A Granular Cell Tumor Arising in a Patient with Long-segment Barrett's Esophagus

Abstract

Esophageal cell tumors are rare. Esophagogastroduodenoscopy performed on a 48-year-old woman revealed an elevated esophageal lesion and the presence of long-segment Barrett's esophagus. Endoscopic ultrasonography showed a 15 mm homogeneous hypoechoic tumor extending from the lamina propria mucosa to the submucosa. Pathological examination of the biopsy tissue revealed a sheet-like cluster of histiocytoid cells with an abundant eosinophilic granular cytoplasm. Immunohistochemical examination revealed S-100(+) and CD68(+), thus suggesting the diagnosis of a granular cell tumor. The tumor was resected by endoscopic submucosal dissection. Pathologically, the background mucosa was Barrett's mucosa. This is the first reported case of an esophageal granular cell tumor in long-segment Barrett's esophagus.

Introduction

Granular cell tumors (GCT) are thought to be derived from Schwann cells (1) and they can occur in any organ of the body, most commonly in the skin and tongue (2). Approximately 5-11% of GCTs occur in the gastrointestinal tract, most of which are found in the esophagus (3). Most cases of esophageal GCT have no symptoms and are discovered incidentally (4). Esophageal GCT usually arise beneath the squamous mucosa (5). We herein report a very rare case of GCT occurring in long-segment Barrett's esophagus (LSBE) which was successfully treated by endoscopic submucosal dissection (ESD).

Case Report

Following a medical examination for a medical checkup, a 48-year-old woman underwent esophagogastroduodenoscopy, which revealed an elevated lesion in her esophagus. The patient had consumed 10 g of pure ethanol and smoked 10 cigarettes daily for 27 years. She had no family history of gastrointestinal disease. Her blood test findings at the first visit were within the normal limits for carcinoembryonic antigen, CA19-9, and other general blood tests. Upon re-examination of the patient's esophagogastroduodenoscopy ten days later, a circumferential LSBE measuring ＞3 cm from the esophagogastric junction was confirmed. In the LSBE lesion, a previously noted submucosal tumor with a central depression was identified in the middle esophagus. The tumor was covered with Barrett's mucosa (Fig. 1A). The tumor was covered with Barrett's mucosa and it was located in the circumferential LSBE measuring more than 3 cm from the esophagogastric junction (Fig. 1B). Narrow band imaging endoscopy of the tumor showed an enlargement of the mucosal pattern, dilation of mucosal microvessels, and no irregular arrangement of glands or tortuous blood vessels. These findings suggested that the lesion was not Barrett's adenocarcinoma (Fig. 1C). Miniature probe endoscopic ultrasonography (mEUS, 20 MHz) revealed a 15 mm-sized homogeneous hypoechoic tumor localized from the lamina propria mucosa to the submucosa (Fig. 1D). These findings ruled out leiomyomas or gastrointestinal stromal tumors. Pathological examination of the biopsy tissue revealed clusters of histiocytoid cells with abundant eosinophilic granular cytoplasm (Fig. 2A), and immunohistochemical examination showed pancytokeration (AE1/AE3)(-), S-100(+) (Fig. 2B), and CD68(+) (Fig. 2C), thus indicating a diagnosis of GCT. Computed tomography revealed no evidence of metastases.

Figure 1.

Findings of esophagogastroduodenoscopy. (A) A submucosal tumor with a central depression in the middle esophagus is seen. The surface of the tumor is covered by a glandular epithelium. (B) Long-segment Barrett’s esophagus is classified as C3M5. (C) Narrow band imaging endoscopy shows an elevated lesion overlaid by a non-neoplastic mucosa with enlargement of mucosal pattern and dilation of mucosal microvessels. (D) The homogeneous hypoechoic tumor is localized from the lamina propria to the submucosa by miniature probe endoscopic ultrasonography (mEUS, 20 MHz).

Figure 2.

(A) Histopathology of biopsy specimens reveals a sheet-like cluster of histiocytoid cells with abundant eosinophilic granular cytoplasm and small oval nuclei (Hematoxylin and Eosin staining, ×400). The histiocytoid cells are positive for S-100 (B) and CD68 (C) (immunohistochemistry, ×400).

Owing to the possibility of malignancy despite the small size of the lesion, we decided to proceed with treatment rather than just observe the patient. EUS revealed that the lesion was located deep in the submucosal layer; therefore, we decided to perform ESD to achieve complete resection. The lesion was removed by ESD and it appeared as a slightly yellowish submucosal tumor approximately 15 mm in size (Fig. 3A). Pathologically, the lesion was localized from the lamina propria mucosa to superficial submucosa (Fig. 3B). The tumor was composed of histiocytoid cells with abundant eosinophilic granular cytoplasm and small, oval nuclei. (Fig. 3C). Both the lateral and deep margins of the resected specimen were negative and vascular invasion was negative. Cardiac gland-type intestinalized mucosa covering the surface of the tumor as well as the background mucosa, the presence of double muscularis mucosae with palisade vessels between them, and the presence of proper esophageal glands and their ducts in the background mucosa made it possible to make a diagnosis of GCT arising in Barrett's esophagus (Fig. 3D). Variable-sized congestive capillaries were observed in the mucosa covering the tumor. Barrett's mucosa circumferentially extended ＞3 cm from the gastroesophageal junction, which is a characteristic finding of LSBE. Repeat endoscopy performed 1 year later revealed no signs of recurrence.

Figure 3.

(A) Macroscopic view of the fresh specimen resected by endoscopic submucosal dissection, showing a lightly yellowish elevated lesion with a central depression, surrounded by a brownish mucosa. (B) In a whole mount histologic view, the lesion is localized from the deep lamina propria mucosa to the superficial submucosa. (C) In a high power view, the lesion reveals a sheet-like cluster of histiocytoid cells with abundant eosinophilic granular cytoplasm and small oval nuclei, covered by regenerative intestinalized cardiac gland-type mucosa with variable-sized congestive capillaries beneath the surface epithelium [Hematoxylin and Eosin (H&E) staining, ×200]. (D) The surrounding mucosa shows irregularly shaped intestinalized pits with deep cardiac-type glands, double muscularis mucosae (thin arrows) with palisade vessels between them (arrowheads), and ducts of esophageal glands (thick arrow), which thus made it possible to diagnose Barrett’s mucosa (H&E staining, ×100).

Discussion

Abrikossoff first reported GCT in 1926 in a lesion located on the tongue (6). He also reported a case of esophageal GCT in 1931 (7). GCTs are mostly benign tumors that can occur anywhere in the body, but they are most commonly found on the skin and tongue (2); however, approximately 5-11% occur in the gastrointestinal tract (3). Among gastrointestinal GCTs, the esophagus is the most common site, but esophageal GCTs account for approximately 1% of all benign esophageal tumors (8). Esophageal GCT most commonly occur in the lower and middle parts of the esophagus (9). No symptoms are observed in most cases (4). GCTs are speculated to be neurogenic in origin (1), arising from Schwann cells that form a part of the submucosal plexus of the esophagus (9).

Most esophageal GCTs occur in the squamous epithelial region (5); however, in the present case it was found in the lamina propria mucosa and submucosa of the LSBE region. In this case, the blood vessels on the surface mucosa of the tumor were more noticeable than those on an ordinary esophageal GCT. To our knowledge, there is only one report of a GCT that developed in the short-segment Barrett's esophagus region (10), and no reports of a GCT that developed in the LSBE region. In the present case, LSBE was categorized as C3M5, according to the Prague classification (11). It has been reported that the length of Barrett's esophagus does not change significantly after a diagnosis has been made (12). However, it is difficult to confirm the present development of GCT in Barrett's esophagus or that an elongation of Barrett's epithelium occurred after the development of GCT.

Endoscopically, GCT appears as a yellowish, elevated flat lesion covered with normal mucosa, and most tumors are less than 20 mm in diameter (13). EUS is very effective for diagnosing GCT (14). The GCT is localized from the lamina propria mucosa to the submucosa and is uniformly hypoechoic. Unlike leiomyomas and gastrointestinal stromal tumors, GCTs localized close to the surface epithelium can be sampled by biopsy to obtain a definitive diagnosis, although the frequency is low (15).

GCT is characterized pathologically as having an alveolar structure, composed of a sheet-like proliferation of tumor cells with small nuclei and abundant eosinophilic, granular cytoplasm, located in the lamina propria mucosa and submucosa (16). Immunohistochemically, the GCT was positive for S-100 and CD68 (17). Recently, mutations in ATP6AP1 and ATP6AP2, which are endosomal pH regulators, have been reported in GCT (18).

Currently, no treatment guidelines have been established for esophageal GCTs. Voskuil et al. reported that most esophageal GCTs smaller than 10 mm are benign tumors with slow growth and can be monitored by biopsy alone (19). However, there have been reports of malignancy even for lesions sized around 10 mm (20), and as the definitive diagnosis rate of biopsy is low, endoscopic treatment is generally considered. Most esophageal GCTs have a tumor diameter of 20 mm or less and can be treated endoscopically. Endoscopic mucosal resection (EMR) and ESD have been reported as endoscopic treatments for GCT (16). EMR includes conventional EMR, ligation-assisted EMR, cap-assisted EMR, and underwater EMR (21). However, ESD, which can ensure negative horizontal and vertical margins, appears to be the most effective treatment option. In the present case, EUS showed that the deepest part of the GCT was in the shallow submucosal layer; therefore, we decided to treat it with ESD. Similar to ESD of the GCT in the squamous epithelial region, the present case was also performed safely, and curative resection was performed. However, even if a benign esophageal GCT is diagnosed based on an analysis of the resected specimen, careful postoperative follow-up is required. As the number of reported cases is very small, the long-term course and recurrence rate are unknown (13).

With the spread of Helicobacter pylori (H. pylori) eradication therapy, the number of gastric cancers discovered after H. pylori eradication therapy and H. pylori-uninfected gastric cancer infections is increasing. Furthermore, the incidence of esophagogastric junction adenocarcinoma has gradually increased in Japan (22). Hence, differentiation of elevated esophageal lesions near the junction should be performed carefully, while including esophageal GCT in the differential diagnosis, which commonly occurs in the middle to lower esophagus, as well as in esophageal cancer.

In conclusion, we herein reported the first case of GCT that developed in LSBE and was successfully treated with ESD. It is important to accumulate further case reports of such rare diseases because prospective research on GCT is difficult.

The authors state that they have no Conflict of Interest (COI).