (29 patients) presented unexpected iCCA
on the explant specimens, eight of which were classified as "Very early" iCCA (< 2 cm). With a mean follow-
up of 3 years for the cohort, the recurrence rate was 24,1%, with a 5-year DFS of 71%. The 5-year actuarial
rate was 45%. However, when performing a subgroup analysis of the 8 patients with very early iCCA, no
patient experienced recurrence and had an impressive 5-year survival rate of 71%. Although the small
sample size limited the statistical value of the study, a benefit for this population seemed evident, with a 2-
cm size cutoff value univariately associated with poorer survival. This was perhaps the initial step towards
the current paradigm shift regarding LT in iCCA. A couple of years later, in 2016, Sapisochin et al.