Due to advancements in liver transplantation (LT) techniques, postoperative management, and the development of immunosuppressive agents, long-term survival after LT has markedly improved. However, long-term transplant survivors undergoing long-time immunosuppression face concerns about the potential risk of de novo malignancy (DNM) due to the direct oncogenicity of immunosuppressive agents and susceptibility to viral infections. Kim et al. [1] reported a study on the long-term outcomes of patients who underwent LT at a single big center over two years from January 2000 to December 2001. The 20-year survival rates after LT were reported to be 62.6% for adult living donor transplants, 68.2% for adult deceased donor transplants, and 77.3% for pediatric transplants. In the study analyzing post-transplant deaths occurring three months later, the most common causes were pneumonia and graft failure, followed by DNM. According to a study by Åberg et al. [2] in 2015, comparing mortality rates of 3,299 North European liver transplant patients from 1985 to 2009 with the general population, patients surviving over one-year post-transplant had a 2.4 times higher risk of death compared to the general population. Notably, those under 75 years old showed a 5.8 times higher risk of mortality. The leading causes of death one-year post-transplant were malignancies, recurrence of liver disease, and cardiovascular diseases, in that order. In conclusion, the incidence of DNM is higher in long-term survivors, emphasizing the need for increased vigilance, especially in the meticulous screening for malignancies compared to the general population. Based on another study utilizing the Canadian Cancer Registry, it is evident that young transplant patients experience a higher incidence of malignancies compared to the general population. Moreover, the occurrence of malignancies significantly rises after the age of 45 in these patients. This study indicates that the incidence of DNM increases within the first year after LT, with a notable surge in mortality due to malignancies occurring between 1- and 7-years post-transplant. Therefore, regular surveillance is crucial from the first year of LT, particularly for young patients who may necessitate more proactive surveillance and treatment strategies [3].

Table 1 provides a comprehensive overview of research on the incidence of DNM after LT in both Western and Asian populations [3-12]. The incidence rate is typically expressed as the standardized incidence rate (SIR), indicating malignancy occurrence relative to the general population. In the United States, as per the United Network for Organ Sharing registry [4], post-transplant lymphoproliferative disorder (PTLD), skin cancer, and head and neck cancer are common DNMs, while prostate and breast cancer are less frequent. Similar trends are observed in the Canadian organ replacement registry database [3], and Italian studies indicate a comparable prevalence of cancer types, with notable proportions of gastric and colorectal cancers in their datasets [5]. According to an interesting study by Haider et al. [13], the investigation into the reasons for readmission of liver transplant patients in the United States from 2016 to 2018 revealed that 7.28% of readmissions were due to DNM. Racial disparities in DNM incidence are identified, with Hispanic patients showing a predisposition to PTLD, gastrointestinal, and urinary cancers, while black patients exhibit higher incidences of lung and reproductive organ cancers. White patients demonstrate higher incidences of PTLD, lung cancer, skin cancer, head and neck cancers, among others. This racial variability underscores diverse DNM patterns among different ethnic groups. Summarizing the overall pattern of DNMs in Western countries, PTLD is the most common, with a higher incidence of skin cancer, lung cancer, and head and neck cancer. The SIR for solid organ cancers is approximately double that of the general population, while for hematological malignancies, it is around 30 times higher. Interestingly, the SIR for prostate cancer and breast cancer is reported to be lower compared to other cancer types.

Table 1 . De novo malignancy (DNM) incidence and standardized incidence rate (SIR) in Western country and East Asia.

Author	Country	Year	Total patients (n)	DNM patients (n)	Transplantation period	SIR	DNM incidence (%)
Jiang et al. [3]	Canada	2008	2,034	113	1983–1998	2.5	5.6
Engels et al. [4]	USA	2011	37,888	1,563	1995–2004	2.1	4.1
Taborelli et al. [5]	Italy	2019	2,832	266	1985–2014	1.8	9.4
Sérée et al. [8]	France	2018	11,226	1,200	1993–2012	2.2	10.7
Park et al. [6]	Korea	2012	1,952	44	1998–2008	7.7 (M), 7.3 (F)	2.3
Shin et al. [9]	Korea	2013	1,180	34	1995–2010	–	2.9
Kaneko et al. [10]	Japan	2013	360	27	1996–2012	1.8	7.2
Gao et al. [11]	China	2015	466	14	2005–2012	9.5	3.0
Park et al. [12]	Korea	2019	3,822	213	2007–2015	3.43 (M), 2.30 (F)	5.6
Kim et al. [7]	Korea	2021	1,793	70	1988–2018	–	3.9

M, male; F, female; –, not available..

In comparison to the Western world, the incidence of post-transplant cancer in Asia, particularly in South Korea, shows a different pattern. Researchers like Park et al. [6] and Kim et al. [7] conducted studies in major transplant centers in South Korea and found consistent results. Their studies identified a high prevalence of PTLD, stomach cancer, colorectal cancer, lung cancer, prostate cancer, and breast cancer among post-transplant patients. The incidence of stomach and colorectal cancers was notably higher among transplant recipients in Korea, which is consistent with the overall cancer landscape in the Korean general population. Interestingly, they also found an increased occurrence of cancers like prostate and breast, which are less common in Western countries.

There are several factors that can contribute to the development of DNM. These factors include the use of immunosuppressive drugs in transplant recipients, which can make them more susceptible to viral infections that have oncogenic properties, ultimately leading to DNM. For example, PTLD is associated with Epstein-Barr virus (EBV), while Kaposi sarcoma is related to human herpesvirus. Other underlying conditions like primary sclerosing cholangitis (PSC) and alcoholic liver cirrhosis can also contribute to DNM. PSC is correlated with colorectal and skin cancers, while alcoholic liver cirrhosis is related to head and neck cancer, lung cancer, colorectal cancer, and other cancers. Lifestyle habits such as smoking, alcohol consumption, sunlight exposure, and dietary factors are also recognized as factors influencing the occurrence of DNM. Smoking is associated with lung cancer, head and neck cancer, stomach cancer, and colorectal cancer, while alcohol consumption is related to colorectal cancer among others. Sunlight exposure is linked to skin cancer, while dietary factors are associated with stomach cancer, among others [14].

PTLD

PTLD is known to occur in 1% to 5.5% of LT patients, with a higher risk when the recipient is EBV seronegative and receives an organ from an EBV seropositive donor. PTLD can develop within a month after LT and may continue to occur for decades. The risk is increased in patients with strong immunosuppression or immunosuppressive agents like azathioprine, calcineurin inhibitors (CNIs), or anti-thymocyte agents. PTLD is recognized as a major complication in both Western and Eastern transplant patients [15].

Stomach Cancer

According to studies reported by various centers in South Korea, except for PTLD, gastric cancer is the most commonly occurring DNM. In a retrospective study conducted by Gong et al. [16] in 2016 involving 19 patients who developed gastric cancer after LT, they suggested that annual screening for post-transplant gastric cancer contributes to early detection and improves patient survival rates. Additionally, Kim et al. [17] emphasized the importance of annual endoscopy and computed tomography (CT) scans, reporting that laparoscopic gastrectomy can be safely performed in patients requiring surgical treatment for gastric cancer after LT. Another study suggested that in terms of surgical treatment, only active surgery following early diagnosis could be expected to have non-inferior mortality rates for transplant recipients compared to the general population [18].

Lung Cancer

In 2023, a meta-analysis was conducted to investigate the occurrence of lung cancer after LT. The study combined data from 15 different studies involving 76,897 liver transplant recipients. The results showed that the incidence of lung cancer was twice as high among these patients compared to the general population (SIR: 2.06). It is worth noting that low-dose chest CT screening was recommended for patients who had risk factors such as a history of smoking or alcoholic liver disease [19]. In another study comparing the survival rates, there was no significant difference in survival between liver transplant recipients and the general population. However, it was notable that liver transplant recipients had a higher rate of early screening. Additionally, when comparing liver transplant recipients with lung cancer to the overall transplant population, a significantly lower survival rate was observed, emphasizing once again the importance of appropriate screening for early diagnosis [20].

Colorectal Cancer

Risk factors for de novo colorectal cancer include primary PSC, non-alcoholic fatty liver disease (NASH) with hepatocellular carcinoma (HCC), obesity, and smoking. Studies on de novo colorectal cancer vary in conclusions across different countries. A multi-center study in the United Kingdom reported that LT alone does not increase the risk of colorectal cancer. However, patients with PSC or ulcerative colitis (UC) were found to have a significantly higher risk [21]. On the other hand, a meta-analysis in the United States suggested that even in the absence of autoimmune-related liver disease, the incidence of colorectal cancer in liver transplant recipients is nearly doubled compared to the general population [22]. In a South Korean study, out of 8,734 patients who underwent liver and kidney transplantation, 66 cases of colorectal cancer were identified. Among them, 33 patients, excluding those with endoscopic resection and 4-stage patients, underwent surgery, and their outcomes were reported. There were no PSC or UC patients in this group. The analysis showed that the incidence of colorectal cancer in liver transplant recipients was 3.10 times higher in men and 2.25 times higher in women compared to the general population. Survival analysis revealed that stage 1 patients did not have significantly lower overall survival than the general population, and even stage 2-3 patients did not show extremely poor survival rates. The study emphasizes the necessity of early diagnosis and suggests that early treatment does not worsen the survival rate compared to the general population [23].

Other DNMs

As mentioned earlier, DNMs such as prostate cancer or breast cancer have been reported to have lower incidence rates in the general population in Western countries. However, in Korea, prostate cancer is considered one of the cancers with a high incidence rate, and it is known to occur in transplant recipients occasionally. Therefore, regular screening is recommended according to the surveillance guidelines for the general population. On the other hand, skin cancer is prevalent in Western countries and is also frequently observed in the DNM of Western transplant recipients. Skin cancer is associated with risk factors such as excessive sun exposure or the use of azathioprine. A full-body skin examination by a dermatologist is crucial for diagnosis. Various non-melanomatous skin tumors, including melanoma, squamous cell carcinoma, and basal cell carcinoma, can occur. However, skin cancer incidence is reported to be very low in Korea.

The well-known guidelines for “post-liver transplantation de novo malignancies (DNM)” are the ILTS-SETH Consensus Conference Guideline published in the Transplantation in 2022. These guidelines provide detailed recommendations on post-transplant screening methods and intervals for various types of cancers. In summary, it is as follows: annual full-body skin exams for skin cancer and annual colonoscopies for individuals with inflammatory bowel disease or PSC. Liver transplant recipients with NASH/HCC after age 50 are advised colonoscopies every five years. Ex-smokers should undergo annual low-dose CT chest scans for lung cancer, and those with oropharyngeal/head and neck cancers should have annual ENT (ear, nose, and throat) exams. Females require annual pelvic exams, Papanicolaou tests, and human papillomavirus testing for cervical/vulvar/vaginal cancer screening. Mammography is recommended annually for breast cancer, and males should follow general population guidelines for prostate-specific antigen screening. Individuals with a history of renal cell cancer, polycystic kidney disease, or Von Hippel-Lindau disease should undergo annual CT abdomen scans for renal cancers.

However, liver transplant recipients in Korea exhibit a DNM occurrence pattern similar to that of the general population, presenting a different trend than Western countries. Excluding PTLD, gastric cancer is the most common, and colorectal cancer unrelated to PSC/UC is also frequently reported. Therefore, directly applying the screening methods recommended by the ILTS guidelines may not be appropriate in Korea, and modifications seem necessary. Furthermore, in Korea, there is a national cancer screening program targeting the entire population. This program recommends screening for five prevalent cancers in Korea—stomach, liver, colorectal, breast, and cervical cancers—and providing financial support for the screenings. Effectively utilizing this system for screening DNM would likely be efficient. Although lung cancer is not included in the free screening, a low-dose CT is recommended every two years for high-risk individuals. On the other hand, due to the common occurrence of stomach and colorectal cancers as DNM, it is recommended to personalize endoscopy screening intervals based on age and prior screening history. A previous study analyzed and recommended approaches in this regard [24]. Considering the situations, the author has outlined the recommended screening for DNM for LT patients in Table 2.

Table 2 . Recommended protocol for de novo malignancy screening.

Cancer type	Risk factor	Screening method	Screening interval	Remarks
Gastric cancer	Age under 40 years	Upper endoscopy	Every 2 years
	Age 40 years and above	Upper endoscopy	Every 2 years	National Cancer Screening Program
	Age 40 years and above	Upper endoscopy	Every 1 year	Previous endoscopy with intestinal metaplasia (+)
Lung cancer	Smoking history (+)	Low-dose chest CT	Every 2 years	National Cancer Screening Program
Colorectal cancer	PSC/UC	Colonoscopy	Every 1 year
	Age under 50 years	Colonoscopy	Every 5 years
	Age 50 years and above	Colorectal screening (stool occult blood)	Every 1 year	National Cancer Screening Program, follow-up colonoscopy if abnormal
		Colonoscopy	Every 3–5 years
		Colonoscopy	Every 1–3 years	Previous colonoscopy with adenoma (+)
Breast cancer	Age 40 years and above (females)	Mammography	Every 2 years	National Cancer Screening Program
Prostate cancer	Age 50 years and above (males with symptoms)	PSA, DRE	Every 1 year
Cervical cancer	Age 20 years and above (females)	Pap smear	Every 2 years	National Cancer Screening Program

CT, computed tomography; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; PSA, prostate-specific antigen; DRE, digital rectal exam; Pap, Papanicolaou..

When a DNM is detected in liver transplant recipients, the treatment strategy can be divided into two main approaches. Firstly, immunosuppressant reduction is considered. Drugs like tacrolimus and cyclosporine, which belong to the CNI class, are known to decrease antiviral immunity, induce DNA damage, and upregulate cytokines promoting tumor growth. Therefore, upon DNM diagnosis, minimizing the use of CNIs is essential. Additionally, mTOR inhibitors or mycophenolate mofetil are recommended as they do not increase the risk of DNM and can reduce the need for CNIs. Secondly, aggressive local treatment, including surgery, is recommended upon early detection. As mentioned earlier, for gastric cancer, active interventions such as endoscopic submucosal dissection or surgical treatment are advisable. Similarly, for colorectal cancer, initiating prompt treatment can lead to a favorable prognosis.

This study investigated the occurrence patterns of prevalent DNMs in various countries using SIR analysis based on several papers. Additionally, it was observed that the types of cancers prevalent in the general population in Korea are similar to those commonly occurring as DNMs after LT. This suggests the need for transplant centers worldwide to develop screening and management strategies tailored to the types of cancers that occur more frequently based on regional and racial characteristics. Naturally, the screening strategies for DNM emphasized in this study are based on cancer incidence rates in Korea, which may limit their global applicability. Therefore, the author hopes that this paper serves as a catalyst for countries with a high prevalence of LT to conduct their research tailored to their respective situations and cancer incidence rates. However, regardless of differences in cancer incidence rates among countries, adherence to well-established guidelines for screening intervals and methods for prevalent cancers is essential. Referring to recognized guidelines such as the ILTS-SETH guidelines or the recently published APASL guidelines would be appropriate [14,25].

Liver transplant recipients face a twofold increased risk of solid organ malignancies and approximately a 30-fold increased risk of hematologic malignancies compared to the general population. Among various DNMs, PTLD is the most common. The types and patterns of DNM vary globally based on regional and lifestyle factors. In South Korea, gastric, colorectal, lung, prostate, and breast cancers are commonly diagnosed, emphasizing the importance of regular screening for post-liver transplant survivors. Upon discovering a DNM, minimizing CNI usage and actively pursuing local treatments offer a promising prognosis.

There was no funding related to this study.

All authors have no conflicts of interest to declare.