Brain Pathology Case of the Month - February 2004



Paragangliomas of the head and neck are uncommon tumors that may arise from any of the paraganglia distributed along the parasympathetic chain, including the carotid bodies, jugulotympanic ganglia, ganglion nodosum of the vagus, and microscopic paraganglia aggregates dispersed in the mouth, nose, nasopharynx, larynx, and orbit (6). The most frequent form is the carotid body tumor, while paragangliomas of the nasal cavity, paranasal sinuses and nasopharynx are rare. In a study of 71 patients with paragangliomas of the head and neck, only three of the tumors were located in the nasal cavity (7). Paragangliomas originating unequivocally from the nasopharynx are truly exceptional and have a striking tendency for intracranial and intraorbital invasion (5, 9).

If anatomical location is typical, the histological diagnosis of paraganglioma is easy. Microscopically, the nests of neoplastic cells ("zellballen") create an organoid pattern that recapitulates the morphology of normal paraganglia: this pattern is usually present in all cases, regardless of anatomical site. Nuclear pleomorphism is mild, and mitotic figures are absent or rare. Tumor cells retain a strong expression of neuroendocrine markers such as synaptophysin and chromogranin, while sustentacular cells at the periphery of "zellballen" are S-100 positive. Head and neck paragangliomas may synthesize a wide range of neuroendocrine products (e.g. serotonin, leu-enkephalin, gastrin, substance P, VIP, etc.), although rarely endocrine activity results in clinical symptoms (2). Ultrastructural studies demonstrate cytoplasmic dense-core granules.

In the present case, the midline location of the tumor and its apparent lack of relationship with major vessels seemed in apparent contrast with the topographical distribution of major paraganglia. The morphologic features and immunohistochemical profile, on the other hand, were highly characteristic of paragangliomas, ruling out diagnostic alternatives such as olfactory neuroblastoma, nasopharyngeal carcinoma, and sinonasal undifferentiated carcinoma. The unusual location of this paraganglioma can be explained by an orgin from one of the microscopic paraganglia, which are found in the upper airways without connection with major vascular structures or parasympathetic ganglia. A jugulotympanic or vagal orgin is unlikely, since tumors arising from these paraganglia develop in a lateral location, not along the midline (5, 6, 9). Paragangliomas have also been reported in other atypical sites, such as the orbit (4) sella turcica (3), and pineal gland (10). These rare tumors, therefore, should be added to an already long list of primary and metastatic neoplasms to consider in the differential diagnosis of a skull base mass (8).

Malignant paragangliomas are said to represent approximately 10% of all cases (6), but morphologic criteria alone do not distinguish unmistakably benign from malignant forms. Features said to be associated with an unfavorable clinical outcome include necrosis, mitotic activity and vascular invasion (7); other authors found that aggressive tumors contain fewer sustentacular cells than benign ones (1). A study of three cases of nasal and paranasal paragangliomas suggested that quantitative DNA analysis and proliferation markers may have prognostic significance (11), but the validity of this approach must be corroborated on larger series of cases. As of now, metastatic spread remains the only unequivocal criterion of malignancy.


  1. Achilles E, Padberg BC, Holl K, Kloppel G, Schroder S (1991) Immunocytochemistry of paragangliomas - value of staining for S-100 protein and glial fibrillary acidic protein in diagnosis and prognosis. Histopathology 18: 453-458.
  2. Apple D and Kreines K (1982) Cushing's syndrome due to ectopic ACTH production by a nasal paraganglioma. Am J Med Sci 283: 32-35.
  3. Bilbao JM, Horvath E, Kovacs K, Singer W, Hudson AR (1978) Intrasellar paraganglioma associated with hypopituitarism. Arch Pathol Lab Med 102: 95-98.
  4. Fisher ER and Hazard JB (1952) Nonchromaffin paraganglioma of the orbit. Cancer 5: 521-524.
  5. Kuhn JA and Aronoff BL (1989) Nasal and nasopharyngeal paraganglioma. J Surg Oncol 40: 38-45.
  6. Lack EE (1999). Paragangliomas. In: Diagnostic Surgical Pathology, Sternberg SS (ed.), 625-648, Lippincott-Williams and Wilkins.
  7. Lack EE, Cubilla AL and Woodruff JM (1979) Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients. Hum Pathol 10: 191-218.
  8. Radner H, Katenkamp D, Reifenberger G, Deckert M, Peitsch T and Wiestler OD (2001) New devlopments in the pathology of skull base tumors. Virchows Arch 438: 321-335.
  9. Schuller DE and Lucas JG (1982) Nasopharyngeal paraganglioma: report of a case and review of literature. Arch Otolaryngol 108: 667-670.
  10. Smith WT, Hughes B, Ermocilla R (1966) Chemodectoma of the pineal region, with observations on the pineal body and chemoreceptor tissue. J Pathol Bacteriol 92: 69-76.
  11. Welkoborsky HJ, Gosepath J, Jacob R, Mann WJ and Amedee RG (2000) Biologic characteristics of paragangliomas of the nasal cavity and paranasal sinuses. AM J Rhinol 14: 419-426.

Contributed by Pier Luigi Di Patre, Ildiko Szalay, and Jacqueline Delavelle

International Society of Neuropathology