Ann Thorac Surg 1996;62:860-865
© 1996 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Granular Cell Tumors of the Esophagus: A Clinical and Pathologic Study of 13 Cases
John R. Goldblum, MD,
Thomas W. Rice, MD,
Gregory Zuccaro, MD,
Joel E. Richter, MD
Departments of Anatomic Pathology, Cardiovascular and Thoracic Surgery, and Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio
Accepted for publication May 1, 1996.
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Abstract
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Background. Fewer than 200 cases of esophageal granular cell tumors (GCT) have been reported. However, determination of malignant potential and appropriate management are as yet unresolved issues.
Methods. We evaluated the clinical and pathologic features of 13 esophageal GCTs.
Results. This group included 11 women and 2 men. Six patients were black. Patient ages ranged from 27 to 69 years (median, 47 years). Tumors were found incidentally in 10 patients. Only 2 patients were symptomatic. Most tumors were in the distal esophagus and were less than 8 mm. In 5 patients, multiple GCTs were found, including 3 patients with multiple esophageal GCTs. In 11 cases, the tumor was diagnosed by endoscopic biopsy. Ten patients were treated with biopsy alone, without further attempt at tumor excision. No recurrent or metastatic disease developed within the follow-up period. In all but 1 case, tumors were characterized by nests of cells with pyknotic nuclei, abundant granular cytoplasm, an absence of mitotic figures, and strong S-100 protein positivity. One patient who presented with dysphagia had a 2.5-cm distal esophageal GCT that showed atypical histologic features, including cellular spindling, nuclear pleomorphism, and mitoses. Because of this patient's symptoms, the large tumor size, and atypical endoscopic ultrasonographic and histologic features, the lesion was surgically excised.
Conclusions. Esophageal GCTs are usually asymptomatic, small, and found incidentally on upper endoscopy done for other reasons. Flexible esophagoscopy and biopsy are the mainstay in diagnosis, and endoscopic ultrasound can provide additional information on the layer of origin and tumor extension. Observation of these tumors is indicated unless the patient is symptomatic or the tumor is greater than 1 cm or has atypical endoscopic ultrasonographic or histologic features.
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Introduction
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Granular cell tumor (GCT), formerly known as granular cell myoblastoma, was first described by Abrikossoff [1] in 1926, when he reported a series of 5 cases of histologically benign tumors removed from the tongue. Since then, lesions were found in many other locations, including the skin, breast, respiratory tract, and biliary system. Several large reviews found that approximately 1% to 8% of all GCTs occur in the gastrointestinal tract [2, 3], and approximately one third of these occur in the esophagus [4]. The first case of an esophageal GCT was also described by Abrikossoff in 1931 [5]. Granular cell tumors in this location were thought to be rare until a flurry of case reports and small series were published in the 1980s, presumably due to their increased detection by flexible fiberoptic endoscopy. Although approximately 200 cases now have been reported, several aspects of this relatively rare esophageal tumor have still to be clarified, such as whether esophageal granular cell tumors undergo malignant degeneration, whether malignancy can be diagnosed preoperatively, and what is the appropriate management. Therefore, we evaluated the clinical and pathologic features of all esophageal GCTs at our institution to address these unresolved issues.
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Material and Methods
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We searched the files of the Department of Anatomic Pathology at the Cleveland Clinic Foundation for all cases of esophageal granular cell tumor between 1970 and the present, finding 13 cases for which hematoxylin and eosin-stained slides were available for review and clinical follow-up was obtainable. In each case, all microscopic slides were examined by a single pathologist (J.R.G.), including all special stains, particularly periodic acid-Schiff with and without prior diastase digestion, which was available in 8 cases. Immunohistochemical analysis for S-100 protein was done in all cases with the labeled streptavidin biotin system, using an automated immunostainer (Ventana 320; Ventana Medical Systems, Tucson, AZ). The referring pathologist, the surgeon, the medical record, or a combination of these sources provided information concerning the patient's age at diagnosis; presenting signs and symptoms; radiographic, endoscopic, endoscopic ultrasound, and operative findings; therapy; and outcome.
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Results
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Clinical and Gross Anatomic Features
The clinical features of the 13 patients with esophageal GCTs are summarized in Table 1
. This group included 11 women and 2 men. Six of the patients were black, and the remainder were white. The patients' ages ranged from 27 to 69 years, with a median age of 47 years. In 10 patients, the esophageal tumor or tumors were found incidentally on esophagogastroduodenoscopy done for other reasons. In 1 patient (patient 2), a single tumor was found as an incidental finding at autopsy in a patient who died of widely metastatic non–small cell carcinoma of the lung. Only 2 patients were symptomatic. One patient (patient 5) presented with hoarseness and dysphagia. Multiple tumors ranging in diameter from 3 to 7 mm were found in the larynx and in the middle and distal esophagus. Another patient (patient 11) presented with heartburn and dysphagia and had a single 2.5-cm tumor located just proximal to the gastroesophageal junction.
Three patients underwent barium esophagogram. In 1 patient, no definite abnormality was identified, but small (3- to 7-mm) nodules were noted on subsequent esophagoscopy. In the other 2 patients, solitary lesions of 7 mm and 25 mm were identified as nodules within the esophageal wall with normal overlying mucosa.
Twelve patients had granular cell tumors identified on esophagoscopy. The typical endoscopic appearance was that of an isolated submucosal nodule. The overlying mucosa was normal or slightly granular; ulceration or mucosal depression was not observed (Fig 1). In 11 of these cases, endoscopic biopsy provided adequate tissue for histologic confirmation.
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Fig 1. . Endoscopic appearance of the "malignant" esophageal granular cell tumor (patient 11). The lesion is located just proximal to the gastroesophageal junction, and the overlying mucosa is endoscopically normal.
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Endoscopic ultrasound was performed in 4 patients. In 2 of the 4, the lesions appeared to arise from the third (submucosal) layer of the esophageal wall (Fig 2). In 1 of these patients (patient 11), the fourth ultrasound layer (muscularis propria) contiguous to the tumor was markedly thickened. In 2 patients, the nodules appeared contiguous with the second (deep mucosa) layer.
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Fig 2. . Endosonographic image from the distal esophagus from patient 11. The granular cell tumor (black arrow) arises in the third ultrasound layer (submucosa) and is in proximity to the aorta. The fourth ultrasound layer (muscularis propria) is markedly thickened and irregular (white arrows). This may reflect the pathologic finding of tumor infiltration through the esophageal wall into the paraesophageal soft tissues.
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The tumors ranged in size from 3 mm to 2.5 cm, with a median size of 4 mm. Five patients had multiple GCTs. Two patients (patients 1 and 3) had multiple GCTs restricted to the esophagus. A third patient (patient 5) had multiple nodules in the larynx and middle and distal esophagus ranging from 3 to 7 mm. Two other patients had solitary esophageal tumors associated with extraesophageal GCTs. One patient (patient 8) had both cutaneous and gastric GCTs, and a second patient (patient 9) had a 4-mm gastric GCT.
Excluding the patient whose tumor was found incidentally at autopsy, 10 of the remaining 12 patients were treated with biopsy alone, without further attempt at tumor excision. No recurrent or metastatic disease developed in any of these patients within the follow-up period. Although 2 cases are recent and have no significant follow-up, the remainder of the patients were free of disease with follow-up periods ranging from 2 months to 11 years (median, 5 years). One patient (patient 5) received radiation therapy for airway control and laryngeal preservation. The remaining patient's tumor was treated with wide local excision with tumor-free margins at frozen section.
Histologic Findings
The histologic features for all but 1 case (patient 11) were similar. At low magnification, all tumors were composed of a proliferation of slightly ovoid cells with abundant eosinophilic granular cytoplasm separated by collagenous septae into distinct nests or clusters (Fig 3). In some cells, larger granules of varying sizes surrounded by a clear zone were identified. Nuclei were generally centrally located, small, and pyknotic, with slight variation in size and shape. Nucleoli were not conspicuous in these cases. Mitotic figures were not seen, nor was there evidence of tumor cell necrosis. In the 8 cases with periodic acid-Schiff staining, periodic acid-Schiff–positive, diastase-resistant granules representing lysosomes were present within the cytoplasm of some cells. Pseudoepitheliomatous hyperplasia was present in 5 cases (Fig 4), although there was never sufficient cytologic atypia within the hyperplastic squamous mucosa to suggest a diagnosis of invasive squamous cell carcinoma.
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Fig 3. . Benign esophageal granular cell tumor. The neoplastic cells are arranged into distinct nests by collagenous septae. The cells have uniform small pyknotic nuclei and abundant eosinophilic granular cytoplasm. (Hematoxylin and eosin stain; x10 before 29% reduction.)
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Fig 4. . Benign esophageal granular cell tumor with pseudoepitheliomatous hyperplasia of the overlying squamous mucosa. Unless one recognizes the underlying granular cell tumor, this change can be misinterpreted as an invasive squamous cell carcinoma. (Hematoxylin and eosin stain; x10 before 29% reduction.)
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Only the tumor in patient 11 had disparate and possibly worrisome histologic features. This was a large 2.5-cm tumor resected from the distal esophagus, which grossly was a well-circumscribed submucosal nodule. However, there was histologic infiltration of granular cells through the esophageal wall into the paraesophageal soft tissue (Fig 5). Although some portions of the tumor showed a nested appearance, in other portions the neoplastic cells that were more spindled were arranged into larger sheets. Nucleoli were more prominent in this case than in the other cases, and rare mitoses were seen (2 mitoses/10 high-power fields) (Fig 6).
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Fig 5. . Immunohistochemical stain for S-100 protein, which outlines nests of neoplastic cells (arrow), which are infiltrating in and around the muscularis propria. Although the tumor in this case was grossly well-circumscribed (patient 11), there was transesophageal tumor infiltration. (Immunohistochemical stain; x10 before 29% reduction.)
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Fig 6. . "Malignant" esophageal granular cell tumor (patient 11) showing neoplastic cells with increased nuclear pleomorphism, macronucleoli, and a mitotic figure (arrow). (Hematoxylin and eosin stain; x20 before 29% reduction.)
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Immunohistochemically, all 13 cases showed strong and diffuse S-100 protein positivity with both nuclear and cytoplasmic staining (Fig 7). The S-100 protein immunostain was useful in highlighting the extent of transesophageal tumor infiltration seen in patient 11.
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Fig 7. . Immunohistochemical stain for S-100 protein in a benign esophageal granular cell tumor. The darkly stained nests of tumor cells are seen immediately beneath the squamous mucosa and are thus frequently present in an endoscopic biopsy specimen. (Immunohistochemical stain; x10 before 29% reduction.)
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Comment
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Granular cell tumors are relatively uncommon, typically benign neoplasms of soft tissue. These tumors were once regarded as arising only within skeletal muscle and were once referred to as granular cell myoblastomas. However, it became apparent that they could arise in many other tissues devoid of skeletal muscle. Both immunohistochemical and ultrastructural data strongly support neural differentiation in this tumor, prompting some authors to refer to these lesions as granular cell schwannomas [6]. Ultrastructurally, the cytoplasmic granules consist of membrane-bound autophagic vacuoles that contain cellular debris, including myelin-like figures [7]. The immunohistochemical expression of S-100 protein in both a diffuse and intense pattern is supportive of Schwann cell differentiation [8].
Although relatively rare in the gastrointestinal tract, GCTs most commonly occur in the esophagus, accounting for approximately one third of all gastrointestinal GCTs [4]. Nearly 200 cases of esophageal GCTs have been described in the literature, mostly as case reports or small series. Granular cell tumors as a group show a striking female predilection [3]; 11 of our 13 patients were women. Our study showed a disproportionate number of patients with esophageal GCT to be black; this has also been previously reported in the literature [9]. Although the patients' ages in this study ranged from 27 to 69 years, the median age was 47 years, similar to that in other reported studies [10].
Esophageal GCTs primarily occur in the distal esophagus. According to the review by Orlowska and associates [10], 65% of esophageal GCTs are found in the distal esophagus, with only 20% and 15% in the middle and proximal esophagus, respectively. In our series, 12 of the 13 patients had a distal esophageal GCT, although 2 patients also had additional lesions in the middle esophagus.
Orlowska and associates' review [10] found that more than 50% of patients with esophageal GCT were symptomatic, with almost half suffering from nonspecific symptoms not related to their tumor. In contrast, the tumors in our study were found incidentally on esophagogastroduodenoscopy in 9 patients, appearing as small, submucosal, nonulcerated lesions. One patient had gradual onset of hoarseness and dysphagia and had numerous laryngeal and middle and distal esophageal GCTs, all of which were 7 mm or smaller. The distribution and number of tumors were interpreted as representing widely metastatic disease, as opposed to multifocal disease. She was treated with radiation therapy to the head and neck region and is alive and well 5 years later. Another patient presented with intermittent dysphagia and heartburn, and was found to have a 2.5-cm submucosal mass in the distal esophagus. Surgical resection was performed to alleviate the symptoms and exclude malignancy. Thus, we believe most esophageal GCTs are found incidentally at upper gastrointestinal endoscopy. Large or multifocal tumors are more likely to present with symptoms.
Most reported cases of esophageal GCT are solitary tumors, but up to 11% of patients have two or more esophageal GCTs [10]. In our study, 3 patients had at least two esophageal GCTs, 1 of whom also had laryngeal GCTs. In all 3 of these cases, the esophageal GCTs were synchronous, although metachronous esophageal GCTs have been reported [11]. Granular cell tumors may occur in multiple locations outside of the gastrointestinal tract, with a frequency ranging from 8.5% [12] to 16% [3] of cases. Several cases of multifocal GCTs localized to the gastrointestinal tract have been reported [13], prompting some authors to suggest complete endoscopic examination of both the upper and lower gastrointestinal tract for extraesophageal intestinal GCTs [14]. In our study, 2 patients had synchronous gastric GCTs in addition to their esophageal tumors.
In our experience, most esophageal GCTs can be diagnosed by endoscopic biopsy, as was done in 11 of 12 cases. Although centered in the submucosa, these tumors frequently have nests of cells immediately beneath the mucosa, allowing for diagnosis if at least some submucosa is present in the biopsy specimen. Obtaining multiple biopsy specimens at the same site ("well technique") allows for better access to the submucosa, facilitating the diagnosis of a submucosal tumor [9]. It is important to note that this tumor may induce pseudoepitheliomatous hyperplasia of the overlying mucosa, which may be mistaken for an invasive squamous cell carcinoma, prompting esophagectomy [15].
Endoscopic ultrasound was used in the evaluation of 4 patients in our series. In 2 cases, the lesions appeared to arise from the third (submucosal) layer of the esophageal wall. In 1 of these cases (patient 11), the fourth ultrasound layer (muscularis propria) contiguous to the tumor was markedly thickened. This is an unusual appearance for a benign submucosal lesion, and given the patient's symptoms, the lesion was surgically excised. On endoscopic ultrasound, the appearance of these tumors may be distinguished from lipomas, which also arise in the third (submucosal) layer, by their internal echoes, as lipomas are far more hyperechoic.
Although the diagnosis of esophageal GCT is relatively straightforward, the issue of appropriate therapy is controversial. Although some authors advocate surgical excision [16], there is a gradual shift to more conservative therapeutic approaches. Esophageal GCTs producing intraluminal polypoid lesions have been completely excised by endoscopic polypectomy [17]. Yasuda and colleagues [18] used endoscopic ultrasonography to judge whether the tumor was small enough (less than 2 cm) and not attached to the muscularis propria before safe removal by endoscopic polypectomy. Others advocate the injection of dehydrated alcohol to separate the lesion from the muscularis propria, thereby allowing more complete excision by endoscopic polypectomy [19]. However, these techniques may be unnecessary, as other authors find that further therapy is not needed as long as the patient is asymptomatic and the lesion is histologically benign [20]. In our study, 11 patients' tumors were diagnosed by endoscopic biopsy with no further attempt at endoscopic or surgical excision. Although the follow-up period was short in 4 patients (7 months or less), the remaining patients had no further evidence of disease with follow-up ranging from 23 months to 11 years. In all but 1 of these 11 patients, the lesion was found incidentally and was small (8 mm or less) and histologically benign. Thus, the data in the literature and our study support conservative therapy of GCT unless the tumor is large (>1 cm) or the patient has symptoms.
The issue of determining histologic malignancy in a GCT is a difficult one. The vast majority of GCTs are histologically benign, and an extensive review of the literature disclosed fewer than 40 reports of malignant GCT (Dr John J. Brooks, personal communication). In virtually all cases, malignancy was diagnosed retrospectively upon discovery of lymph node metastases, and re-review of the original tumors found most lesions to be indistinguishable from histologically and clinically benign GCTs [21].
To our knowledge, there are only 3 reported cases of malignant esophageal GCT. Crawford and DeBakey [22] reported a case in which a cervical esophageal GCT locally invaded the cricoid cartilage and trachea. However, after incomplete resection, the patient was still alive without evidence of disease 22 years later. Obiditsch-Mayer and Salzer-Kuntschik [23] reported a case of an esophageal GCT that metastasized to cervical lymph nodes. Unfortunately, the histologic details of both of these cases are sketchy. Finally, Ohmori and associates [24] reported a case of a histologically malignant GCT, but lymph node metastases were not found, and the follow-up was not given.
Recently, Fanburg and co-workers [25] proposed histologic criteria for prospectively diagnosing malignancy in GCTs, including tumor cell necrosis, tumor cell spindling, increased nuclear size, large nucleoli, mitotic activity, and nuclear pleomorphism. In their study, tumors that showed at least three of the above criteria were classified as histologically malignant; the majority of these tumors metastasized and resulted in patient death. One of our cases (patient 11) met these criteria, in addition to showing extensive transmural infiltration and spread into the paraesophageal soft tissues. Thus, the histologic features of this case suggest that excision was the appropriate therapy given the possibility of malignant clinical behavior.
In summary, granular cell tumors are uncommon esophageal tumors that show a female and black predominance. Most tumors are asymptomatic, as only 2 patients in this series presented with symptoms referable to their tumor. Flexible esophagoscopy and biopsy are the mainstay in diagnosis, as was the case in 11 patients in our series. Endoscopic esophageal ultrasonography provides additional information on the layer of origin and extension into other tissues. As with all granular cell tumors, the prospective diagnosis of malignancy is difficult. One patient in this series met the proposed histologic criteria for malignancy. She was symptomatic, with the largest (2.5 cm) and only tumor greater than 1 cm in diameter, which also had atypical endoscopic ultrasound features. These findings should alert the physician to the potential for malignancy and prompted resection in this particular case. Otherwise, observation of these uncommon esophageal tumors is indicated.
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Footnotes
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Address reprint requests to Dr Goldblum, The Cleveland Clinic Foundation, 9500 Euclid Ave L25, Cleveland, OH 44105.
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References
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Abstract
Introduction
