Paraganglioma

* Paragangliomas arising in the sellar region are rare. We report a case of intrasellar paraganglioma of a 54-year-old man who presented with gradually decreasing visual acuity. Physical examination revealed bitemporal hemianopsia with no apparent signs of endocrinologic dysfunction. Magnetic resonance imaging revealed a large sellar mass believed to be a nonfunctioning pituitary adenoma. The tumor was removed transsphenoidally and submitted for histologic examination. The morphologic features, based on histologic, immunocytochemical, and electron microscopic analyses, were consistent with the diagnosis of paraganglioma. The diagnostic morphologic features and the immunocytochemical profile of the tumor are reported. (Arch Pathol Lab Med. 1999;123:429-432)

Paragangliomas are infrequent neuroendocrine tumors of neural crest origin. They include neoplasms of the adrenal medulla (pheochromocytomas) and paraganglia and are located in diverse anatomic sites of the body.1,2 The most frequent sites of extra-adrenal paragangliomas are in the head and neck region and include the carotid body and jugulotympanic paraganglia.3 Several other sites of development, such as pituitary where paraganglion cells do not normally occur, have also been reported.4

Paragangliomas of the sellar region are rare. To our knowledge, only 4 previous cases arising within the pituitary fossa have been reported.4-7 We describe a case of morphologically documented intrasellar paraganglioma with clinical presentation and imaging findings consistent with the diagnosis of a nonfunctioning pituitary adenoma.

REPORT OF A CASE

A 54-year-old man presented at the Department of Neurosurgery, G. Gennimatas Athens General Hospital, with gradually decreasing visual acuity during the preceding 2 months. Examination revealed bitemporal hemianopsia and nonendocrine abnormalities. Previous cerebral computed tomographic scan showed a lesion of 1 cm adjacent to the circle of Willis, which was regarded as a possible aneurysm of the anterior communicating cerebral artery. Cerebral angiography showed no aneurysm and no pathology in the internal carotid and vertebrobasilar arteries. Subsequent magnetic resonance imaging scan demonstrated a clepsydra-shaped mass measuring 2.8 x 2.0 x 1.8 cm, filling the pituitary fossa, with suprasellar extension to the optic chiasm, causing thinning of the posterior clinoid processes and possibly eroding the clivus (Figure 1). The findings were strongly suggestive of a nonfunctioning pituitary adenoma. The patient had no symptoms of endocrine dysfunction and complained of perspiration, but no flushes or high blood pressure or diarrhea was noted. Preoperative serum prolactin levels were slightly elevated (22.6 (mu)g/L), whereas the levels of other pituitary hormones and thyroid function test results were within normal limits. The patient was given thyroxine (100 mg daily) and hydrocortisone (30 mg daily) preoperatively. By transsphenoidal approach, a grayish-to-pinkish soft tumor was removed. The patient had an uncomplicated recovery and received replacement therapy. No adjuvant radiotherapy was given, and 1 year later the patient is alive and has no complications.

MORPHOLOGIC METHODS

For histology, 4 to 6-(mu)m sections from formalin-fixed and paraffin-embedded tissue were stained with hematoxylin-eosin, periodic acid-Schiff, and the Gordon-Sweet silver method for the demonstration of the reticulin fiber network. For immunocytochemical analysis, the standard avidin-biotin complex (ABC) technique was applied using the Elite Vectastain kit (Vector Laboratories Inc, Burlingame, Calif). Small tissue fragments were forwarded for electron microscopy. Details of the morphologic methods were described elsewhere.8

PATHOLOGIC FINDINGS

The surgical specimen included several soft, small, grayish-brown tissue fragments, measuring 2.0 x 1.5 x 0.5 cm. By light microscopy, the lesion was highly vascularized, mimicking an unusual pituitary adenoma with sinusoidal growth pattern. It was composed of large, irregular polyhedral or elongated cells, with pale eosinophilic cytoplasm and irregular, round to oval nuclei with slight pleomorphism and few mitoses. The neoplastic cells were mostly arranged in anastomosing broad trabecules and a few spheroid clusters (Zellballen pattern), separated by delicate fibrovascular septa, with focal dilatation of the sinusoidal lumens (Figure 2). One fragment showed features of nontumorous adenohypophysial parenchyma. The tumor cells were negative for periodic acid-Schiff. By the Gordon-Sweet stain, reticulin fibers were noted around vascular spaces. The immunocytochemical findings, using the standard ABC technique, are presented in the Table. The tumor cells were strongly positive for chromogranin A and neurofilament protein (Figure 3), whereas only scarce cells were immunoreactive for S-100 protein. Immunocytochemical analysis revealed strong reactivity for serotonin and vasoactive intestinal peptide. In contrast, the tumor cells were immunonegative for all pituitary hormones studied but were immunoreactive in various types of adenohypophysial cells included in the nontumorous fragment. By electron microscopy, the tumor consisted of closely apposed elongated cells, with strikingly pleomorphic, convoluted nuclei containing 1 or more prominent nucleoli and an unusual number of highly conspicuous nuclear inclusions (Figure 4). The cytoplasm contained rough endoplasmic reticulum, Golgi apparatus, and a small number of electron dense secretory granules measuring 150 to 250 nm. There were also varying degrees of oncocytic change, with accumulation of many slender and rod-shaped mitochondria, with a few of them displaying significant enlargement and electron dense tubular structures. In a few foci, prominent intercellular junctions were noted. The histologic features, combined with the immunocytochemical and ultrastructural findings, confirmed the histologic diagnosis of a paraganglioma.

COMMENT

Extra-adrenal paragangliomas are assumed to originate from elements of the dispersed neuroendocrine system (ie, paraganglia), which are derived from neural crest progenitor cells.9 Paragangliomas have also been reported in organs that do not normally contain paraganglion cells. Such sites include the sellar region4-7,10-13 and the pineal gland.14

To our knowledge, only 4 well-documented cases of intrasellar paraganglioma have been reported. The first published case occurred in a 37-year-old man with a history of postpubertal arrest of sexual development and delayed growth4; the second case was in a 17-year-old girl with decreased visual acuity5; the third case was in a 14-yearold boy with associated von Hippel-Lindau disease6; and the fourth case occurred in a 76-year-old woman with visual defects.7 In our case, the tumor was intrasellar with suprasellar extension, mimicking by imaging procedures a pituitary adenoma.

In addition to frank intrasellar paragangliomas, 1 case of mostly suprasellar10 and 3 cases of parasellar paragangliomas12,13 have been described. One other case involved the right cavernous sinus and semilunar ganglion,ll and another originated from the petrous ridge within the middle cranial fossa.15

According to Bilbao et al,4 paraganglion cells do not exist in the pituitary or adjacent structures. These authors suggested the possible origin of their reported case from a nest of paraganglion tissue that may have been entrapped in or around the adenohypophysis during pituitary development, since it is assumed that neural crest may contribute to the formation of hypophysial primordium. Steel et al13 have postulated that, in their 2 cases, the tumors appeared to arise in cavernous sinus structures, rather than in the pituitary. It is conceivable that the histogenesis of these tumors involves aberrant migration of small aggregates of paraganglion cells along the branches of tympanic or ciliary nerves within or close to the cavernous sinus, an explanation also favored by Ho et al.11 In our case, the tumor might have been derived in intrapituitary embryonic remnants of paraganglion cells, as suggested by Bilbao et al.4

The microscopic features of paragangliomas are the same, regardless of location and include well-defined cells nests (Zellballen), separated by highly vascularized, usually delicate fibrous septa. By electron microscopy, the predominant neoplastic chief cells contain variable numbers of cytoplasmic dense-core secretory granules.3,9 A second cell type is the sustentacular cell, which surrounds the chief cells, lacks dense-core secretory granules, and shows immunopositivity for S-100 protein and occasionally for glial fibrillary acidic protein.16 In our case, Zellballen nests and S-100 protein positive cells, corresponding to sustentacular cells were scarce, and the chief cells contained few secretory granules. Mild tendency to form nests and a paucity or absence of sustentacular cells were also noted by Steel et al.13 These authors have regarded their 2 tumors with few sustentacular cells as more aggressive forms of paragangliomas, similar to those described in the orbit and larynx, that require a longer follow-up after surgery and adjunctive radiotherapy. Although the scarcity or absence of sustentacular cells may indicate more aggressive clinical course,9,17 other studies have failed to document correlation between the presence of sustentacular cells and clinical behavior.3 Currently, there are no reliable morphologic criteria for diagnosing malignancy, although high mitotic activity and decreased neuropeptide immunoreactivity usually correlate with malignant behavior18,19

Although paragangliomas have been found by immunocytochemical analysis to express various hormones and neuropeptides, they are only occasionally associated with endocrinologic symptoms, most often with catecholamine excess.3 In our case, serotonin immunopositivity may be related to the referred perspiration of the patient. Regarding vasoactive intestinal peptide immunoreactivity, no diarrhea or other relevant symptoms were noted; the absence of such symptoms may also be documented in vasoactive intestinal peptide-positive paragangliomas.19

Regarding the differential diagnosis between paparangliomas and unusual types of pituitary adenomas, the presence of oval cell nests (Zellballen) suggests paraganglioma. It is well known that pituitary adenomas are immunopositive for cytokeratins, particularly of low molecular weight,20,21 whereas the substantial majority of paragangliomas yield negative results.3 In addition, lack of immunoreactivity for hypophysial hormones and diffuse cytoplasmic immunopositivity for neurofilament protein and nonpituitary-derived peptides support the diagnosis of paraganglioma. Electron microscopy can contribute to the diagnosis.

We conclude that paragangliomas of the sellar region are rare, and their morphologic diagnosis represents a real challenge for the pathologist. However, they must be included in the spectrum of differential diagnosis of pituitary tumors.

This work was supported in part by grants E-52/96 from the National Health Council of Greece (G.K.) and the Medical Research Council of Canada (K.K.). The authors wish to thank Magda Pateraki and Elizabeth McDermott for their contribution to the morphologic studies and the National Hormone and Pituitary Program, of the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md, for donating the pituitary hormone antibodies.

References

1. Glener GG, Grimely PM. Tumors of the Extra Adrenal Paragangl/ion System (Including Chemoreceptors). Washington, DC: Armed Forces Institute of Pathology; 1974:13-86. Atlas of Tumor Pathology 2nd series, fascicle 9.

2. Tischler AS. The adrenal medulla and extra-adrenal paraganglia. In: Kovacs K, Asa SL, eds. Functional Endocrine Pathology. 2nd ed. Boston, Mass: Blackwell Scientific Publications Inc; 1998:550-595.

3. Lack EE. Pathology of Adrenal and Extra-Adrenal Paraganglia. Philadelphia, Pa: WB Saunders Co; 1994. Major Problems in Pathology vol 29.

4. Bilbao JM, Horvath E, Kovacs K, Singer W, Hudson AR. Intrasellar paraganglioma associated with hypopituitarism. Arch Pathol Lab Med. 1978;102:95-98.

5. Flint EW, Classen D, Pang D, Hirsch WL. Intrasellar and suprasellar paraganglioma: CT and MR findings. AJNR Am / Neuroradiol.1993;14:1191-1193.

6. Scheithauer BW, Parameswaran A, Burdick B. Intrasellar paraganglioma: report of a case in a sibship of von Hippel-Lindau disease. Neurosergery. 1996;38:395-399.

7. Mokry M, Kleinert R, Clarici G, Obermayer-Pietsch B. Primary paraganglioma simulating pituitary macroadenoma: a case report and review of the literature. Neuroradiology. 1998;40:233-237.

8. Kontogeorgos G, Horvath E, Kovacs K, Killinger DW, Smyth HS. Null cell adenoma of the pituitary with features of plurihormonality and plurimorphous differentiation. Arch Pathol Lab Med. 1991;115:61-64.

9. Kliewer KE, Cochran AJ. A review of the histology, ultrastructure, immunohistology and molecular biology of extra-adrenal paragangliomas. Arch Pathol Lab Med. 1989;113:1209-1218.

10. Chytil L. A case of nonchromaffin paraganglioma, originating in the suprasellar region and invading the nose through the sphenoid sinus. Chesk Otolaryngol.1967;16:115-119.

11. Ho KC, Meyer G, Garancis J, Hanna J. Chemodectoma involving the cavernous sinus and semilunar ganglion. Hum Pathol. 1982;13:942-943.

12. Prabhakar S, Sawhney IM, Chopra IS, Kak VK, Banerjee AK. Hemibase syndrome: an unusual presentation of intracranial paraganglioma. Surg NeuroL 1984;22:39-42.

13. Steel TR, Dailey AT, Born D, Berger MS, Mayberg MR. Paragangliomas of the sellar region: report of two cases. Neurosurgery. 1993;32:844-847.

14. Smith WT, Hughes B, Ermocilla R. Chemodectoma of the pineal region, with observations of the pineal body and chemoreceptor tissue. J Pathol Bacteriol. 1966;92:69-76.

15. Kruse F. Petrous ridge chemodectoma (nonchromaffin paraganglioma) simulating meningioma: case report. J Neurosurg. 1960;17:1108-1111.

16. Schroder HD, Johansen L. Demonstration of S-100 protein in sustentacular cells of phaechromocytomas and paragangliomas. Histopathology. 1986;10: 1023-1033.

17. Lloyd RV, Blaivas M, Wilson BS. Distribution of chromogranin and S-100 protein in normal and abnormal adrenal medullary tissues. Arch Pathol Lab Med. 1985;109:633 635.

18. Lack EE, Cubila AL, Woodruff JM, Lieberman PH. Extra-adrenal paragangliomas of the retroperitoneum: a clinicopathologic study of 12 tumors. Am J Surg Pathol 1980;4:109-120.

19. Linnoila RI, Lack EE, Steinberg SM, Keiser HR. Decreased expression of neuropeptides in malignant paragangliomas. An immunohistochemical study. Hum Pathol. 1988;19:41-50.

20. Ogawa A, Sugihara S, Hasegawa M, et al. Intermediate filament expression in pituitary adenomas. Virchows Arch. 1990;58:341-249.

21. Sano T, Ohshima T, Yamada S. Expression of glycoprotein hormones and intracytoplasmic distribution of cytokeratin in growth hormone-producing pituitary adenomas. Pathol Res Pract. 1991:187:530531.

Demetrios Sambaziotis, MD; George Kontogeorgos, MD; Kalman Kovacs, MD; Eva Horvath, PhD; Athanassios Levedis, MD

Accepted for publication November 25, 1998.

From the Department of Pathology and Neurosurgery, G. Gennimatas Athens General Hospital, Athens, Greece (Drs Sambaziotis, Kontogeorgos, and Levedis), and Department of Laboratory Medicine and Pathology, St Michael's Hospital, University of Toronto, Toronto, Ontario (Drs Kontogeorgos, Kovacs, and Horvath).

Reprints: George Kontogeorgos, MD, Department of Pathology, G. Gennimatas Athens General Hospital, 154 Messogion Ave, 115 27 Athens, Greece.

Copyright College of American Pathologists May 1999
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