Hepatobiliary primary cancers include hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). HCC is the sixth most common malignant tumor worldwide and ranks as the fourth leading cause of cancer-related death (1). The incidence of BTC is relatively low, which refers to a group of cancers, that include cholangiocarcinoma (cancers arising in the intrahepatic, perihilar, or distal biliary tree) and gallbladder carcinoma. The incidence of cholangiocarcinoma is 0.35–2 cases per 100,000 each year in high-income countries. While, the incidence in endemic regions of China is up to 40x higher. Meanwhile, the incidence of intrahepatic cholangiocarcinoma is increasing in high-income countries (2). Curative surgical resection is the most recommended treatment for patients with early-stage BTC (2, 3). However, most patients with these malignant tumors are diagnosed at an advanced stage when they have already missed the opportunity for traditional curative resection (2, 4). The liver is a common site for metastases (5) and it is recommended that metastatic liver tumors, such as those from colorectal carcinoma (CRC) and gastrointestinal stromal tumor (GIST), should be treated using resection in conjunction with systemic therapy (5, 6).

Conversion therapy aims to downstage tumors so that patients with initially unresectable or borderline resectable malignancies can undergo radical resection. This method has been used to treat various solid tumors, such as colorectal, pancreatic, gastric, and hepatobiliary cancer (7–9). Since 2017, combination treatment with the anti-angiogenesis targeting agent of lenvatinib and anti-programmed cell death protein 1 (PD-1) antibodies, has achieved high therapeutic response rates for HCC and BTC (10). A high overall response rate (ORR) (42.1%) was obtained in a phase II study of first-line treatment for initially unresectable BTC using lenvatinib and PD-1 inhibitors (11). In another phase II study of patients receiving toripalimab combined with lenvatinib and chemotherapy of GEMOX, a higher ORR (80%) was achieved (12). Although the combination therapy has not yet become first-line therapy for unresectable HCC and BTC patients in China, these high tumor treatment response rates of the therapy had converted some unresectable hepatobiliary cancers into resectable in some clinical practice (7, 11). Conversion therapy has also been used to treat liver metastases from colonic carcinomas (13) and metastases from gastrointestinal stromal tumors (14).

While systematic treatment is effective in some patients, however, tumors that invade important blood vessels such as the inferior vena cava, hepatic arteries, and veins, cannot be resected using traditional partial hepatectomy. Improvements in liver resection and liver transplantation technologies have allowed surgeons to explore ex vivo liver resection and autotransplantation (ELRAT) (15). This surgery was first performed by Pichlmayr et al. in 1988 (16). Its primary purpose is to achieve radical (R0) resection in demanding cases (17, 18). ELRAT involves in vivo hepatectomy and extracorporeal liver resection, followed by autologous transplantation of the remnant hepatic parenchyma. Surgery involving in vivo total hepatectomy followed by ex vivo liver resection and autotransplantation (ITH-ELRAT) for malignant tumors has been used for more than 100 patients (15, 19). While, surgery involving in vivo partial hepatectomy followed by ex vivo liver resection and autotransplantation (IPH-ELRAT) has not yet been used for patients with malignant tumors. The use of this procedure, which was called auxiliary partial autologous liver transplantation, has only been reported in one patient with hepatic alveolar echinococcosis (20). ELRAT has been performed for patients with various types of liver tumors, including malignancies (e.g., HCC, BTC, CRC metastasis, and GIST metastasis) and benign lesions including hepatic alveolar echinococcosis, focal nodular hyperplasia, and hemangioma (19, 21, 22). Of these, alveolar echinococcosis is the most frequently reported disease (23). There have been few reports on the use of ELRAT for malignant cases due to the extremely challenging nature and questionable efficacy of the surgical procedure (19). To date, there are only two studies that reported at least 10 cases of ELRAT for malignancies (15, 24). In the present study, we report ten patients with malignant tumors who underwent ELRAT and analyzed systemic therapy, surgical skills, and postoperative prognoses were assessed. Five of the cases received IPH-ELRAT and were the first to ever undergo this treatment for malignant tumors.

Detailed information on patient demographics, tumor location, vascular involvement, systemic therapy, operative details, and outcomes are shown in Tables 1 , 2 . A summary of the findings is shown in Table 3 .

The liver cannot tolerate a long period of ischemia in vivo. When a tumor invades the important blood vessels of the liver, including the confluence of the hepatic veins or the inferior vena cava, conventional surgery cannot be performed (17). ELRAT can be used for a variety of benign and malignant liver lesions and is often regarded as the last treatment option (25). This treatment can effectively reduce warm ischemic injuries and allow the tumor can be removed from a bloodless area outside the body following perfusion. ELRAT has technical requirements that require multidisciplinary cooperation. The surgical team must be experienced in both the liver transplantation process and complex perioperative anesthesia management (23).

ELRAT is most often used to treat hepatic alveolar echinococcosis (19) and also suitable for large liver tumors and/or difficult anatomical locations, including severe compression or infiltration of large blood vessels or biliary structures such as the inferior vena cava, portal vein, and hepatic vein (26, 27). ELRAT is also a reasonable choice when the risk of in situ resection is high, due to uncontrollable massive bleeding or liver failure, and there is a need to extend the operation time (17). However, ELRAT has several contraindications, including cirrhosis, cholestasis, Budd-Chiari syndrome, and deficiency of residual liver volume after lesion resection (<40%) (28). Relative contraindications include two conditions: 1. hepatic echinococcosis with extrahepatic lesions that can be controlled by albendazole; 2. hepatic malignancy with limited extrahepatic metastasis that can be controlled using systemic therapy (such as chemotherapy, targeted therapy, and immunotherapy) (29).

The most appropriate resection option should be carefully planned prior to surgery to reduce or avoid complications. Residual liver volume should be evaluated quantitatively and qualitatively before surgery to avoid small liver syndrome (30). The present study reported the first five cases of patients with malignant tumors who received IPH-ELRAT. The advantages of this procedure are its ability to preserve a high amount of liver parenchyma to avoid small-for-size syndrome and the lack of a need for postoperative immunosuppressants or organ donors (20). Compared to autologous liver transplantation after total hepatectomy, autologous liver transplantation after partial hepatectomy often involves more delicate and complex vascular and bile duct reconstruction. In our study, two patients who underwent autologous liver transplantation after partial hepatectomy underwent synchronous Whipple procedure, which resulted in longer operation time and greater amount of blood loss. However, compared with total hepatectomy, patients with partial hepatectomy had more stable intraoperative hemodynamics due to the retention of the left liver during ex vivo tumor resection, as well as the no need for resection and reconstruction of the inferior vena cava. The procedure of partial hepatectomy in vivo also avoids cold ischemia-reperfusion injury for the retention of the left liver.

While ELRAT has had increasing success as a treatment for patients with benign and malignant liver tumors, the risk of serious complications and even death during the perioperative period remains high. Previous studies have shown that the prognosis of patients with liver malignancies after ELRAT remains disappointing due to the high rates of recurrence and mortality after surgery (19). To date, the use of ELRAT for BTC patients remains limited (15, 26, 29, 31). Ameta-analysis of 53 studies included 244 patients who underwent ELRAT, of whom 160 (65.6%) had benign tumors and 84 (34.4%) had malignancies. The most common malignant lesions were colorectal cancer metastases (11.5%) and cholangiocellular carcinomas (9.4%) (19). The 30-day and 90-day mortality rate in the malignant subgroup was 11.3% and 21.6%, respectively, the one-year survival rate was 65.0%, and the rate of tumor recurrence during follow-up was 34.4% (19). Of the 23 cholangiocellular carcinoma cases, 21 had invasion of the major vessels. Four patients with intrahepatic cholangiocarcinomas (17.4%) died within 30 days of surgery, and only eight survived 12 months after surgery. Three patients experienced tumor recurrence. Liver allotransplantation was performed in eight (34.8%) patients (19). Another recent study demonstrated relatively favorable outcomes (15). The current study reported on ten patients who received ELRAT for conventionally unresectable hepatobiliary primary cancers or hepatic metastases, including eight with BTC. Encouragingly, the survival rate one month after surgery was 100%. One patient with BTC died from sepsis after two months while the remaining patients are currently alive, with a median follow-up of 8.5 months (range 6–16.5 months). To date, seven of the nine patients (77.78%) have had no cancer recurrence, including six with BTC.

In recent years, the efficacy of systematic treatments, including PD-1 inhibitors, targeted therapy, and chemotherapy, has been confirmed by many studies of hepatobiliary cancers and liver metastases of gastrointestinal malignant tumors, allowing large and initially unrectable tumors to become resectable (7, 11). Six of the ten patients in this study received preoperative systematic therapy, which effectively controlled the tumor and made radical surgery possible. This study also reports on the first four patients with BTC who were treated with systematic therapy using a combination of PD-1 inhibitor, lenvatinib, and chemotherapy, and then successfully received ELRAT with good outcomes.

ELRAT is a complex surgery that can facilitate radical resection in patients with malignancies. However, the effectiveness of this surgery remains controversial. In recent years, progress in the development of systematic therapies, such as PD-1 inhibitors and targeted treatment, may promote the use of ELRAT. The current study demonstrated relatively favorable outcomes and reported on the first five patients to receive IPH-ELRAT for advanced malignancies. These findings suggest that this may provide a new surgical option for patients with conventionally unresectable hepatobiliary malignancies, while also helping to alleviate organ shortages.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Institutional Review Board of the Second Affiliated Hospital, School of Medicine, Zhejiang University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

SX, CH, and ZJ collected case data. SX and CH wrote the manuscript. GL, BZ, ZG, WW and SY proofread and revised the manuscript. All authors contributed to the article and approved the submitted version.