Recently, POEM has been developed in Japan  as a less invasive and effective curative treatment option with no cases of severe complications. Other therapeutic options include endoscopic balloon dilatation and surgical myotomy. Endoscopic balloon dilatation is still widely performed because of its relative noninvasiveness and simplicity, but it has a relatively lower success rate and often requires multiple treatment sessions . Inoue et al. reported that there was no recurrence after the POEM procedure in their 17 case series of achalasia in their short-term results . They also reported the lack of recurrence on 43 patients of maximum of 1 year 9 months observation  (Japanese manuscript). In the present 15 cases, no severe complications such as perforation and severe mediastinitis occurred, and the clinical course was uneventful in each case. Although the term has been relatively short, there has been no disease recurrence during the observation period. Surgical myotomy has been thought to be the curative therapeutic choice for symptomatic achalasia. However, it requires skin incisions and additional anti-reflux surgical intervention. Thus, POEM could be one of the most promising treatment options for symptomatic achalasia.
On the basis of prior data, the overall prevalence of esophageal squamous cell carcinoma in patients with achalasia has been estimated to be up to 8.6%, accounting for a 50-fold increase in cancer risk . In achalasia patients, it has been suggested that chronic food stasis leads to chronic inflammation, epithelial hyperplasia, multifocal dysplasia, and squamous cell carcinoma (SCC) [1, 16, 17]. Previous studies showed that it would take a mean of 24 (range 10–43) years to establish carcinoma after symptom onset, and 3 to 4 years for carcinoma to develop from dysplasia [1, 18, 19]. Goldblum et al. noted that several epithelial abnormalities were seen in achalasia, including high-grade squamous dysplasia, superficial squamous cell carcinoma, and lymphocytic esophagitis , exclusively accompanied by diffuse squamous hyperplasia reflecting accelerated cellular turnover and proliferation.
The changes in endocytoscopic images were examined together with the cellular proliferative ability of the mucosal surface in order to evaluate whether the POEM procedure improved cellular proliferation as well as mucosal inflammation. The ultra-high magnification enables us to observe cellular irregularity, similar to conventional pathological images [12, 21]. Inoue et al. reported that there was a significant correlation between endocytoscopic images and histopathological images in various gastrointestinal disorders [12, 21]. As shown in Figure 5, comparison of endocytoscopic images between before and after POEM revealed significant improvements in the nuclear counts and the irregularity of cellular arrangement. The endocytoscopic nuclear counts after POEM reached almost the same levels as healthy controls. The POEM procedure substantially reduced Ki-67 positivity. There was a significant correlation between Ki-67 expression and endocytoscopic nuclear counts (Figure 4d). Collectively, cellular proliferation ability could be assessed by endocytoscopic images. At the same time, endocytoscopy allows us to obtain information about cellular atypia [12, 21].
Fujii et al. reported cases of esophageal squamous cell carcinoma concomitant with achalasia and found higher Ki-67 positivity in cancer lesions than in non-cancerous lesions . Leeuwenburgh evaluated the expressions of both p53 and Ki-67 in achalasia patients and reported that overexpression of p53 could be an early marker of neoplastic progression in achalasia . In esophageal adenocarcinoma, Reid and Kerkhof reported that both p53 and Ki-67 were effective for early discrimination [24, 25]. The present data showed decreases of both Ki-67 and p53 expressions after POEM, which implies that POEM could reduce the future risk of developing esophageal squamous cell carcinoma.
Leeuwenburgh documented that Ki-67 expression was not a discriminative factor for carcinogenesis in achalasia patients. However, they targeted the GEJ, which could be easily affected by distention of food and fermentation. Expression of the Ki-67 protein is associated with the clinical course of cell proliferation that is closely linked to tissue inflammation . Leeuwenburgh and his colleagues suggested taking a biopsy from the thoracic esophagus, not from the EGJ, to avoid the effects of severe inflammation. In the present series, biopsies were taken from the middle-thoracic esophagus to avoid sampling severely inflamed mucosa.
Furthermore, advanced achalasia may conceal the dysphagia caused by cancer growth. Stasis of the esophageal contents and a severely inflamed mucosa make it almost impossible to detect early cancers. Improving visualization via the therapeutic intervention allows detailed observation and cancer inspection at an earlier stage. Therefore, we strongly insist that early release of the obstruction is essential for finding early cancers and preventing the development of advanced cancer.
Brossard et al. showed that the incidence of squamous cell carcinoma was eight times higher in untreated patients with achalasia and 4.5 times higher in patients treated with pneumatic dilatation than in those treated with surgical myotomy . Endoscopic myotomy may provide less risk of SCC development with a higher success rate than other options. Endoscopic balloon dilatation has a lower success rate  than the POEM procedure. Unlike surgical myotomy, POEM allows us to preserve the anatomical integrity of the LES and possibly minimize postoperative reflux [28, 29]. Nevertheless, these LES pressure-lowering therapies could be ultimately complicated by the development of Barrett’s esophagus and adenocarcinoma. Therefore, longer follow-up is obviously necessary to clarify the risk of Barrett’s cancer due to reflux esophagitis, which was observed in some of our cases [19, 30].