Endoscopic management of early esophageal cancer in patients with concomitant cirrhosis

To the Editor: Based on a recent study examining the burden of digestive diseases in China and its provinces from 1990 to 2019, esophageal cancer ranks as the third leading cause of death among neoplastic digestive diseases, while cirrhosis has the highest incidence among non-neoplastic digestive diseases.[1] Recent advancements in endoscopic techniques have significantly enhanced the ability to diagnose and treat early esophageal cancer (EEC). However, managing EEC in cirrhotic patients presents a complex challenge due to the unique pathophysiological changes associated with portal hypertension and abnormal liver function resulting from liver cirrhosis. Endoscopic treatment is complicated by the need to avoid or manage massive hemorrhage from injured varices and to overcome the submucosal fibrosis caused by previous preventive modalities. This study reviews the latest clinical research findings on the endoscopic management of EEC in patients with liver cirrhosis, providing valuable insights for endoscopists. Besides, the published reports, which focus on cases of endoscopic treatment of early esophageal lesions in patients with liver cirrhosis, have been summaried in Supplementary Table 1, https://links.lww.com/CM9/C187. Management of esophageal varices (EVs): At present, endoscopic variceal ligation (EVL) is the most widely utilized modality for variceal eradication. However, the management of EVs before or during endoscopic resection (ER) in cirrhotic patients remains controversial. Considering the potential risk of procedure-related massive bleeding, ER is only recommended in patients who previously underwent variceal eradication. The optimal interval between ER and EVL for esophageal lesions is another important consideration. A recent study reported that varicose vein size was significantly reduced or completely disappeared 4 weeks after EVL, with no evident submucosal adhesion.[2] In addition, ulcers usually heal within 3-4 weeks post-EVL, with necrosis and fibrosis limited to the mucosa and submucosa. These findings suggest that a 4-week interval between ER and EVL may be optimal for eliminating varicose veins. Importantly, repeated EVL may lead to more severe submucosal fibrosis and should be avoided. Endoscopic injection sclerotherapy (EIS) has also been applied in the treatment of EVs in EEC patients.[3] The severity of submucosal adhesions during resection and the appropriate interval between ER and EIS in these cases remains poorly understood; moreover, EIS induces submucosal fibrosis, complicating ER treatment in EEC.[3] Furthermore, some scholars have reported that EIS may cause secondary esophageal and gastric cardiac cancer.[4,5] The eradication of EVs may take time with EIS, whereas EVL can achieve this effect more expeditiously. Thus, EVL may be superior to EIS in practical applications. Transjugular intrahepatic portosystemic shunt (TIPS) implantation followed by ER also appears to be a promising strategy in treating EVs. TIPS may reduce the risk of hemorrhage during the ER procedure by relieving portal pressure. More importantly, submucosal adhesions are minimized during subsequent endoscopic therapy. A retrospective study revealed frequent intraoperative bleeding in patients who underwent EVL before undergoing endoscopic submucosal dissection (ESD), but less intraoperative bleeding was measured in patients who underwent TIPS 4 weeks before ESD.[2] Hence, TIPS implantation at least 4 weeks before ER may represent a superior option to achieve the eradication of varicose veins without submucosal fibrosis. However, TIPS carries procedural and hepatic encephalopathy risks, and further studies are required to assess the safety and efficacy of this approach. Depending on the specific location of the esophageal lesion, such as the esophagogastric junction, EVL or EIS of varices may be difficult to perform before endoscopic therapy. In this setting, visible varices can be coagulated and transected directly with hemostatic forceps during the procedure.[6] Another advantage of this method is that EVs can be treated simultaneously by cutting off varices during ESD. Nonetheless, direct varices coagulation may only be applied to small varices; if large EVs are encountered, direct variceal coagulation may increase the risk of massive hemorrhage, and preventive modalities should be performed first, such as EVL or TIPS. Management of coagulation disorder: Despite the absence of severe bleeding, low platelet counts and a high international normalized ratio may result in a small amount of oozing, which prolongs the ER procedure duration as hemostasis must be secured. Therefore, infusion of fresh frozen plasma and platelets is often administered to improve coagulopathy before endoscopic therapy. Consequently, the difficulty and duration of the procedure are effectively decreased.[7] ER techniques: ESD is one of the main techniques used to treat EEC with cirrhosis and EVs. Based on our literature search, a total of 241 patients with EEC and cirrhosis received ESD treatment, and the most serious and worrying complication was major bleeding during ESD, which occurred in 8 out of 241 patients. Mochimaru et al[8] reported two cases of esophageal ESD in patients with alcoholic cirrhosis accompanied by EVs. In one patient, ESD could not be completed due to insufficient endoscopic view caused by frequent intraoperative bleeding. Although all cases could be successfully controlled endoscopically, one patient exhibited severe variceal bleeding during ESD, leading to incurable resection. Reassuringly, no post-ESD bleeding was observed in the 241 patients reported. In recent years, several modified ESD techniques have emerged to mitigate the risk of intraoperative bleeding associated with EVs. Dhaliwal et al[9] reported a case of EEC with varices that was successfully treated using the water-pocket ESD technique. With this refined method, smooth submucosal dissection is achieved within a locally created water pool, facilitating the creation of a submucosal tunnel. Moreover, Miyazaki et al[10] described a unique case of esophageal ESD utilizing a red dichromatic imaging (RDI) technique during submucosal injection for high-risk EEC. Under the RDI mode, submucosal vessels can be easily identified during injection, minimizing damage to these vessels and preventing bleeding and hematoma formation. In addition, in 2022, Zhu et al[11] validated the feasibility and safety of esophageal endoscopic submucosal tunnel dissection in cirrhotic patients in a retrospective cohort study, revealing that the intraoperative bleeding and 30-day post-ESD bleeding rates were comparable between cirrhotic and non-cirrhotic patients. This procedure facilitates the observation and identification of vessels in the submucosa, allowing for prophylactic coagulation to prevent bleeding. Endoscopic mucosal resection (EMR) is another commonly used minimally invasive technique for EEC. In recent years, EMR has been performed on 46 patients with EEC and cirrhosis. Major bleeding and other EMR-related complications were not reported in these patients, except for one patient who died of an accidental mesenteric infarct 1 week after EMR. Although EMR is associated with lower technical difficulty and less risk of bleeding, the procedure does have some limitations. EMR does not allow en-bloc resection of large neoplasia and does not offer a full specimen for pathological examination. Additionally, residual lesions may persist due to piecemeal resection of EMR, which could necessitate further surgical resection or lead to local tumor recurrence. Compared with ESD, multiband mucosectomy (MBM) is less frequently performed for EEC in cirrhotic patients with varices. Patients treated with MBM are potentially at risk of non-en-bloc resection, which may lead to recurrence or metastasis. Additionally, MBM incurs the risk of postoperative esophageal stenosis. Although esophageal strictures can be relieved by endoscopic dilatation and glucocorticoid treatment, dilatation of the stenosis might be difficult due to the bleeding from the coexistent EVs. Endoscopic non-resection techniques: EVL has also been used in initial attempts to treat esophagogastric junction cancer complicated by EVs. Despite the promising results showing no recurrence at 2 years of follow-up, an important caveat should be considered. The lesion could not be excised by using EVL and may result in ischemia, necrosis, and ulceration. Thus, the full specimen could not be provided for further histological examination, and the exact extent and infiltration depth of the lesion could not be determined. Similar to MBM, patients treated with EVL are also at risk of residual disease, which may lead to local recurrence. Therefore, EVL should not be recommended for the treatment of EEC in cirrhotic patients. In 2017, a case series study first described the application of radiofrequency ablation (RFA) in flat-type lesions of the esophagus in cirrhotic patients with varices.[12] No major bleeding or other serious adverse events were reported. The RFA procedure resulted in a complete response in seven out of eight patients after a single ablation, and all patients achieved a complete response at 12 months. Despite having established the safety and efficacy of RFA for EEC in cirrhotic patients with EVs, the clinical application of RFA also requires strict indications.[2,12] Endoscopic spray cryotherapy of EEC in the setting of cirrhosis with varices and thrombocytopenia was first reported in 2020.[13] In this case series study, no intraoperative bleeding or other adverse events occurred during or after the ablation procedure. After 2 years of endoscopic surveillance, no recurrence was observed at the previous ablation site. The obvious advantage of this technique is avoiding the ablation, which circumvents the risk of variceal bleeding. Nonetheless, large-scale prospective studies are still required to confirm its efficacy and safety in populations at high risk of bleeding. Post-endoscopic management: In recent studies, postoperative complications associated with endoscopic intervention primarily included fever, pneumonia, hemorrhage, and esophageal stricture. These adverse events were promptly and appropriately managed in previous reports, with no occurrence of more serious complications or deaths. However, managing complications associated with cirrhosis presents challenges, such as esophagogastric variceal bleeding, hepatic encephalopathy, and high mortality rates. In a recent retrospective study, 37 patients died after a median follow-up of 38.6 months, with the main causes of death including sepsis, cirrhosis liver failure, hepatocellular carcinoma, extrahepatic cancer, and variceal bleeding.[14] Another retrospective cohort study reported that seven patients (7/25) in the cirrhosis group died within 40 months after ESD due to complications of decompensated cirrhosis, including one who died from acute upper gastrointestinal bleeding and six from hepatic encephalopathy.[11] Therefore, preventing and prioritizing the complications associated with cirrhosis is essential. Survival: Currently, large-scale controlled studies exploring long-term survival outcomes after endoscopic treatment in patients with EEC and cirrhosis are lacking. A recent case-control study of esophageal ESD indicated that patients with cirrhosis exhibited poorer overall survival compared to those without cirrhosis, although no significant difference in disease-specific survival was found.[15] Similar survival outcomes were observed in another retrospective cohort study involving 25 cirrhotic patients with EEC and 75 non-cirrhotic matched patients using propensity score matching. Furthermore, no significant disparities were observed in disease-specific survival and recurrence-free survival between the cirrhotic and non-cirrhotic patients.[11] Therefore, current evidence suggests that patients with EEC and cirrhosis have poorer long-term survival outcomes than those without cirrhosis after endoscopic therapy. We speculate that the substantial difference in overall survival may be attributed to cirrhosis-related complications rather than endoscopic therapy or esophageal cancer itself. In summary, managing EEC in cirrhotic patients poses significant challenges, necessitating aggressive cirrhosis management, careful selection of endoscopic techniques, and meticulous postoperative care. Further large-scale prospective studies are required to validate the efficacy of endoscopic therapy in this patient population. Moreover, ongoing improvements in endoscopic techniques and equipment are expected to enhance procedural safety and reduce the risk of intraoperative bleeding. Acknowledgements We thank Home for Researchers editorial team (www.home-for-researchers.com) for the language editing service. Funding Sichuan Province Medical Young Innovative Research Project Program (No.Q23041). Conflicts of interest None.