The recent advances in surgical maneuvers and perioperative care, as well as optimized use of immunosuppressive agents, have improved the clinical outcomes of LTx. Among the adult population; however, de novo malignancy has been reported as one of the major causes of late mortality after LTx. Non-Hodgkin lymphoma, skin cancer, and Kaposi’s sarcoma have been reported as the most common malignancies developing after LTx [7]. Several major risk factors have been associated with the development of de novo malignancy after LTx, including advanced age, alcohol consumption, smoking, oncogenic viruses, long-term use of immunosuppressive drugs, and others [8]. The impaired anti-carcinogenesis actions of T lymphocytes, macrophages, and natural killer cells for immune surveillance, delaying tumor progression, and preventing angiogenesis, vascular invasion, and metastasis have been proposed as the mechanisms by which tumorgenesis develops in patients with immunosuppressive therapy [9]. Helicobacter pylori and EBV infections have also been known as risk factors for gastric cancer in patients with LTx, with the eradication of these microorganisms possibly being necessary for reducing the risk of de novo gastric cancer in transplant recipients [10]. However, the present patient exhibited no obvious specific findings to suspect Helicobacter pylori infection, with his tumor specimen being immunopathologically negative for EBV. A family history of tongue cancer in his father and the use of tacrolimus had been considered to contribute toward the development of de novo gastric cancer in the present case.
In particular, de novo gastric cancer developing after LTx is rare in Western countries. A study in South Korea reported that de novo malignancy occurring after LTx in adults most commonly develops in the stomach, with an incidence rate of 0.64%—a figure higher than that in Western countries [11]. Recently, a national survey in Japan had published findings regarding de novo malignancies developing after solid organ transplantation in adult patients [2], with post-LTx malignancy most frequently involving sites of being PTLD (18.3%), lung cancer (12.9%), colon cancer (11.8%), and stomach cancer (10.2%). Thus, Asian countries including Japan, have higher incidence rates of de novo gastric cancer after LTx compared to Western countries, which could be attributed to differences in patient characteristics.
Meanwhile, PTLD has been reported to be the most common and important post-LTx-associated malignancy among pediatric patients, with prevalence rates ranging from 2–27% [3, 4], accounting for 80% of all de novo malignancies [12]. The development of PTLD in pediatric patients is usually secondary to EBV infection and immunosuppression [13]. However, de novo solid malignant tumors are generally rare in pediatric patients who receive LTx. A previous survey from Turkey on de novo malignancy in pediatric patients receiving LTx for BA reported that 13/206 (6.3%) pediatric patients with LTx were diagnosed with de novo malignancies, including 7 patients with BA [6]. Among them, one case of liver sarcoma had been included as a de novo solid malignant tumor. Moreover, only one case of solid organ malignancy after LTx for BA had been reported. Accordingly, this case involved de novo hepatocellular carcinoma occurring 14 years after LTx for BA, which developed from progressive liver fibrosis in the absence of underlying viral infections [5]. To the best of our knowledge, no report has been available on patients developing gastric cancer after LTx for BA.
As described earlier, prolonged immunosuppressive therapy may increase the risk of developing de novo malignancy, with one study identifying tacrolimus as an independent risk factor for post-transplant malignancy developing in patients who had undergone renal transplantation [14]. Indeed, studies have showed that tacrolimus was associated with the risk of solid organ tumors, not limited to gastric cancer [10]. Given that the present case had been receiving tacrolimus for approximately 19 years after LTx, such long-term use of tacrolimus might have contributed to the development of gastric cancer. Although careful selection of immunosuppressive drugs could be a preventive measure against post-transplant malignancy, no replacement for tacrolimus is available in the current clinical settings throughout Japan. A previous analysis of adult LTx recipients who had received tacrolimus revealed a dose–response relationship between tacrolimus and the occurrence rate of solid cancer [15]. However, we could not find any study indicating a safe tacrolimus trough for the prevention of carcinogenesis. Therefore, careful monitoring of tacrolimus levels to avoid excessive immunosuppression is imperative.
To reduce cancer-related mortality and morbidity, early detection and treatment of post-transplant and ordinary malignancies are crucial. Generally, patients who develop de novo malignancies after organ transplantation tend to present with advanced disease stage upon diagnosis, resulting in poor prognosis [16]. We did not consider providing any additional examinations in the present case apart from the routine blood tests (e.g., for malignancy screening) until after the patient started complaining about his symptoms. Had earlier upper gastrointestinal endoscopy been scheduled, his gastric cancer might have been detected and treated at an earlier stage. However, to date, no protocol for cancer screening after organ transplantation has yet been established in Japan, even for adult patients. Considering the expected increase in the number of long-term survivors following LTx for BA, strategies for long-term follow-up should be established to enable the timely detection and treatment of de novo malignancies. We recommend upper and lower gastrointestinal endoscopic examination at least once a year among organ transplantation recipients considering the higher incidence rates of de novo gastric and colorectal cancer in Japan compared to Western countries. Moreover, pediatric patients with organ transplantation should receive careful surveillance for solid organ malignancies.
