Endoscopic ultrasound-guided ethanol ablation for small pancreatic neuroendocrine neoplasm

With recent advances in diagnostic imaging, pancreatic neuroendocrine neoplasm (PNEN) has been found in small size, and its handling has changed depending on grade according to the Ki-67 index and mitotic rate, based on the 2017 World Health Organization (WHO) classification. Of note, high-grade well-differentiated NEN is defined as neuroendocrine tumor (NET) and divided into grades 1–3, with PNET showing values of >20% for both Ki-67 index and mitotic index classified as grade 3 by the latest WHO classification. On the other hand, poorly differentiated PNEN with values of >20% for both Ki-67 index and mitotic index is classified as neuroendocrine carcinoma (NEC), which may be further subdivided into small-cell and large-cell types. The management of PNEN remains controversial. Cases with distant metastases need multidisciplinary efforts, including surgery, somatostatin analogues (SSAs), hepatic artery embolization, percutaneous ablation, and cytotoxic chemotherapy. However, for localized PNEN, surgery remains standard given the high rate of cure. According to recent guidelines for the management of PNEN, surgical treatment is recommended for all PNENs larger than 1 cm in maximal diameter and functional tumors. Resection of PNETs may be accomplished by pancreaticoduodenectomy (Whipple surgery) or distal pancreatectomy with an option such as enucleation for those with small PNEN without evidence of lymph metastasis. However, these major surgeries with relatively high morbidity led to the adoption of more conservative strategies, especially for incidentally discovered PNENs <2 cm in diameter, as these generally exhibit benign behavior. Endoscopic ultrasound-guided ethanol ablation (EUSEA) was first reported in 2006 by Jurgensen et al. and was applied for symptomatic insulinoma in a patient unfit for surgery. Tumor diameter was 13 mm and 8 mL of 95% ethanol was injected, resulting in complete resolution of the hypersecretion syndrome. Choi et al. recently described the single largest reported cohort of non-functional PNENs (NF-PNENs) treated by EUS-EA in 2018. They included 39 lesions from a total of 32 patients who are at high risk in surgical treatment. EUS-EAwas performed using a 1:1 ratio of 99% ethanol and lipiodol. Biopsy could determine the grade for 29 lesions before ethanol injection, showing 28 lesions of G1 NET and 1 lesion of G2 NET. Complete ablation was achieved in 60% of cases, although two cases of acute pancreatitis and subsequent PD strictures occurred in one case. To date, several case reports and a small case series of EUS-EA have been reported, showing a success rate of 50– 100% if success rate is defined as symptom disappearance in patients with functional PNEN (F-PNEN) and radiological evidence of complete tumor ablation in patients with NF-PNEN. As a basic method for local injection of ethanol, needle puncture is recommended at the far end of the tumor, with gradual withdrawal while injecting a small amount of ethanol. Ethanol comes out from a different puncture hole if multiple punctures are performed in the same session. Injection from the same puncture site at a different angle is therefore desirable if the tumor is large. Moreover, before removal, the needle should be held in place for about 1 min until the liquid can spread inside the tumor, so that ethanol can be prevented from leaking from the pancreas. The incidence of adverse events (AEs) has been reported as between 0% and 20%, including abdominal pain, bleeding, and acute pancreatitis. Among cases of acute pancreatitis, there was a case with severe pancreatitis resulting in pancreatic duct strictures and pancreatic necrosis. These AEs seem to be associated with the amount of injected ethanol in a single session. In this issue of Digestive Endoscopy, Matsumoto et al. described a case study assessing the safety and feasibility of scheduled early EUS-guided ethanol reinjection to prevent AEs by reducing the volume of ethanol required while maintaining efficacy. They performed EUS-EA for patients with pathologically diagnosed G1 or G2 NF-PNEN that were smaller than 2 cm in diameter, who were poor candidates or rejected for surgery. Pure ethanol was injected using a 25-G FNA needle until a hyperechoic blush extended to the whole margin of the tumor, but the volume