Post-Transplant Outcomes in Patients with Previously Treated Extrahepatic Malignancies Undergoing Living Donor Liver Transplantation

Introduction

Liver transplantation (LT) is a well-established treatment option for patients with end-stage liver disease [1]. Some potential LT recipients present with a history of extrahepatic malignancy (EHM). Many current guidelines, however, regard EHM as a relative contraindication for living donor liver transplantation (LDLT) because of the potentially high risk of post-transplant tumor recurrence. The minimum mandatory tumor-free period for transplantation after curative cancer treatment usually depends on the type, stage, and grade of malignancy [2]. However, it is unclear whether a long wait-time is required, considering the possible life-threatening consequences of not undergoing LT. Indeed, few studies to date have evaluated the possible impact of EHM on patient prognosis after LDLT [2].

The present study therefore investigated the clinical outcomes of LT in patients with end-stage liver disease who were previously treated for EHM, focusing on EHM recurrence rates and long-term post-transplant survival.

Material and Methods

STUDY DESIGN AND PATIENT SELECTION:

The LT database at our institution was retrospectively searched to identify adult patients who underwent LDLT from January 2000 to December 2022. The study population consisted of adult LDLT recipients who received curative treatment for primary EHM at least 6 months before LDLT surgery.

All patients were followed up until November 2024 or patient death. Patient characteristics were recorded, including age at LDLT, sex, types of primary EHM, timing and method of EHM treatment, EHM stage based on American Joint Committee on Cancer (AJCC) staging Manual 8th edition [3], primary liver disease, presence of hepatocellular carcinoma (HCC), and LDLT timing. Post-transplant outcomes included EHM recurrence status and overall survival. The study was approved by the institutional review board of our institution (2025-0732).

PRETRANSPLANT EVALUATION IN ADULT PATIENTS WITH MALIGNANCIES:

Patients with HCC or other hepatic malignancies who were indicated for LDLT and those with a history of EHM before LDLT were screened prior to LDLT [4]. Screening evaluations included abdomino-pelvic and chest computed tomography (CT) scans, abdominal magnetic resonance imaging (MRI), 2-F18-fluoro-2-deoxy-D-glucose positron emission tomography, upper gastrointestinal endoscopy, and colonoscopy/sigmoidoscopy. The details of pre-LDLT evaluation have been described previously [5,6].

POST-TRANSPLANT IMMUNOSUPPRESSIVE REGIMENS:

The standard immunosuppressive regimens at our institution consisted primarily of interleukin-2 receptor blocker, intravenous or oral calcineurin inhibitors, and corticosteroids [7–10]. Patients who experienced adverse effects related to calcineurin inhibitors were administered mycophenolate mofetil, either in addition to or as a substitute for calcineurin inhibitors, to enhance the immunosuppression effect. Some selected patients were prescribed mammalian target of rapamycin (mTOR) inhibitors for HCC recurrence, newly diagnosed or de novo malignancy (DNM), or impaired kidney function. Because health insurance coverage in Korea did not include everolimus until early 2016, and because this treatment was excluded from our institution’s standard initial immunosuppressive therapy, its use in the present study was limited to a small number of patients.

POST-TRANSPLANT SURVEILLANCE FOR MALIGNANCY:

At our institution, adult LT recipients are subjected to a comprehensive routine surveillance protocol that includes chest radiography, abdominopelvic and thoracic CT imaging, endoscopic evaluations, tumor marker assessments, and breast and cervical cancer screenings. CT imaging is scheduled every 6 months for the first 3 years post-transplantation, annually for the following 2 years, and then every 2 years thereafter. Patients considered at elevated risk for cancer, such as those with HCC exceeding the Milan criteria or those with EHMs, are monitored more closely, particularly within the first 2 years after transplantation [11]. Patients with pretransplant EHM are assessed using specialized, disease-specific surveillance strategies.

STATISTICAL ANALYSIS:

Continuous variables are reported as means and standard deviations or medians and ranges. Overall survival and tumor recurrence rates were calculated using the Kaplan-Meier method. All statistical analyses were performed using SPSS version 22 (IBM, New York, NY, USA) and MedCalc version 23.2.1 (MedCalc Software Ltd, Ostend, Belgium).

Results

OVERALL PATIENT PROFILES:

Of the 6355 adult patients who underwent primary LDLT operation during the 23-year the study period, 109 (1.7%) patients were treated for EHM before transplantation. The demographic and clinical characteristics of these patients, including the diagnoses of primary EHMs, are described on Table 1. Mean age at LT was 57.2±8.5 years, and mean model for end-stage liver disease score was 15.5±8.8. Of the 109 included patients, 49 (45.0%) were concurrently diagnosed with HCC before LT, with 39 (79.6%) of the latter satisfying the Milan criteria.

The most common primary EHM was stomach cancer (n=30 [27.5%]), followed by thyroid (n=12 [11.0%]), breast (n=12 [11.0%]), colorectal (n=11 [10.1%]), and kidney (n=11 [10.1%]) cancer. The mean and median intervals between final EHM treatment and LT were 84.9±78.0 months and 27 months (range: 6–336 months), respectively (Figure 1)

During a mean follow-up period of 84.9±78.0 months, 15 patients (13.8%) died. The 1-, 5-, 10-, and 20-year overall patient survival rates were 96.3%, 88.5%, 85.0%, and 70.8%, respectively (Figure 2).

During the follow-up period, 5 patients (4.6%) experienced post-transplant recurrence of their primary EHM (lymphoma [n=3], stomach cancer [n=1] and breast cancer [n=1]). Of these 5 patients, 2 died due to sepsis during chemotherapy for lymphoma recurrence; 1 died due to stomach cancer recurrence/unrelated pneumonia; and another patient died due to progression of lymphoma recurrence. One patient with breast cancer recurrence has survived for more than 14 years with stable disease.

Post-transplant DNM occurred in 2 patients (de novo stomach cancer in a colorectal cancer patient after 1 year and de novo penile melanoma in a gallbladder cancer patient after 6 years); thus, the incidence of DNM was 1.8%.

The mean and median intervals between LT and recurrence of the pretransplant EHM were 71.6±82.8 months and 25 months (range: 19–213 months), respectively. The cumulative 1-, 5-, 10-, and 20-year recurrence rates of pretransplant EHMs were 0%, 3.1%, 4.6%, and 18.3%, respectively (Figure 3).

OUTCOMES OF PATIENTS WITH STOMACH CANCER:

Of the 30 patients treated for stomach cancer before LT, 23 (76.7%), 5 (16.7%), 1 (3.3%), and 1 (3.3%) were diagnosed with stages I, IIA, IIIA, and IIIB disease, respectively. Of the 30 stomach cancer patients, 25 (83.3%) underwent surgical treatment, including the 2 with stage III disease who also underwent adjuvant chemotherapy; and 5 (16.7%) who underwent endoscopic submucosal dissection.

One patient with stage IA stomach cancer who underwent subtotal gastrectomy 15 years prior to LT experienced stomach cancer recurrence 6 years after LT. This patient was treated with total gastrectomy, but died 1 year later due to pneumonia. Two other patients died of pneumonia and 1 died of HCC recurrence. The remaining 26 (86.7%) patients are alive without stomach cancer recurrence.

OUTCOMES OF PATIENTS WITH THYROID CANCER:

Twelve patients had been previously treated for thyroid cancer, including 10 with stage I and 2 with stage II disease. All of them underwent surgical resection with or without adjuvant radiotherapy. All 12 patients are alive without thyroid cancer recurrence.

OUTCOMES OF PATIENTS WITH BREAST CANCER:

Of the 12 patients with breast cancer, 1 had stage 0, 7 had stage I, 2 had stage II, and 1 had stage IIIA disease. All underwent surgical resection with or without adjuvant chemo-radiation therapy.

The patient with stage IIIA disease experienced lung and bone metastases of breast cancer 22 months after LT; this patient, who has since received chemotherapy, has survived for more than 14 years with stable disease. The other 11 patients are alive without breast cancer recurrence.

OUTCOMES OF PATIENTS WITH COLORECTAL CANCER:

Of the 11 patients who were diagnosed with and treated for colorectal cancer before LT, 1 had stage I, 5 had stage IIA, 2 had stage IIIA, and 1 had stage IVA disease. All 11 patients underwent surgical resection, with 4 also receiving adjuvant chemotherapy. None of these patients experienced colorectal cancer recurrence, although 1 died of de novo stomach cancer 18 months after LT.

OUTCOMES OF PATIENTS WITH KIDNEY CANCER:

The 11 patients with renal cell carcinoma were all diagnosed with stage I disease. These patients underwent surgical resection a mean 37.0±30.2 (range: 7–93 months) before LT. One patient experienced acute cellular rejection 22 months after transplantation, which caused a liver abscess and ultimately resulted in patient death. A second patient died of graft-versus-host-disease 7 months after LT. The other 9 patients are alive without kidney cancer recurrence.

OUTCOMES OF PATIENTS WITH OTHER CANCERS:

Of the 9 patients with lymphoma, 3 had stage IA, 3 had stage IIA, 2 had stage IIB, and 1 had stage IV disease. Eight of these patients received chemotherapy with or without radiotherapy at a mean 16.1±10.2 months before LT, whereas the ninth patient, who had conjunctival lymphoma, underwent surgical excision 17 months before LT.

The patient with stage IV lymphoma experienced a life-threatening condition due to acute-on-chronic hepatic failure. After a thorough evaluation of this patient and a multidisciplinary discussion, LDLT was performed, but the lymphoma recurred 2 years after LT, resulting in death.

One of the patients with stage IIA lymphoma experienced lymphoma recurrence 18 years after LT and died of sepsis while receiving chemotherapy. The other patient with stage IIA lymphoma also had tumor recurrence 18 years after transplantation, and died while receiving chemotherapy.

Of the 5 patients with prostate cancer, 3 had stage I and 2 had stage III disease. Three of these patients underwent surgical treatment and 2 received radiotherapy at a mean 82.0±29.4 months (range: 43–110 months) before LT. One of these patients died 1 year after LT due to pneumonia, whereas the other 4 are alive without prostate cancer recurrence.

All 4 patients with stage 0 to stage I cervical cancer underwent surgical resection a mean 146.0±91.1 months (range: 36–252 months) before LT. All 4 are alive without cervical cancer recurrence.

Two patients with stage IA endometrial cancer underwent surgical resection 8 and 11 years, respectively, prior to LT. Both are alive without endometrial cancer recurrence.

Of the 2 patients with lung cancer, 1 had stage IB non-small cell lung cancer (NSCLC) and was treated with radiotherapy 7 months before LT. This patient showed NSCLC recurrence 19 months after LT. The disease has remained stable after chemo-radiotherapy and the patient is still alive. The other lung cancer patient was treated with radiotherapy for left NSCLC 1 year before LT. One month later, this patient was diagnosed with a contralateral lung metastasis by video-assisted thoracic surgery biopsy. The process of LT in this patient was carefully evaluated after multidisciplinary discussions, including with the patient. This patient has survived for 10 years after LT without evidence of lung cancer recurrence.

The profiles of patients who underwent treatment for other uncommon EHMs before LT are summarized in Table 2. None of these patients experienced EHM recurrences, although 3 died of HCC recurrence.

Discussion

The general guidelines regarding the eligibility for LT of patients with a history of EHM remain conservative. Although long-term immunosuppression increases the risk of DNMs [12–14], the impact of immunosuppression on EHM recurrence in patients who have undergone LT has not been determined. In addition, significant improvements in cancer treatments have resulted in better patient prognosis and survival [15–20].

Low post-transplant tumor recurrence rates have been reported in studies of patients with treated for EHM prior to LT. For example, a German single-center cohort study of 606 adult LT recipients found that 37 of these patients had preexisting EHMs, including 26 with solid tumors and 11 with hematological malignancies. Of these 37 patients, 34 were tumor-free at the time of LT. The median interval from tumor diagnosis to LT was 44 months. After a median follow-up of 66 months, only 1 patient experienced EHM recurrence, with a stage IIIC colon carcinoma incidentally detected during LT. The cumulative 5- and 10-year EHM recurrence rates in these patients were 2.9% each. When limited to patients who underwent LT at least 6 months after treatment of EHM, as in the present study, no patient had post-transplant EHM recurrence. By contrast, the DNM rates at 5 and 10 years after LT were 6.8% and 14.6%, respectively. These results indicate that post-transplant EHM recurrence rates are low in properly selected patients, with survival not inferior to patients without EHM [21].

We previously reported post-transplant outcomes of 41 patients diagnosed with EHM shortly before LDLT and of 92 treated for EHM more than 6 months before LDLT. EHM recurrence rates were significantly higher (14.6% vs 3.3%; P=0.025) and survival rates lower (P=0.046) in the 41 patients with incidental EHM than in those treated for EHM. These findings suggested that patients with earliest-stage EHM detected shortly before LDLT can benefit from upfront LDLT combined with peri-transplant EHM treatment. In addition, carefully selected patients with previously treated EHM may be eligible for LDLT [22].

The results of this study showed that rates of EHM recurrence following LDLT are sufficiently low, suggesting that LDLT can be an acceptable treatment option for end-stage liver disease patients with previously treated EHM. The present study included patients with early-stage EHMs as well as more advanced EHMs, up to stage IV, who had been meticulously selected through a multidisciplinary approach.

Advances in medical care have increased the population of elderly persons, with transplant surgeons/physicians encountering more LT candidates with a previous history of EHM. Eligibility criteria for LT should be expanded rather than exempting all LT candidates with a history of EHM or adhering to a 2–5-year waiting period as suggested in treatment guidelines, while the liver function of these patients deteriorates [23,24]. The results of this study may contribute to establishing evidence-based guidelines for LDLT in patients previously treated for EHMs.

The oncological risk of treated EHMs should be compared with that of DNMs after LT. Post-transplant DNM is a major cause of late mortality, being the most common cause of death in the second decade after LT. The abovementioned German study of 606 adult LT recipients found that the EHM recurrence rate 10 years after LT was 2.9%, whereas the rate of DNM was 14.6% [21]. A Japanese study found that 24 (13.3%) of 180 adult LDLT recipients were diagnosed with DNMs, with 10- and 20-year DNM incidence rates of 11% and 20%, respectively [25]. An Indian study found that 21 (1.0%) of 2100 adult LDLT recipients were diagnosed with DNMs at a mean 42 months (range, 32–73 months) after LT [26], and a Turkish study reported that DNMs were present in 23 (0.8%) of 2814 adult LDLT recipients, at a median 36 months (range, 6–75 months) after LT [27]. In the present study, DNM was diagnosed in 1.8%.

The incidence of DNM gradually increases over time after LT. Extrahepatic DNMs have been reported in 45 (4.4%) of 1012 patients with and 25 (2.3%) of 1064 patients without pretransplant hepatic malignancy, with the rates of extrahepatic DNM after 8 years being 5.4% and 2.8%, respectively (P=0.006) [28]. These findings indicated that pretransplant hepatic malignancy was a significant risk factor for post-transplant de novo EHM.

The reported incidence of DNMs after LT ranges from 3.1% to 14.4%, with transplant recipients exhibiting a 2- to 3-fold higher risk than healthy individuals of similar age and sex. Prolonged use of immunosuppressive agents is widely recognized as contributing to this increased cancer risk. Nonetheless, the frequency and types of DNMs are influenced by a variety of factors, including demographic characteristics, the etiology of chronic liver disease, lifestyle habits such as tobacco and alcohol use, and the presence of premalignant conditions prior to transplantation. The standardized incidence ratios for specific DNMs vary accordingly. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has published guidelines regarding screening, tumor-specific surveillance, immunosuppression strategies, and cancer management [12]. These guidelines are also relevant for LT recipients with a history of EHM prior to transplantation.

This study had several limitations, including its retrospective design and its inclusion of a relatively small number of patients from a single institution. Despite these limitations, this study describes the largest single-center cohort of LDLT recipients analyzed to date. This study included patients a wide range of EHMs, each treated with differing therapeutic approaches, contributing to clinical heterogeneity. Multi-center studies involving larger patient populations and extended follow-up durations are needed to better understand the actual risk of EHM recurrence in LDLT recipients.

Conclusions

The findings of this study indicate that patients with previously treated EHMs may be considered for LDLT following careful multidisciplinary evaluation and implementation of individualized post-transplant surveillance strategies. Larger multi-center studies are needed to establish evidence-based guidelines for managing LDLT in patients with a history of EHM.