—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 1 - Sclerosing Paraganglioma

Cesar A. Moran
M D Anderson Cancer Center
Houston, TX


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Clinical History
A 49-year-old female presented with chest pain and some respiratory difficulty of several months. Radiographic examination revealed the presence of an anterior mediastinal mass. Surgical resection of the anterior mediastinal tumor was performed.


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Gross Features:
The tumor was described as well demarcated, irregular, measuring approximately 3.5 cm in greatest diameter. At cut surface, the tumor had a homogenous tan surface and a fibrotic consistency. Hemorrhage and/or necrosis were not present.

Histopathologic Features:
On scanning magnification, the tumor was characterized by striking stromal collagenization in which one could appreciate a cellular proliferation arranged in cords and nests dissecting some areas of the hyalinized stroma. At higher magnification, the cellular proliferation was composed of large cells ranging from round to polygonal with focal spindling areas. The round and polygonal cells showed abundant eosinophilic cytoplasm, large hyperchromatic nuclei, and prominent nucleoli. In addition, large megalic, multinucleated, bizarre cells were present. Despite the presence of nuclear pleomorphism, the tumor did not show increased mitotic activity. Necrosis and hemorrhage were absent.

Immunohistochemical Features:
A panel of immunohistochemical studies including neuron specific enolase (NSE), chromogranin, synaptophysin, S-100 protein, cytokeratin, EMA, CEA, MOC-31, SMA, CD-34, and CD-99. The tumor showed strong positive reaction for chromogranin, synaptophysin, and NSE. S-100 protein showed positive reaction in scattered (sustentacular) cells. All other immunohistochemical studies performed were negative. In addition, a histochemical study for amyloid was performed with negative results.

Diagnosis: Sclerosing Paraganglioma


Sclerosing Paragangliomas
Extra-adrenal Paragangliomas are tumors of ubiquitous distribution that have been described in many locations including the head and neck, mediastinum, spine, and bladder [1, 2, 3, 4, 5]. In the great majority of cases, the histology is such that it does not represent a problem in interpretation. However, the histology of these neoplasms may vary, and tumors displaying spindle cell features, granular cell features, and melanin pigment attest to the variability of histologic growth patterns that these neoplasms may have, and consequently the problem in arriving at a more precise diagnosis when the classic histology is not present. Moreover, recently Plaza et al [6] described a series of paragangliomas that were characterized by extensive collagen deposition, which the authors coin as sclerosing paragangliomas.

In the series of Plaza et al [6] consisting on 19 cases, the tumors were located more commonly in different areas of the aerodigestive tract. The patients were predominantly women (16 women – 3 men) and the ages of all the patients ranged from 32 to 69 years. None of the patients presented with acute symptomatology. Nor did any of the patients have a history of a previous neoplasm. All the patients underwent surgical removal of the tumor. Grossly, the tumors were described as partly encapsulated, irregular, firm, with extensive fibrosis. Histologically, the tumors most important characteristic was the presence of extensive areas of collagenization, thus the term sclerosing paraganglioma. In the cellular areas, the tumors displayed more conventional features of paraganglioma. Immunohistochemical studies supported the finding, and the clinical follow up obtained is in keeping with paragangliomas.

The presence of "sclerosing" lesions in the anterior mediastinum may pose a different set of problems of interpretation when a small mediastinoscopic biopsy is obtained. It is well known that several pathologic entities ranging from non-neoplastic, namely sclerosing mediastinitis [7] to neoplastic processes may occur in the mediastinal area. Among the neoplastic lesions, lymphomas, thymomas, and other neuroendocrine tumors including ectopic "mediastinal" parathyroid adenomas may have to be considered in limited biopsies [8, 9]. In this setting, the use of immunohistochemical studies may prove useful. In cases of lymphomas, appropriate use of lymphoid markers may lead to a correct interpretation, while in cases of thymomas the use of epithelial markers should also prove beneficial. The most problematic area would be in cases of neuroendocrine tumors. Recently, a large series of ectopic parathyroid adenoma describing the histopathologic spectrum of these tumors shows that although not frequent, the presence of extensive areas of collagenization may be encountered in these tumors. In this latter setting, the use of neuroendocrine immunohistochemical markers may be shared by either tumor (positive chromogranin and/or synaptophysin). However, parathyroid adenomas are expected to show positive staining for keratin and parathyroid hormone, while sclerosing paragangliomas are expected to show negative results for those markers. Nevertheless, as stated before in cases in which the cellularity is scant in a limited mediastinoscopic biopsy, it will be important to entertain all of these possibilities. On the other hand, one last possibility that may be considered in the differential diagnosis is that of alveolar soft part sarcoma [10]. This latter tumor, although very uncommon to occur as a primary mediastinal neoplasm, may also show extensive areas of collagenization and an alveolar pattern reminiscent of that seen in paragangliomas. In this setting, the use of neuroendocrine markers may prove beneficial since alveolar soft part sarcomas will show negative staining for chromogranin and synaptophysin contrary to the immunophenotype present in paragangliomas.

Regarding behavior in sclerosing paragangliomas, the presence of extensive areas of collagenization should not be viewed as a feature of better-or-worse prognosis. Among features that have been associated with "malignant" paragangliomas are increased mitotic activity, vascular invasion, perineural invasion, and cellular pleomorphism. However, none of these features has been conclusively demonstrated to predict prognosis.

In short, sclerosing paragangliomas need to be considered in the differential diagnosis of mediastinal lesions showing extensive areas of collagenization. In addition, it is important to keep in mind that paragangliomas, regardless of their anatomic location, may show extensive areas of sclerosis.

References

  1. Moran CA, Suster S, Fishback N, Koss MN. Mediastinal Paragangliomas: a clinicopathologic and immunohistochemical study of 16 cases. Cancer 1993; 72:2358-2364.

  2. Moran CA, Rush W, Mena H. Primary spinal paragangliomas: a clinicopathologic and immunohistochemical study of 30 cases. Histopathology 1997; 31:167-173.

  3. Moran CA, Albores-Saavedra J, Wenig BM, Mena H. Pigmented extraadrenal paragangliomas. A clinicopathologic and immunohistochemical study of five cases. Cancer 1997; 15:79(2):398-402.

  4. Aubertine CL, Flieder DB. Primary paraganglioma of the lung. Ann Diagn Pathol 2004; 8:237-241.

  5. Zhou M, Epstein JL, Young RH. Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol 2004; 28:94-100.

  6. Plaza JA, Wakely PE, Moran C, Fletcher CDM, Suster S. Sclerosing paraganglioma: report of 19 cases of an unusual variant of neuroendocrine tumor that may be mistaken for an aggressive malignant neoplasm. Am J Surg Pathol 2005 In Press.

  7. Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis in morphologic heterogeneity. Mod Pathol 1999; 12(3):257-264.

  8. Moran CA, Suster S. Ancient (sclerosing) thymomas: a clinicopathologic study of 10 cases. Am J Clin Pathol 2004; 121(6): 867-871.

  9. Moran CA, Suster S. Primary parathyroid tumors of the mediastinum: a clinicopathologic and immunohistochemical study of 17 cases. Am J Clin Pathol 2005 In Press.

  10. Flieder DB, Moran CA, Suster S. Primary alveolar soft part sarcoma of the mediastinum: a clinicopathological and immunohistochemical study of two cases. Histopathology 1997; 31(5): 469-473.