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Hilar pulmonary granular cell tumor: A case report and review of the literature
RADIOLOGIC-PATHOLOGIC CORRELATIONS
Hilar Pulmonary Granular Cell Tumor: A Case Report and Review of the Literature Abdul M. Al-Ghamdi, MD, Julia D.A. Flint, MD, Nestor L. Muller, MD, and Ken C. Stewart, MD We present a case of pulmonary granular cell tumor (GCT). A 35-year-old man underwent pulmonary resection for metastatic testicular mixed germ cell tumor when two interlobar lymph nodes were found to be enlarged and abnormal. Intraoperative frozen section examination showed their involvement by GCT. Histologic examination of the lobectomy specimen showed a benign, predominantly hilar GCT as well as metastatic germ cell tumor. This location, with no endobronchial component and with extension into regional hilar lymph nodes, is unusual. The differential diagnosis and the association with the metastatic testicular cancer are discussed and the literature on pulmonary GCT is reviewed. Ann Diagn Pathol 4: 245-251, 2000. Copyright r 2000 by W.B. Saunders Company Index Words: Granular cell tumor, granular cell myoblastoma, lung, lymph node, testicular tumors
G
RANULAR cell tumor (GCT) is an uncommon benign mesenchymal neoplasm of presumed schwannian origin typically presenting as a small solitary skin or submucosal nodule. Granular cell tumor of the lung is rare, accounting for 6% to 10% of all GCTs.1,2 Four percent to 10% of pulmonary GCTs are multicentric3,4 and are most commonly found in an endobronchial location.5 Almost half of the pulmonary tumors are discovered incidentally.5 The small size of most endobronchial lesions makes them amenable to conservative local excision, either endoscopically6 or by laser therapy.7 Sleeve resection is another available therapeutic approach.6 Large resections are justified for large tumors or if extensive damage to the distal lung parenchyma has occurred, such as postobstructive pneumonia. It is very unusual to see infiltration into the pulmonary parenchyma or involvement of a regional lymph node. These features do not necessarily indicate malignancy. To our knowledge, distant metastasis from a primary endobronchial GCT has not been described. We present a case of predominantly hilar GCT with From the Departments of Pathology, Thoracic Radiology, and Surgery, Vancouver General Hospital and University of British Columbia. Address reprint requests to Julia D.A. Flint, MD, Department of Pathology, Vancouver General Hospital and University of British Columbia, 855 W 12th Ave, Vancouver, BC Canada V5Z 1M9. Copyright r 2000 by W.B. Saunders Company 1092-9134/00/0404-0005$10.00/0 doi:10.1053/adpa.2000.8128
extension into the peribronchial lung parenchyma and with extension into two regional lymph nodes. This is only the third such case reported to date. Case Report A 35-year-old white man with a background of asthma and cigarette and marijuana smoking presented with a 2-month history of left testicular enlargement. In August 1996, he underwent left orchidectomy and inguinal node dissection, which showed a 6.5-cm mixed germ cell tumor. It was dominated by embryonal carcinoma and seminoma with a small amount of yolk sac tumor and mature and immature teratoma; choriocarcinomatous elements were absent. Immediate postoperative chest x-ray evaluation revealed three nodules in the lung fields. Radiologic evaluation in September 1996 showed five pulmonary nodules (one in the left upper lobe and four scattered in the right lung). The mediastinum was normal. These were believed to be metastatic disease; therefore, the patient was treated with a 4-week course of genitourinary etoposide and cisplatin chemotherapy. Repeat chest x-ray failed to demonstrate any nodules. In April 1997, radiologic evaluation showed persistence of only the left upper lobe lesion but also the development of a new 2.5-cm nodule in the apical segment of the right upper lobe as well as prominence of the upper aspect of the right hilum (Fig 1). The serum alpha fetoprotein level was 10 ng/mL (the normal value is ⬍20 ng/mL). A bone scan was negative. The patient was referred to the thoracic surgery unit for resection of these presumed metastatic lesions. In May 1997, he underwent a median sternotomy, wedge resection for the left upper lobe nodule, and right upper lobectomy. Frozen section analysis of the left upper lobe lesion confirmed metastatic embryonal
Annals of Diagnostic Pathology, Vol 4, No 4 (August), 2000: pp 245-251
245
246
Al-Ghamdi et al
Figure 1. View of the right upper chest from a posteroanterior radiograph shows a nodule (straight arrow) and prominence of the upper aspect of the right hilum (curved arrow) due to hilar lymph node enlargement.
carcinoma. At the time of resecting the apical segment of the right upper lobe, location 11 and 12 lymph nodes8 were noted to be enlarged and abnormal in texture. Intraoperative frozen section analysis of these lymph nodes showed GCT. Subsequently, the right upper lobectomy specimen contained metastatic embryonal carcinoma.
Pathologic Findings Macroscopically, each node measured 1 cm in maximum dimension and was composed of white firm tissue. Intraoperative frozen section and the subsequent permanent sections showed histologic features of benign GCT replacing most of the nodal tissue (Fig 2). In addition to the metastatic nodule, the right upper lobectomy specimen showed a thickened area around the bronchus at the hilum. Microscopic examination of the thickened peribronchial tissue at the hilum showed a predominantly hilar and partially circumscribed tumor that was close to, but not in continuity with, the bronchial wall (Fig 3). It measured 0.8 cm in greatest dimension. In some areas the tumor had no distinct border and displayed tongue-like extension into the loose fibrofatty tissue around the bronchial wall. The interface with the adjacent pulmonary parenchyma was
smooth with microscopic extension into the parenchyma (Fig 3). At high power, the constituent neoplastic cells were large and spindle-shaped (Fig 4A), occasionally oval and plump, and arranged in sheets and fascicles separated by variably thickened fibrous bands. The cytoplasm of the tumor cells was eosinophilic and finely granular. The nuclei were small, central, slightly spindled, and with a low nuclear to cytoplasmic ratio. There was only minimal variation in nuclear size and shape; the nuclei were focally vesicular with visible nucleoli. No mitoses were present and there were no areas of necrosis. Histochemically, the cytoplasmic granules gave a positive reaction with the periodic acid-Schiff stain. Immunohistochemically, the neoplastic cells expressed strong and diffuse nuclear and cytoplasmic reactivity for S-100 protein (Fig 4B). CD 68 (KP1) and vimentin were moderately and diffusely positive. Neuron-specific enolase immunohistochemical stain showed weak positivity. Stains for neurofilamen, actin, smooth muscle actin, desmin, keratin, and p53 were negative. The proliferative index with Ki-67 (MIB-1) was less than 1% in the tumor cells. Ultrastructurally, tumor cells showed abundance of the membrane-bound cytoplasmic granules,
Hilar Pulmonary Granular Cell Tumor
Figure 2.
247
Low-power magnification showing replacement of most of the lymph node structure by granular cell tumor.
with a heterogeneous electron density consistent with lysosomes, typical for granular cell tumors (Fig 5). Based on the features described, diagnosis of a benign GCT was rendered. Following confirmation of the metastatic disease in his lung, the patient was started on full salvage chemotherapy. Because of its known adverse effect on the bone marrow, this therapy necessitated bone marrow autotransplantation, which was done shortly after. Thirty-seven months after resection of his lung lesions, the patient is alive with no evidence of metastasis of the testicular tumor or recurrence of the GCT. Discussion Pulmonary GCT is a rare neoplasm, comprising 6% to 10% of all GCTs.1,2 More common sites include tongue, skin, breast, and chest wall. Abrikossoff9 originally described GCT in 1926. He thought they were derived from skeletal muscle and named them myoblastoma.9 Most studies support the concept that GCTs are of neurogenic (Schwann cell) origin.10-14 This concept is
based on several factors15: (1) the occurrence of tumors typical for GCT within nerves; (2) histochemical studies showing products of myelin degeneration in the tumor cells; (3) immunohistochemical studies showing tumor cells positivity for S-100 and myelin basic proteins; (4) ultrastructural similarities between GCTs and schwannomas, which include lysosomes, replicated external elastic lamina, Luse bodies, and angulate lysosomes; and (5) the reported occurrence of typical granular cells in neurofibromas from a case of neurofibromatosis. Over 90% of pulmonary GCTs are endobronchial in location.4,5 They can rarely occur in the posterior mediastinum,16 in the interlobar fissure, or as a peripheral lung lesion.5 Similar to extrathoracic GCT, multicentricity of pulmonary lesions is a well-recognized phenomenon, being present in 4% to 10% of cases.3,4 This occurrence is not unexpected and is, in fact, consistent with its presumptive neurogenic (schwannian) histogenesis. Neurogenic tumors, like neurofibromatosis, are frequently multicentric. Multicentricity does not necessarily indicate malignancy. However, when these tumors are
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Figure 3. Scanning power of the tumor shows no endobronchial component and no continuity with the bronchial wall. There are irregular extensions into the adjacent hilar fibrofatty tissue and the parenchyma.
multicentric they can mimic pulmonary metastasis, especially in a patient with another cancer. Although rare, metastasis from an extrapulmonary malignant GCT also should be considered in cases that are multicentric. Nearly half of pulmonary GCTs are discovered as incidental radiologic, bronchoscopic, or, as in our case, operative findings. Most of the published data are from isolated case reports. The only large series on pulmonary GCT is from the Armed Forces Institute of Pathology, where Deavers et al5 described the clinicopathologic features of 20 cases.5 All their patients were adults with a median age of 42 years; there was an equal number of men and women. Tumors were incidental in nine cases. Ten patients had evidence of bronchial obstruction and the other three complained of hemoptysis. Twenty-five percent of the tumors were multiple. Two tumors were peripheral in location, one of which appeared as though it may have arisen within a lymph node. In the remaining cases, the tumor was endobronchial. Peribronchial tissue extension was present in 40% of the patients.
Only one case showed direct extension into an adjacent lymph node. Distant metastasis from pulmonary GCT has not been described. Local extension beyond the bronchial wall into the pulmonary parenchyma has been reported only once.17 True malignant GCTs are rare, accounting for 1% to 2% of all GCTs.12 Due to their rarity, establishing reliable criteria for malignancy in GCTs has been difficult. In contrast to previous publications of single case reports, in 1998 Fanburg-Smith et al18 described 46 cases of malignant GCT of soft tissue. In their study, adverse prognostic factors and features suggestive of malignancy were proposed, including large tumor size, presence of necrosis, increased mitotic rate, spindling of the tumor cells, p53 immunoreactivity, and Ki-67 values greater than 10%. In our case, the tumor was predominantly hilar with focal extension into the parenchyma, and no direct extension to the adjacent bronchus. Moreover, two regional lymph nodes (location 11 and 12 nodes) were
Hilar Pulmonary Granular Cell Tumor
249
Figure 4. (Top) High-power view of the tumor. The cytoplasm is abundant and granular and the nuclei are small. Note the moderate to marked spindling of the tumor cells and the absence of mitosis. (Bottom) The strong and uniform immunohistochemical staining of the neoplastic cells for S-100 protein. The adjacent small lymph node is uninvolved by tumor.
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Al-Ghamdi et al
Figure 5.
Ultrastructural photomicrograph of the tumor cells demonstrating the membrane bound lysosomal granules.
extensively involved by tumor. The tumor, however, was small in size and, except for tumor cell spindling, exhibited no histologic features suggestive of the malignant counterpart. The apparent infiltration at the tumor periphery is a frequent histologic observation in benign GCT elsewhere in the body.19 p53 stain was negative and Ki-67 value was less than 1%. We interpreted the nodal spread as being a direct extension and not as metastatic disease. Thirty-seven months following resection of his lung lesions, the patient was alive with no evidence of metastatic testicular tumor or of recurrent GCT. We would like to point out two potential difficulties. First, encountering an unexpected GCT on frozen section suggests a broad list of diagnostic possibilities, such as oncocytic carcinoid, oncocytoma, acinic cell carcinoma, granular cell variant of squamous cell carcinoma and renal cell carcinoma, and, rarely, metastasis from an extrapulmonary malignant GCT (a clinically aggressive neoplasm with propensity for metastasis to lymph nodes, lungs, and bone). It is clear how important
it is clinically to histologically distinguish between these entities. In most cases this distinction can be accomplished with the histologic appearance coupled with cytochemical and immunohistochemical studies. Second, one should be cautious in interpreting nodal involvement as evidence of metastasis in a case of pulmonary GCT. If the GCT is morphologically benign and the node is in the vicinity, the more appropriate explanation is direct extension, as is the case here. Up to 13% of pulmonary GCTs have been reported to coexist with other neoplasms,20 most commonly with lung carcinoma.21-25 Other epithelial malignancies included esophageal and renal carcinoma. The association with the latter neoplasm was an incidental finding during resection for pulmonary metastasis. Other reported associations with nonneoplastic diseases included pulmonary chondroid hamartoma,5 sarcoidosis,5,26 cerebral arteriovenous malformation,5 and human immunodeficiency virus infection.27 We believe that these, as well as the association of GCT with the pulmonary metastasis of the testicular mixed germ cell tumor in
Hilar Pulmonary Granular Cell Tumor
our present case, are chance findings and have no apparent cause–effect relationship. The increased scrutiny in evaluating patients with these associated conditions may have resulted in discovering an otherwise asymptomatic GCT. Acknowledgment The authors thank Caron Fournier for her photographic assistance.
References 1. De Clerq D, Van Der Straeten M, Roels H: Granular cell myoblastoma of the bronchus. Eur J Respir Dis 1983;64:72-76 2. Ostermiller WE, Comer TP, Barker WL: Endobronchial granular cell myoblastoma. A report of three cases and review of the literature. Ann Thorac Surg 1970;9:143-148 3. Valenstein SL, Thurer RJ: Granular cell myoblastoma of bronchus. Case report and literature review. J Thorac Cardiovasc Surg 1978;76:465-468 4. Young CD, Gay RM: Multiple endobronchial granular cell myoblastomas discovered at bronchoscopy. Hum Pathol 1984;15:193194 5. Deavers M, Guinee D, Koss MN, et al: Granular cell tumors of the lung. Clinicopathologic study of 20 cases. Am J Surg Pathol 1995;19:627-635 6. Daniel TM, Smith RH, Faunce HF, et al: Transbronchoscopic versus surgical resection of tracheobronchial granular cell myoblastoms. Suggested approach based on follow-up of all treated cases. J Thorac Cardiovasc Surg 1980;80:898-903 7. Epstein LJ, Mohsenifar Z: Use of Nd: YAG laser in endobronchial granular cell myoblastoma. Chest 1993;104:958-960 8. Naruke T, Suemasu K, Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-839 ¨ ber Myome, ausgehend von der quergestreiften 9. Abrikossoff A: U willku ¨rlichen Muskulatur. Virchows Arch Pathol Anat 1926;260:215233 10. Sobel HJ, Marguet E, Avrin E, et al: Granular cell myoblastoma: An electron microscopic and cytochemical study illustrating the genesis of granules and aging of myoblastoma cells. Am J Pathol 1971;65:59-71 11. Abenoza P, Sibley RK: Granular cell myoma and schwannoma: Fine structural and immunohistochemical study. Ultrastruct Pathol 1987;11:19-28
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12. Enzinger FM, Weiss SW: Soft Tissue Tumors. St Louis, MO, Mosby, 1995, pp 872-875 13. Mazur MT, Shultz JJ, Myers JL: Granular cell tumor. Immunohistochemical analysis of 21 benign tumors and one malignant tumor. Arch Pathol Lab Med 1990;114:692-696 14. Steffansson K, Wollmann RL: S100 Protein in granular cell tumors. Cancer 1982;49:1834-1838 15. Ghadially FN: Lysosomes, in Ultrastructural Pathology of the Cell and Matrix: A text and Atlas of Physiological and Pathological Alterations in the Fine Structure of the Cellular and Extracellular Components. Toronto, Butterworths, 1988, pp 684-689 16. Robinson JM, Knoll R, Henry DA: Intrathoracic granular cell myoblastoma. South Med J 1988;81:1453-1457 17. Novi I: I tumori a cellule granulose (cosiddetti ‘miomi mioblastici’ di abrikossof): A proposito di un raro caso di tumore a cellule granulose del polmone ad evoluzione infiltrante. Arch Ital Chir 1958;83:333-336 18. Fanburg-Smith JC, Meis-Kindblom JM, Fante R, et al: Malignant granular cell tumor of soft tissue: Diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 1998;22:779-794 19. Ordo´n ˜ez NG, Mackay B: Granular cell tumor: A review of the pathology and histogenesis. Ultrastruct Pathol 1999;23:207-222 20. McSwain GR, Colpitts R, Kreutner A, et al: Granular cell myoblastoma. Surg Gynecol Obstet 1980;150:703-710 21. Gabriel JB Jr, Thomas L, Mendoza CB, et al: Granular cell tumor of the bronchus coexisting with a bronchogenic carcinoma: A case report. J Surg Oncol 1983;24:103-106 22. Hurwitz SS, Conlan AA, Gritzman MC, et al: Coexisting granular cell myoblastoma and squamous carcinoma of the bronchus. Thorax 1982;37:392-393 23. Majmudar B, Thomas J, Gorelkin L, et al: Respiratory obstruction caused by a multicentric granular cell tumor of the laryngotracheobronchial tree. Hum Pathol 1981;12:283-286 24. Rogers DR: Coincidental pulmonary granular cell schwannoma and bronchogenic adenocarcinoma. Alaska Med 1973;15:4-5 25. Tamayo JL, Rojas MC: Granular cell myoblastoma (granular cell schwannoma) of the right upper bronchus coexisting with a bronchogenic carcinoma. Report of the first case in the literature. J Thorac Cardiovasc Surg 1971;62:268-270 26. Liebman J, Linthicum CM: Granular cell myoblastoma (schwannoma) of the carina in a patient with sarcoidosis. South Med J 1976;69:1613-1615 27. Ganti S, Marino W: Granular cell myoblastoma in an HIV positive patient. N Y State J Med 1991;91:265-266
Hilar Pulmonary Granular Cell Tumor: A Case Report and Review of the Literature Abdul M. Al-Ghamdi, MD, Julia D.A. Flint, MD, Nestor L. Muller, MD, and Ken C. Stewart, MD We present a case of pulmonary granular cell tumor (GCT). A 35-year-old man underwent pulmonary resection for metastatic testicular mixed germ cell tumor when two interlobar lymph nodes were found to be enlarged and abnormal. Intraoperative frozen section examination showed their involvement by GCT. Histologic examination of the lobectomy specimen showed a benign, predominantly hilar GCT as well as metastatic germ cell tumor. This location, with no endobronchial component and with extension into regional hilar lymph nodes, is unusual. The differential diagnosis and the association with the metastatic testicular cancer are discussed and the literature on pulmonary GCT is reviewed. Ann Diagn Pathol 4: 245-251, 2000. Copyright r 2000 by W.B. Saunders Company Index Words: Granular cell tumor, granular cell myoblastoma, lung, lymph node, testicular tumors
G
RANULAR cell tumor (GCT) is an uncommon benign mesenchymal neoplasm of presumed schwannian origin typically presenting as a small solitary skin or submucosal nodule. Granular cell tumor of the lung is rare, accounting for 6% to 10% of all GCTs.1,2 Four percent to 10% of pulmonary GCTs are multicentric3,4 and are most commonly found in an endobronchial location.5 Almost half of the pulmonary tumors are discovered incidentally.5 The small size of most endobronchial lesions makes them amenable to conservative local excision, either endoscopically6 or by laser therapy.7 Sleeve resection is another available therapeutic approach.6 Large resections are justified for large tumors or if extensive damage to the distal lung parenchyma has occurred, such as postobstructive pneumonia. It is very unusual to see infiltration into the pulmonary parenchyma or involvement of a regional lymph node. These features do not necessarily indicate malignancy. To our knowledge, distant metastasis from a primary endobronchial GCT has not been described. We present a case of predominantly hilar GCT with From the Departments of Pathology, Thoracic Radiology, and Surgery, Vancouver General Hospital and University of British Columbia. Address reprint requests to Julia D.A. Flint, MD, Department of Pathology, Vancouver General Hospital and University of British Columbia, 855 W 12th Ave, Vancouver, BC Canada V5Z 1M9. Copyright r 2000 by W.B. Saunders Company 1092-9134/00/0404-0005$10.00/0 doi:10.1053/adpa.2000.8128
extension into the peribronchial lung parenchyma and with extension into two regional lymph nodes. This is only the third such case reported to date. Case Report A 35-year-old white man with a background of asthma and cigarette and marijuana smoking presented with a 2-month history of left testicular enlargement. In August 1996, he underwent left orchidectomy and inguinal node dissection, which showed a 6.5-cm mixed germ cell tumor. It was dominated by embryonal carcinoma and seminoma with a small amount of yolk sac tumor and mature and immature teratoma; choriocarcinomatous elements were absent. Immediate postoperative chest x-ray evaluation revealed three nodules in the lung fields. Radiologic evaluation in September 1996 showed five pulmonary nodules (one in the left upper lobe and four scattered in the right lung). The mediastinum was normal. These were believed to be metastatic disease; therefore, the patient was treated with a 4-week course of genitourinary etoposide and cisplatin chemotherapy. Repeat chest x-ray failed to demonstrate any nodules. In April 1997, radiologic evaluation showed persistence of only the left upper lobe lesion but also the development of a new 2.5-cm nodule in the apical segment of the right upper lobe as well as prominence of the upper aspect of the right hilum (Fig 1). The serum alpha fetoprotein level was 10 ng/mL (the normal value is ⬍20 ng/mL). A bone scan was negative. The patient was referred to the thoracic surgery unit for resection of these presumed metastatic lesions. In May 1997, he underwent a median sternotomy, wedge resection for the left upper lobe nodule, and right upper lobectomy. Frozen section analysis of the left upper lobe lesion confirmed metastatic embryonal
Annals of Diagnostic Pathology, Vol 4, No 4 (August), 2000: pp 245-251
245
246
Al-Ghamdi et al
Figure 1. View of the right upper chest from a posteroanterior radiograph shows a nodule (straight arrow) and prominence of the upper aspect of the right hilum (curved arrow) due to hilar lymph node enlargement.
carcinoma. At the time of resecting the apical segment of the right upper lobe, location 11 and 12 lymph nodes8 were noted to be enlarged and abnormal in texture. Intraoperative frozen section analysis of these lymph nodes showed GCT. Subsequently, the right upper lobectomy specimen contained metastatic embryonal carcinoma.
Pathologic Findings Macroscopically, each node measured 1 cm in maximum dimension and was composed of white firm tissue. Intraoperative frozen section and the subsequent permanent sections showed histologic features of benign GCT replacing most of the nodal tissue (Fig 2). In addition to the metastatic nodule, the right upper lobectomy specimen showed a thickened area around the bronchus at the hilum. Microscopic examination of the thickened peribronchial tissue at the hilum showed a predominantly hilar and partially circumscribed tumor that was close to, but not in continuity with, the bronchial wall (Fig 3). It measured 0.8 cm in greatest dimension. In some areas the tumor had no distinct border and displayed tongue-like extension into the loose fibrofatty tissue around the bronchial wall. The interface with the adjacent pulmonary parenchyma was
smooth with microscopic extension into the parenchyma (Fig 3). At high power, the constituent neoplastic cells were large and spindle-shaped (Fig 4A), occasionally oval and plump, and arranged in sheets and fascicles separated by variably thickened fibrous bands. The cytoplasm of the tumor cells was eosinophilic and finely granular. The nuclei were small, central, slightly spindled, and with a low nuclear to cytoplasmic ratio. There was only minimal variation in nuclear size and shape; the nuclei were focally vesicular with visible nucleoli. No mitoses were present and there were no areas of necrosis. Histochemically, the cytoplasmic granules gave a positive reaction with the periodic acid-Schiff stain. Immunohistochemically, the neoplastic cells expressed strong and diffuse nuclear and cytoplasmic reactivity for S-100 protein (Fig 4B). CD 68 (KP1) and vimentin were moderately and diffusely positive. Neuron-specific enolase immunohistochemical stain showed weak positivity. Stains for neurofilamen, actin, smooth muscle actin, desmin, keratin, and p53 were negative. The proliferative index with Ki-67 (MIB-1) was less than 1% in the tumor cells. Ultrastructurally, tumor cells showed abundance of the membrane-bound cytoplasmic granules,
Hilar Pulmonary Granular Cell Tumor
Figure 2.
247
Low-power magnification showing replacement of most of the lymph node structure by granular cell tumor.
with a heterogeneous electron density consistent with lysosomes, typical for granular cell tumors (Fig 5). Based on the features described, diagnosis of a benign GCT was rendered. Following confirmation of the metastatic disease in his lung, the patient was started on full salvage chemotherapy. Because of its known adverse effect on the bone marrow, this therapy necessitated bone marrow autotransplantation, which was done shortly after. Thirty-seven months after resection of his lung lesions, the patient is alive with no evidence of metastasis of the testicular tumor or recurrence of the GCT. Discussion Pulmonary GCT is a rare neoplasm, comprising 6% to 10% of all GCTs.1,2 More common sites include tongue, skin, breast, and chest wall. Abrikossoff9 originally described GCT in 1926. He thought they were derived from skeletal muscle and named them myoblastoma.9 Most studies support the concept that GCTs are of neurogenic (Schwann cell) origin.10-14 This concept is
based on several factors15: (1) the occurrence of tumors typical for GCT within nerves; (2) histochemical studies showing products of myelin degeneration in the tumor cells; (3) immunohistochemical studies showing tumor cells positivity for S-100 and myelin basic proteins; (4) ultrastructural similarities between GCTs and schwannomas, which include lysosomes, replicated external elastic lamina, Luse bodies, and angulate lysosomes; and (5) the reported occurrence of typical granular cells in neurofibromas from a case of neurofibromatosis. Over 90% of pulmonary GCTs are endobronchial in location.4,5 They can rarely occur in the posterior mediastinum,16 in the interlobar fissure, or as a peripheral lung lesion.5 Similar to extrathoracic GCT, multicentricity of pulmonary lesions is a well-recognized phenomenon, being present in 4% to 10% of cases.3,4 This occurrence is not unexpected and is, in fact, consistent with its presumptive neurogenic (schwannian) histogenesis. Neurogenic tumors, like neurofibromatosis, are frequently multicentric. Multicentricity does not necessarily indicate malignancy. However, when these tumors are
248
Al-Ghamdi et al
Figure 3. Scanning power of the tumor shows no endobronchial component and no continuity with the bronchial wall. There are irregular extensions into the adjacent hilar fibrofatty tissue and the parenchyma.
multicentric they can mimic pulmonary metastasis, especially in a patient with another cancer. Although rare, metastasis from an extrapulmonary malignant GCT also should be considered in cases that are multicentric. Nearly half of pulmonary GCTs are discovered as incidental radiologic, bronchoscopic, or, as in our case, operative findings. Most of the published data are from isolated case reports. The only large series on pulmonary GCT is from the Armed Forces Institute of Pathology, where Deavers et al5 described the clinicopathologic features of 20 cases.5 All their patients were adults with a median age of 42 years; there was an equal number of men and women. Tumors were incidental in nine cases. Ten patients had evidence of bronchial obstruction and the other three complained of hemoptysis. Twenty-five percent of the tumors were multiple. Two tumors were peripheral in location, one of which appeared as though it may have arisen within a lymph node. In the remaining cases, the tumor was endobronchial. Peribronchial tissue extension was present in 40% of the patients.
Only one case showed direct extension into an adjacent lymph node. Distant metastasis from pulmonary GCT has not been described. Local extension beyond the bronchial wall into the pulmonary parenchyma has been reported only once.17 True malignant GCTs are rare, accounting for 1% to 2% of all GCTs.12 Due to their rarity, establishing reliable criteria for malignancy in GCTs has been difficult. In contrast to previous publications of single case reports, in 1998 Fanburg-Smith et al18 described 46 cases of malignant GCT of soft tissue. In their study, adverse prognostic factors and features suggestive of malignancy were proposed, including large tumor size, presence of necrosis, increased mitotic rate, spindling of the tumor cells, p53 immunoreactivity, and Ki-67 values greater than 10%. In our case, the tumor was predominantly hilar with focal extension into the parenchyma, and no direct extension to the adjacent bronchus. Moreover, two regional lymph nodes (location 11 and 12 nodes) were
Hilar Pulmonary Granular Cell Tumor
249
Figure 4. (Top) High-power view of the tumor. The cytoplasm is abundant and granular and the nuclei are small. Note the moderate to marked spindling of the tumor cells and the absence of mitosis. (Bottom) The strong and uniform immunohistochemical staining of the neoplastic cells for S-100 protein. The adjacent small lymph node is uninvolved by tumor.
250
Al-Ghamdi et al
Figure 5.
Ultrastructural photomicrograph of the tumor cells demonstrating the membrane bound lysosomal granules.
extensively involved by tumor. The tumor, however, was small in size and, except for tumor cell spindling, exhibited no histologic features suggestive of the malignant counterpart. The apparent infiltration at the tumor periphery is a frequent histologic observation in benign GCT elsewhere in the body.19 p53 stain was negative and Ki-67 value was less than 1%. We interpreted the nodal spread as being a direct extension and not as metastatic disease. Thirty-seven months following resection of his lung lesions, the patient was alive with no evidence of metastatic testicular tumor or of recurrent GCT. We would like to point out two potential difficulties. First, encountering an unexpected GCT on frozen section suggests a broad list of diagnostic possibilities, such as oncocytic carcinoid, oncocytoma, acinic cell carcinoma, granular cell variant of squamous cell carcinoma and renal cell carcinoma, and, rarely, metastasis from an extrapulmonary malignant GCT (a clinically aggressive neoplasm with propensity for metastasis to lymph nodes, lungs, and bone). It is clear how important
it is clinically to histologically distinguish between these entities. In most cases this distinction can be accomplished with the histologic appearance coupled with cytochemical and immunohistochemical studies. Second, one should be cautious in interpreting nodal involvement as evidence of metastasis in a case of pulmonary GCT. If the GCT is morphologically benign and the node is in the vicinity, the more appropriate explanation is direct extension, as is the case here. Up to 13% of pulmonary GCTs have been reported to coexist with other neoplasms,20 most commonly with lung carcinoma.21-25 Other epithelial malignancies included esophageal and renal carcinoma. The association with the latter neoplasm was an incidental finding during resection for pulmonary metastasis. Other reported associations with nonneoplastic diseases included pulmonary chondroid hamartoma,5 sarcoidosis,5,26 cerebral arteriovenous malformation,5 and human immunodeficiency virus infection.27 We believe that these, as well as the association of GCT with the pulmonary metastasis of the testicular mixed germ cell tumor in
Hilar Pulmonary Granular Cell Tumor
our present case, are chance findings and have no apparent cause–effect relationship. The increased scrutiny in evaluating patients with these associated conditions may have resulted in discovering an otherwise asymptomatic GCT. Acknowledgment The authors thank Caron Fournier for her photographic assistance.
References 1. De Clerq D, Van Der Straeten M, Roels H: Granular cell myoblastoma of the bronchus. Eur J Respir Dis 1983;64:72-76 2. Ostermiller WE, Comer TP, Barker WL: Endobronchial granular cell myoblastoma. A report of three cases and review of the literature. Ann Thorac Surg 1970;9:143-148 3. Valenstein SL, Thurer RJ: Granular cell myoblastoma of bronchus. Case report and literature review. J Thorac Cardiovasc Surg 1978;76:465-468 4. Young CD, Gay RM: Multiple endobronchial granular cell myoblastomas discovered at bronchoscopy. Hum Pathol 1984;15:193194 5. Deavers M, Guinee D, Koss MN, et al: Granular cell tumors of the lung. Clinicopathologic study of 20 cases. Am J Surg Pathol 1995;19:627-635 6. Daniel TM, Smith RH, Faunce HF, et al: Transbronchoscopic versus surgical resection of tracheobronchial granular cell myoblastoms. Suggested approach based on follow-up of all treated cases. J Thorac Cardiovasc Surg 1980;80:898-903 7. Epstein LJ, Mohsenifar Z: Use of Nd: YAG laser in endobronchial granular cell myoblastoma. Chest 1993;104:958-960 8. Naruke T, Suemasu K, Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-839 ¨ ber Myome, ausgehend von der quergestreiften 9. Abrikossoff A: U willku ¨rlichen Muskulatur. Virchows Arch Pathol Anat 1926;260:215233 10. Sobel HJ, Marguet E, Avrin E, et al: Granular cell myoblastoma: An electron microscopic and cytochemical study illustrating the genesis of granules and aging of myoblastoma cells. Am J Pathol 1971;65:59-71 11. Abenoza P, Sibley RK: Granular cell myoma and schwannoma: Fine structural and immunohistochemical study. Ultrastruct Pathol 1987;11:19-28
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