Neurogenic Tumors of the Mediastinum Workup

Updated: Aug 02, 2021
  • Author: Dale K Mueller, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Workup

Laboratory Studies

Serum assays can be performed to obtain total or fractionated levels of catecholamines. Individual fractionated values can be obtained for epinephrine, norepinephrine, and dopamine.

Several authors note that for these levels to be accurate, the patient must be supine, euvolemic, and in a fasting state at the time the blood sample is taken. Also, blood must be drawn from an intravenous (IV) access site that has been in place for at least 30 minutes. Falsely positive vanillylmandelic acid (VMA) levels are possible in patients who consume products with high vanilla content, such as coffee and tea.

Because numerous medications can interfere with assaying techniques and with endogenous catecholamine release, those that interfere must be carefully screened for and stopped, if necessary, to obtain an accurate result.

Serum and 24-hour urinary catecholamine levels should be measured in all infants and children who present with a posterior mediastinal or paravertebral mass. These levels are frequently elevated in patients with neuroblastoma and ganglioneuroblastoma.

In addition, appropriate clinical signs and symptoms and elevated levels of serum catecholamines and urinary VMA mandate studies to identify the presence of a pheochromocytoma. Approximately 1-2% of pheochromocytomas are located in the thorax. Elevated levels of serum and urinary catecholamines are present in approximately 90% of individuals with a functioning pheochromocytoma.

Serum metanephrine levels also may be measured.

Urinary VMA, homovanillic acid, and metanephrine levels can be assayed in 24-hour, 12-hour, or 2- to 3-hour urine collections. Levels may be elevated in patients undergoing an evaluation for neuroblastoma, ganglioneuroblastoma, and pheochromocytoma. These levels have been found to be elevated in 85-95% of children with neuroblastoma and in approximately 50% of those with ganglioneuroblastoma.

Again, urinary excretion of these substances can be altered by medications or by increased intake of foods with high levels of phenolic acids and vanillin, such as coffee and tea. Attention should be paid to these factors prior to testing to avoid invalid results.

Note that assays of baseline serum and urinary free catecholamine levels and urinary metanephrines and VMA levels should all be obtained when these studies are undertaken. This is advised because a small percentage of patients with pheochromocytoma may have a positive result in only one of these measured assays.

Serum glucose and insulin levels may be suppressed by the production of an insulinlike substance by certain tumors (eg, some fibrosarcomas and neurosarcomas and occasional carcinoid tumors).

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Chest Radiography

Posteroanterior (PA) and lateral radiography of the chest for an unrelated cause is the usual means by which an asymptomatic mediastinal mass in identified. Chest radiography is obviously the first study that would be performed in an individual with symptoms referable to the thorax. [10, 11, 12]  (See the image below.)

Asymptomatic mediastinal mass found during a routi Asymptomatic mediastinal mass found during a routine chest radiograph evaluation of a 34-year-old woman. At surgery, this was found to be a benign neurofibroma.

Lateral chest radiograph findings are very helpful for determining the compartment of the mediastinum involved. This information, combined with the age, sex, and associated clinical findings, aids the physician in the proper choice of subsequent diagnostic studies. (See the image below.)

Lateral chest radiograph of a mediastinal mass fou Lateral chest radiograph of a mediastinal mass found during a routine chest radiograph evaluation of a 34-year-old woman. At surgery, this was found to be a benign neurofibroma (same patient as in the image above).
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Computed Tomography of Chest and Mediastinum

Computed tomography (CT) is a routine part of the diagnostic evaluation of mediastinal tumors, cysts, and other masses. [10, 11]

CT scans can greatly assist in determining the exact location of the mediastinal tumor and in determining its relationship to adjacent structures. CT is also useful in differentiating masses that originate in the mediastinum from those that encroach on the mediastinum from the lung or other structures.

Though not infallible, CT is very useful in helping differentiate tissue densities. This greatly assists in distinguishing structures that are cystic or vascular from those that are solid.

CT scans can reveal evidence of local invasion of adjacent structures by a mass or the presence of intrathoracic metastases. In the past, CT was recommended in the evaluation of all paravertebral masses to help determine the presence of intraspinal extension or invasion. Magnetic resonance imaging (MRI) has since come to be considered better for this purpose.

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Magnetic Resonance Imaging

MRI is useful both in the initial diagnosis of a mediastinal mass and in follow-up evaluations after treatment. [13, 10, 11, 14]  It provides superior vascular imaging and can help better delineate the relationship of an identified mediastinal mass to nearby intrathoracic vascular structures. MRI can help differentiate between a possible mediastinal mass and a vascular abnormality such as an aortic aneurysm.

MRI offers direct multiplanar images. It can be used when iodinated contrast is contraindicated. It provides increased detail in the subcarinal and aortopulmonary window areas and in the inferior aspects of the mediastinum at the level of the diaphragm.

MRI is especially superior to CT for the evaluation of neurogenic tumors of the mediastinum and can eliminate the need for additional studies such as myelography. It can be augmented with magnetic resonance angiography if more extensive evaluation of associated vascular structures is needed, eliminating the need for separate conventional angiography studies.

MRI is more useful than the CT in the evaluation of invasion or extension of tumors, especially neurogenic tumors extending into the spinal canal or tumors closely associated with the heart.

MRI is superior to CT for the evaluation of masses located at the thoracic inlet or at the thoracoabdominal level. It is increasingly being used for the evaluation of residual or recurrent disease after treatment of lymphoma. Although histologic analysis of any residual mass after chemotherapy and radiotherapy remains the standard, MRI evaluation findings from questionable areas have been found to correlate well with histologic findings when attempting to differentiate residual tumor from fibrosis.

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Radionuclide Scanning

Findings from scans using iodine I-131 iodine metaiodobenzylguanidine (MIBG) have been shown to be useful for the identification of pheochromocytomas and neuroblastomas.

The octreotide scan using indium In-111–labeled pentetreotide is useful for localizing various neuroendocrine neoplasms, including carcinoid tumors, pheochromocytomas, and paragangliomas. It has been used at some centers for the evaluation of certain lymphomas.

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Ultrasonography and Echocardiography

Ultrasonographic methods have been used to help differentiate solid from cystic mediastinal masses and to assist in determining a connection between a mass and adjacent structures.

The results from these studies are more useful in evaluating masses associated with the heart and in vascular abnormalities.

In view of the accuracy and detail provided by CT, MRI, and selected radionuclide studies, ultrasound techniques are not generally used as primary tools in the evaluation of mediastinal tumors and cysts.

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Positron Emission Tomography

Positron emission tomography (PET) has proved to be a useful test in for helping identify some pheochromocytomas.

Agents used in these PET studies include 11C-hydroxyephedrine, 11C-epinephrine, and 18F-fluorodeoxyglucose. The results from these tests may be positive even when other test results, such as from MIBG scans, are negative.

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Arteriography

Conventional angiography has been used to help differentiate mediastinal masses from vascular abnormalities and to help determine the relationship between known masses and adjacent vascular structures. This is usually unnecessary, given that CT is able to distinguish mediastinal masses from vascular structures and abnormalities.

In most cases, it has been replaced by MRI and magnetic resonance angiography (MRA).

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Other Tests

In the past, suppressive or provocative tests were used to assist in the diagnosis of pheochromocytoma. They include the use of phentolamine to elicit a hypotensive response and the use of glucagon, histamine, or tyramine to elicit a hypertensive response. These studies are considered obsolete and are no longer used. Currently, the only study used is the clonidine suppression test, which should be used only in individuals whose plasma and urinary catecholamine assay results are borderline.

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Procedures

Transthoracic needle biopsy

In the past, percutaneous biopsy methods were believed too dangerous to use in the evaluation of mediastinal masses, and open surgical biopsy was the diagnostic procedure of choice.

Although still controversial, CT-guided fine-needle aspiration (FNA) biopsy (FNAB) and core needle biopsy (CNB) techniques have been increasingly used with success at several centers. [10, 15, 16]  Note that expert clinical judgment is necessary for selecting appropriate cases for this diagnostic method. In addition, considerable expertise in tissue processing and analysis is necessary for diagnostic accuracy.

FNAB has been described for use with neurogenic tumors, although because surgical resection is the treatment for these lesions after adequate workup, needle biopsy may be deemed an unnecessary step.

Cervical mediastinoscopy

Cervical mediastinoscopy is a commonly used surgical diagnostic procedure in the evaluation of the retrovascular, pretracheal area of the middle mediastinum. [16]

Cervical mediastinoscopy is most commonly used for the staging of bronchogenic carcinoma and for the evaluation of hilar and paratracheal lymphadenopathy, but it can be modified into what has been termed a substernal extended mediastinoscopy to evaluate the prevascular area of the mediastinum.

This diagnostic test is best used for evaluation or biopsy of masses of the anterior mediastinal compartment. Using this approach, the thymus, any tumors or cysts found in the thymic area, and lymph nodes of the aortopulmonary window are accessible for biopsy. Tumors located in the posterior mediastinum, where most neurogenic tumors are found, are not approachable using this method. Some lesions of neurogenic origin, when located high in the mediastinum in the region of the thoracic inlet, may be approached and resected through a cervical approach.

Anterior mediastinotomy

This parasternal approach to the mediastinum has been used most commonly in situations in which standard cervical mediastinoscopy was believed or found to be inadequate. [16]  The classic approach is the upper left parasternal area, in order to gain access to the aortopulmonary window and areas of the anterior mediastinum inferior to the aortic arch.

This procedure can afford access to areas of the anterior and middle mediastinum, but it is ill-suited as an approach to masses or structures of the posterior mediastinum.

Posterior mediastinotomy

This is a rarely used procedure for biopsy of some of the posteriorly situated lymph nodes or a mass in the paravertebral sulcus. Posterior mediastinotomy is most often performed on the right side in a paravertebral location immediately lateral to the paravertebral muscles. Similar to the anterior mediastinotomy, small segments of several ribs in the area can be excised for extrapleural access to the ipsilateral paravertebral sulcus. The mediastinoscope also may be used for lymph node biopsy with this approach.

This approach is rarely used for mediastinal tumors and cysts because these are more appropriately managed by either standard thoracotomy or video-assisted thoracoscopic surgery (VATS) techniques.

Video-assisted thoracoscopic surgery

VATS techniques have been used successfully for biopsy of various mediastinal masses and are often used for the sampling of perihilar lymph nodes. [3]  VATS can also be used to resect benign posterior mediastinal tumors. [17]  Shorter hospital stay and faster return to work have been demonstrated with this technique. [18, 19]

VATS is one of the commonly used methods for the evaluation of mediastinal lymphoma.

Sternotomy and thoracotomy

In spite of the numerous minimally invasive options available for histologic diagnosis of mediastinal tumors and cysts, open surgical access is needed at times. Posterior mediastinal tumors are typically approached through a thoracotomy, if not with VATS. [18]

In some cases, standard sternotomy or thoracotomy may be the safest method available to obtain adequate tissue for diagnosis.

Another option for some thoracic surgeries is the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, Calif), a robotic surgical system. Advanced general thoracic procedures have been performed with the use of the robot. A major limitation is the lack of more appropriate instrumentation. [5]

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Histologic Findings

Various benign and malignant neurogenic tumors occur in the mediastinum, essentially the posterior mediastinum.

Schwannomas (neurilemmoma, neurinoma)

Schwannomas are of nerve sheath origin. [20] They are often found in individuals with neurofibromatosis or von Recklinghausen disease. These well-encapsulated, soft, yellowish tumors are attached to peripheral nerves.

Microscopically, schwannomas are composed of spindle cells with twisted nuclei and amphophilic cytoplasm. Densely cellular areas of the tumor are given the designation Antoni A areas, while less-cellular areas with a myxoid stroma are called Antoni B areas. Mitoses are rare in schwannomas. Patients with neurofibromatosis are likely to display a variant form of this tumor called plexiform schwannoma. Melanocytic schwannoma is a variant form, which has a pronounced brownish cytoplasmic pigment. Some authorities consider this variant potentially malignant.

Neurofibroma

Neurofibromas are of peripheral nerve origin. [20] A variant form, called plexiform neurofibroma, is commonly associated with neurofibromatosis. Grossly, these tumors are pseudoencapsulated. They are soft, grayish-white tumors that appear to be part of the nerve of origin rather than attached to it.

Microscopically, neurofibromas are composed of spindle cells and fibroblasts, which can often be seen to extend through the epineurium and infiltrate adjacent tissues. Tumor cells are often arranged in loose whorls and can be accompanied by various inflammatory cells. Atypia and frequent mitotic figures are not characteristic. While neurofibromas are benign neoplasms, some can have a very cellular appearance and exhibit atypia. However, they do not display the frequent mitoses of neurosarcomas.

Ganglioneuroma

Ganglioneuromas are benign tumors arising from the sympathetic or parasympathetic paraganglia. [20] These are firm, well-defined, encapsulated neoplasms that are gray or tan. On cut surface, they resemble leiomyomas. Ganglioneuromas are composed of a combination of mature ganglion cells, spindle cells, and nerve fibers. Ganglion cells have a large nucleus with distinct nucleoli and granular, basophilic cytoplasm.

Granular cell tumors

These benign tumors are believed to be of Schwann cell origin. [20] They are soft in consistency, nonencapsulated, and have a grayish or yellowish color. Granular cell tumors consist of polygonal cells with round central nuclei and granular eosinophilic cytoplasm. Cells are arranged in nests or ribbons and are mixed with a fibrous stroma.

Malignant schwannoma

These tumors are the malignant version of schwannomas and neurofibromas. Grossly, malignant schwannomas are large, oval, or fusiform masses. In many cases, the nerve from which they originate can be easily identified. They are soft tumors with a gray-to-pinkish color and commonly have areas of necrosis or hemorrhage within.

Microscopically, malignant schwannomas consist of sheets or bundles of pleomorphic spindle cells. The cells are aligned in a manner that closely resembles the architecture of leiomyosarcomas or other spindle cell sarcomas. They have numerous mitotic figures and areas of necrosis. A characteristic feature of malignant schwannomas is their ability to exhibit other cellular components such as clusters of epithelial cells; mucin-secreting glands; and even mesenchymal features such as bone, cartilage, or skeletal muscle.

Neuroblastoma

Neuroblastomas of the mediastinum originate from ganglion cells. Grossly, they are large, soft, lobulated, pseudoencapsulated tumors ranging from white to pink in color and displaying significant hemorrhage, necrosis, and calcifications.

At a cellular level, they consist of small cells with round nuclei and sparse cytoplasm. Chromatin within the nuclei has a characteristic dusty appearance. An eosinophilic fibrillary stroma is present in varying amounts. Mitoses are frequent, as are regions of extensive necrosis and calcification. Pseudorosettes are a characteristic feature of well-differentiated tumors.

Neuroblastomas exhibit a range of differentiation that is directly related to prognosis. Tumors exhibiting large amounts of stroma are often better differentiated and are associated with a better prognosis, while stroma-poor tumors are more poorly differentiated.

Ganglioneuroblastoma

These tumors are neuroblastomas that display distinct differentiation of the ganglion cells and often have neurons with various levels of differentiation present. Additionally, ganglioneuroblastomas have plentiful extracellular neurofibrillary material.

Melanotic progonoma

These darkly pigmented malignant tumors usually occur in the jaw but can occur in the mediastinum. They are composed of neuroepithelial cells mixed with irregular spaces lined by cuboidal cells that contain melanin.

Askin tumor

These highly malignant tumors are believed to be of neuroectodermal origin, possibly arising from a peripheral nerve such as an intercostal nerve. Askin tumors contain numerous small cell neurosecretory granules.

Mediastinal paragangliomas and pheochromocytomas

Paragangliomas are usually soft vascular tumors. While they histologically resemble adrenal pheochromocytomas, they do not functionally mimic them and produce no catecholamines. They display nests of small oval cells separated by reticulin. Mitoses are uncommon. A mediastinal paraganglioma that is found to secrete catecholamines is termed an extraadrenal pheochromocytoma or a functioning paraganglioma.

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Staging

Well-established staging systems exist for several tumors that occur within the mediastinum. Most noted are those for thymoma, lymphoma, and neuroblastoma.

No specific staging systems are described for the many other types of tumors that occur, most likely because of their infrequent occurrence.

The International Neuroblastoma Staging System (INSS) is widely used for the staging of neuroblastoma and has essentially replaced other staging systems.

The staging system for neuroblastomas is as follows:

  • Stage I - Tumor localized and confined to area of origin; complete gross excision possible (residual microscopic disease may or may not be present); negative findings upon microscopy of ipsilateral and contralateral lymph nodes removed at surgery
  • Stage 2A - Incomplete gross excision of unilateral tumor; negative findings upon microscopy of ipsilateral and contralateral lymph nodes removed at surgery
  • Stage 2B - Complete or incomplete gross excision of a unilateral tumor with positive findings from ipsilateral lymph nodes; negative findings upon microscopy of identifiable contralateral lymph nodes
  • Stage 3 - Tumor found to infiltrate across the midline, with or without regional lymph node involvement, tumor is unilateral but contralateral lymph node involvement is found, or, tumor is midline with bilateral lymph node involvement
  • Stage 4 - Tumor dissemination to bone, bone marrow, distant lymph nodes, liver, and other organs, except as defined for stage 4S
  • Stage 4S - Localized primary tumor as defined by stage 1 or 2 but with disseminated disease to liver, less than 10% of bone marrow, skin, or all, diagnosed in patients ranging in age from newborn to younger than 1 year
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