Granular Cell Tumor of the Esophagus: Report of a Pediatric Case and Literature Review (2003)

INTRODUCTION Granular cell tumors (GCT) are submucosal or subcutaneous tumors most commonly found in skin, tongue, and breast. Tumors involving the gastrointestinal tract account for 8% of all GCT (1), and only 2% are found in the esophagus (2,3). In 1926, Abrikossoff reported the first five cases of GCT of the tongue, designating them as “myoblastomas,” and in 1931 he reported the first GCT of the esophagus (4). By 1998, approximately 270 cases of GCT of the esophagus had been reported. Esophageal GCT are more common in women and black patients, and most occur in the fourth, fifth, and sixth decade (5–7). To our knowledge no cases of GCT of the esophagus have been reported in children. We report the first GCT of the esophagus in a pediatric patient and review the literature concerning clinicopathologic aspects and management of these uncommon tumors. CASE REPORT A 14-year-old Caucasian girl had a 5-year history of progressively worsening, intermittent dysphagia for solid food culminating in an esophageal food impaction. The child was evaluated in the emergency room, where a barium esophagogram excluded an esophageal stricture. The impacted food was dislodged by passing a nasogastric tube, and the child was discharged from hospital. However, ongoing dysphagia lead to her referral to Pediatric Gastroenterology. A repeat esophagogram 7 months after the food impaction demonstrated normal esophageal caliber and significantly delayed primary wave activity. Esophageal motility studies showed normal resting lower esophageal sphincter pressure, with only slightly impaired relaxation to swallows (61% with normal values of 70%–100%), making the diagnosis of esophageal achalasia unlikely. An upper gastrointestinal endoscopic analysis demonstrated a pale and edematous distal esophageal mucosa with reduced vascular markings. A small, pale, yellow, 1 × 0.5 × 0.3 cm lesion was noted protruding into the esophageal lumen approximately 33 cm from the incisors (Fig. 1). Biopsies were taken from all levels of the esophagus and showed basilar hyperplasia, papillary elongation, and an infiltrate of eosinophils. The changes were consistent with gastroesophageal reflux disease and were most prominent in the distal esophagus. Histologic analysis of the yellow lesion was consistent with the diagnosis of GCT. The patient began proton-pump inhibitor therapy but had incomplete resolution of symptoms.FIG. 1.: Endoscopic appearance of the esophageal GCT showing a pale, yellow, 1- × 0.5- × 0.3-cm lesion protruding into the esophageal lumen approximately 33 cm from the incisors.Six months later, upper endoscopic analysis demonstrated no progression of the lesion. Esophageal endosonography performed at 7.5 and 12 MHz (GF-UM-130 Echoendoscope; Olympus, Tokyo, Japan) revealed an 8 × 2-mm thick hypoechoic mass in the third layer of the anterior esophageal wall (Fig. 2). The mass was located in the submucosa, and the muscularis propria was intact. There were no periesophageal or celiac lymph nodes. The mass was removed by saline-assisted endoscopic mucosal resection (EMR) using a therapeutic endoscope and an EMR cap (endoscope Olympus 1T140 and EMR kit K-004; Olympus, Tokyo, Japan). A sclerotherapy needle was used to inject approximately 4 mL of saline under the lesion to separate the tumor from the esophageal wall. The lesion was suctioned into the EMR chamber and removed using snare cautery. There were no complications. The specimen consisted of a 1.5 × 1.1 cm ovoid mucosal excision measuring as large as 0.5 cm thick (Fig. 3). The tumor, 1.0 cm in maximum dimension, replaced the muscularis mucosa and extended into the submucosa, with a small extension approaching close to the deep margin. Histologic examination revealed nonkeratinizing, stratified squamous epithelium with basilar hyperplasia and moderate eosinophilic infiltrate; the submucosa showed a uniform proliferation of low cellularity, with cells containing round, vesicular bland nuclei and abundant amphiphilic granular cytoplasm staining uniformly with S-100 protein (Fig. 4). These findings confirmed the diagnosis of GCT. Histologic evidence of reflux esophagitis in the distal esophagus was also demonstrated. The patient tolerated the procedure well and continued to receive proton-pump inhibitor therapy. Six months after the procedure, she was completely symptom free, and endoscopy and endoscopic ultrasound (EUS) at that time showed no evidence of residual tumor. Multiple jumbo biopsies of the postresection scar (Fig. 5) were taken, and pathologic examination showed no tumor cells. Evidence of mild esophagitis was present in the distal esophageal biopsy specimens.FIG. 2.: Endoscopic ultrasonography of the esophageal GCT showed a 8- × 2-mm thick hypoechoic submucosal mass in the third layer of the anterior esophageal wall. The muscularis propria was intact.FIG. 3.: Macroscopic appearance of the esophageal GCT after endoscopic mucosal resection. The specimen consisted of a 1.5- × 1.1-cm ovoid mucosal excision measuring as large as 0.5 cm thick.FIG. 4.: Histologic appearance of the esophageal GCT. A, The nonkeratinizing, stratified squamous epithelium showed basilar hyperplasia with moderate eosinophilic infiltrate; the submucosa showed a uniform proliferation of cells containing round, vesicular bland nuclei and abundant amphiphilic granular cytoplasm. B, The cytoplasm stained uniformly for S-100 protein using standard immunohistochemistry technique and fast red as Chromagen (Biogenex, San Ramon, CA).FIG. 5.: Endoscopic appearance of the distal esophagus 6 months after removal of the tumor. Scar tissue from prior mucosal resection is evident (arrows). No masses or nodules were detected.We plan to perform esophagogastroduodenoscopy and EUS every 6 to 12 months for the next 2 to 3 years in this child to monitor her for tumor recurrence. DISCUSSION Granular cell tumors are uncommon tumors in adults and very rare in childhood. This report is the first case of esophageal GCT in a child, the youngest previously reported patient being 19 years old (8). Only three cases of GCT of the gastrointestinal tract have been reported in pediatric patients. The appendix was the site in two patients aged 15 and 16 years who presented with acute appendicitis. The cecum was the site in a 17-year-old patient (3). The most common site in children is the skin (9). Other rare locations are tongue (9), larynx (9,10), trachea (11,12), nasal septum (13), bronchus (14), and genitalia (9,15). Multiple tumors or familial involvement are reported to occur in childhood (11,16,17). Neurofibromatosis and other neurologic or systemic defects (18–20) have been described in association with multiple cutaneous GCT in children. Congenital GCT, or “congenital epulis,” appears to be a different entity because of its almost exclusive occurrence in newborns, characteristic location in the oral cavity, and lack of immunostaining for S-100 (21). In adults, most esophageal GCT are solitary. They are found in the distal esophagus in 50% to 65% of cases, in the proximal esophagus in 15% to 40%, and in the midesophagus in 20% (6). In 10% of reported cases there are multiple lesions in the esophagus. In this instance, there are often GCT in other organs, including skin and gastrointestinal tract (5,22–24). A few cases of synchronous GCT and squamous cell carcinoma of the esophagus have been reported (25,26). Most esophageal GCT are found incidentally during endoscopy, upper gastrointestinal contrast studies, or at autopsy. Although patients usually have no symptoms, those with tumors larger than 1 cm may report dysphagia (5,7). Nausea, vomiting, and retrosternal or epigastric pain occur less frequently (22,27). The histogenesis of the tumor is uncertain, thus the several synonyms used to describe this entity. Different authors suggest a myogenic (4), histiocytic (28), fibroblastic (29), or primitive mesenchymal origin (30). More recently, the evidence of close association of tumor cells with peripheral nerves, the presence of S-100 protein, neuron-specific enolase, and myelin proteins on immunohistochemical stains support a Schwann cell derivation (31–34). The endoscopic appearance of a GCT is characteristic. The tumor appears as a yellow, firm, polypoid submucosal mass. Differential diagnosis should include esophageal cyst, epithelial lesions such as glycogenic acanthosis, inflammatory polyp, and squamous papilloma and other submucosal tumors, such as leiomyoma, lipoma, and hamartoma. Even if the macroscopic features of an esophageal lesion are suggestive of a benign process, definitive diagnosis is based on histopathology. In our case, the initial diagnosis was made with conventional histologic stains of mucosal biopsy specimens. However, conventional biopsies may not always reveal the diagnosis, and deep (jumbo) biopsies may be required. Jumbo biopsies of most submucosal esophageal tumors usually can be obtained safely in adults without prior EUS. However, EUS may provide important diagnostic information, including the size, the layer of origin, and tumor extension. When reported, ultrasonography shows the tumor arising in the inner layers of the esophageal wall (second echo-poor layer or third echo-rich layer) in 95% of cases, with a hypoechoic solid pattern and smooth margins (35). EUS is the best procedure for determining whether a tumor meets the criteria for endoscopic removal, including small size (<2 cm) and nonattachment to the muscularis propria. Histologically, these tumors consists of polygonal and fusiform cells disposed in compact “nests” (22). Cells have small dark nuclei and abundant, fine, granular eosinophilic acid-Schiff–positive, diastase-resistant cytoplasm (23). Immunohistochemical (immunoperoxidase) staining for S-100 protein supports the proposed Schwann cell derivation of the tumor. GCT of the skin, larynx, and esophagus are known to induce pseudoepitheliomatous hyperplasia in the Malpighian epithelium (3,22,36). This feature may simulate a primary squamous cell carcinoma, although cytologic atypia usually is not relevant. Electron microscopic examination shows the presence of a prominent basement membrane and a cytoplasm packed with lysosomes (23,36). The natural history of this tumor is unclear. In nonesophageal GCT, the rate of malignancy is estimated to be 1–2%. Approximately 100 malignant cases have been reported in the literature (37,38). Malignancy is reported in 2–4% of esophageal GCT (6,37). Deaths have been reported from tumors with extensive transmural infiltration and regional lymph node metastases (39–41). The infiltrative pattern of growth and the presence of metastases are important features in differentiating between malignant and benign tumors because they may appear histologically very similar. Malignant lesions usually are larger than 4 cm, display rapid recent growth, tend to recur locally after resection, and may have such subtle histologic features as nuclear pleomorphism, increased nuclear size, tumor cell necrosis, large nucleoli, mitotic figures (2 or more/10 HPF), and tumor cell spindling (38). Multifocality does not seem to carry an increased risk of malignancy (41). The rate of recurrence after excision is not clear from reported experience and ranges from 0% to 10% (3,42). Most esophageal GCT have a benign clinical course, and patients monitored without therapy for as long as 60 months have shown stable tumor size or even regression (7,27,43,44). For this reason many authors suggest that small, asymptomatic lesions may be managed conservatively, with endoscopic follow-up and excision only if the tumor grows rapidly or produces symptoms of dysphagia (5,7,27). In our opinion, endoscopic excision of these tumors should be strongly considered, particularly because benign and malignant tumors may be similar in clinical presentation, and histologic discrimination may be difficult. Saline-assisted EMR is considered a safe procedure, and complications are uncommon (45). In a recent series of 650 esophageal mucosal cancers removed with EMR, Makuuchi reported a complication rate of 4.8% (perforation 0.7%, bleeding 3.1%, stricture 1.6%) (46). There are no reports of perforation associated with endoscopic resection of esophageal GCT (24,47,48). The injection of saline under the lesion and the use of EUS reduce the risk of perforation or incomplete removal of the tumor (48,49). To our knowledge the use of EMR for esophageal tumor resection in children has not been reported in the literature, thus the complication rate in this subset of patients has not been evaluated. The small but real risk of malignant transformation of adult esophageal GCT and the paucity of available pediatric data and parental opinion were critical in defining the care of our patient and the decision to resect the tumor. The lesion was well defined and potentially resectable with only minimal risk attached. The child's symptoms resolved completely once the tumor was removed, although they were more likely related to gastroesophageal reflux disease, rather than to the tumor itself. An alternative management plan for this tumor would have been to leave the lesion in situ and to perform regular endoscopic and EUS surveillance with deep biopsies looking for dysplastic changes. In summary, granular cell tumors of the esophagus are rare and mostly benign neoplasms. Endoscopic biopsies are the mainstay of diagnosis. Endosonographic evaluation of the lesion defines the location and extension of the tumor and its suitability for endoscopic resection. Saline-assisted endoscopic mucosal resection is a safe and accurate procedure.