While the long-term survival outcome following liver transplantation (LT) has improved, but hepatocellular carcinoma recurrence or de novo malignancy have been the major causes of patient death [1]. In fact, novo malignancy has been described as a leading cause of late mortality after LT [2]. Prolonged immunosuppression therapy is reported to increase the risk of de novo malignancy [3]. The development of de novo malignancy has been ascribed to a multifactorial combination of individual and regional predispositions to malignancy, pretransplant disease states, the type of immunosuppressive regimens, and elapsed time after LT. Because of high LT volume, the majority of studies on posttransplant novo malignancy have been performed in Western countries; hence, there is lack of information on de novo malignancy in Asian countries. Gastric cancer is one of the most frequent malignancies in Asian countries including Korea, Japan and China. In this study, we reviewed the incidence of de novo gastric cancer following LT in Asian countries.

De novo malignancies after liver transplantation: incidence comparison with the Korean cancer registry: A Korean single-center study [4]. Between January 1998 and December 2008, 1,952 adult LTs were performed, including 1,714 living donor and 238 deceased donor grafts, at the Asan Medical Center. Among them, 44 patients (2.3%) showed de novo malignancies after a mean posttransplant period of 41 months. Among the 14 types of malignancy the most frequent was stomach cancer (n=11; 25.0%), colorectal cancer (n=9; 20.5%), breast cancer (n=4; 9.1%), and thyroid cancer (n=3; 6.8%). These patients underwent aggressive treatment, including surgery, chemotherapy, and radiotherapy, except for one patient with an aggressive primary liver cancer. Over a mean follow-up of 45 months after the diagnosis of de novo malignancy, 13 patients (29.5%) died; the overall 3-year patient survival rate was 67.5%. The relative risk of malignancy following LT was 7.7-fold higher in males and 7.3-fold higher in females than the Korean general population. The authors concluded that LT recipients must be checked periodically for de novo malignancy throughout their lives, especially for cancers common in the general population.

De novo gastric cancer after liver transplantation: A Korean single-center study [5]. This study sought to identify clinicopathologic characteristics in gastric cancer patients after liver transplantation, and to help manage these cases. The authors investigated gastric cancer patients after LT at the Asan Medical Center. Authors analyzed the sex, age, cause of liver transplantation, initiation of immunosuppressant, pre-transplantation gastric fibroscopy findings, time interval between transplantation and gastric cancer occurrence, follow-up period, existence of gastric cancer screening, Helicobacter pylori infection, family cancer history, gastric cancer treatment, cancer location, size of tumor, macroscopic gross type, World Health Organization histologic type, Lauren's classification, Tumor-Node-Metastasis stage, and survival. Of 2,968 adult LT patients, 19 were diagnosed with gastric cancer. The mean age at the time of gastric cancer diagnosis was 60.2±6.8 (46–71) years, while the mean time interval between liver transplantation and the diagnosis of gastric cancer was 56.0±30.7 (3.20–113) months. Endoscopic submucosal dissection was done for 10 patients, 4 of whom underwent surgical resection. Surgical resection as an initial treatment was done in 8 patients. One patient received chemotherapy first. The standard incidence ratio of gastric cancer in these patients was 1,036 per 100,000 persons (95% Confidence Interval [CI], 623.7–1,619) in males and 318.9 per 100,000 (95% CI, 4.170–1,774) in females. In conclusion, early detection of de novo cancer is necessary for long-term survival of liver transplant patients. Therefore, annual screening for gastric cancer after liver transplantation is needed, especially in areas where the incidence of gastric cancer is high, such as South Korea.

Clinical outcomes of gastric cancer surgery after liver transplantation: A Korean single-center study [6]. This study aimed to investigate the feasibility and safety of gastric cancer surgery after LT. Seventeen patients underwent gastric cancer surgery after LT at a single institution between January 2013 and June 2021. The authors retrospectively collected data on surgical complications, survival, and the recurrence status of these cases. Fifteen patients (88.2%) underwent curative gastrectomy, with 10 open distal (66.7%) and 5 laparoscopic distal (33.3%) gastrectomies. Surgical and severe complication rates were 3 of 15 (20.0%) and 1 of 15 (6.7%), respectively. There were no significant differences between laparoscopic (33.3%) and open surgery (66.7%) in terms of operation time and complication rate. No surgery-related mortalities occurred. Immunosuppressants could be maintained without difficulty, and no suspicious acute rejection was identified during the perioperative period. There was one recurrence after curative surgery (recurrence rate, 6.7%), and the 5-year cancer-specific survival rate after curative surgery was 93.3%. The authors concluded that laparoscopic gastrectomy can be safely done even after LT in terms of postoperative complications and graft safety.

Survival benefit of early cancer detection through regular endoscopic screening for de novo gastric and colorectal cancers in Korean liver transplant recipients: A Korean single-center study [7]. Gastric cancer is one of the most common malignancies in both the Korean general population and LT recipients, and colorectal cancer prevalence is gradually increasing. Among 3,690 adult recipients who underwent LT from January 1999 to December 2013, the screening patterns and prognosis of 26 cases of gastric cancer and 22 cases of colorectal cancer were analyzed. For gastric cancer, the mean patient age was 54.6±6.2 years at LT and 59.5±6.7 years at cancer diagnosis, with a post-transplant interval of 60.2±29.8 months. Patients were divided into regular (n=18) and non-regular (n=8) screening groups, with early cancer found in 14 and 0 patients; their 2-year survival rates after cancer diagnosis were 93.1% and 33.3% (p=0.006), respectively. Endoscopic resection was successfully performed in 8 patients, all in the regular screening group. For colorectal cancer, the mean patient age was 53.3±6.1 years at LT and 58.1±6.7 years at cancer diagnosis, with a post-transplant interval of 54.3±38.0 months. Patients were divided into regular (n=19) and non-regular (n=3) screening groups, with early cancer found in 12 and 0 patients; their 2-year survival rates after cancer diagnosis were 92.3% and 33.3% (p=0.003), respectively. Endoscopic resection was successfully performed in 6 patients, all in the regular screening group. In conclusion, LT recipients are strongly advised to undergo regular screening studies for various de novo malignancies, especially cancers common in the general population. Regular endoscopic screening contributes to the timely detection of gastric and colorectal cancers, improving post-treatment survival outcomes.

National survey of de novo malignancy after solid organ transplantation in Japan: A Japanese multicenter study [8]. In Japan, there have been no national surveys on the incidence of de novo malignancy after solid organ transplantation, which is one of the leading causes of death in transplant recipients. A questionnaire was distributed to institutions that perform solid organ transplantation in Japan, and clinical information was collected from patients who underwent transplantation between 2001 and 2010 and who exhibited de novo malignancies. A total of 9,210 solid organ transplants (kidney, 49.9%; liver, 45.9%; heart, 0.9%; lung, 1.2%; pancreas, 1.9%; small intestine, 0.2%) were performed. A total of 479 (5.2%) cases of de novo malignancy were identified. The transplanted organs of the patients included the kidney (n=260, 54.8%), liver (n=186, 38.8%), heart (n=5, 0.1%), lung (n=18, 3.8%), pancreas (n=9, 1.9%), and small intestine (n=1, 0.02%). The most common malignancies were post-transplant lymphoproliferative disorder (n=87) and cancers of the kidney (n=43), stomach (n=41), large intestine (n=41), and lung (n=36). In conclusion, this is the first national survey of the incidence of de novo malignancy in Japan. Further study is required to identify the risk of de novo malignancy in organ transplant recipients in comparison to the general population, namely the standardized incidence ratio.

De novo malignancies after liver transplantation with 14 cases at a single center: A Chinese single-center study [9]. The authors analyzed the clinical characteristics, risk factors, and prevention of de novo malignant tumors after LT. Fourteen patients who underwent LT were identified as having de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed. Fourteen cases of de novo malignancies after LT occurred for an incidence rate of 1.94% (14/722), including 11 males (78.6%, mean age, 48 years) and 3 females (21.4%, mean age, 50 years). The mean period from transplantation to cancer diagnosis was 55.0±35.0 months. The distribution of tumor histologic types included colon cancer, lung cancer, esophageal cancer, nasopharyngeal cancer, liver cancer, parotid carcinoma, bone cancer, post-transplantation lymphoproliferative disorder, stomach cancer, bladder cancer, and laryngeal cancer. Twelve cases (85.7%) had hepatitis B. Five patients (35.7%) underwent operations, and the other 9 patients underwent chemotherapy or radiotherapy. During a mean follow-up period of 37.0±26.0 months after the diagnosis of de novo malignancy, 8 patients (57.1%) died, with only 1 dying of causes not related to the de novo malignancy. The survival analysis showed 1-, 5-, and 7-year survival rates of 85.7%, 71.4%, and 42.9%, respectively. De novo malignancies after organ transplantation have been suggested to be a major cause of late mortality. De novo malignancy after orthotopic LT was found to be related to smoking, sex, and low immune function due to immunosuppressive agents. Solid tumors should be removed, and the patient should receive chemotherapy or radiotherapy as early as possible. Early diagnosis and treatment are very important for improving the prognosis.

De novo malignancy after heart, kidney, and liver transplant: A nationwide study in Taiwan: A Taiwanese multicenter study [10]. In the Asian population, patterns and risk factors for de novo malignancies after solid-organ transplant are not well understood. Insurance claims from Taiwan's National Health Institute Research Database from 1997 to 2011 revealed 687 deceased-donor heart transplant recipients, 5,038 kidney transplant recipients (50% living related-donor, 50% deceased-donor transplants), and 2,127 LT recipients (mainly living related-donor transplants, 30% deceased-donor transplants). During the follow-up period, rates of malignancy incidence were calculated with standardization based on national age, sex, and year-specific incidence. We used multivariate regression analyses to determine risk factors of posttransplant de novo malignancies. Compared with the general population, several de novo cancers were more common posttransplant (p<0.05): lung cancer (2.6-fold), non-melanoma skin cancer (5.8-fold), and non-Hodgkin lymphoma (5.4-fold) in heart recipients; transitional cell carcinoma (31.4-fold), renal cell carcinoma (37.3-fold), and non-Hodgkin lymphoma (3.6-fold) in kidney recipients; and gastric cancer (3.0-fold) and lymphatic-hematopoietic malignancy (4.5-fold) in liver recipients. Independent risk factors for posttransplant malignancy in kidney transplant recipients were increased age, female, hepatitis B virus, and mycophenolate use (adjusted hazard ratio 1.5; 95% CI, 1.2–1.8; p<0.001). In LT recipients, old age was an independent risk factor. Kidney transplant recipients without diabetes or hypertension had higher risk of transitional cell carcinoma (adjusted hazard ratio 3.0; 95% CI, 2.1–4.4; p<0.001) and renal cell carcinoma (adjusted hazard ratio 1.9; 95% CI, 1.1–3.3; p<0.05). In conclusion, regional endemic epidemiologic factors play significant roles in the development of de novo cancers, particularly in kidney transplant recipients due to causes of renal failure other than diabetes and hypertension. Each regional organ transplant program should tailor and establish its surveillance protocol based on epidemiologic data. However, the type and intensity of surveillance require further and long-term investigations in this patient cohort.

This review confirmed that gastric cancer is one of the most common de novo malignancies following LT in Asian populations. Patterns of de novo malignancies differed in Western and Asian countries, suggesting that the occurrence of malignancy is influenced by various racial and social factors, including endemic circumstances [1,7,9,10]. In Korea, the most frequent malignancies after LT were stomach cancer and colon cancer in males and breast cancer in females, with a relative risk >10-fold higher compared with the Korean general population [4,7,11].

LT recipients should be screened periodically for the cancers common in the general population, which can lead to timely detection of de novo cancers [12]. In Korea, where the incidence of gastric cancer is very high, there is a nationwide health screening program for stomach cancer for all individuals over 40 years age. The detection of early cancer also enabled less invasive endoscopic mucosal resection. The survival outcomes of patients with less aggressive cancers, such as thyroid and breast cancers, are more favorable when the tumors are detected through routine screening. Since these screening guidelines are compatible with the general recommendations of the Korean nationwide social health program, most of these examinations are cost-free to the general population in Korea [13].

To date, it is still not proven that routine screening for gastric cancer after LT improves patient survival. However, the prognosis of de novo gastric cancer in LT patients was thought to be acceptably favorable because gastric cancer could be detected at a relatively early stage [7,14]. In LT recipients, additional gastric cancer surgery is more difficult owing to severe postoperative adhesions, changes in lymphatic drainage, and the risk of graft loss with vascular injuries. Therefore, with respect to perioperative mortality and morbidities, early detection and early management measures, such as endoscopic mucosal resection or endoscopic submucosal dissection, would be attractive options to avoid these difficulties in LT recipients [15]. However, if lymph node metastasis is suspected at the time of diagnosis, radical gastrectomy with lymph node dissection should be performed [5].

Along with the recent preference for laparoscopic gastrectomy, it has been performed even in the LT recipients with gastric cancer. The world-first case of totally laparoscopic distal gastrectomy for gastric cancer was performed in a 63-year-old man who underwent LT for cryptogenic liver cirrhosis [16]. Eight years later, gastric cancer was diagnosed during the follow-up. Endoscopic submucosal dissection was performed and additional surgical resection was needed. Totally laparoscopic distal gastrectomy and D1+ lymph node dissection were performed, and the patient was discharged on the 8th postoperative day without any complications. Laparoscopy-assisted distal gastrectomy for gastric cancer was also performed in a 72-year-old LT recipient [17]. In a Korean single-center study, 5 of 15 LT recipients successfully underwent laparoscopic distal gastrectomy [6].

In conclusion, LT recipients should be checked periodically for de novo malignancy throughout their lives, especially for cancers common in the general population, such as gastric cancer. Aggressive surgical treatment contributes to the improvement of post-treatment survival outcomes.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: CSP. Data curation: All. Investigation: All. Methodology: All. Supervision: CSP. Validation: CSP. Writing - original draft: All. Writing - review & editing: All.