- Email: [email protected]
Granular Cell Tumor of the Esophagus: Report of Five Cases and Review of the Literature
Granular Cell Tumor of the Esophagus: Report of Five Cases and Review of the Literature SRI LAKSHMI NARRA, MD; CLAUDIO TOMBAZZI, MD; VIVEKANAND DATTA, MD, PHD; MOHAMMAD K. ISMAIL, MD
ABSTRACT: Granular cell tumor (GCT) is an uncommon esophageal neoplasm. It commonly presents as a nonspecific painless mass. The purpose of this study is to describe our experience with 5 patients newly diagnosed with GCT at VA Medical Center in Memphis, Tennessee from February 2001 to June 2005. Clinical manifestation, endoscopic appearance, histology, different modalities of treatment and prognosis are discussed. Based on this experience, we conclude that GCTs are
relatively rare in occurrence. They usually present as a firm to hard submucosal nodule on esophagogastroduodenoscopy. Diagnosis can be made by endoscopic biopsy in most cases. Treatment options include endoscopic surveillance, endoscopic resection, or surgery. The usual course of GCTs is benign. KEY INDEXING TERMS: Granular cell tumor; Esophagus; Myoblastoma; Esophageal benign tumor; Submucosal nodule. [Am J Med Sci 2008;335(5):338–341.]
G
utive patients who underwent an endoscopic procedure at VA Medical Center, Memphis, Tennessee, from Feb 2001 to June 2005. During this review, from a total of 4556 upper endoscopies of the GI tract, 5 cases of GCT were identified. This diagnosis constituted only 0.1% of all patients who underwent endoscopy of the upper GI tract at our institution during that period.
ranular cell tumor (GCT) is a relatively uncommon, typically benign tumor, formerly known as GC myoblastoma. It was first described by Abrikossoff, in 1926, who described a series of 5 cases of such tumors occurring in the tongue.1 He was also the first one to report its occurrence in the esophagus in 1931.2 GCT commonly presents as a nonspecific painless mass in virtually any anatomic location including the oral cavity, orbit, gastrointestinal (GI) tract, respiratory tract, biliary tract, skin, breast, external genitalia, skeletal muscle, cranial and peripheral nerves.3 There was much controversy earlier concerning the origin of GCT. The fact that S100 is positive on immunohistochemistry favors a neural (Schwann or neural crest) rather than muscular derivation.4,5 The purpose of this article is to discuss the clinical, endoscopic, and pathologic features of 5 cases of GCT seen and treated at our institution, VA Medical Center in Memphis, Tennessee. Methods and Case Reports This study represents a retrospective review of medical records, endoscopic, pathologic, and radiologic databases of all the consec-
Case 1 A 56-year-old man presented with abdominal pain, nausea, vomiting, heart burn, and hematemesis. Esophagogastroduodenoscopy (EGD) showed a partially healed Mallory-Weiss tear with no active bleeding along with a 15-mm smooth, hard submucosal nodule in the distal esophagus (Figure 1). Biopsy revealed a tumor with polyhedral cells arranged in sheets, nests, and lobules. The tumor cells had abundant granular eosinophilic cytoplasm with centrally located nuclei (Figures 2 and 3). The description was considered to be consistent with a GCT. Abdominal computed tomography (CT) showed no abnormalities. However, a follow-up CT abdomen 6 months later showed a distal esophageal mass and prominent but not significantly enlarged celiac and gastroesophageal nodes (Figure 4). A repeat EGD showed 10 ⫻ 15-mm hard, submucosal nodule in the distal esophagus, and biopsy was nondiagnostic. Keeping in view the normal results of biopsy and abnormal findings of the CT scan, the patient opted for surgery. Frozen section at the time of surgery revealed GCT, so intramural resection was done and a mass measuring 0.9 ⫻ 1.9 cm was removed. Lymph nodes were negative. His surveillance endoscopies did not reveal any recurrent disease despite positive margins. Patient is currently asymptomatic. Case 2
From the Division of Gastroenterogy, Department of Medicine (SLN, CT, MKI), University of Tennessee, Memphis, Tennessee; Department of Pathology (VD), University of Tennessee Health Science Center, Memphis, Tennessee; and Veteran Affair Medical Center (CT, VD, MKI), Memphis, Tennessee. Submitted April 27, 2007; accepted in revised form July 25, 2007. Correspondence: Claudio Tombazzi, MD, Division of Gastroenterogy, Department of Medicine, University of Tennessee, Memphis, Veteran Affair Medical Center, 920 Madison Avenue, Suite 240, Memphis, TN 38103 (E-mail: [email protected]).
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A 60-year-old man with a history of prior gastric surgery for a bleeding peptic ulcer presented with iron deficiency anemia. Hemoccult test results were normal. Colonoscopy result was also normal. EGD revealed a well-defined yellow tan, firm to hard submucosal nodule measuring 1 cm in diameter in the distal esophagus. CT scans of the chest and abdomen were normal. Biopsy revealed a GCT. After various options were discussed with the patient, he opted for surgery and underwent surgical resection. Frozen section showed negative margins, and the tumor was S100⫹ on immunostaining. Lymph nodes were negative. The May 2008 Volume 335 Number 5
Narra et al
Figure 1. Esophageal resection showing sheets, nests, lobules, and trabeculae of uniform epithelioid cells in superficial lamina propria (original magnification ⫻100).
Figure 3. Distal esophageal submucosal nodule.
patient died 18 months after operation because of causes unrelated to surgery.
surgical repair. There was no recurrent tumor on subsequent EGDs, and he is doing well 66 months postoperatively.
Case 3 A 52-year-old man was admitted for treatment of deep venous thrombosis. He reported nausea and vomiting and was found to have elevated levels of alkaline phosphatase and gamma-glutamyl transferase/transpeptidase. CT of the abdomen showed a thickening at the level of the GE junction, and a 1-cm retrocrural lymph node. On EGD, there was a hiatal hernia and a 15-mm firm, polypoid nodule in the fundus, which was removed using a snare. Biopsy revealed GCT. A surveillance EGD 10 months later showed a new submucosal nodule in the distal esophagus extending into the GE junction, with biopsy showing GCT. In view of recurrent GCT, the patient opted for surgery (distal esophagectomy). Lymph nodes were negative. Eighteen months postoperatively, the patient was admitted for an upper GI bleeding and was noted to have an atrioesophageal fistula and underwent
Case 4 A 56-year-old man presented with dysphagia and heart burn. EGD revealed a 4-mm white plaque in the mid esophagus. Biopsy revealed a GCT. CT scan results were normal. Keeping in view the small size of the lesion, a conservative approach was preferred. The patient opted for no further endoscopic surveillance. Case 5 A 52-year-old man was being evaluated for anemia. EGD revealed a ⬍10-mm submucosal distal esophageal nodule (endoscopic picture GCT), which on biopsy proved to be a GCT. An endoscopic ultrasound scan (EUS) was performed, which revealed a small hypoechoic 7-mm lesion in the submucosa. Because the lesion was asymptomatic, we planned for careful observation with endoscopic surveillance. A subsequent EGD 12 months later revealed stable size of the lesion.
Discussion Granular cell tumors are uncommon and typically benign. Most of these neoplasms are usually located in the head and neck region, and only 4% to 6% of granular cell tumors are located in the GI tract6,7 1/3
Figure 2. The tumor cells have abundant granular eosinophilic cytoplasm with centrally placed nuclei. Markedly enlarged lysosomes in tumor cells give it its “granular” appearance. These granules stain positive with periodic acid-Schiff (PAS) staining and are resistant to diastase. Tumor cells diffusely and strongly positive for S100 (original magnification ⫻400). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 4. Distal esophageal mass.
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of which in the esophagus1,8 –11 followed by the large intestine, in which GCT usually occurs in the anorectal area and ascending colon.12 GCTs are usually solitary lesion localized in distal esophagus; however, multifocal GCTs have been reported as well.13 Although in general there seems to be a female predilection,8 esophageal GCTs are frequently noted in men.6,14,15 Esophageal GCTs can occur at any age but are most commonly seen in the fifth decade of life. The majority of the patients with granular cell tumor of the esophagus, as in the cases presented, have not had symptoms attributable to the tumor, and the lesion is discovered in the course of investigation for other problems such as reflux esophagitis, iron deficiency anemia, or other symptoms in the GI tract.16 In patients who present with symptoms related to GCT, the most commonly encountered is dysphagia, whereas a minority of patients report retrosternal discomfort or pain.17 In the remaining cases, a vague epigastric pain, nausea, or vomiting have been reported.18 The frequency of symptoms increased in parallel to the size and multiplicity of the lesion. The endoscopic appearance as in the cases presented is usually a grayish-yellow intramural lesion covered by normal appearing mucosa with firm to hard consistency, also described as “submucosal pill” appearance.7 Biopsy has been performed without incident in a number of patients with granular cell tumor, including the cases discussed here. Endosonographic findings are usually hypoechoic, homogenous lesions with smooth margins arising from the mucosa or submucosa.19 Histologic examination of the tissue specimens typically reveal a benign neoplasm consisting of polygonal and fusiform cells disposed in compact “nests,” separated in places by collagen fiber bundles or projections of fiber cells originating in the muscularis mucosae. The cells have abundant eosinophilic cytoplasm and markedly enlarged lysosomes, which give them a granular appearance. These granules are PAS positive, diastase resistant, and also stain red with the trichrome strain. The monoclonal antibody KP-1 that recognizes the lysosome-associated glycoprotein CD68, are positive in these tumors.20 The cells, as in our cases, are S-100 positive on immunohistochemical (immunoperoxidase) testing. Whether multifocal or recurrent, the histologic appearance of GCT seems to remain unchanged. The proposed histologic criteria of malignancy of GCTs include tumor necrosis, tumor cell spindling, large nucleoli, increased mitotic activity, high nuclear to cytoplasmic ratio, and pleomorphism. Tumors fulfilling at least 3 of these criteria are classified as malignant.21 About 2% of the GCTs referred to in the literature proved to be malignant.21,22 Clinical evidence suggesting malignancy will be found with a history of local recurrence, rapid and recent 340
growth, and large tumor dimensions.18 Crawford and DeBakey reported a case of granular cell tumor, which had locally invaded the trachea and cricoid cartilage. After incomplete resection of this lesion, the patient was alive and well 22 years later.23 Chatelain also described similar presentation in 2 cases where GCT showed infiltrative growth, with invasion of the muscularis propria and adventitia. There was no recurrence, even after an incomplete resection. The author concluded that the infiltrative feature of the granular cell tumors of the esophagus, by itself, cannot be considered as a malignant feature. The diagnosis of malignant granular cell tumor of the esophagus lies on the discovery of metastases.24 Obiditsch-Mayer and Salzer-Kuntschik reported a case with cervical lymph node metastases, a rare occurrence in this usually benign neoplasm.22 Rare cases of synchronous presence of GCT and squamous cell carcinoma of the esophagus have also been reported. In some cases, lymphadenopathy without metastatic disease might be present, but it is usually benign as one of our patient representing a reactive process. The views concerning treatment of esophageal GCTs have been changing over the years. According to Coutinho et al, surgical excision was first preferred, with only a small proportion of endoscopic removal.25 In the subsequent time period, long-term observation in conservatively treated patients demonstrated the benign course of these tumors. Currently, endoscopic or surgical removal of esophageal GCTs should be restricted to the lesions that give symptoms of dysphagia or either are large, encircling, or with infiltrative margins. Surgical local excision of the tumor has its associated risks of bleeding, perforation, mediastinitis, abscess, and stricture. In our series, we had an unusual complication with atrioesophageal fistula presenting as bleeding in the upper GI tract that required an additional surgery. EUS aids in the identification of the location of the tumor and possible lymph-node involvement and is helpful in determining the choice of treatment.26 Unfortunately, EUS was not available earlier at our institution and only 1 patient underwent EUS evaluation. If located in the submucosa, without muscularis propria involvement, endoscopic polyectomy can be performed.27 Yasuda et al have suggested criteria for endoscopic removal which include small size (⬍20 mm) and nonattachment to the muscularis propria.28 Intratumoral polidocanol injections have been used in some instances to achieve necrosis of the submucosal neoplastic cells.8 Studies have suggested an 8% recurrence rate following surgery in patients with follow-up information.29 Absence of symptoms, tumor size ⬍1 cm, or general unsuitability for surgery currently indicate a conservative approach, with only endoscopic and histologic monitoring at 1- to 2-year intervals.30 May 2008 Volume 335 Number 5
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New therapeutic options including laser and diatherapy loop have been introduced.28 In a study conducted in Italy, from November 1992 to December 2000, 4 patients with GCTs of the esophagus underwent EUS evaluation followed by endoscopic YAG laser. At each session, a biopsy at the tumor site was obtained. The treatment was continued until endoscopic and histologic evidence of the tumor disappeared. After the YAG laser therapy, no evidence of the tumor was found in any of the 4 patients with esophageal GCT. Patients remained disease free after a mean follow-up period of 66 months. No complication was observed. However, laser treatment is expensive and is not always readily available, whereas the diatherapy loop has a high risk of perforation.31,32 Recently, endoscopic mucosal resection following EUS has shown to be effective and safe technique for endoscopic removal of GCT.33 Based on the retrospective review of the cases seen at our institution, we conclude that GCTs are relatively rare in occurrence. They are usually asymptomatic and present as a firm to hard submucosal nodule on EGD. Diagnosis can be made by endoscopic biopsy in most cases. The usual course of GCTs is benign. Even without therapy, they remain stable or change at a very slow rate. If small and asymptomatic, conservative management can be opted for and the lesion can be followed by surveillance endoscopies. Symptomatic lesions can be removed surgically; however, if endoscopic and EUS criteria (small size, ie, less than 2 cm, and nonattachment to the muscularis propria) are satisfied and local expertise is available, then endoscopic resection can be attempted.
9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
References 1. Abrikossoff A. Uber Myome, ausgehend von der quergestreiften willkurlichen Muskulatur. Virchows Arch Pathol Anat. 1926;260:215–33. 2. Abrikossoff A. Weitere Untersuchunger uber Myoblastemyome. Virchow’s Arch Pathol Anat 1931;280:723– 40. 3. Ordonez NG. M.B. Granular cell tumor: a review of the pathology and histogenesis. Ultrastruc Pathol 1999;23: 207–22. 4. Seo ISAB, Warner TF. Multiple visceral and cutaneous granular cell tumors. Ultrastructural and immunocytochemical evidence of Schwann cell origin. Cancer 1984;53: 2104 –10. 5. Yoshimi N. Minute esophageal granular cell tumor: a case report with immunohistochemical and ultrastructural examination. Jpn J Clin Oncol 1988;18:275– 81. 6. Parfitt JR. Granular cell tumours of the gastrointestinal tract: expression of nestin and clinicopathological evaluation of 11 patients. Histopathology 2006;48:424 –30. 7. Harikumar R. Abrikosoff’s tumor of the esophagus: case report and review of literature. Trop Gastroenterol 2006;27: 52–3. 8. Johnston J, Helwig EB. Granular cell tumors of the gas-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
25. 26. 27. 28. 29. 30. 31. 32. 33.
trointestinal tract and perianal region: a study of 74 cases. Dig Dis Sci 1981;26:807–16. Morrison JG. Granular cell tumors. Am Surg 1987;53: 156 – 60. Paskin DL, Hull JD, Cookson PJ. Granular cell myoblastoma: a comprehensive review of 15-years experience. Ann Surg 1972;175:501– 4. Peterson LJ. Granular-cell tumor. Review of the literature and report of a case. Oral Surg Oral Med Oral Pathol 1974; 37:728 –35. Nakachi AMH, Oshiro T, Shimoji H, Shiraishi M. Granular cell tumor of the rectum: a case report and review of the literature. J Gastroenterol 2000;35:631– 4. David O, Jakate S. Multifocal granular cell tumor of the esophagus and proximal stomach with infiltrative pattern: a case report and review of the literature. Arch Pathol Lab Med 1999;123:967–73. Orlowska J. A conservative approach to granular cell tumors of the esophagus: four case reports and literature review. Am J Gastroenterol 1993;88:311–5. Billeret Lebranchu V. [Granular cell tumor Epidemiology of 263 cases]. Arch Anat Cytol Pathol 1999;47:26 –30. Flood CA. Granular cell tumor of the esophagus. Gastrointest Endosc 1981;27:225–7. Patel RM. Granular cell tumor of the esophagus. Am J Gastroenterol 1981;76:519 –23. Giacobbe A. Granular cell tumor of the esophagus. Am J Gastroenterol 1988;83:1398 – 400. Palazzo L. Endosonographic features of esophageal granular cell tumors. Endoscopy 1997;29:850 –3. Le BHBP, Lewis JE, Kapadia SB. Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation. Arch Pathol Lab Med 2004; 128:771–5. Fanburg-Smith JC. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 1998;22:779 –94. Obiditsch-Mayer I, Salzer-Kuntschik M. [Malignant “granular cell neuroma”, so-called “myoblastmyoma” of the esophagus]. Beitr Pathol Anat 1961;125:357–73. Crawford ES, De Bakey ME. Granular-cell myoblastoma; two unusual cases. Cancer 1953;6:786 –9. Chatelain D. [Infiltrating granular cell tumor of the esophagus: a description of two cases]. Ann Pathol 2000;20:158 – 62. Coutinho DS. Granular cell tumors of the esophagus: a report of two cases and review of the literature. Am J Gastroenterol 1985;80:758 – 62. Saito H. EUS-guided endoscopic resection using band ligation of oesophageal granular cell tumour: report of a case. Acta Gastroenterol Belg 2005;68:272–5. Tada S. Granular cell tumor of the esophagus: endoscopic ultrasonographic demonstration and endoscopic removal. Am J Gastroenterol 1990;85:1507–11. Yasuda I. Endoscopic removal of granular cell tumors. Gastrointest Endosc 1995;41:163–7. Lack EE. Granular cell tumor: a clinicopathologic study of 110 patients. J Surg Oncol 1980;13:301–16. Savides TJ. Gastrointestinal submucosal masses. In: Gress FG, Battacharya I, editors. Endoscopic ultrasonography. Malden (MA): Blackwell Science; 2001. Fotiadis C. Endoscopic resection of a large granular cell tumor of the esophagus. J Surg Oncol 2000;75:277–9. Norberto L. Yttrium-aluminum-garnet laser therapy of esophageal granular cell tumor. Surg Endosc 2002;16: 361–2. Battaglia G. Single-band mucosectomy for granular cell tumor of the esophagus: safe and easy technique. Surg Endosc 2006;20:1296 – 8.
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ABSTRACT: Granular cell tumor (GCT) is an uncommon esophageal neoplasm. It commonly presents as a nonspecific painless mass. The purpose of this study is to describe our experience with 5 patients newly diagnosed with GCT at VA Medical Center in Memphis, Tennessee from February 2001 to June 2005. Clinical manifestation, endoscopic appearance, histology, different modalities of treatment and prognosis are discussed. Based on this experience, we conclude that GCTs are
relatively rare in occurrence. They usually present as a firm to hard submucosal nodule on esophagogastroduodenoscopy. Diagnosis can be made by endoscopic biopsy in most cases. Treatment options include endoscopic surveillance, endoscopic resection, or surgery. The usual course of GCTs is benign. KEY INDEXING TERMS: Granular cell tumor; Esophagus; Myoblastoma; Esophageal benign tumor; Submucosal nodule. [Am J Med Sci 2008;335(5):338–341.]
G
utive patients who underwent an endoscopic procedure at VA Medical Center, Memphis, Tennessee, from Feb 2001 to June 2005. During this review, from a total of 4556 upper endoscopies of the GI tract, 5 cases of GCT were identified. This diagnosis constituted only 0.1% of all patients who underwent endoscopy of the upper GI tract at our institution during that period.
ranular cell tumor (GCT) is a relatively uncommon, typically benign tumor, formerly known as GC myoblastoma. It was first described by Abrikossoff, in 1926, who described a series of 5 cases of such tumors occurring in the tongue.1 He was also the first one to report its occurrence in the esophagus in 1931.2 GCT commonly presents as a nonspecific painless mass in virtually any anatomic location including the oral cavity, orbit, gastrointestinal (GI) tract, respiratory tract, biliary tract, skin, breast, external genitalia, skeletal muscle, cranial and peripheral nerves.3 There was much controversy earlier concerning the origin of GCT. The fact that S100 is positive on immunohistochemistry favors a neural (Schwann or neural crest) rather than muscular derivation.4,5 The purpose of this article is to discuss the clinical, endoscopic, and pathologic features of 5 cases of GCT seen and treated at our institution, VA Medical Center in Memphis, Tennessee. Methods and Case Reports This study represents a retrospective review of medical records, endoscopic, pathologic, and radiologic databases of all the consec-
Case 1 A 56-year-old man presented with abdominal pain, nausea, vomiting, heart burn, and hematemesis. Esophagogastroduodenoscopy (EGD) showed a partially healed Mallory-Weiss tear with no active bleeding along with a 15-mm smooth, hard submucosal nodule in the distal esophagus (Figure 1). Biopsy revealed a tumor with polyhedral cells arranged in sheets, nests, and lobules. The tumor cells had abundant granular eosinophilic cytoplasm with centrally located nuclei (Figures 2 and 3). The description was considered to be consistent with a GCT. Abdominal computed tomography (CT) showed no abnormalities. However, a follow-up CT abdomen 6 months later showed a distal esophageal mass and prominent but not significantly enlarged celiac and gastroesophageal nodes (Figure 4). A repeat EGD showed 10 ⫻ 15-mm hard, submucosal nodule in the distal esophagus, and biopsy was nondiagnostic. Keeping in view the normal results of biopsy and abnormal findings of the CT scan, the patient opted for surgery. Frozen section at the time of surgery revealed GCT, so intramural resection was done and a mass measuring 0.9 ⫻ 1.9 cm was removed. Lymph nodes were negative. His surveillance endoscopies did not reveal any recurrent disease despite positive margins. Patient is currently asymptomatic. Case 2
From the Division of Gastroenterogy, Department of Medicine (SLN, CT, MKI), University of Tennessee, Memphis, Tennessee; Department of Pathology (VD), University of Tennessee Health Science Center, Memphis, Tennessee; and Veteran Affair Medical Center (CT, VD, MKI), Memphis, Tennessee. Submitted April 27, 2007; accepted in revised form July 25, 2007. Correspondence: Claudio Tombazzi, MD, Division of Gastroenterogy, Department of Medicine, University of Tennessee, Memphis, Veteran Affair Medical Center, 920 Madison Avenue, Suite 240, Memphis, TN 38103 (E-mail: [email protected]).
338
A 60-year-old man with a history of prior gastric surgery for a bleeding peptic ulcer presented with iron deficiency anemia. Hemoccult test results were normal. Colonoscopy result was also normal. EGD revealed a well-defined yellow tan, firm to hard submucosal nodule measuring 1 cm in diameter in the distal esophagus. CT scans of the chest and abdomen were normal. Biopsy revealed a GCT. After various options were discussed with the patient, he opted for surgery and underwent surgical resection. Frozen section showed negative margins, and the tumor was S100⫹ on immunostaining. Lymph nodes were negative. The May 2008 Volume 335 Number 5
Narra et al
Figure 1. Esophageal resection showing sheets, nests, lobules, and trabeculae of uniform epithelioid cells in superficial lamina propria (original magnification ⫻100).
Figure 3. Distal esophageal submucosal nodule.
patient died 18 months after operation because of causes unrelated to surgery.
surgical repair. There was no recurrent tumor on subsequent EGDs, and he is doing well 66 months postoperatively.
Case 3 A 52-year-old man was admitted for treatment of deep venous thrombosis. He reported nausea and vomiting and was found to have elevated levels of alkaline phosphatase and gamma-glutamyl transferase/transpeptidase. CT of the abdomen showed a thickening at the level of the GE junction, and a 1-cm retrocrural lymph node. On EGD, there was a hiatal hernia and a 15-mm firm, polypoid nodule in the fundus, which was removed using a snare. Biopsy revealed GCT. A surveillance EGD 10 months later showed a new submucosal nodule in the distal esophagus extending into the GE junction, with biopsy showing GCT. In view of recurrent GCT, the patient opted for surgery (distal esophagectomy). Lymph nodes were negative. Eighteen months postoperatively, the patient was admitted for an upper GI bleeding and was noted to have an atrioesophageal fistula and underwent
Case 4 A 56-year-old man presented with dysphagia and heart burn. EGD revealed a 4-mm white plaque in the mid esophagus. Biopsy revealed a GCT. CT scan results were normal. Keeping in view the small size of the lesion, a conservative approach was preferred. The patient opted for no further endoscopic surveillance. Case 5 A 52-year-old man was being evaluated for anemia. EGD revealed a ⬍10-mm submucosal distal esophageal nodule (endoscopic picture GCT), which on biopsy proved to be a GCT. An endoscopic ultrasound scan (EUS) was performed, which revealed a small hypoechoic 7-mm lesion in the submucosa. Because the lesion was asymptomatic, we planned for careful observation with endoscopic surveillance. A subsequent EGD 12 months later revealed stable size of the lesion.
Discussion Granular cell tumors are uncommon and typically benign. Most of these neoplasms are usually located in the head and neck region, and only 4% to 6% of granular cell tumors are located in the GI tract6,7 1/3
Figure 2. The tumor cells have abundant granular eosinophilic cytoplasm with centrally placed nuclei. Markedly enlarged lysosomes in tumor cells give it its “granular” appearance. These granules stain positive with periodic acid-Schiff (PAS) staining and are resistant to diastase. Tumor cells diffusely and strongly positive for S100 (original magnification ⫻400). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 4. Distal esophageal mass.
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Granular Cell Tumor of the Esophagus
of which in the esophagus1,8 –11 followed by the large intestine, in which GCT usually occurs in the anorectal area and ascending colon.12 GCTs are usually solitary lesion localized in distal esophagus; however, multifocal GCTs have been reported as well.13 Although in general there seems to be a female predilection,8 esophageal GCTs are frequently noted in men.6,14,15 Esophageal GCTs can occur at any age but are most commonly seen in the fifth decade of life. The majority of the patients with granular cell tumor of the esophagus, as in the cases presented, have not had symptoms attributable to the tumor, and the lesion is discovered in the course of investigation for other problems such as reflux esophagitis, iron deficiency anemia, or other symptoms in the GI tract.16 In patients who present with symptoms related to GCT, the most commonly encountered is dysphagia, whereas a minority of patients report retrosternal discomfort or pain.17 In the remaining cases, a vague epigastric pain, nausea, or vomiting have been reported.18 The frequency of symptoms increased in parallel to the size and multiplicity of the lesion. The endoscopic appearance as in the cases presented is usually a grayish-yellow intramural lesion covered by normal appearing mucosa with firm to hard consistency, also described as “submucosal pill” appearance.7 Biopsy has been performed without incident in a number of patients with granular cell tumor, including the cases discussed here. Endosonographic findings are usually hypoechoic, homogenous lesions with smooth margins arising from the mucosa or submucosa.19 Histologic examination of the tissue specimens typically reveal a benign neoplasm consisting of polygonal and fusiform cells disposed in compact “nests,” separated in places by collagen fiber bundles or projections of fiber cells originating in the muscularis mucosae. The cells have abundant eosinophilic cytoplasm and markedly enlarged lysosomes, which give them a granular appearance. These granules are PAS positive, diastase resistant, and also stain red with the trichrome strain. The monoclonal antibody KP-1 that recognizes the lysosome-associated glycoprotein CD68, are positive in these tumors.20 The cells, as in our cases, are S-100 positive on immunohistochemical (immunoperoxidase) testing. Whether multifocal or recurrent, the histologic appearance of GCT seems to remain unchanged. The proposed histologic criteria of malignancy of GCTs include tumor necrosis, tumor cell spindling, large nucleoli, increased mitotic activity, high nuclear to cytoplasmic ratio, and pleomorphism. Tumors fulfilling at least 3 of these criteria are classified as malignant.21 About 2% of the GCTs referred to in the literature proved to be malignant.21,22 Clinical evidence suggesting malignancy will be found with a history of local recurrence, rapid and recent 340
growth, and large tumor dimensions.18 Crawford and DeBakey reported a case of granular cell tumor, which had locally invaded the trachea and cricoid cartilage. After incomplete resection of this lesion, the patient was alive and well 22 years later.23 Chatelain also described similar presentation in 2 cases where GCT showed infiltrative growth, with invasion of the muscularis propria and adventitia. There was no recurrence, even after an incomplete resection. The author concluded that the infiltrative feature of the granular cell tumors of the esophagus, by itself, cannot be considered as a malignant feature. The diagnosis of malignant granular cell tumor of the esophagus lies on the discovery of metastases.24 Obiditsch-Mayer and Salzer-Kuntschik reported a case with cervical lymph node metastases, a rare occurrence in this usually benign neoplasm.22 Rare cases of synchronous presence of GCT and squamous cell carcinoma of the esophagus have also been reported. In some cases, lymphadenopathy without metastatic disease might be present, but it is usually benign as one of our patient representing a reactive process. The views concerning treatment of esophageal GCTs have been changing over the years. According to Coutinho et al, surgical excision was first preferred, with only a small proportion of endoscopic removal.25 In the subsequent time period, long-term observation in conservatively treated patients demonstrated the benign course of these tumors. Currently, endoscopic or surgical removal of esophageal GCTs should be restricted to the lesions that give symptoms of dysphagia or either are large, encircling, or with infiltrative margins. Surgical local excision of the tumor has its associated risks of bleeding, perforation, mediastinitis, abscess, and stricture. In our series, we had an unusual complication with atrioesophageal fistula presenting as bleeding in the upper GI tract that required an additional surgery. EUS aids in the identification of the location of the tumor and possible lymph-node involvement and is helpful in determining the choice of treatment.26 Unfortunately, EUS was not available earlier at our institution and only 1 patient underwent EUS evaluation. If located in the submucosa, without muscularis propria involvement, endoscopic polyectomy can be performed.27 Yasuda et al have suggested criteria for endoscopic removal which include small size (⬍20 mm) and nonattachment to the muscularis propria.28 Intratumoral polidocanol injections have been used in some instances to achieve necrosis of the submucosal neoplastic cells.8 Studies have suggested an 8% recurrence rate following surgery in patients with follow-up information.29 Absence of symptoms, tumor size ⬍1 cm, or general unsuitability for surgery currently indicate a conservative approach, with only endoscopic and histologic monitoring at 1- to 2-year intervals.30 May 2008 Volume 335 Number 5
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New therapeutic options including laser and diatherapy loop have been introduced.28 In a study conducted in Italy, from November 1992 to December 2000, 4 patients with GCTs of the esophagus underwent EUS evaluation followed by endoscopic YAG laser. At each session, a biopsy at the tumor site was obtained. The treatment was continued until endoscopic and histologic evidence of the tumor disappeared. After the YAG laser therapy, no evidence of the tumor was found in any of the 4 patients with esophageal GCT. Patients remained disease free after a mean follow-up period of 66 months. No complication was observed. However, laser treatment is expensive and is not always readily available, whereas the diatherapy loop has a high risk of perforation.31,32 Recently, endoscopic mucosal resection following EUS has shown to be effective and safe technique for endoscopic removal of GCT.33 Based on the retrospective review of the cases seen at our institution, we conclude that GCTs are relatively rare in occurrence. They are usually asymptomatic and present as a firm to hard submucosal nodule on EGD. Diagnosis can be made by endoscopic biopsy in most cases. The usual course of GCTs is benign. Even without therapy, they remain stable or change at a very slow rate. If small and asymptomatic, conservative management can be opted for and the lesion can be followed by surveillance endoscopies. Symptomatic lesions can be removed surgically; however, if endoscopic and EUS criteria (small size, ie, less than 2 cm, and nonattachment to the muscularis propria) are satisfied and local expertise is available, then endoscopic resection can be attempted.
9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
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