Primary hepatic malignancies are increasing in incidence and are now the third leading cause of cancer-related deaths worldwide [1]. Combined or mixed hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA), accounting for around 0.4%–14.2% of primary liver cancers, is rare and often misclassified as HCC pre-transplant with worse outcomes [2]. Studies indicate that HCC-CCA tumors are more aggressive than HCC tumors and are associated with poorer prognosis than either HCC and or CCA alone [2–5].

Unlike HCC, HCC-CCA has largely been considered a contraindication for liver transplantation (LT) due to the increased risk of post-transplant recurrence and poor outcomes [6]. LT does provide a survival benefit over resection in patients with mixed tumors [7–9], but that benefit has traditionally been outweighed by the need to pursue utility in deceased donor grafts allocation. Importantly, most HCC-CCA cases in LT recipients were considered to be HCC alone prior to transplantation due to the difficulty in distinguishing HCC-CCA from HCC radiologically [10–13]. Thus, incidental diagnosis seems to be the norm for patients with HCC-CCA undergoing LT.

Some reports indicate an increasing incidence of incidental HCC-CCA in LT recipients in recent years [8, 10]. It is important to determine optimal treatment regimens to provide the best medical care possible to patients with HCC-CCA. Given the rarity of this type of tumor and that LT is not standard-of-care, a detailed description of the trajectory of patients with HCC-CCA provides important information on clinical outcomes. The primary aim of this paper is to describe the outcomes of LT recipients presumed to have HCC alone pre-LT and received neoadjuvant treatment for HCC but found to have HCC-CCA on explant. The secondary aims were to compare pre-LT (representing clinical decision making) versus explant predictors and to examine the patterns of recurrence and treatment.

Medical records of 1,898 adult patients undergoing LT at a single, quaternary care institution between June 2008 and September 2023 were reviewed. Patients diagnosed with mixed HCC-CCA on explant were included in the primary analysis. All work was carried out with approval from the Houston Methodist Research Institute Institutional Review Board under protocol number Pro00000587 with a waiver of authorization. The center follows the guidance of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.

A multidisciplinary tumor board reviewed the medical records of patients referred for LT who had a diagnosis of liver cancer and made clinical care recommendations, including systemic therapy and locoregional therapy (LRT). Patients with large, single tumors (>5 cm in diameter), multifocal lesions, or poorly differentiated tumors received combined neoadjuvant systemic therapy and LRT. Neoadjuvant treatment was HCC-directed, as all patients with HCC-CCA were believed to have HCC prior to undergoing LT. All patients in the study were appropriately treated and down staged with LRT. Microwave ablation, TACE, and TARE were the LRT modalities utilized. Decisions to place patients on the LT waitlist were made by a multidisciplinary transplant medical review board. While on the LT waitlist, patients underwent close monitoring, including cross-sectional imaging every 3 months to rule out disease progression.

Patients with HCC-CCA had significantly worse OS and RFS than HCC, despite similar clinical features. This reflects the aggressive biology and challenges of pre-LT diagnosis. These comparisons identified patients with HCC with similar features that inform pre-LT clinical decision making and that approximate actual pathologic risk, respectively. Unfortunately, the mixed tumor patients had low AFP and CA19-9 levels and were radiographically similar to patients with HCC alone, making correct pre-LT diagnosis difficult. Like many other studies, the patients with mixed tumor in this cohort were originally diagnosed with HCC and thus received HCC-directed neoadjuvant therapy. It is likely that the CCA component of the mixed HCC-CCA lesions did not receive appropriate neoadjuvant systemic treatment, such as standard chemotherapy regimens for CCA. All patients with intrahepatic CCA considered for LT at our institution receive neoadjuvant gemcitabine and cisplatin as bridging and downstaging therapy, which is also used to inform patient selection [17]. It was not possible to follow the standard protocol in patients who were determined to have HCC-CCA only at the time of examination of the liver explant. These patients did receive CCA-focused adjuvant therapy. Due to the small sample size, we are unable to make conclusions regarding the efficacy of one adjuvant therapy over another, and the adjuvant regimens remain hypothesis-generating only.

The propensity match analysis provides insight into the clinical presentation and biology of HCC-CCA compared to HCC with similar pre-LT (Match 1) and post-LT (Match 2) characteristics. Matching on a small subset of prognostic variables allows us to better understand differences in mixed tumors and HCC when controlling for tumor burden. In both analyses, patients with HCC-CCA were more likely to have received neoadjuvant MWA. MWA has been shown to be an effective treatment in both HCC [18] and iCCA [19], and single-center studies have demonstrated its efficacy as a bridging [20, 21] and downstaging therapy [22]. Thus, it is unlikely that the use of MWA significantly affected outcomes. Patients matched on pre-LT characteristics (Match 1) were more likely to be outside Milan criteria on explant, highlighting the difficulty of radiologic staging in biologically aggressive tumors. This result highlights the difficulty of estimating tumor burden pre-LT in patients whose tumors have aggressive biology, such as HCC-CCA. It is interesting that 9 of the HCC-CCA patients with tumors inside Milan criteria radiologically pre-LT were outside Milan on explant pathology. Only 2 patients were outside Milan criteria due to lymphovascular invasion, which is very difficult to detect radiologically.

The 3- and 5-year OS rates for the cohort of 19 patients with HCC-CCA described here were much lower than other papers have reported (Table 3). Most patients with mixed tumors were thought to be within Milan criteria pre-LT (16, 84.2%), demonstrating that poor outcomes can occur even with a small tumor burden. Other papers have also shown that patients with HCC-CCA have worse outcomes than matched patients with HCC alone [13, 23–25], although some centers have reported similar survival rates [8, 9, 26, 27]. The OS rates reported here are also much lower than what our own center has demonstrated for patients with large HCC tumor burden (beyond UCSF criteria) [28], and for patients with intrahepatic CCA [17]. Penzkofer and colleagues noted that outcomes seemed to be more strongly associated with the CCA component of the mixed tumors [11]; our data also support this conclusion.

This study highlights the need for unique biomarkers, whether blood, tissue, or imaging, to distinguish HCC from HCC-CCA. Other studies of LT recipients have shown that CCA-specific biomarkers like CA19-9 were similar between patients with pure HCC and patients with mixed tumors [13]. Given that patients with mixed tumors have reduced expected post-LT survival, better methods for diagnosing HCC-CCA pre-LT are needed, particularly as the number of patients undergoing LT for oncologic indications increases. Patients whose lesions are identified as liver imaging reporting and data system (LIRADS)-M, presumed to have likely or definite malignancy, or imaging characteristics not typical of HCC, should undergo image-guided biopsy for definitive diagnosis. If a patient is confirmed to have HCC-CCA, centers should obtain genetic profiling/next-generation sequencing data to optimize tailoring treatment. Such genomic data can help guide physicians in selecting neoadjuvant systemic options that will treat both components (hepatocellular and adenocarcinoma) of the cancer. Given poor outcomes and high rates of recurrence, institution-based protocols are necessary for treating these aggressive cancers, considering the dearth of data in post-transplant outcomes in patients with HCC-CCA.

This study is limited by its retrospective nature and because it only incorporates patients from a single center. Additionally, very few patients underwent LT for HCC-CCA during the study period, limiting the sample size of this cohort, particularly at longer follow-up (>3 years post-LT) when many patients had died. Thus, the small number of patients could reduce the confidence in long-term follow up outcomes. Although our institution is in a region with high racial and ethnic diversity, the results presented here may not accurately reflect the experiences at other centers. There might be residual confounding arising from unmeasured patients’ attributes. Despite these limitations, this study has several strengths. To our knowledge, this manuscript presents the largest propensity score matching analysis of patients undergoing LT for HCC-CCA vs. HCC using multiple variables to select patients with similar disease burden. Thus, the conclusions drawn here provide important insight into the surgical treatment of patients with HCC-CCA. Another major strength of this cohort is the diverse patient population at our center. Although most patients with HCC-CCA were non-Hispanic White, this work still provides an accurate representation of the incidence of HCC-CCA in a diverse transplant population.

This manuscript provides a propensity-score matched comparison utilizing granular center medical records of patients receiving LT from deceased donors for HCC where incidental HCC-CCA occurred. Although LT can offer superior OS relative to resection [7, 9, 11], the study showed that survival is still much lower for patients with HCC-CCA than for HCC, the most common oncologic indication for LT. Given that most patients with HCC-CCA are diagnosed incidentally after transplant and are associated with inferior outcomes, allocation policy may need to weigh whether LT for HCC-CCA is justified without better selection tools and treatment options. Accurate pre-LT diagnosis may have allowed patients with HCC-CCA to receive adequate neoadjuvant treatment for the CCA component of the tumor, potentially improving outcomes. Better screening techniques are needed to identify patients with these rare tumors pre-transplant to ensure they receive the most appropriate treatment possible. Liquid biopsy and next-generation sequencing show promise in helping to accurately distinguish HCC-CCA from HCC [29]. Given the improved survival after LT for HCC-CCA relative to resection, increasing utilization of machine perfusion [30] and extended criteria donor grafts [31–34] may allow greater expansion of LT to well-selected patients.