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.
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.
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