Case 11 -

Infiltrative granular cell tumor of the esophagus Gregory Y. Lauwers, M.D. Director, Gastrointestinal Pathology Service Massachusetts General Hospital Harvard Medical School

Clinical history: A 22-year-old woman, with no significant past medical history, presented to her general practitioner complaining of dysphagia. She was treated symptomatically but maintained her complaints, and eventually consulted a gastroenterologist, who performed an upper endoscopy. The examination was unremarkable, and biopsies of the distal esophagus revealed a normal squamous epithelium. She was then sent to an ear, nose, and throat specialist, who did not notice evidence of nasopharyngeal regurgitation, hoarseness, or aspiration. Given the persistence of symptoms, she finally had a CT scan that revealed a poorly defined, circumferential thickening of the esophageal wall. A second set of biopsies was performed that again came back negative. She eventually underwent a partial esophagectomy. Case 11 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Infiltrative granular cell tumor of the esophagus Granular cell tumors (GCTs) are uncommon tumors of neurogenic origin that rarely occur in the esophagus, where it was described for the first time in 1931. [1] Between 1% and 8% of all GCTs occur in the GI tract and among those, about one third occur in the esophagus, where about 200 cases have been reported. [12, 14, 16] The great majority of esophageal GCTs are benign. Fewer examples of a particular infiltrating variant associated with a good outcome have been reported and only a few truly malignant esophageal GCTs have been diagnosed. Clinical Features Most esophageal GCTs are diagnosed incidentally on upper endoscopy done for other reasons. It has been reported that about 50% of patients with esophageal GCT were symptomatic but that almost half have complaints not related to the tumor. When symptomatic, dysphagia is commonly reported and is related to tumor size. Hoarseness and heartburn also have been noted. [11] GCTs occur in patients of all ages, but are most common between the fourth and sixth decade of life. A noted female predilection is not unanimously reported. [14] However, there is a disproportionate number of esophageal GCTs diagnosed in the black population. [11, 26] Gross and Endoscopic Features Endoscopically, GCTs typically appear as an isolated submucosal nodule with a normal or slightly granular overlying mucosa. Most (65%) of the tumors are found in the distal esophagus, with only 20% and 15% in the middle and proximal esophagus, respectively. [22] Endoscopic ultrasound can provide additional information, such as the layer of origin as well as the depth of tumor extension. In one series, 95% of GCTs arising in the esophageal inner layer display a hypoechoic solid pattern with smooth margins. [23] Nearly all esophageal GCTs are solitary, but between 11% and 5 of 13 of patients have two or more tumors. [22] The tumors are usually synchronous, although metachronous esophageal GCTs have been reported. [4] Several cases of multifocal GCTs localized to the gastrointestinal tract have been reported. [11, 13] For example, in one case, multiple tumors ranging in diameter from 3 to 7 mm were found in the larynx and in the middle and distal esophagus. [11] Another patient presented with a solitary esophageal tumor associated with extraesophageal GCTs, including cutaneous and gastric localization. [11] Microscopic Features GCTs are composed of a proliferation of slightly ovoid cells with abundant eosinophilic granular cytoplasm. The cells are usually organized in distinct nests. The nuclei are small and pyknotic, and generally centrally located. When present, only a minimal variation in size and shape is seen. Nucleoli are inconspicuous, and mitotic figures and tumor cell necrosis are usually not seen. The cytoplasm shows PAS-positive, diastase-resistant granules that represent the numerous lysosomes characteristic of these cells. An important pitfall is the pseudoepitheliomatous hyperplasia of the epithelium overlying the tumor, which should not be incorrectly interpreted as a well-differentiated squamous carcinoma. Natural History Most GCTs are histologically and clinically benign, and malignant tumors are extremely rare, estimated to be 1-2% of all cases. [21] The same is true for esophageal GCTs, with only few definitive case of malignant GCTs reported. Fifteen cases of infiltrating GCTs of the esophagus have been reported. [2] Like typical tumors, the mean age of the patients is about 40 years, and most complained of dysphagia (from a range of months to years). The tumors measured between 1.6 and 3 cm and were characterized by deep infiltration. The GCTs infiltrated the muscularis in 7 cases, the adventitia in 4, and regional organs (trachea, pharynx, or larynx) in another 4 patients. [2, 3, 5, 7, 10, 11, 12, 15, 19, 20, 25] Morphologically, the tumor cells are similar to typical cases, although nuclear atypia and mitosis can be seen. Although several of these tumors were originally considered to be malignant on the basis of the infiltrative growth pattern, no metastasis or death has been reported for them. On the contrary, patients can experience extended survival. In addition to the case presented today one patient was reported to be alive and well 22 years after incomplete surgical excision. [5] Few definitive cases of malignant esophageal granular cell tumor have been reported. Mayer and Salzer-Kuntschik reported a case of an esophageal GCT that metastasized to cervical lymph nodes. In this case, the patient died 7 months later. [19] Wyatt et al. reported a 78-year-old female patient with malignant granular cell tumor with mitotic figures and vascular invasion. [27] Yoshizawa presented the case of a 71-year-old man who after complaining of dysphagia for 10 months was diagnosed with a 10x5 cm submucosal tumor with central ulceration of the mid-esophagus. [30] Four years later, the patient developed bilateral pleural metastases and multiple nodular lesions in his liver, and died shortly thereafter. Although the histologic details were sketchy, in several reports the presence of necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity, and pleomorphism seem to indicate malignant behavior, as previously noted with malignant granular cell tumor of the soft part. [6, 19] Pathogenesis Formerly known as granular cell myoblastoma, both immunohistochemical and ultrastructural data support neural differentiation in this tumor. Ultrastructurally, the cytoplasmic granules consist of membrane-bound autophagic vacuoles that contain cellular debris, including myelin-like figures similar to Schwann cells, while the immunohistochemical expression of S-100 protein in both a diffuse and intense pattern is supportive of Schwann cell differentiation. [8, 17, 18] In a recent series, nestin, an intermediate filament protein expressed in neuroectodermal stem cells and skeletal muscle progenitor cells, has been shown to be in GI GCTs, suggesting that these lesions may arise from a multipotential stem cell in the GI tract. [24] Treatment After exclusion of muscularis propria invasion by EUS, small esophageal GCTs can be successfully excised by endoscopic polypectomy. [28, 29] In the case of infiltrative GCTs, surgical resection, even when incomplete, has been associated with prolonged survival. 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