History of endoscopic diagnosis and treatment for esophageal and pharyngeal squamous cell carcinoma

Abstract

Developments and progress in endoscopy have greatly contributed to improvements in medical practice. We herein present the contribution of endoscopy to advancements in the diagnosis and treatment of esophageal and pharyngeal cancers in the past century. Esophageal cancer is the seventh most common cancer and the sixth most common cause of cancer-related mortality worldwide, with 572,000 new cases and 509,000 deaths in 2018.1 Esophageal squamous cell carcinoma (SCC) is the predominant subtype, accounting for 80% of esophageal cancers in the world and over 90% of esophageal cancers in Japan. Superficial esophageal cancer is an early-phase cancer defined as cancer limited to the mucosa or the submucosa. The first case of superficial esophageal cancer was reported in 1966.2 Although endoscopy was performed in the case, the diagnosis was not made by endoscopy but by cytology, using gastric juice. Dawning of endoscopic detection of esophageal cancer was brought by the introduction of pan-endoscopy in 1973. Pan-endoscopy provided entire observation from the esophagus to the second part of the duodenum; thus, creating the basis for the screening and detection of esophageal cancer. Two subsequent innovations facilitated the detection of esophageal cancer. The first innovation was image enhancement technology. Iodine staining, introduced in Japan in the late 1970s,3 enabled clear visualization of esophageal cancer and also facilitated detection of intraepithelial cancer. Applying this method to high-risk populations for esophageal cancer, e.g. heavy alcohol drinkers or patients with a history of pharyngeal cancer, realized efficient detection of superficial esophageal cancer. In addition, the number of Lugol-voiding lesions in the esophagus reflected the risk of metachronous cancer in the esophagus and the pharynx.4 However, iodine solution can cause mucosal irritation leading to retrosternal pain and discomfort; therefore, this method is rather unpleasant when it is used as routine practice. A novel, noninvasive image enhancement technology, narrow-band imaging (NBI), was developed in 20035 (Fig. 1). NBI uses reflected light to visualize the organ surface and enhances the superficial structure and epithelial microvascular pattern. The utility of NBI to detect esophageal and pharyngeal cancer was confirmed in a randomized study,6 and this technology is widely used as the primary modality for observing the esophagus. The second innovation was magnifying function. The first report of magnifying observation for superficial esophageal cancer was reported in 1991.7 Higher magnification, 80-fold or more, was introduced in the late 1990s (Fig. 2), and the technology spread widely after it was combined with NBI in the early 2000s. Inoue found that dilatation, tortuosity, caliber change, and various shapes of intraepithelial papillary capillary loops were observed with the development of cancer, and that non-loop vessels or new tumor vessels were observed with the invasion of cancer.8 Arima et al. also found that the size of the avascular area surrounded by stretched non-loop vessels correlated well with the depth of cancer invasion, and that reticular-type vessels were observed in esophageal cancer with the infiltrative c growth pattern.9 The authors' findings were integrated into the Japan Esophageal Society classification in 2011.10 Ultra-high magnification technology, such as confocal endoscopy11 and endocytoscopy,12 enabled visualization of the cellular structures of the superficial epithelial layer in a plane parallel to the mucosal surface at image resolutions rivaling those of histology. For the esophagus, iodine staining enables clear delineation of SCC, and subsequent methylene blue staining realizes observation of nucleus and cell body.13 These recent technological advances offer the potential for real-time optical biopsy and lesion characterization. Ultra-high magnification instruments include probe-based and endoscope-based systems. Probe-based instruments consist of a flexible catheter-type device, while endoscope-based instruments integrate an endocytoscopy component within the endoscope. Endocytoscopic visualization of subcellular structures (e.g. nuclei) necessitates prestaining of the mucosa with an absorptive contrast agent, such as 0.5%–1% methylene blue or 0.25% toluidine blue (Fig. 3). The ability to obtain cellular images in real-time has several potential clinical benefits, but further studies are needed to better define the utility of this technology relative to standard endoscopic biopsy. Simultaneous and metachronous cancers in the upper aerodigestive tract are likely to develop in patients with esophageal cancer. This phenomenon has been explained by the field cancerization theory, which hypothesizes that the entire epithelial surface of the upper aerodigestive tract has an increased risk of developing cancers because of its repeated exposure to carcinogens, such as alcohol and cigarette smoke. Pharyngeal cancer is the most common second cancer in patients with esophageal cancer. Early detection of pharyngeal caner using digestive endoscopy was first reported in 2003.14 In their report, Nagai et al. observed the pharynx of patients with esophageal cancer, using digestive endoscopy, from 1993 to 2002, and identified 20 early-phase pharyngeal cancers. The authors showed the potential for early detection of pharyngeal cancer; however, contrary to the esophagus, iodine staining cannot be used for the early detection of this cancer. Thus, the early detection of pharyngeal cancer was challenging until the early 2000s. The development of NBI dramatically changed the situation. NBI allowed clear visualization of the pharyngeal mucosal surface and microvasculature, similar to the esophagus. NBI facilitated the detection of early-phase pharyngeal cancers that were difficult to detect by otolaryngological endoscopy.6 Previously, the oral cavity and pharynx were not meticulously observed during digestive endoscopy. However, after the development of NBI, pharyngeal observation was included in routine digestive endoscopy for populations with a high risk of developing pharyngeal cancers. Subsequently, increasing numbers of pharyngeal cancers have been detected during digestive endoscopy. Early detection of cancers allowed cure of even aggressive cancers. In the 1980s, esophagectomy was the mainstay of treatment for curable esophageal cancer. However, esophagectomy was only possible in patients able to tolerate the procedure, and was associated with significant mortality and substantial morbidity. Following strong desire for less invasive treatment, initial attempts at endoscopic resection for esophageal cancer began in the late 1980s. Because superficial esophageal cancers are usually flat, endoscopic resection methods should combine snaring methods with methods to pull the lesion into the snare. In approximately 1990, three endoscopic mucosal resection (EMR) methods, 2-channel EMR,15 EMR using a transparent plastic cap-fitted panendoscope,16 and endoscopic EMR,17 were developed in Japan. EMR allowed complete removal of cancer in the esophagus, and favorable outcomes have been reported for superficial esophageal cancers with minimal risk of metastasis. However, despite its efficacy, this method is sometimes associated with local recurrence, especially when lesions larger than 20 mm are resected in a piecemeal manner. In piecemeal-resected specimens, histologic assessment is sometimes difficult because of the effects of burning on the lesion. Furthermore, the patients’ fear of recurrence is an important problem in piecemeal resection. Endoscopic submucosal dissection (ESD), which uses specially-developed endoscopic knives, is an endoscopic resection method that was developed in the late 1990s.18 ESD enabled en bloc resection of large lesions and reduced local recurrence after ESD. This technique also allowed detailed histologic assessment of resected specimens. Owing to the development of ESD, the indication for endoscopic resection was widened to lesions measuring ≥5 cm or those with circumferential spread. Following the ability to detect early-phase pharyngeal cancers, these cancers became good candidates for local resection. Endoscopic resection techniques for esophageal cancer, e.g. EMR or ESD, have been used to treat these cancers. Endoscopic laryngopharyngeal surgery (ELPS) is another method of treating pharyngeal cancer, developed in the early 2000s.19 In ELPS, a curved rigid laryngoscope is inserted to provide a working space in the pharyngeal lumen. Resection is then performed using specially-designed curved forceps and a curved electrosurgical needle knife under the guidance of a magnifying endoscope inserted transorally by a gastroenterologist. These treatments contributed to favorable survival in patients with early-phase pharyngeal cancers. Although ESD is associated with high local curability, this technique cannot be applied to advanced cancer. Photodynamic therapy (PDT) can cure even T2 esophageal cancer or cancers with severe fibrosis. In 1982, PDT through the endoscope was performed for gastric cancer in Japan for the first time worldwide.20 This first-generation PDT using porfimer sodium had some disadvantages, such as a long sun avoidance period of approximately 6 weeks to avoid the risk of skin phototoxicity, and the need for an expensive excimer dye laser system. Conversely, second-generation PDT using talaporfin sodium requires a shorter sun avoidance period of approximately 2 weeks and has a low incidence of skin phototoxicity. Following the favorable results of a phase II study examining the local complete response of second-generation PDT in esophageal cancer with local failure after chemoradiotherapy or radiotherapy,21 PDT was approved in Japan in October 2015. In the field of endoscopy, as we introduced here, many innovations and ingenious improvements were developed in Japan. We feel proud of our predecessors’ achievements in the past century, and feel that we should reaffirm our determination to continue leading the world in the field of endoscopy. We thank Dr Arima and Dr Kumagai for providing valuable endoscopic images. We also thank Jane Charbonneau, DVM, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. Authors declare no conflict of interest for this article. None.

Topics & Concepts