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Neuroendocrine carcinoma of the jugular foramen.


We describe what might have been the first reported case of a neuroendocrine carcinoma of the jugular foramen. A 50-year-old woman presented with progressive left-sided sensorineural hearing loss, vertigo, pulsatile tinnitus, headaches, and ataxia. Magnetic resonance imaging revealed a 4-cm left-sided jugular foramen tumor. The patient underwent near-total resection of the tumor. Despite lower cranial nerve preservation, postoperative paralysis of cranial nerves IX and X occurred, and vocal fold medialization was performed 5 days later. The final pathologic diagnosis was neuroendocrine carcinoma. The patient was treated with concurrent chemotherapy and intensity-modulated radiation therapy. This article will discuss the pathologic features and the management of jugular foramen tumors, along with the differential diagnosis of these rare tumors.


Jugular foramen tumors may cause lower cranial nerve symptoms or very few clinical findings due to contralateral cranial nerve compensation. Tumors of the temporal bone and skull base arise in three locations: (1) the mastoid or middle ear, (2) the jugular foramen, or (3) the petrous apex. Our discussion focuses on jugular foramen tumors. These tumors may be highly vascular, mayinvolve important neurovascular structures, and can present a diagnostic and management challenge.

Paragangliomas are the most common jugular foramen tumors. (1) The differential diagnosis includes schwannomas, meningiomas, chordomas, chondrosarcoma, and metastatic lesions. To our knowledge, neuroendocrine carcinoma (NEC) has not been reported as a primary tumor of the jugular foramen.

Case report

On October 27, 2004, a 50-year-old woman was referred to our skull base center with a 1-month history of progressive left-sided sensorineural hearing loss, vertigo, pulsatile tinnitus, headaches, and ataxia. Her medical history was significant only for diet-controlled diabetes mellitus. The patient denied any hoarseness or dysphagia. No lower cranial nerve deficits were identified. Audiometry showed a severe, left-sided high-frequency sensorineural hearing loss (figure 1).

Magnetic resonance imaging (MRI) with gadolinium showed a 4-cm left-sided tumor of the posterior cranial fossa adjacent to the medial wall of the jugular foramen, with extension into the jugular foramen and likely occlusion of the sigmoid sinus (figure 2, A and B). Four-vessel cerebral angiography revealed a tumor blush in the jugular foramen (figure 3). The distal left sigmoid sinus and the internal jugular vein were occluded, and an emissary vein was identified draining off the left transverse sinus into the external jugular vein. Retrograde filling of the right transverse sinus, jugular bulb, and jugular vein was noted.

The patient underwent near-total resection of the tumor through a left retrosigmoid craniotomy on November 9, 2004. Only a small portion of the tumor was left within the jugular foramen. Despite lower cranial nerve preservation and successful stimulation at the conclusion of the surgery, paralysis of left cranial nerves IX and X was noted postoperatively. Vocal fold paralysis was managed early with endoscopic medialization.

The final pathologic diagnosis was NEC. Metastatic evaluation included computed tomography (CT) of the neck, chest, and abdomen/pelvis, as well as positron emission tomography (PET); all were negative. PET showed uptake only in the region of the left temporal bone (figure 4).

The patient was treated with concurrent chemotherapy in two cycles (cisplatin and etoposide) and intensity-modulated radiation therapy (IMRT; 46 Gy in 23 fractions over 5 weeks). Cisplatin was delivered at a dose of 50 mg/[m.sup.2]/day intravenously on treatment days 1, 8, and 29. Etoposide was also administered at a dose of 50 mg/[m.sup.2]/day intravenously, but on treatment days 1 through 5 and 29. Post-treatment MRI showed a 1.2 x 0.8-cm lesion at the jugular foramen (figure 2, C and D), but the patient recovered without complication. She was able to tolerate a general oral diet and demonstrated excellent voice recovery at 6 months post-treatment.


The tumor showed cytologic and architectural features of NEC (figure 5). Special stains were positive for chromogranin and synaptophysin, and negative for S-100 protein. Histology confirmed features of dense-core granules, tumor cells separated by fibrous stroma, and cells showing pleomorphism and hyperchromatism. Numerous individual cells with bland salt-and-pepper nuclei were also seen. The Ki-67 index, a marker for proliferation, was 3 to 5%.



Neuroendocrine differentiation of tumors can occur in any organ. Most NECs occurring in the head and neck arise from the larynx or the salivary glands. (2,3) We report a case of primary NEC of the jugular foramen. The differential diagnosis for tumors of the jugular foramen includes paragangliomas, schwannomas, meningiomas, chordomas, chondrosarcomas, and metastatic lesions. Patients with tumors at this site may present with pulsatile tinnitus, hearing loss, aural fullness, hoarseness, and/or dysphagia.

Paragangliomas are tumors that derive from the migration of neural crest cells during fetal development. (1) Glomus jugulare and glomus tympanicum tumors are both found in the temporal bone. The latter type arises within the middle ear from paraganglionic cells on the promontory. Glomus jugulare paragangliomas arise within the jugular foramen from paraganglionic cell rests associated with cranial nerves IX, X, and XI. The arterial blood supply is typically the ascending pharyngeal artery and the stylomastoid branch of the occipital artery. (1)

Histologically, these tumors appear highly vascular and are composed of clusters (Zellballen, which is German for "cell balls") of chief cells supported by sustentacular cells and small blood vessels. (4)

Paragangliomas are the most common jugular foramen tumors. In a series of 102 patients with jugular foramen tumors, Ramina et al reported that 58 patients (57%) had paragangliomas. (1) The most common presenting complaints were hearing loss and pulsatile tinnitus. Patients with an actively secreting tumor may have tachycardia, arrhythmia, flushing, or labile hypertension. (1) Perioperative beta-blockade is therefore critical for these patients. (1) Treatment options include observation (in patients with minimal symptoms), radiation, and surgery. Radiation therapy, although a controversial option, maybe useful for reducing tumor growth in elderly or debilitated patients, but it may change tumor biology. Cole and Beiler describe a case of radiation-induced malignancy occurring after the treatment of benign jugular foramen tumor. (5) Complete tumor removal by microsurgical techniques is the treatment of choice.

Schwannomas and meningiomas are the next most common jugular foramen tumors. (1) Schwannomas arise from Schwann cells in the nerve sheath. Meningiomas in this region arise from arachnoid cells in the jugular bulb. (6) Like paragangliomas, most of these lesions are benign. Patients can present with hearing loss and lower cranial nerve deficits if tumors are of sufficient size. In one series of jugular foramen tumors, all patients with meningiomas of the jugular foramen presented with lower cranial nerve paralysis. (1)


Metastaticlesions of the jugular foramen are rare. Ramina et al reported only 4 cases in a series of 102 jugular foramen tumors. (1) Streitmann and Sismanis studied 141 cases of carcinoma metastatic to the temporal bone but found no evidence of disease metastatic to the jugular foramen. (7)

Historically, classification of NEC has been poor. In the head and neck, these tumors are generally classified into group I (showing epithelial differentiation) and group II (showing primarily neural features). Group I tumors include well-differentiated, moderately differentiated, and poorly differentiated (small-cell type and large-cell type) NECs and pituitary adenomas/carcinomas. Group II tumors include granular cell tumors, malignant peripheral nerve sheath tumors, malignant melanomas, neurofibromas, olfactory neuroblastomas, paragangliomas, schwannomas, and peripheral neuroectodermal tumors. (2)



NEC can be confused with paraganglioma based on routine histology alone. Specialized staining patterns help distinguish these two tumors. Both NECs and paragangliomas stain for the neuroendocrine markers chromogranin and synaptophysin. (2,8) Sustentacular cells of paragangliomas stain strongly for S-100 protein, (2,8) but this staining pattern is not seen in NECs because of their lack of sustentacular cells.

The Ki-67 proliferation index was 3 to 5% in our case. Ki-67 protein is expressed in all phases of the cell cycle except [G.sub.0] and serves as a good marker for proliferation. Studies have shown that higher proliferation rates are associated with shorter disease-free and overall survival rates. (9-11) The cutoff for high proliferation has not been well established, but patients with an index greater than 20% are considered to be at high risk. (9) The Ki-67 proliferation index in our case indicates that the patient's tumor is a well-differentiated NEC.

The risk of neurovascular damage when treating tumors of the jugular foramen must be discussed preoperatively with patients. Management entails a thorough preoperative neurotologic examination, with MR and/or CT imaging. Because of the vascularity of these lesions, preoperative angiography is recommended. The utility of a PET scan in evaluating distant metastasis with NEC has been described. (12,13)

The surgical treatment of jugular foramen tumors includes (1) the intact-canal-wall approach, without facial nerve rerouting; (2) the canal-wall-down approach, without facial nerve rerouting; and (3) the canal-wall-down approach, with anterior facial nerve rerouting. (11) The first option preserves the structure of the ear, with the possibility of preserving hearing. In this approach, a retrosigmoid craniotomy is performed to expose the posterior fossa dura and jugular foramen. The lateral process of C1 and the posterior border of the jugular foramen are removed to expose the tumor. (1) This exposure allows extradural and intradural tumor resection. Complete tumor removal maybe difficult without lower cranial nerve resection.

Surgical damage of lower cranial nerves was the most common complication in the treatment of these tumors in one large series. (1) Our patient had postoperative left vocal fold paralysis and associated aspiration with oral intake. This was managed by early vocal fold medialization, with resolution of her dysphonia and aspiration.

Most studies of NEC have involved laryngeal NECs. (2,3) Primary treatment for this disease includes the use of chemotherapy and radiation. Barker et al, in their study of 23 patients with NEC of the head and neck, recommended induction chemotherapy followed by radiation. (14) They showed that concurrent chemotherapy did not improve early response, local control, or survival and that it was more toxic than induction chemotherapy. Cisplatin and etoposide have been found to be the most effective chemotherapy regimen for treating these tumors. (14)

Treatment was carefully planned by using 3-D CT images of the patient in conjunction with computerized dose calculations to determine the dose intensity pattern that would best conform to the tumor shape. Since the patient was treated with IMRT, with the reduced potential for treatment toxicity, concurrent chemotherapy was used in this case with minimal systemic toxicity.

Rates of local failure tend to be much higher with NECs than with similarly sized squamous cell carcinomas. (14,15) Distant metastasis is the most common pattern of failure, and the brain seems to be a sanctuary for metastatic NEC. Barker et al reported rates of metastatic disease from primary head and neck NEC to the brain at 2 years and 5 years as 25% and 44%, respectively. (14) Most experts recommend combined chemotherapy and radiotherapy as the initial treatment.

The histiogenesis of NEC at the jugular foramen has not been elucidated. Several previous studies have demonstrated the presence of neuroendocrine cells in normal laryngeal tissue, but no such studies have been performed at the jugular foramen. (8,15) Future studies may focus on demonstrating neuroendocrine cells at the jugular foramen by immunohistochemical markers.


(1.) Ramina R, Maniglia JJ, Fernandes YB, et al. Jugular foramen tumors: diagnosis and treatment. Neurosurg Focus 2004;17(2):E5.

(2.) Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Patho1 2002; 15 (3): 264-278.

(3.) Browne JD. Management of nonepidermoid cancer of the larynx. Otolaryn Clin North Am 1997;30(2):215-229.

(4.) Guild SR. The glomus jugulare, a nonchromaffin paraganglion, in man. Ann Otol Rhinol Laryngol 1953;62(4):1045-71.

(5.) Cole JM, Beiler D. Long-term results of treatment for glomus jugulare and glomus vagale tumors with radiotherapy. Laryngoscope 1994; 104(12):1461-65.

(6.) Molony TB, Brackmann DE, Lo WW. Meningiomas of the jugular foramen. Otolaryngol Head Neck Surg 1992;106(2): 128-36.

(7.) Streitmann MJ, Sismanis A. Metastatic carcinoma of the temporal bone. Am J Otol 1996;17(5):780-83.

(8.) Chung JH, Lee SS, Shim YS, et al. A study of moderately differentiated neuroendocrine carcinomas of the larynx and an examination of non-neoplastic larynx tissue for neuroendocrine cells. Laryngoscope 2004;114(7):1264-70.

(9.) Veronese SM, Maisano C, Scibilia J. Comparative prognostic value of Ki-67 and MIB-1 proliferation indices in breast cancer. Anticancer Res 1995;15(6B):2717-22.

(10.) Szyldergemajn SA, O'Connor J, Mendez G, et al. Neuroendocrine tumors of the gastroenteropancreatic system (NET-GEP) correlation between Ki-67 immunostaining, histological features and clinical behaviour. J Clin Oncol 2005;23(June 1 Suppl):4192.

(11.) Martin B, Paesmans M, Mascaux C, et al. Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis. British J Cancer 2004;91(12):2018-25.

(12.) Whitaker D, Dussek J. PET scanning in thymic neuroendocrine tumors. Chest 2004;125(6):2368-69.

(13.) Vento JA, Solis V, Spencer RP, Karimeddini MK. Mastoid bone as a single site of metastasis of neuroendocrine tumor. Clin Nucl Med 2003;28(4):345-46.

(14.) Barker JL Jr., Glisson BS, Garden AS, et al. Management of nonsinonasal neuroendocrine carcinomas of the head and neck. Cancer 2003;98(11):2322-28.

(15.) Yu YC, Miyazaki J, Shin T. Neuroendocrine cells in the cat laryngeal epithelium. Eur Arch Otorhinolaryngol 1996;253(4-5):287-93.

John P. Leonetti, MD; Mobeen A. Shirazi, MD; Sam Marzo, MD; Douglas Anderson, MD

From the Department of Otolaryngology-Head and Neck Surgery, Skull Base Surgery Center (Dr. Leonetti, Dr. Shirazi, and Dr. Marzo) and the Department ofNeurosurgery (Dr. Anderson), Loyola University Medical Center, Maywood, Ill.

Corresponding author: John P. Leonetti, MD, Department of Otolaryngology-Head and Neck Surgery, Skull Base Surgery Center, 2160 South First Ave., Bldg. 105, Room 1870, Maywood, IL 60153. Phone: (708) 216-4804; fax: (708) 216-4834; e-mail:
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Comment:Neuroendocrine carcinoma of the jugular foramen.(ORIGINAL ARTICLE)
Author:Leonetti, John P.; Shirazi, Mobeen A.; Marzo, Sam; Anderson, Douglas
Publication:Ear, Nose and Throat Journal
Article Type:Clinical report
Geographic Code:1USA
Date:Feb 1, 2008
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