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Akabane et al. Hepatoma Res 2023;9:29 https://dx.doi.org/10.20517/2394-5079.2023.45 Page 5 of 9

transplantation, primarily based on tumor size and number, may be overly restrictive, disqualifying some
patients who could potentially benefit from this treatment. Additionally, the risk of recurrence post-
[8]
transplantation remains a concern, underscoring the need for more robust selection criteria . One potential
approach for expanding the indications for liver transplantation in early iCCA could involve initially
targeting smaller tumors, such as those measuring 2 cm or less. This would facilitate the gradual
incorporation of criteria to encompass multiple tumors (up to two) or solitary tumors measuring up to 3 or
4 cm with low tumor marker levels (i.e., carbohydrate antigen 19-9).

The Milan Criteria, which have been widely adopted for determining liver transplant eligibility in HCC,
concentrate primarily on tumor morphology. However, this approach may be insufficient for iCCA, as
tumor biology plays a pivotal role in determining prognosis and the risk of recurrence following
transplantation. Potential candidates for tumor biology markers include molecular profiling, immune cell
infiltration, and the tumor microenvironment. Integrating these factors into the selection criteria could
[4]
result in more accurate prognostic predictors and improved patient outcomes .

LIVER TRANSPLANTATION FOR ADVANCED ICCA
Historically, liver transplantation has been regarded as a high-risk treatment option for advanced iCCA due
to elevated rates of tumor recurrence and suboptimal OS outcomes. In contrast, perihilar CCA (phCCA) is
now increasingly recognized as an indication for liver transplantation under the Mayo Protocol [51,52] . In early
efforts at liver transplantation for CCA, the specific subtypes were often not distinguished, which included
iCCA in the transplantations. However, the results remained disappointing until the introduction of
neoadjuvant protocols, such as the Mayo Protocol applied solely to phCCA. Studies that incorporate
neoadjuvant therapy before liver transplantation, similar to the Mayo Protocol, are currently limited to
small case series. In general, it can be inferred that while liver transplantation can enhance outcomes
compared to palliative therapy for unresectable iCCA, the outcomes, compared to transplantation for other
indications, including phCCA, are presently inferior, albeit evidence remains limited. Nevertheless, recent
promising studies suggest that liver transplantation may be a viable option for patients with non-resectable
iCCA. An exploratory study by Hong et al. analyzed the data from patients who received liver transplants
for locally advanced iCCA to identify potential beneficiaries , revealing that patients in the group without
[53]
any predictive recurrence factors (e.g., multiple tumors, perineural invasion, invasive growth patterns,
absence of neoadjuvant and adjuvant therapy, and lymphovascular invasion) could achieve a high 5-year
RFS rate of up to 78%. Liver transplantation appeared to provide superior RFS compared to radical liver
resection accompanied by bile duct resection in cases of locally advanced iCCA . Notably, transplant
[54]
patients who underwent neoadjuvant and adjuvant treatment demonstrated a more pronounced survival
advantage (5-year RFS: 47% vs. 20%). In a recent prospective study, six patients with non-resectable locally
advanced iCCA who demonstrated at least 6 months of stable or regressing disease after neoadjuvant
[9]
chemotherapy underwent liver transplantation . The median duration of follow-up for transplant
recipients was 36 months, with 5-year OS and RFS rates of 83.3% and 50%, respectively. Nonetheless, liver
transplantation following a regimen of gemcitabine and cisplatin should be reserved for highly selected
cases only.

DONOR LIVER FOR LIVER TRANSPLANTATION FOR ICCA
The demand for donor livers far exceeds the available supply, resulting in patients with HCC and other
[55]
malignancies often encountering extended waiting times for transplantation . This scarcity is particularly
problematic in transplant oncology, as patients with advanced-stage cancers may have a limited timeframe
before their disease progresses beyond the point where transplantation remains a viable option. Studies have
suggested that hepatectomy and liver transplantation show comparable postoperative outcomes and