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Cystic paraganglioma of the anterior mediastinum
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Annals of Diagnostic Pathology 14 (2010) 341 – 346
Radiologic-Pathologic Correlations
Cystic paraganglioma of the anterior mediastinum Pablo F. Ortega, MDa , Luis Antonio Sosa, MDb , Manan Patel, MDc , Eduardo Zambrano, MDa,⁎ a
Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA b Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA c Pathology Laboratory, ProHealth Care, Waukesha, WI 53188, USA
Abstract
Keywords:
Paraganglioma of the mediastinum is an extremely uncommon neoplasm, and the concurrent finding of cystic changes has yet to be reported in the literature. We report a case of a 43-year-old man presenting with chest pain and left arm paresthesias. Imaging studies revealed a well-defined cystic lesion located in the anterior mediastinum, with the patient undergoing subsequent surgical resection of the mass. Grossly, the heterogenous mass measured 6.0 × 3.6 × 1.7 cm, with prominent cystic spaces and scattered solid areas. Microscopic examination revealed pseudocystic spaces with proliferation of large epithelioid cells with abundant eosinophilic cytoplasm, moderate pleomorphic nuclei, and prominent nucleoli, in a nested pattern of growth along the cysts walls. Immunohistochemical stains showed strong positivity for chromogranin, synaptophysin, and CD56 in the epithelioid cells, with negative staining for cytokeratin AE1/AE3, confirming the diagnosis of paraganglioma. S-100 was positive in the intervening sustentacular cells throughout the tumor. Cystic paraganglioma of the anterior mediastinum is a rare neoplasm, which , to our knowledge, has not yet been reported in the English literature, and should be added to the differential diagnosis of cystic lesions of the mediastinum. © 2010 Elsevier Inc. All rights reserved. Paraganglioma; Cystic; Mediastinum
1. Introduction Paraganglioma is a neuroendocrine cell neoplasm arising from chromaffin cells associated with sympathetic tissues, which are widely dispersed groups of specialized neural crest-derived cells. Anterior mediastinal paragangliomas originate from aorticopulmonary paraganglia, which are distributed in the superior and middle mediastinum or from aorticosympathetic paraganglia in the posterior mediastinum. Paragangliomas of the mediastinum are extremely rare tumors representing less than 10% of all neuroendocrine tumors of the mediastinum. Herbert Maier [1] is thought to be the first to describe paragangliomas of the mediastinum, in 1949. Since then, more than 200 cases have been published in the literature [2-4], with more than 60% of the cases located in the anterior and middle mediastinum. Usually, the patients are asymptomatic at the time of diagnosis, and the tumors are frequently discovered
⁎ Corresponding author. E-mail address: [email protected] (E. Zambrano). 1092-9134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.04.008
incidentally on routine chest radiographs. To the best of our knowledge, cystic paragangliomas of the mediastinum have not yet been reported in the English literature. We present the clinicopathologic and radiologic findings of a paraganglioma with cystic features located in the anterior mediastinum. Because a large variety of pathologic processes in the mediastinum can undergo cystic changes, the differential diagnosis for this lesion in this location becomes more challenging.
2. Case report The patient is a 43-year-old man who presented with a vague clinical history of intermittent dizzy spells and headaches over the last 4 years. His medical history included gastroesophageal reflux disease and possible hepatitis B. Over the last several months before his diagnosis he noticed chest pain, more significant in the left side, as well as left arm paresthesias. He denied shortness of breath, diaphoresis, or palpitations. A positive D-dimer test raised the clinical suspicion for pulmonary embolism, and a subsequent
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computed tomography scan revealed a 5.9 × 5.9 × 4.7-cm complex, well-defined cystic mass located in the anterior mediastinum at the level of the carina and the main pulmonary artery. There was no evidence of vascular invasion or pulmonary embolism. Contrast enhanced images showed cystic areas within the tumor (Fig. 1). The patient underwent right-sided video-assisted thoracoscopic surgery. During surgery, the scope was advanced toward the upper anterior mediastinum, and a subpleural, grayish-white, lobulated “tennis ball”-sized mass was identified. Incision of the pleura anterior to the phrenic nerve was carried out and the mass was elevated. Dissection was then carried out using electrocautery to free up the mass. A complete excision was then performed without any complications. A frozen-section intraoperative consultation was preliminarily interpreted as an atypical lymphoid population. Subsequent flow cytometry analysis was negative for a lymphoproliferative process. Postoperatively, the patient's course was fairly uncomplicated with the exception of pain issues.
Fig. 2. Well-demarcated lesion surrounded by a thin fibrous capsule. Partially involuted thymic tissue is present adjacent to the neoplasm (lowpower view).
2.1. Gross and microscopic findings An intact mediastinal mass weighing 23 g and measuring 6.0 × 3.6 × 1.7 cm was received. The surface appeared red, glistening, and vaguely nodular. Upon sectioning, the mass was predominantly cystic with scattered solid areas. The walls within the cystic areas ranged in thickness from 0.1 to 0.3 cm. Histologically, the tumor appeared well circumscribed and delimited by a fibrous capsule. In some areas, involuted thymic tissue was noted adjacent to the lesion (Fig. 2). Prominent cystic spaces separated by fibrous septa and thickened walls containing tumor cells arranged in nests were present throughout the lesion (Figs. 3 and 4). The tumor cells were characterized by a monomorphous epithelioid
Fig. 1. (A and B) Axial contrast-enhanced CT images at the level of the carina and main pulmonary artery showing a well-defined cystic lesion in the anterior mediastinum.
Fig. 3. Prominent cystic spaces lined by tumor cells (scanning magnification).
P.F. Ortega et al. / Annals of Diagnostic Pathology 14 (2010) 341–346
343
Fig. 4. Organoid pattern of growth (zellballen).
Fig. 6. Tumor cells were strongly positive for CD56.
appearance containing abundant eosinophilic cytoplasm, with occasional cells featuring moderately enlarged pleomorphic nuclei, some containing prominent nucleoli (Fig. 5). A low mitotic count was appreciated (less than 5 mitoses per 10 high-power fields). In other areas, the tumor cells were flattened due to compression of the cells by the contents of the cysts.
AE3. S-100 protein was positive in intervening sustentacular cells (Fig. 9). Also, additional stains for parathyroid hormone to rule out an ectopic parathyroid adenoma and p63 to rule out an unusual thymoma were negative. The differential diagnosis in this case includes paraganglioma versus neuroendocrine carcinoma (carcinoid tumor); however, the observed immunoprofile favors a diagnosis of paraganglioma.
2.2. Immunohistochemical studies The tumor cells were diffusely positive for neuroendocrine markers, including chromogranin, synaptophysin, and CD56 (Figs. 6-8), and negative for cytokeratin AE1/
Fig. 5. Moderate nuclear pleomorphism was present, with some cells featuring prominent nucleoli (high-power view).
3. Discussion The first description of paraganglionic tissue is credited to Von Haller in 1743 [5]. Historically, several classification
Fig. 7. Tumor cells showed strong synaptophysin expression.
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Fig. 8. The tumor cells were strongly positive for chromogranin.
systems and nomenclatures have been used to describe tumors arising from these tissues. Glenner and Grimley [6] classified extraadrenal paraganglion system into several groups according to their distribution, microscopic structure, and innervations. According to this classification, anterior mediastinum paragangliomas originate from aorticopulmonar paraganglia (also known as aortic body), distributed in the superior and middle mediastinum [7], and intimately associated with great vessels, whereas posterior mediastinum paragangliomas arise from aorticosympathetic paraganglia. Herbert Maier [1] seems to be the first to describe a mediastinal paraganglioma, in 1949, although the largest series of these tumors at this specific location was published more than 40 years later by Moran et al [8], who described 16 cases, mostly located in the posterior mediastinum. Anterior mediastinum paragangliomas usually affect adults (median
Fig. 9. Sustentacular cells within the tumor were positive for S-100.
age, 49 years) with slight female predominance. More than 50% of patients are asymptomatic and are usually incidentally diagnosed on routine chest radiographs. Functional catecholamine-secreting paragangliomas are rare in the mediastinum. Paragangliomas may occur as part of Carney triad (paraganglioma, gastric stromal sarcoma, and pulmonary chondroma), which is a rare disorder that primarily affects young women [9]. Mutations in the succinate dehydrogenase (SDH) subunit genes (eg, SDHB, SDHD, or SDHC) are associated with most cases of familiar paragangliomas and norepinephrine and/or dopamine secreting tumors. Malignant behavior has been reported in tumors with SDHD mutation [10]. Cystic lesions of the mediastinum are uncommon, representing 10% to 20% of all mediastinal spaceoccupying lesions [11]. They are usually located in the anterior superior mediastinum, although they can also be present in the middle or posterior mediastinum. They can be true cysts or cystic-like lesions. The former group can be divided into congenital and acquired conditions. Congenital lesions are the most common and include bronchogenic, esophageal, gastroenteric, tracheoesophageal, celomic (pericardial, mesothelial), and thymic cysts [12,13], whereas acquired lesions are less frequent, usually representing thoracic duct lymphangiomas [14]. Cystic-like lesions of the mediastinum are mainly hamartomas and parasitic infections (hydatid cyst), the latter being more frequent in endemic regions [15]. Cystic changes can also be present in neoplastic conditions in this location, thymic neoplasms being the most common [16,17], followed by germ cell tumors [18,19] and lymphomas [20]. Metastatic conditions can occasionally be cystic and simulate primary tumors of the thymus [21]. Although paragangliomas with cystic changes have not been reported in this location, it is not uncommon to find cystic changes in adrenal pheochromocytomas [22-24]. From the radiologic point of view, the differential diagnosis of a simple cystic lesion located in the anterior mediastinal compartment generally includes benign lesions such as pericardial cyst, thymic cyst, parathyroid cyst, or thyroid cyst. Other congenital cystic lesions such as duplication cysts have similar appearance, but in most cases, they are located in the middle or posterior mediastinum [25]. Solid or cystic lesions cannot be distinguished on x-ray images, but CT scans with or without contrast can help to make this distinction in some but not all cases. On CT, the main features that help distinguish benign cystic lesions at this specific location are a smooth oval- to tubular-shaped mass with well-defined thin walls, homogeneous attenuation in the range of water (0-20 HU), no enhancement of cysts components, and no infiltration of adjacent tissues [24]. Due to their rarity, the CT and magnetic resonance imaging (MRI) appearances of paragangliomas of the mediastinum are poorly defined. However, in other locations, paragangliomas show significant contrast enhancement and vascular flow void on CT or MRI, except for necrotic areas that
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enhance poorly [24,26,27]. Magnetic resonance imaging shows intermediate signal intensity on T1-weighted images and high-signal intensity on T2-weighted images [25]. In the mediastinum, on CT scan, the enhancement of paragangliomas is comparable with adjacent mediastinal vessels, thereby decreasing the conspicuity of these tumors. On MRI, paragangliomas have a higher T1-weighted signal, whereas the hypointense flow voids within the adjacent vessels, making the paraganglioma very conspicuous [28]. 123 I-metaiosobenzylguanidine scintigraphy and positron emission tomography CT scan with 18-fluorodeoxyglucose are used for localization and staging of these tumors. Due to their increased vascularity, angiography may be a helpful technique for the diagnosis and evaluation of the size and location of these tumors [29]. Thallium single-photon emission CT is reported to be useful for the differential diagnosis between benign and malignant forms of paragangliomas of the mediastinum [30]. In our case, the diagnosis of paraganglioma was not suspected before surgery; therefore additional imaging studies were not performed. Histologic features of paraganglioma are well established and are essentially similar regardless of their anatomic site of origin, such as typical nesting (zellballen) pattern of growth composed of islands of large cells with eosinophilic cytoplasm containing round to oval nuclei, separated by fibrous collagenous septa. Mild to moderate nuclear pleomorphism may be present in these tumors, and a few mitoses can be identified occasionally. Histopathologically, the main differential diagnosis of these tumors is welldifferentiated neuroendocrine carcinoma of the thymus; however, paragangliomas lack the ribbons, festoons, and rosette-like growth patterns frequently seen in well-differentiated neuroendocrine carcinomas. In addition, paragangliomas do not express low-molecular-weight cytokeratins [8]. Mediastinal paragangliomas are very low-grade neoplasms, with only 10% of cases developing metastases to bone, lung, and lymph nodes. Retrospective data suggest that paragangliomas located in the anterior mediastinum have a more aggressive behavior [3]. However, the main prognostic factor is the size of the tumor at the time of diagnosis, and the only histologic parameter found to correlate with aggressive behavior is the extent of circumscription and/or local infiltration of the tumor at initial resection [8]. Therefore, surgery alone is the treatment of choice for well-circumscribed mediastinal paragangliomas [3]. In summary, we present a case of cystic paraganglioma of the mediastinum, a finding that, to the best of our knowledge, has not been reported previously. This case report adds to the differential diagnosis when evaluating cystic lesions of the mediastinum.
References [1] Maier HC. Intrathoracic pheochromocytoma with hypertension. Ann Surg 1949;130(6):1059-65 [illust].
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[2] Rachid H, El Biaze M, Yassine N, et al. Mediastinal paraganglioma with pleural metastasis. A case report. Rev Pneumol Clin 2005;61 (5 Pt 1):315-8. [3] Lamy AL, Fradet GJ, Luoma A, Nelems B. Anterior and middle mediastinum paraganglioma: complete resection is the treatment of choice. Ann Thorac Surg 1994;57(1):249-52. [4] Paul S, Jain SH, Gallegos RP, Aranki SF, Bueno R. Functional paraganglioma of the middle mediastinum. Ann Thorac Surg 2007;83 (6):e14-e16. [5] Evans RW. Histological appearances of tumours with a consideration of their histogenesis and certain aspects of their clinical features and behaviour. 2nd ed. Edinburgh (London): E. & S. Livingstone; 1966. [6] Glenner GG, Grimley PM. Tumors of the extra-adrenal paraganglion system (including chemoreceptors). Washington: Armed Forces Institute of Pathology; for sale by the American Registry of Pathology, Armed Forces Institute of Pathology; 1974. [7] Kliewer KE, Cochran AJ. A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas. Arch Pathol Lab Med 1989;113(11):1209-18. [8] Moran CA, Suster S, Fishback N, Koss MN. Mediastinal paragangliomas. A clinicopathologic and immunohistochemical study of 16 cases. Cancer 1993;72(8):2358-64. [9] Carney JA. The triad of gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma. Cancer 1979;43(1):374-82. [10] Ghayee HK, Havekes B, Corssmit EP, et al. Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior. Endocr Relat Cancer 2009;16(1): 291-9. [11] Marchevsky AM, Kaneko M. Surgical pathology of the mediastinum. 2nd ed. New York: Raven Press; 1992. [12] Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive process. Study of 18 cases. Am J Surg Pathol 1991;15(4):388-98. [13] Suster S, Barbuto D, Carlson G, Rosai J. Multilocular thymic cysts with pseudoepitheliomatous hyperplasia. Hum Pathol 1991;22(5): 455-60. [14] Mortman KD. Mediastinal thoracic duct cyst. Ann Thorac Surg 2009; 88(6):2006-8. [15] Kabiri el H, al Aziz S, el Maslout A, Benosman A. Hydatid cyst: an unusual disease of the mediastinum. Acta Chir Belg 2001;101(6): 283-6. [16] Suster S, Rosai J. Cystic thymomas. A clinicopathologic study of ten cases. Cancer 1992;69(1):92-7. [17] Moran CA, Suster S. Thymoma with prominent cystic and hemorrhagic changes and areas of necrosis and infarction: a clinicopathologic study of 25 cases. Am J Surg Pathol 2001;25(8):1086-90. [18] Moran CA, Suster S. Mediastinal seminomas with prominent cystic changes. A clinicopathologic study of 10 cases. Am J Surg Pathol 1995;19(9):1047-53. [19] Moran CA, Suster S. Mediastinal yolk sac tumors associated with prominent multilocular cystic changes of thymic epithelium: a clinicopathologic and immunohistochemical study of five cases. Mod Pathol 1997;10(8):800-3. [20] Kamiya N, Yokoi K, Mori K, Tominaga K, Miyazawa N. Thymic Hodgkin's disease with cystic variants: a case report. Nihon Kyobu Shikkan Gakkai Zasshi 1995;33(9):999-1002. [21] Moran CA, Suster S, Silva EG. Low-grade serous carcinoma of the ovary metastatic to the anterior mediastinum simulating multilocular thymic cysts: a clinicopathologic and immunohistochemical study of 3 cases. Am J Surg Pathol 2005;29(4):496-9. [22] Lee TH, Slywotzky CM, Lavelle MT, Garcia RA. Cystic pheochromocytoma. Radiographics 2002;22(4):935-40. [23] Klingler PJ, Fox TP, Menke DM, Knudsen JM, Fulmer JT. Pheochromocytoma in an incidentally discovered asymptomatic cystic adrenal mass. Mayo Clin Proc 2000;75(5):517-20. [24] Rozenblit A, Morehouse HT, Amis Jr ES. Cystic adrenal lesions: CT features. Radiology 1996;201(2):541-8.
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[25] Balcombe J, Torigian DA, Kim W, Miller Jr WT. Cross-sectional imaging of paragangliomas of the aortic body and other thoracic branchiomeric paraganglia. AJR Am J Roentgenol 2007;188(4): 1054-8. [26] Kim Y, Lee KS, Yoo JH, et al. Middle mediastinal lesions: imaging findings and pathologic correlation. Eur J Radiol 2000;35(1):30-8. [27] Wald O, Shapira OM, Murar A, Izhar U. Paraganglioma of the mediastinum: challenges in diagnosis and surgical management. J Cardiothorac Surg 2010;5(1):19.
[28] Sahdev A, Sohaib A, Monson JP, Grossman AB, Chew SL, Reznek RH. CT and MR imaging of unusual locations of extra-adrenal paragangliomas (pheochromocytomas). Eur Radiol 2005;15(1):85-92. [29] Lack EE, Stillinger RA, Colvin DB, Groves RM, Burnette DG. Aortico-pulmonary paraganglioma: report of a case with ultrastructural study and review of the literature. Cancer 1979;43(1):269-78. [30] Namba R, Saika Y, Nakata Y, et al. A case of benign paraganglioma arising in the middle mediastinum; 201Tl-SPECT for differentiation from malignant tumor. Kaku Igaku 1993;30(9):1097-101.
Annals of Diagnostic Pathology 14 (2010) 341 – 346
Radiologic-Pathologic Correlations
Cystic paraganglioma of the anterior mediastinum Pablo F. Ortega, MDa , Luis Antonio Sosa, MDb , Manan Patel, MDc , Eduardo Zambrano, MDa,⁎ a
Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA b Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA c Pathology Laboratory, ProHealth Care, Waukesha, WI 53188, USA
Abstract
Keywords:
Paraganglioma of the mediastinum is an extremely uncommon neoplasm, and the concurrent finding of cystic changes has yet to be reported in the literature. We report a case of a 43-year-old man presenting with chest pain and left arm paresthesias. Imaging studies revealed a well-defined cystic lesion located in the anterior mediastinum, with the patient undergoing subsequent surgical resection of the mass. Grossly, the heterogenous mass measured 6.0 × 3.6 × 1.7 cm, with prominent cystic spaces and scattered solid areas. Microscopic examination revealed pseudocystic spaces with proliferation of large epithelioid cells with abundant eosinophilic cytoplasm, moderate pleomorphic nuclei, and prominent nucleoli, in a nested pattern of growth along the cysts walls. Immunohistochemical stains showed strong positivity for chromogranin, synaptophysin, and CD56 in the epithelioid cells, with negative staining for cytokeratin AE1/AE3, confirming the diagnosis of paraganglioma. S-100 was positive in the intervening sustentacular cells throughout the tumor. Cystic paraganglioma of the anterior mediastinum is a rare neoplasm, which , to our knowledge, has not yet been reported in the English literature, and should be added to the differential diagnosis of cystic lesions of the mediastinum. © 2010 Elsevier Inc. All rights reserved. Paraganglioma; Cystic; Mediastinum
1. Introduction Paraganglioma is a neuroendocrine cell neoplasm arising from chromaffin cells associated with sympathetic tissues, which are widely dispersed groups of specialized neural crest-derived cells. Anterior mediastinal paragangliomas originate from aorticopulmonary paraganglia, which are distributed in the superior and middle mediastinum or from aorticosympathetic paraganglia in the posterior mediastinum. Paragangliomas of the mediastinum are extremely rare tumors representing less than 10% of all neuroendocrine tumors of the mediastinum. Herbert Maier [1] is thought to be the first to describe paragangliomas of the mediastinum, in 1949. Since then, more than 200 cases have been published in the literature [2-4], with more than 60% of the cases located in the anterior and middle mediastinum. Usually, the patients are asymptomatic at the time of diagnosis, and the tumors are frequently discovered
⁎ Corresponding author. E-mail address: [email protected] (E. Zambrano). 1092-9134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.04.008
incidentally on routine chest radiographs. To the best of our knowledge, cystic paragangliomas of the mediastinum have not yet been reported in the English literature. We present the clinicopathologic and radiologic findings of a paraganglioma with cystic features located in the anterior mediastinum. Because a large variety of pathologic processes in the mediastinum can undergo cystic changes, the differential diagnosis for this lesion in this location becomes more challenging.
2. Case report The patient is a 43-year-old man who presented with a vague clinical history of intermittent dizzy spells and headaches over the last 4 years. His medical history included gastroesophageal reflux disease and possible hepatitis B. Over the last several months before his diagnosis he noticed chest pain, more significant in the left side, as well as left arm paresthesias. He denied shortness of breath, diaphoresis, or palpitations. A positive D-dimer test raised the clinical suspicion for pulmonary embolism, and a subsequent
342
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computed tomography scan revealed a 5.9 × 5.9 × 4.7-cm complex, well-defined cystic mass located in the anterior mediastinum at the level of the carina and the main pulmonary artery. There was no evidence of vascular invasion or pulmonary embolism. Contrast enhanced images showed cystic areas within the tumor (Fig. 1). The patient underwent right-sided video-assisted thoracoscopic surgery. During surgery, the scope was advanced toward the upper anterior mediastinum, and a subpleural, grayish-white, lobulated “tennis ball”-sized mass was identified. Incision of the pleura anterior to the phrenic nerve was carried out and the mass was elevated. Dissection was then carried out using electrocautery to free up the mass. A complete excision was then performed without any complications. A frozen-section intraoperative consultation was preliminarily interpreted as an atypical lymphoid population. Subsequent flow cytometry analysis was negative for a lymphoproliferative process. Postoperatively, the patient's course was fairly uncomplicated with the exception of pain issues.
Fig. 2. Well-demarcated lesion surrounded by a thin fibrous capsule. Partially involuted thymic tissue is present adjacent to the neoplasm (lowpower view).
2.1. Gross and microscopic findings An intact mediastinal mass weighing 23 g and measuring 6.0 × 3.6 × 1.7 cm was received. The surface appeared red, glistening, and vaguely nodular. Upon sectioning, the mass was predominantly cystic with scattered solid areas. The walls within the cystic areas ranged in thickness from 0.1 to 0.3 cm. Histologically, the tumor appeared well circumscribed and delimited by a fibrous capsule. In some areas, involuted thymic tissue was noted adjacent to the lesion (Fig. 2). Prominent cystic spaces separated by fibrous septa and thickened walls containing tumor cells arranged in nests were present throughout the lesion (Figs. 3 and 4). The tumor cells were characterized by a monomorphous epithelioid
Fig. 1. (A and B) Axial contrast-enhanced CT images at the level of the carina and main pulmonary artery showing a well-defined cystic lesion in the anterior mediastinum.
Fig. 3. Prominent cystic spaces lined by tumor cells (scanning magnification).
P.F. Ortega et al. / Annals of Diagnostic Pathology 14 (2010) 341–346
343
Fig. 4. Organoid pattern of growth (zellballen).
Fig. 6. Tumor cells were strongly positive for CD56.
appearance containing abundant eosinophilic cytoplasm, with occasional cells featuring moderately enlarged pleomorphic nuclei, some containing prominent nucleoli (Fig. 5). A low mitotic count was appreciated (less than 5 mitoses per 10 high-power fields). In other areas, the tumor cells were flattened due to compression of the cells by the contents of the cysts.
AE3. S-100 protein was positive in intervening sustentacular cells (Fig. 9). Also, additional stains for parathyroid hormone to rule out an ectopic parathyroid adenoma and p63 to rule out an unusual thymoma were negative. The differential diagnosis in this case includes paraganglioma versus neuroendocrine carcinoma (carcinoid tumor); however, the observed immunoprofile favors a diagnosis of paraganglioma.
2.2. Immunohistochemical studies The tumor cells were diffusely positive for neuroendocrine markers, including chromogranin, synaptophysin, and CD56 (Figs. 6-8), and negative for cytokeratin AE1/
Fig. 5. Moderate nuclear pleomorphism was present, with some cells featuring prominent nucleoli (high-power view).
3. Discussion The first description of paraganglionic tissue is credited to Von Haller in 1743 [5]. Historically, several classification
Fig. 7. Tumor cells showed strong synaptophysin expression.
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Fig. 8. The tumor cells were strongly positive for chromogranin.
systems and nomenclatures have been used to describe tumors arising from these tissues. Glenner and Grimley [6] classified extraadrenal paraganglion system into several groups according to their distribution, microscopic structure, and innervations. According to this classification, anterior mediastinum paragangliomas originate from aorticopulmonar paraganglia (also known as aortic body), distributed in the superior and middle mediastinum [7], and intimately associated with great vessels, whereas posterior mediastinum paragangliomas arise from aorticosympathetic paraganglia. Herbert Maier [1] seems to be the first to describe a mediastinal paraganglioma, in 1949, although the largest series of these tumors at this specific location was published more than 40 years later by Moran et al [8], who described 16 cases, mostly located in the posterior mediastinum. Anterior mediastinum paragangliomas usually affect adults (median
Fig. 9. Sustentacular cells within the tumor were positive for S-100.
age, 49 years) with slight female predominance. More than 50% of patients are asymptomatic and are usually incidentally diagnosed on routine chest radiographs. Functional catecholamine-secreting paragangliomas are rare in the mediastinum. Paragangliomas may occur as part of Carney triad (paraganglioma, gastric stromal sarcoma, and pulmonary chondroma), which is a rare disorder that primarily affects young women [9]. Mutations in the succinate dehydrogenase (SDH) subunit genes (eg, SDHB, SDHD, or SDHC) are associated with most cases of familiar paragangliomas and norepinephrine and/or dopamine secreting tumors. Malignant behavior has been reported in tumors with SDHD mutation [10]. Cystic lesions of the mediastinum are uncommon, representing 10% to 20% of all mediastinal spaceoccupying lesions [11]. They are usually located in the anterior superior mediastinum, although they can also be present in the middle or posterior mediastinum. They can be true cysts or cystic-like lesions. The former group can be divided into congenital and acquired conditions. Congenital lesions are the most common and include bronchogenic, esophageal, gastroenteric, tracheoesophageal, celomic (pericardial, mesothelial), and thymic cysts [12,13], whereas acquired lesions are less frequent, usually representing thoracic duct lymphangiomas [14]. Cystic-like lesions of the mediastinum are mainly hamartomas and parasitic infections (hydatid cyst), the latter being more frequent in endemic regions [15]. Cystic changes can also be present in neoplastic conditions in this location, thymic neoplasms being the most common [16,17], followed by germ cell tumors [18,19] and lymphomas [20]. Metastatic conditions can occasionally be cystic and simulate primary tumors of the thymus [21]. Although paragangliomas with cystic changes have not been reported in this location, it is not uncommon to find cystic changes in adrenal pheochromocytomas [22-24]. From the radiologic point of view, the differential diagnosis of a simple cystic lesion located in the anterior mediastinal compartment generally includes benign lesions such as pericardial cyst, thymic cyst, parathyroid cyst, or thyroid cyst. Other congenital cystic lesions such as duplication cysts have similar appearance, but in most cases, they are located in the middle or posterior mediastinum [25]. Solid or cystic lesions cannot be distinguished on x-ray images, but CT scans with or without contrast can help to make this distinction in some but not all cases. On CT, the main features that help distinguish benign cystic lesions at this specific location are a smooth oval- to tubular-shaped mass with well-defined thin walls, homogeneous attenuation in the range of water (0-20 HU), no enhancement of cysts components, and no infiltration of adjacent tissues [24]. Due to their rarity, the CT and magnetic resonance imaging (MRI) appearances of paragangliomas of the mediastinum are poorly defined. However, in other locations, paragangliomas show significant contrast enhancement and vascular flow void on CT or MRI, except for necrotic areas that
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enhance poorly [24,26,27]. Magnetic resonance imaging shows intermediate signal intensity on T1-weighted images and high-signal intensity on T2-weighted images [25]. In the mediastinum, on CT scan, the enhancement of paragangliomas is comparable with adjacent mediastinal vessels, thereby decreasing the conspicuity of these tumors. On MRI, paragangliomas have a higher T1-weighted signal, whereas the hypointense flow voids within the adjacent vessels, making the paraganglioma very conspicuous [28]. 123 I-metaiosobenzylguanidine scintigraphy and positron emission tomography CT scan with 18-fluorodeoxyglucose are used for localization and staging of these tumors. Due to their increased vascularity, angiography may be a helpful technique for the diagnosis and evaluation of the size and location of these tumors [29]. Thallium single-photon emission CT is reported to be useful for the differential diagnosis between benign and malignant forms of paragangliomas of the mediastinum [30]. In our case, the diagnosis of paraganglioma was not suspected before surgery; therefore additional imaging studies were not performed. Histologic features of paraganglioma are well established and are essentially similar regardless of their anatomic site of origin, such as typical nesting (zellballen) pattern of growth composed of islands of large cells with eosinophilic cytoplasm containing round to oval nuclei, separated by fibrous collagenous septa. Mild to moderate nuclear pleomorphism may be present in these tumors, and a few mitoses can be identified occasionally. Histopathologically, the main differential diagnosis of these tumors is welldifferentiated neuroendocrine carcinoma of the thymus; however, paragangliomas lack the ribbons, festoons, and rosette-like growth patterns frequently seen in well-differentiated neuroendocrine carcinomas. In addition, paragangliomas do not express low-molecular-weight cytokeratins [8]. Mediastinal paragangliomas are very low-grade neoplasms, with only 10% of cases developing metastases to bone, lung, and lymph nodes. Retrospective data suggest that paragangliomas located in the anterior mediastinum have a more aggressive behavior [3]. However, the main prognostic factor is the size of the tumor at the time of diagnosis, and the only histologic parameter found to correlate with aggressive behavior is the extent of circumscription and/or local infiltration of the tumor at initial resection [8]. Therefore, surgery alone is the treatment of choice for well-circumscribed mediastinal paragangliomas [3]. In summary, we present a case of cystic paraganglioma of the mediastinum, a finding that, to the best of our knowledge, has not been reported previously. This case report adds to the differential diagnosis when evaluating cystic lesions of the mediastinum.
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