Tumors of the Paraganglion System
Related narrative: Multiple Paragangliomas
Paraganglia are a group of specialized cells (chemoreceptors) that are distributed throughout the body, some connected with the sympathetic nervous system and others with the parasympathetic nervous system. The paraganglion system includes the adrenal medulla (comprising the largest collection of these cells); the chemoreceptors (i.e., carotid and aortic bodies); vagal body; small groups of cells in the head and neck; and thoracoabdominal autonomic ganglion cells.
Adrenal pheochromocytomas are functioning tumors of chromaffin cells that are adrenal in origin and comprise about 93% of paraganglia tumors. The other 7% of paraganglia tumors occur at other sites of the body mostly intra-abdominal. When they are functioning tumors, which is very rarely, they are called extra-adrenal pheochromocytomas or functioning paragangliomas. These paragangliomas (occurring in organs of Zuckerkandl and bladder, for example) have sympathetic connections and are chromaffin positive. About half excrete catecholamines, like adrenal pheochromocytomas do. Local recurrence or metastasis is more common in these extra-adrenal pheochromocytomas, and bilateral and extra-adrenal tumors are more common in children.
The other type of paraganglioma is the nonchromaffin paraganglioma, which does not usually release catecholamines and is innervated by the parasympathetic nervous system. Carotid body tumors fall into this category that also includes tumors of the aorta and its major branches, vagal bodies, jugular bodies, tympanic bodies, the nasal cavity and sinuses, the larynx, and the orbit. This tumor is sometimes called a chemodectoma or a glomus complex tumor.
There are many reports of cases of synchronous nonfunctioning paragangliomas and pheochromocytomas.
Genetic Risk Factors
A definite relationship between paraganglionic tumors and carcinoma of the thyroid has been shown to exist. The familial multiple endocrine neoplasia type I syndrome (MEN type I), consisting of pituitary adenomas, parathyroid adenomas, and pancreatic islet cell adenomas, has been definitely associated with paragangliomas. On the other hand, MEN type II, consisting of medullary carcinoma of the thyroid, parathyroid adenomas, and adrenal pheochromocytomas, has not been found to be associated with extra-adrenal paragangliomas. The MEN type III, or multiple mucosal neuroma syndrome, consists of papillary carcinoma of the thyroid, pheochromocytomas, multiple neuromas, and ganglioneuromas of the gastrointestinal tract. (See medullary thyroid carcinoma discussion).
An estimated 800 cases of pheochromocytoma are diagnosed in the U.S. every year. The incidence is highest in young to middle-aged people; about 10% of diagnoses are made in (usually male) children. In adults, no gender difference is seen. Autopsy series indicate that the incidence of pheochromocytoma increases progressively with age, and suggest that 50% to 75% of pheochromocytomas may be undiagnosed during life. In fact, patients older than 60 years with pheochromocytoma are likely to report minor or no symptoms. About 90% of pheochromocytomas exist as solitary, unilateral, encapsulated adrenal medullary tumors. Bilaterality, which occurs around 10% of the time, is much more common in the MEN type II syndromes; therefore, all patients with bilateral pheochromocytomas should be screened for MEN-II disease.
Diagnosis and Staging
Functioning tumors of the paraganglion tissue, (i.e., pheochromocytomas) are responsible for the classic clinical picture of paroxysmal hypertension, palpitations, and headaches. Pheochromocytoma is diagnosed through elevated 24-hour urinary excretion of free catecholamines or catecholamine metabolites. After biochemical determination, the localization of disease should be determined: 97% are found in the abdomen, 2%-3% in the thorax, and 1% in the neck. Chest films and abdominal CT scan are used, and 131-I-meta-iodobenzylguanidine (MIBG) is a useful scintigraphic localization agent. MRI is occasionally used. CT and MRI scans are about 98-100% sensitive, while MIBG scanning is only 80% sensitive. However, MIBG scanning has a specificity of 100%, compared to 70% for CT and MRI. There is no accepted staging system for malignant pheochromocytoma.
Surgical resection is the standard treatment. For localized pheochromocytoma in one or both adrenal glands, adequate treatment is complete surgical resection of the gland. If the tumor is both benign and localized, then the patient can assume normal life expectancy. Though patients with MEN II syndrome are at risk for bilateral tumors, the use of prophylactic contralateral adrenalectomy is not recommended if the patient's tumor is confined to one gland. Overall, with an experienced surgeon, the operative mortality is less than 2%-3%.
Approximately 10% of pheochromocytomas are considered malignant, but there are no histologic features that distinguish benign from malignant tumors. Malignancy is suggested by metastatic deposits or microvascular invasion. Malignancy occurs more frequently in extra-adrenal tumors. Each pheochromocytoma should be considered potentially malignant and should be removed with the capsule intact. Surrounding connective tissue and fat should also be removed. It is important to remove the entire adrenal gland. Patients with locally recurrent disease commonly have undergone procedures in which an attempt was made to spare the normal adrenal tissue. In patients with unresectable, recurrent, or metastatic disease, the 5-year survival is less than 50%. Drug treatment of the catecholamine excess is mandatory, and surgery, radiation therapy, or chemotherapy may provide palliative benefit.
Carotid Body Tumors
Carotid paragangliomas are the most common tumors of the head and neck paraganglia, comprising between 60% and 67% of the total. They are considerably more frequent in areas of high altitude, such as Peru, Mexico, and Colorado. They occur at all ages, from children to patients in the ninth decade of life, but the mean age is between 45 and 50 years. Between 2% and 10% of patients have bilateral tumors, either initially or subsequently. Rarely are carotid body tumors functional.
Most commonly, a carotid body tumor presents as a painless, palpable mass over the carotid bifurcation region of the neck, though they can occur at other head and neck sites such as orbit and middle ear. Cranial nerve involvement has been estimated at 20%; most frequently, the vagal and hypoglossal nerves are involved. The definitive study for diagnosing carotid body tumors is selective bilateral cerebral arteriography. Microscopically, they have the characteristic "zellballen" pattern or well-defined organoid arrangement of neoplastic chief cells.
The malignant potential of carotid body tumors is disputed, and reported figures range from 2.6% to 50%. Standard pathologic criteria for malignancy do not correlate well with the biologic behavior of the tumor. The metastatic rate of these tumors is approximately 5%, and regional lymph nodes are the most common site of metastatic spread.
Current treatment of carotid body tumors is primarily surgical, with excision of the tumor and maintenance of the integrity of carotid flow. The most important advancement in surgical therapy of these tumors has been recognition of and dissection along the subadventitial plane, which almost always allows complete removal of the tumor while maintaining carotid artery integrity. Studies have shown that embolization before surgery decreases blood loss and helps tumor removal. When there is deeper involvement of the carotid bifurcation wall, or when combined endarterectomy of the carotid bifurcation is necessary, full-thickness excision of the base of the tumor with vein or synthetic patch closure of the defect facilitates the surgery. When the tumor is large, invasive, or malignant, the carotid artery may have to be sacrificed. If the artery is already blocked, this poses no hazard. If the artery is unobstructed, carotid circulation may be restored by means of an arterial graft, using a shunt for cerebral protection. For the rare tumor that is unresectable, radiation therapy may be of some value.
Resection of even small tumors is associated with a low incidence of neurologic complications; however, observation of these tumors is not recommended because progressive growth is associated with increased risk of neurologic deficits.
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