Pre-transplant existing extra-hepatic malignancy (EHM) has long been considered a contraindication to solid organ transplantation, because immunosuppressants raise the concern of de novo malignancy and recurrence of pretransplant malignancy (PTM) for recipients. Otherwise, transplantation is considered after ‘minimum cancer remission times’ (ranging from 1 to ≥5 years) have passed depending on the type of pre-existing malignancy involved [1,2]. Advances in medicine and cancer screening programs have led to more elderly patients being eligible for transplantation and an increased number of candidates diagnosed with malignancy before transplantation. Furthermore, hepatic dysfunction may disqualify patients from proceeding with proper therapy for their pre-existing malignancy, posing a dilemma for the surgeon who must decide whether to proceed with liver transplantation (LT) in expectation of future remission of the PTM or deem the patient ineligible for LT.

A previous study showed that cancer recurrence was low in carefully selected patients with pre-existing malignancy [3]. Recent guidelines from the International Liver Transplantation Society (ILTS) state that the assessment of the suitability and timing of LT in patients with a history of non-hepatic cancer should be multidisciplinary and include detailed cancer-specific treatment information [4].

In South Korea, living donor liver transplantation (LDLT) is the primary choice LT patients because of the shortage of liver grafts. Few studies have been published concerning LDLT in patients with PTM; most are based on patients whose cancer has been in remission for at least 1–2 years [1,2,4-7]. Recent or active malignancies in the perioperative transplant period have not been the focus of discussion.

In this study, we defined ‘concurrent (recent or active) extrahepatic malignancy (EHM)’ as a pre-existing EHM that underwent primary therapy before, during, or soon after transplant surgery. We analyzed the type of cancer, treatment timing, and survival outcomes of LDLT in adult patients with concurrent EHM.

Our study was designed as a single-institution, retrospective analysis. During a period of 27 years between May 15, 1996 and January 24, 2023, a total of 2,729 patients received LDLT at our transplant center.

After excluding 281 pediatric patients, 2,448 adult recipients were identified, of which 63 (2.6%) had a history of pre-existing EHM. Among the patients with EHM, we identified 16 recipients (25.4%) who either had active EHM at the time of LDLT or received treatment for EHM within 6 months of LDLT, which included treatment before, during, or after LDLT. These patients were classified as recipients with ‘recent or active EHM’ at the time of LDLT and were the focus of our study (Fig. 1).

Figure 1. Patient population. LDLT, living donor liver transplantation; EHM, extrahepatic malignancy.

We stratified the risk of malignancy according to each cancer type and stage based on risk classifications described in previous studies, such as the guidelines of the ILTS/Sociedad Española De Trasplante Hepático (SETH) Consensus Conference [4]. Gastric cancer was classified as low risk in cases of in situ or stage IA cancer, whereas stages IIB to III were classified as intermediate risk. Colorectal cancer was classified as low risk for stage I (T1/T2, N0, M0). In the case of lymphomas, non-Hodgkin’s lymphoma and locoregional Hodgkin’s lymphoma were seen as intermediate-risk malignancies. The risk of acute myeloid leukemia has not yet been determined in the literature. According to this classification, eight of the 16 patients (50.0%) had low-risk EHM, five (31.3%) had ‘intermediate-risk’, one (6.3%) had a high-risk malignancy, and two (12.5%) had an undetermined risk.

The long-term outcomes of patients with recent or active EHM at the time of LDLT were analyzed retrospectively. The timing of EHM treatment was classified as preoperative, intraoperative, or postoperative, based on LDLT. The treatment method for EHM was based on the electronic medical records. The interval between the date of EHM treatment and LDLT was calculated in days to highlight the most recent treatment of EHM. The primary outcomes were recurrence of EHM, recurrence of hepatocellular carcinoma (HCC) (if present), and patient survival. Finally, we distinguished between cancer-related and non-cancer causes of death. This study was approved by the Institutional Review Board of Samsung Medical Center (SMC-2024-07-131) and complied with the Declaration of Helsinki. As this was a retrospective analysis of de-identified data, the need for informed consent was waived.

The Kaplan-Meier method was used to estimate survival rates using log-rank tests. All statistical analyses were conducted using the IBM SPSS Statistics 22.0 (IBM Co., Armonk, NY, USA).

The sex, age, LT-related liver etiology, type, and stage of EHM, malignancy risk, baseline liver function (classified by Child-Pugh score), and treatment received for EHM of our 16 individuals are detailed in Table 1.

Table 1 . Patient characteristics.

Patient no.	Sex	Age (yr)	Liver etiology	Extrahepatic malignancy	EHM stage	EHM risk	Child-Pugh score (class)	EHM treatment regard to LDLT
1	M	62	HBV (acute)	Gastric cancer	IA	Low	12 (C)	Subtotal gastrectomy [intra]
2	M	59	HBV (cirrhosis), HCC	Gastric cancer	IA	Low	7 (B)	Subtotal gastrectomy [intra]
3	F	54	LC, HBV, HCC	Papillary thyroid carcinoma	I	Low	10 (C)	Total thyroidectomy CLND [post]
4	M	46	HBV (acute on chronic)	Diffuse large B-cell lymphoma	N/A	Intermediate	13 (C)	Chemotherapy (R-CHOP) [pre]
5	M	50	HBV (cirrhosis)	Diffuse large B-cell lymphoma	N/A	Intermediate	11 (C)	Chemotherapy (R-CHOP) [pre]
6	M	25	HBV (acute on chronic)	Hodgkin's lymphoma	IIB	Intermediate	11 (C)	Chemotherapy (ABVD) [pre]
7	F	50	Toxic/autoimmune(acute on chronic)	Thyroid cancer	I	Low	12 (C)	Total thyroidectomy CLND [pre]
8	F	47	Alcoholic (cirrhosis)	Cervical cancer	Ib1	Intermediate	10 (C)	Conization, whole pelvis radiation [pre]
9	M	64	HBV (cirrhosis), HCC	Gastric cancerGoblet cell carcinoma	IIIA	Low	5 (A)	ESD [pre]Right hemicolectomy [pre]
10	F	45	Toxic (acute on chronic)	Chronic myeloid leukemia	N/A	Undetermined	12 (C)	Targeted therapy (nilotinib) [pre]
11	F	54	HBV (acute on chronic)	Breast cancer	IIIA	High	12 (C)	Neoadjuvant chemotherapy (AC) [pre]
12	F	64	HBV (cirrhosis), HCC	Gastric cancer	IA	Low	5 (A)	ESD [pre]
13	F	56	Liver failure (unknown)	Acute myeloid leukemia	N/A	Undetermined	10 (C)	Chemotherapy (cytarabine) [pre]
14	F	62	HBV (cirrhosis), HCC	Gastric cancer	IIA	Intermediate	8 (B)	Subtotal gastrectomy [pre]
15	M	70	HBV (cirrhosis), HCC	Colon cancer	I	Low	9 (B)	Right hemicolectomy [intra]
16	M	55	Alcoholic (acute on chronic)	Colon cancer	I	Low	10 (C)	Low anterior resection [post]

M, male; F, female; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LC, liver cirrhosis; CLND, central lymph node dissection; N/A, non applicable; R-CHOP, rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone; ABVD, adriamycin, bleomycin, vinblastine, dacarbazine; ESD, endoscopic submucosal dissection; AC, adriamycin, cyclophosphamide..

EHM risk was ‘low’ for eight patients, ‘intermediate’ for five patients, ‘high’ for one patient, and ‘undetermined’ for two patients. Eleven patients underwent EHM treatment before LT, while two underwent post-transplant treatment (within 6 months of transplantation; patient no.3, 16). Three patients underwent EHM simultaneously with LDLT (patient no.1, 2, 15). Most patients’ liver function was classified as Child-Pugh class C, with a median Child-Pugh score of 10 points.

The survival outcomes of our patients are shown in Table 2, which distinguishes between non-hematologic EHM and hematologic EHM patients, and both groups of patients are listed in the order of ascending EHM risk.

Table 2 . Tumor recurrence between hematologic extrahepatic malignancy and non-extrahepatic malignancy groups.

Patient no.	EHM type	EHM stage	EHM risk	EHM recurrence	HCC recurrence	Death	Cause of death
1	Gastric cancer	IA	Low	No	N/A	Yes	Aspiration pneumonia
2	Gastric cancer	IA	Low	No	No	No	N/A
3	Papillary thyroid carcinoma	I	Low	No	Yes	Yes	Multiple lung metastasis due to HCC recurrence
7	Thyroid cancer	I	Low	No	N/A	No	N/A
9	1. Gastric cancer 2. Goblet cell carcinoma	1. I 2. IIA	Low	No	No	No	N/A
12	Gastric cancer	IA	Low	No	Yes	No	N/A
15	Colon cancer	I	Low	No	No	No	N/A
16	Colon cancer	I	Low	No	N/A	No	N/A
8	Cervical cancer	Ib1	Intermediate	No	N/A	Yes	N/A
14	Gastric cancer	IIA	Intermediate	Yes	No	No	N/A
11	Breast cancer	IIIA	High	Progressive	N/A	Yes	Septic shock due to bowel perforation
4	Diffuse large B-cell lymphoma	N/A	Intermediate	No	N/A	No	N/A
5	Diffuse large B-cell lymphoma	N/A	Intermediate	No	N/A	Yes	Septic shock, ARDS
6	Hodgkin's lymphoma	IIB	Intermediate	No	N/A	No	N/A
10	Chronic myeloid leukemia	N/A	N/A	No	N/A	No	N/A
13	Acute myeloid leukemia	N/A	Undetermined	No	N/A	Yes	Postoperative liver failure

EHM, extrahepatic malignancy; HCC, hepatocellular carcinoma; N/A, not applicable; ARDS, acute respiratory distress syndrome..

The mean follow-up period was approximately 57 months, and five of the 16 patients died during follow-up. Of these, only one cancer-related death occurred. One patient died due to postoperative liver failure and the other died 3 months post-surgery due to bowel perforation. Among the eight patients with low-risk EHM, no recurrence was observed. The rate of EHM recurrence or progression (12.5%) was lower than that of HCC recurrence (33.3%) on the last visit.

Overall survival rates were 87.5% for 1-year survival, 78.8% for 3-year survival, and 68.9% for 5-year survival. Finally, a Kaplan-Meier analysis comparing our hematologic EHM and non-hematologic EHM patients (Fig. 2) showed no significant difference in survival (p=0.891), despite a higher mean Child-Pugh class in hematologic EHM patients (class C [score=11.4] versus class B [score=9.1] in non-hematologic EHM patients).

Figure 2. Overall survival. (A) Overall survival from LDLT, (B) overall survival between hematologic EHM and non-hematologic EHM. LDLT, living donor liver transplantation.

Our study showed high survival rates for LDLT in adults with active or recently treated (within 6 months) extrahepatic malignancies, including cancers beyond a low-grade risk. In this study, we defined ‘concurrent EHM’ as a pre-existing EHM that underwent primary therapy within 6 months of transplant surgery (before, during, or after). We analyzed the type of cancer, timing of therapy, and long-term outcomes of LDLT in adults with active extrahepatic malignancies at our center. We were concerned about EHM recurrence after LDLT. The cumulative overall survival rates at 1-year, 3-year, and 5-year were 87.5%, 78.8%, and 68.9%, respectively. The number of EHM recurrences was low in only two cases. Compared to LDLT survival rates in Korea based on a recent study, our 1-year and 3-year survival rates appear similar to those of the general population [8]. In addition, the overall survival rates for hematologic malignancies are not different from those for non-hematologic malignancies.

When a concurrent malignancy is diagnosed during LT evaluation, it is typically considered a contraindication to LT. Otherwise, transplantation is considered after ‘minimum cancer remission times’ have passed, depending on the type of PTM involved [1,2,4,5,7,9-11]. EHM and chronic liver disease coexist in a considerable number of patients [7]. Guidelines recommend that candidates with active cancer should be excluded from LT, except for those with selected indolent or very low-grade cancers [4]. No recurrences were observed among the eight patients with low-risk EHM, supporting studies that suggest low-risk EHM patients can safely undergo LDLT even in an untreated or recently treated state [1,2,4,12]. The rate of HCC recurrence (if present) was higher than that of low-risk EHM recurrence, occurring in two of six patients with concurrent HCC.

The present study demonstrated that the rate of EHM recurrence or progression (12.5%) was lower than that of HCC (33.3%). Therefore, patients with HCC should be monitored regularly. A previous study also reported promising survival rates and low recurrence rates in LDLT recipients with concurrent EHMs when adequately managed and monitored perioperatively [12]. Similarly, a Japanese study reported that 14 patients with prior or concurrent extrahepatic malignancies showed a 5-year survival rate of 100% after undergoing LDLT; nine of the 14 patients were diagnosed with EHM during pre-LDLT assessments, and eight of these patients underwent LDLT first, in the setting of active EHM [13].

Evidence for LDLT outcomes in patients with high-stage EHMs is lacking, and our study is noteworthy in that it included patients with more advanced EHMs, including stage IIA to IIIA. Our cases underscore the importance of individualized patient management and the potential for successful LDLT outcomes, even in high-risk patients with extrahepatic malignancies. The cultural values of family-centered decision-making may play an additional role in the increasing proportion of LDLT, which is often the only option for many patients.

Our study has several limitations, including its single-institutional retrospective nature, heterogeneous cases, small sample size, and the lack of a control group. The heterogeneity of EHMs was not further analyzed, and variability in transplant regimens was inevitable considering the long study period (27 years). Nonetheless, our findings contribute to the growing body of evidence suggesting the need to reconsider traditional contraindications to LDLT in patients with concurrent EHM.

We suggest that concurrent EHM should not be a contraindication to LDLT, even when the minimum cancer remission times have not yet elapsed. LDLT may serve as both a life-saving option for liver failure and a bridge to therapy for concurrent EHM. Our study supported that, while challenges remain, the increasing evidence for the feasibility of LDLT in carefully selected patients with concurrent EHM suggests a shift toward more inclusive transplant candidacy. Long-term, multi-center studies are required to redefine the criteria and immunosuppression regimens for such patients.

This research was supported by the Basic Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2023R1A2C2005946).

The Korean NRF does not influence the study design, data analysis, data interpretation, or manuscript drafting.

Jongman Kim is a chief editor of the journal but was not involved in the review process of this manuscript. Any other authors have no conflict of interest.

Conceptualization: JHP, JK. Data curation: All. Formal analysis: JHP, JK. Funding acquisition: JK. Investigation: JK. Methodology: JHP, JK. Project administration: JK. Resources: JK. Software: JK. Supervision: JK, JWJ. Validation: JK. Visualization: JHP, JK. Writing – original draft: JHP. Writing – review & editing: JK.