Paragangliomas

PARAGANGLIOMA

Paragangliomas (paraganglion tumors) arise from neuroendocrine tissues (paraganglia) symmetrically distributed along the paravertebral axis from their predominant location at the base of the skull and neck to the pelvis

Thus paragangliomas may arise anywhere along these tracts and common sites of occurrence include abdomen, retroperitoneum, chest and mediastinum and various head and neck locations such as jugulotympanic membrane, orbit, nasopharynx, larynx, vagal body and carotid body.

• Paragangliomas in the head and neck are primarily associated with the parasympathetic nervous system and generally do not hypersecrete catecholamines or other hormones. Approximately 5% of head and neck paragangliomas hypersecrete catecholamines.

In the head and neck region the normal paraganglia are associated with the parasympathetic nervous system and paragangliomas arising from these parasympathetic sites account for up to 70% of extra-adrenal paragangliomas. The most common site is the carotid body. Carotid body paragangliomas arise at the bifurcation of the internal and external carotid arteries and have classic radiographic features.

Carotid body tumors and paragangliomas of the head and neck are typically painless, slow growing tumors that are often present for years prior to the patient seeking medical attention. They may attain large size and infiltrative growth and local recurrence may lead to death. Although it is estimated that less than 10% of paragangliomas are malignant, in some studies malignancy rates are as high as 50%. It is important to remember that all have malignant potential and it is not always possible to predict malignant behavior based on histologic features alone. There are some studies that have undertaken the task of identifying histologic criteria for malignancy, some of which are helpful, but further studies need to be performed. Some worrisome histologic features include necrosis, extensive capsular or vascular invasion, increased mitotic activity, atypical mitotic figures, loss of a well-differentiated zellballen pattern with loss of the S-100 positive sustentacular cell population and tumor cell spindling. At this point however there are no definitive, well-accepted, reproducible histologic criteria for malignancy in extra-adrenal paraganglioma.

• Paragangliomas in the thorax, abdomen, and pelvis are typically associated with the sympathetic nervous system and usually hypersecrete catecholamines.

Sympathetic paragangliomas located along the paravertebral axis (and not in the adrenal gland) are called “extra-adrenal sympathetic paragangliomas.”

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be considered in all individuals with paragangliomas and/or pheochromocytomas, particularly those with the following findings [1, 2]:

Tumors that are:

  • Multiple (i.e., more than one separate tumor or tumor type), including bilateral tumors
  • Multifocal with multiple synchronous or metachronous tumors
  • Recurrent
  • Early onset (i.e., age <40 years)
  • A family history of such tumors

Recent literature suggests a molecular basis for the development of some paragangliomas, i.e. germline mutations. Six genes have been identified and are thought to contribute to the development of pheochromocytoma/paraganglioma. These include RET, VHL, NF1 and SDH subunits SDHB, SDHC, and SDHD. SDHD and SDHB mutations account for a significant percentage of head and neck paragangliomas. It is well know that paragangliomas may be hereditary and may be part of genetic syndromes such as Von Hippel-Lindau syndrome, neurofibromatosis type I (von Recklinghausen disease), MEN 2A and MEN 2B. When features of these more commonly known syndromes are not present, many familial cases, often associated with the above mentioned germline mutations, go unrecognized.

The diagnosis of paragangliomas

The diagnosis of paragangliomas is based on physical examination, imaging studies, and biochemical testing.

  • Detailed family history, including specific knowledge of any relatives with unexplained or incompletely explained sudden death
  • Personal medical history for the following:
  • Symptoms of catecholamine excess that can include sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations (perceived episodic, forcible, often rapid heart beat), pallor, and apprehension or anxiety
  • Paroxysmal symptoms that may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), exercise, or micturition in the case of urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria
  • Evidence of head and neck paragangliomas. These tumors may present as enlarging masses that are asymptomatic or associated with symptoms of mass effects from the size and/or location of the tumors. Associated symptoms may include unilateral hearing loss, pulsatile tinnitus, cough, hoarseness of voice, pharyngeal fullness, swallowing difficulty, pain, and/or problems with tongue motion.
  • Physical examination directed toward signs suggestive of PGL/PCC:
  • For sympathetic paragangliomas and pheochromocytomas, signs may include documentation of elevated blood pressure, tachyarrhythmias or other arrhythmias, and palpable abdominal masses.
  • For head and neck paragangliomas, signs may include head and neck masses:
  • A carotid body tumor is likely to be vertically adherent and may be associated with bruits or palpable thrills.

    Note: The carotid bodies are located at or near the bifurcations of the carotid arteries, in the lateral upper neck at approximately the level of the fourth cervical vertebra.

  • A jugulotympanic tumor may be visible as a blue-colored pulsating mass behind the intact tympanic membrane [1, 3].

The differential diagnosis of head and neck paragangliomas depends greatly on the actual location of the lesion. The differential diagnoses in tumors arising in the jugulotympanic area include middle ear adenoma, meningioma, and schwannoma, among others. The tumors in this location may be quite fragmented and histologic differentiation may be quite difficult and immunohistochemistry often plays a big role. In carotid body tumors the histologic features are more readily identified and the differential diagnosis includes other neuroendocrine tumors such as medullary thyroid carcinoma and neuroendocrine carcinoma. Hyalinizing trabecular adenoma of the thyroid gland should also be considered but typically does not display neuroendocrine features on immunohistochemistry.

Imaging studies

For diagnosis and tumor localization, the following studies can be used [1, 4, 5, 6].

MRI/CT

Carotid body paragangliomas are vascular lesions, and this is reflected in their imaging appearance. These lesions splay apart the internal (ICA) and external carotid arteries (ECA), and as it enlarges, it will encase, but not narrow the ICA and ECA. Upon contrast administration the lesions avidly enhance reflecting their vascular nature. Flow voids from the numerous vessels are typically seen on MR imaging, and this finding is part of the classic “salt and pepper” imaging appearance of these lesions seen on T2 weighted images. The “pepper” refers to the low signal flow voids, and the “salt” refers to high signal foci of hemorrhage and/or slow flow. The lesions tend to be isointense relative to muscle on T1 weighted imaging and hyperintense on T2. Avid enhancement is seen on post-contrast imaging (Figure 1 and 2)

Figure 1. Paraganglioma of the neck, MRI, sagital view

Figure 2. Paraganglioma of the neck, MRI, transverse view

•Paragangliomas may be identified anywhere along the paravertebral axis from the head to the pelvis, including the paraortic sympathetic chain. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall.

•Chromaffin tumors usually exhibit high signal intensity on T2-weighted MRI, which helps distinguish pheochromocytomas from benign adrenal cortical adenomas.

•Multiple tumors can be present.

•The diagnostic sensitivities and specificities of CT and MRI are equivalent, approximately 90%-100% and 70%-80%, respectively.

•Whole-body short tau inversion recovery (STIR) MRI with targeted MRI for positive tumors may be a reasonable approach for both diagnosis and monitoring. This strategy minimizes radiation exposure associated with CT scanning, while taking advantage of the high sensitivity of T2-weighted MRI.

MRI and CT are also used for tumor staging [1, 4, 5, 6].

Sonography.

B-mode sonography coupled with color-coded Doppler sonography is useful for diagnosis of carotid body and vagal paragangliomas.

Figure 3. Paraganglioma of the neck, ultrasound, transverse view

Figure 4. Paraganglioma of the neck, ultrasound, sagital view

Digital subtraction angiography (DSA)

•DSA is sensitive for the detection of small paragangliomas and can be diagnostically definitive.

•DSA is essential if preoperative embolization or carotid artery occlusion is to be performed.

To detect metastases, the following studies can be used [1, 3].

123I-metaiodobenzylguanidine (MIBG) scintigraphy, a technique that measures tumor uptake of a catecholamine analog radioisotope:

•MIBG has greater specificity for localization than CT and MRI, but lower sensitivity.

•It may be used to:

•Further characterize masses detected by CT or MRI

•Look for additional sites of disease

•Identify tumors when CT or MRI results are negative [1, 2]

Octreotide scintigraphy, a technique that measures tumor uptake of a somatostatin analog radioisotope, can be used in addition to MIBG scintigraphy as some MIBG-negative tumors are positive with octreotide scintigraphy.

Indium-111 octreotide, which is a somatostatin analog, is nuclear medicine imaging study that is useful in the evaluation of paragangliomas, since these are neuroendocrine neoplasms that have surface receptors for somatostatin. A focal area of early intense radiotracer uptake will be seen in the region of the paraganglioma, and is sensitive for detecting tumors greater than 1.5 cm. Octreotide scanning is useful for detecting the presence of multicentric or metastatic paragangliomas, and for distinguishing scar from residual tumor after surgery.

2-18F-fluoro-2-deoxy-D-glucose position emission tomography (FDG-PET), or PET using other imaging compounds, can also assist in detecting metastatic disease.

Treatment.

Surgical resection is the treatment of choice, but these neoplasms are very vascular making resection challenging. A surgical classification system was developed by Shamblin et al. in order to better predict surgical morbidity, which is related to the relationship of the tumor with the carotid vessels. The Shamblin classification divides the tumors into three groups based on operative notes and gross examination. Group 1 tumors are minimally attached to vessels and easily removed. Group 2 lesions partially surround the vessels and are more adherent to the adventitia, and group 3 lesions were adherent to the entire surface of the carotid bifurcation making surgical resection impossible. Arya et al. demonstrated that preoperative MR imaging can predict the Shamblin group based on the degree of circumferential contact of the paraganglioma with the internal carotid artery on axial imaging.

The treatment of choice for carotid body tumor paragangliomas is surgical resection. Pre-operative adrenergic blockade should be considered and due to the high vascularity of these tumors pre-operative embolization is prudent. Overall prognosis is quite good with complete surgical resection. Continued follow-up is necessary, however, as recurrence and metastasis may occur years later. It is estimated that malignant paragangliomas have less than a 50% 10 year survival rate. Surgery remains the treatment choice for these malignant tumors since chemotherapy and radiation do not appear to be of significant benefit.

References

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