Adult Chest Surgery

Chapter 138. Neurogenic Tumors of the Posterior Mediastinum 

Neurogenic tumors arise in tissues derived from the embryonic neural crest. Further classification is based on whether the tumor cell originates from nerve sheath, nerve cells (ganglia), paraganglia, or peripheral nerve (Table 138-1). In the thorax, the latter nerve is represented by the intercostal nerve. The chief impediment to understanding thoracic neurogenic tumors is the lack of uniformity in the nomenclature used in the published literature, and thus multiple descriptors exist at each taxonomic level (Table 138-2). This chapter relies on the nomenclature endorsed by the most recent revision of the World Health Organization classification of tumors derived from neural tissue.1

Table 138-1. Classification of Neurogenic Tumors

 
 

Table 138-2. Neurogenic Tumor Nomenclature

Tumor

Also Known As

Neurilemoma

Schwannoma, neurilemoma, neurinoma

Granular cell tumor

Myoblastoma

Malignant peripheral nerve sheath tumor (MPNST)

Malignant schwannoma, neurosarcoma, neurofibrosarcoma, malignant fibroma, malignant tumor of nerve sheath origin (MTNSO)

Paraganglioma

(functioning)

Pheochromocytoma

Paraganglioma

(nonfunctioning)

Chemodectoma, paraganglionoma

Primitive neuroectodermal tumor (PNET)

Peripheral neuroectodermal tumor, peripheral neuroepithelial tumor, Askin tumor

 

Neural crest-derived tissues can be found throughout the body. In the thorax, neurogenic tumors are found most commonly in the posterior mediastinum (63–96%).1–6 In fact, neurogenic tumors account for 75% of all posterior mediastinal neoplasms.The epidemiology of neurogenic tumors depends primarily on whether the patient is an adult or a child. Whereas one-third of mediastinal tumors diagnosed and treated in children are neurogenic, the incidence is only 12–14% in adults.7,8 Adults also have a lower rate of malignancy (5–10% in adults compared with 40–60% in children)1,7 (Fig. 138-1). The most common neurogenic tumors in adults arise from the nerve sheath (e.g., neurilemoma and neurofibroma), whereas in pediatric populations the cells of origin are the ganglia (e.g., ganglioneuroma and neuroblastoma)1,9 (Table 138-3).

Figure 138-1.

 

Malignancy rate according to patient's age. (Reproduced with permission from Takeda S, Miyoshi S, Minami M, Matsuda H: Intrathoracic neurogenic tumors: 50 years' experience in a Japanese institution. Eur J Cardiothorac Surg 26:807–12, 2004.)

Table 138-3. Comparison of Children and Adults for Histologic Type of Neurogenic Tumor

Histologic Class

Adults, 86 Cases

Children, 60 Cases

P Value

Gender

M/F: 48/38

M/F: 27/33

0.20

Malignancy (%)

Benign/Malignant, 81/5 (5.8%)

Benign/Malignant, 35/25 (41.7%)

<0.001

Ganglioneuroma

18 (M/F: 8/10)

33 (M/F: 17/16)

<0.001

Schwannoma

37 (M/F: 21/16)

0

<0.001

Neurofibroma

28 (M/F: 16/12)

2 (M/F: 0/2)

<0.001

Neuroblastoma

0

18 (M/F: 8/10)

<0.001

Ganglioblastoma

0

5 (M/F: 1/4)

0.023

PNET

0

2 (M/F: 1/1)

0.081

Neurofibrosarcoma

2 (M/F: 2/0)

0

0.23

Pheochromocytoma

1 (M/F: 1/0)

0

0.40

Others

2 (M/F: 0/2)

0

0.23

 

M/F, male/female; PNET, primitive neuroectodermal tumor.

Used with permission from ref. 1.

NEUROGENIC TUMORS

The mainstay of treatment for neurogenic tumors, benign or malignant, is complete surgical extirpation. Since most neurogenic tumors are benign, the rationale for resection is to prevent symptoms related to local growth, confirm the diagnosis (i.e., exclude malignancy and determine other options for treatment), and avoid the remote possibility of malignant degeneration.The exceptions to this strategy involve cases of advanced neuroblastoma and ganglioneuroblastoma. Although these tumors are encountered more commonly in pediatric practice, we address them in this chapter to give a comprehensive understanding of mediastinal tumor biology. Specific treatments are presented by tumor type.

Nerve Sheath Tumors

Benign nerve sheath tumors have an excellent prognosis, with negligible rates of local recurrence after complete resection.2,10,11 One should not expect, even after subtotal resection, that recurrence (or continued growth) of a benign nerve sheath tumor will adversely affect long-term survival.1,5 Surgical resection of benign tumors is indicated to ascertain diagnosis, prevent or alleviate effects from local invasion, and avoid the rare malignant transformation of a benign lesion.

Approximately 30–45% of patients with neurofibromas also carry a diagnosis of neurofibromatosis, and the presence of multiple neurofibromas or a single plexiform tumor is highly suggestive of this link.12 von Recklinghausen's disease also may be associated with ganglion cells tumors, neurilemoma, and malignant peripheral nerve sheath tumors, with the incidence of malignancy several-fold higher than that of the general population.2,5,10 In cases of malignant peripheral nerve sheath tumors, von Recklinghausen's disease confers a worse prognosis.5,12 Postoperative radiation has been used to obtain local control of malignant peripheral nerve sheath tumors, but the efficacy of this strategy remains unproved.1,2,11 There is no effective adjunctive chemotherapy.1,2,5,11

Granular cell tumors are found rarely in the posterior mediastinum.13 Such tumors are thought to arise from the Schwann cell and can be found throughout the body.14 Few granular cell tumors are malignant (2–3%).15Complete surgical resection is the treatment of choice. Absent a total resection, the local recurrence rate may be as high as 20%.13

Ganglion Cell Tumors

Neuroblastoma is a tumor that is seen rarely in adults. Most cases are diagnosed in children under 5 years of age.The International Neuroblastoma Staging System has established disease stages that span from local tumor growth to lymph node involvement and distant metastasis.16 Patients with early-stage disease are treated by surgical resection. Intermediate-risk patients are treated with a combined chemotherapeutic regimen (e.g., cyclophosphamide/doxorubicin), potentially with the addition of etoposide, surgical resection, and adjuvant radiation. Advanced-stage disease with evidence of dissemination of tumor to distant sites is treated aggressively with chemotherapy, sometimes in conjunction with bone marrow transplantation.9,17 A recent report on incompletely resected posterior mediastinal neuroblastomas in a pediatric population noted that thoracic neuroblastoma tends to demonstrate better 5-year survival rates than extrathoracic tumors. Moreover, the presence of positive margins on the resected specimen did not alter the excellent prognosis.18 The adult literature is far less developed than that of children, but surgical resection with chemotherapy and possible adjuvant radiation has been reported to be effective for long-term survival and freedom from recurrence.19

Ganglioneuroma represents the benign end of the spectrum of ganglion cell tumors and is diagnosed at a median age of 6.5 years, in contrast to the 22-month age observed with neuroblastoma.17,20 The histology of ganglioneuroma reveals mature ganglion cells, whereas neuroblastoma contains neuroblasts. Ganglioneuroblastoma has a mixture of these immature and mature cell types. It is the presence of immature tumor cells that confers the risk of malignancy to neuroblastomas and ganglioneuroblastomas, and these tumors generally are grouped together for purposes of assigning treatment and analyzing outcomes.17 The 5-year survival of posterior mediastinal ganglioneuroblastoma has been reported to be as high as 88%, which exceeds survival with neuroblastoma.21 Surgical resection of ganglioneuroma should be curative for this benign tumor.

Paraganglion Cell Tumors

Paraganglion cell tumors can be functioning or nonfunctioning, and either type has the possibility of being malignant or benign.22–25 Local invasion, as evidenced by vertebral collapse, spinal cord compression, or contiguous neural, pleural, or lung involvement, is a hallmark of malignant paragangliomas that is seen much less frequently with benign cases.24 Surgical resection is standard treatment, with en bloc resection of involved structures, if possible.

PREOPERATIVE ASSESSMENT

Neurogenic tumors exhibit bioactivity. This feature, along with immunohistochemistry, can be harnessed for diagnostic purposes (see Table 138-1). For example, paragangliomas produce catecholamines, which may account for the characteristic symptoms of hypertension, headache, diaphoresis, and palpitations associated with adrenal pheochromocytomas. Similarly, immunostaining may detect chromogranin and S-100 protein.22 Adults with neurogenic tumors, however, generally are asymptomatic. As few as 16–37% of patients exhibit symptoms or signs related to the tumor.1,5 In children, when considering all mediastinal tumors, most specifically neurogenic tumors, the absence of symptoms tends to favor a malignant diagnosis.4,5 In adults, perhaps as a result of the very low incidence of malignancy, the presence or absence of symptoms does not accurately predict malignancy.The most common symptom reported by adults is pain, whereas in children respiratory symptoms, such as cough or dyspnea, predominate.1,5

The workup of a patient with a posterior mediastinal mass must begin with a thorough physical examination and accurate history. A review of symptoms may detect evidence of local growth or invasion (e.g., pain, dyspnea, stridor, cough, dysphagia, neuropathy, or Horner's syndrome), bioactivity (e.g., catecholamine, vasoactive intestinal peptide, or insulin-releasing substance production), or associated syndromes (e.g., von Recklinghaus and neurofibromas). Rarely, evidence of cord compression from tumor extension within the spinal canal may be detected by history and physical examination.26

Imaging with CT scanning is ordered to define the morphology and location of the tumor, as well as some features of local invasion, such as bony or airway involvement27 (Fig. 138-2). Features such as enhancement and homogeneity of density on CT scan can help to differentiate different types of neurogenic tumors.28,29 A tumor size greater than 10 cm has been correlated with malignancy, as well as the findings of pleural effusion and significant mediastinal displacement.When the neural foramen is effaced by tumor on CT scan and intraspinal extension is suspected (known as a dumbbell tumor), MRI should be acquired to further define the anatomy.27In practice, unless the mass is fully circumscribed by pleura on CT scan or small enough that involvement of the foramen obviously is excluded by anatomy alone, an MRI should be ordered to clarify the relationship of the tumor to the neural foramen and spinal canal. The intraoperative dissection of the tumor (described below) may be markedly altered by extension through the neural foramen. Similar to CT scanning but perhaps more specific, MRI also can be used to narrow the differential diagnosis of a posterior mediastinal mass because several common neurogenic tumors have characteristic appearances on MRI.30 Magnetic resonance or conventional arteriography also can be used to identify the artery of Adamkiewicz for dumbbell tumors located in the lower posterior mediastinum (T8-L1) (Fig. 138-3). This practice has been advocated as part of the preoperative workup to minimize spinal cord ischemia during resection.31 Finally, the tumor bioactivity may be targeted with radiologic modalities such as [123I]meta-iodobenzylguanidine (MIBG) scanning, which detects neuroblastomas or functioning paragangliomas.32 MIBG scanning may detect occult multifocal disease or metastatic deposits and is used to monitor for recurrence after therapy. More recently, PET scanning has been examined as an alternative to MIBG scanning.33 Recent studies involving PET scans have used [18F]fluorodopamine, [18F]fluorohydroxyphenylalanine, [11C]epinephrine, or [11C]hydroxyephedrine to detect paragangliomas, neuroblastomas, and ganglioneuromas by targeting characteristic metabolic pathways.34

Figure 138-2.

 
 
 
 

CT and MRI appearance of neurogenic tumors. A. Neurilemoma (white arrow) clearly not invading the neural foramen (black arrow) on CT scan. B. Neurilemoma (white arrow) in closer proximity to neural foramen on CT scan. C. Neurilemoma (dotted white outline) invading neural foramen (black arrow) on CT scan. D. Neurilemoma (white arrow) in proximity to neural foramen (black arrow) but not extending into it on T1-weighted MRI.

 

Figure 138-3.

 

Artery of Adamkiewicz. Inadequate control of vascular structures can lead to dural leak.

Laboratory testing includes 24-hour urinary homovanillic acid, vanillylmandelic acid, and metanephrine, as well as serum and urine free catecholamine levels in cases of suspected functioning paragangliomas or some tumors of ganglion cell origin that produce catecholamines. In cases where catecholamine excess was found, preoperative preparation was broadened to include the initiation of the alpha-blocking agent, phenoxybenzamine 2 weeks before the planned tumor resection to minimize the likelihood of hypertensive crises. Occasionally, beta blockade may be instituted (after the alpha blockade is established) for heart rate or arrhythmia control.

Insulin and glucose levels are checked when a malignant peripheral nerve sheath tumor is suspected of secreting an insulin-releasing substance that could lead to hypoglycemia. Electrolytes and serum vasoactive intestinal protein levels are monitored in patients who report persistent diarrhea because this raises the suspicion of a ganglion cell tumor that is producing excess vasoactive intestinal protein.35 Adjunctive preoperative workup, such as pulmonary function testing or cardiac risk stratification, is pursued on a case-by-case basis. For example, a cardiopulmonary workup might be warranted if there is tumor-related airway obstruction or lung parenchymal collapse or with excess catecholamine production that has led to hypertension and other cardiovascular sequelae.

A final preoperative consideration is whether one should obtain a biopsy to confirm the diagnosis prior to definitive resection. The differential diagnosis of a posterior mediastinal mass includes bronchogenic or esophageal duplication cysts,36 metastatic disease to the pleura, soft tissue tumors,37 infectious/inflammatory diseases such as tuberculosis and sarcoidosis,38 pleural-based neoplasms such as solitary fibrous tumor,39 lymphoma,40Castleman's disease,41 pulmonary sequestration,42 and lateral thoracic meningocele.43 More unusual posterior mediastinal masses that have been mistaken for possible neurogenic tumors have included pancreatic pseudocysts, extramedullary hematopoiesis, achalasia, pulmonary sequestration, thoracic splenosis, variant azygos lobe, and teratoma.42,44–49 Fine-needle aspiration may provide a diagnosis for neurogenic tumors, but cytology alone potentially may be misleading.50–52 Because the treatment of most neurogenic tumors in the posterior mediastinum involves complete surgical resection, in most cases a preoperative biopsy will not alter the surgical plan.

TECHNIQUE

The standard approach for most posterior mediastinal masses is a lateral or posterolateral thoracotomy.A double-lumen endotracheal tube is used to obtain lung isolation for exposure. Preoperative bronchoscopy or esophagoscopy is considered when the tumor may involve aerodigestive structures, although, in practice, this is a rare necessity. Because of the predominance of benign neurogenic tumors in the adult population, en bloc resection of major adjacent structures (e.g., vertebral body or chest wall) is not usually required. Rather, the mass is enucleated from its subpleural origin. The site of the thoracotomy is determined by the level of the tumor. In cases of neurilemomas, the nerve root may be preserved with careful dissection of the tumor after incising the epineurium, but this is often not possible. Neurofibromas are intercalated with the nerve fibers, and thus the nerve root is taken en bloc with the tumor.53

Dumbbell tumors pose a special challenge for complete resection because of extension into the neural foramen and spinal canal. Approximately 10% of benign nerve sheath tumors have this type of anatomy.12Complications such as hemorrhage within the spinal canal leading to neurologic deficits or dural leak can arise with improperly approached dumbbell tumors secondary to excessive traction on the nerve root or improper control of vascular structures2,54,55 (see Fig. 138-3). In addition, thoracotomy alone may provide only enough exposure for an incomplete resection, leaving tumor in the foramen and spinal canal, with the consequences of continued tumor progression and eventual spinal cord compression.Various approaches have been described for resection. The degree of foraminal involvement dictates the need for a spinal approach in addition to the transthoracic resection. In some cases the tumor simply may extend to the distal aspects of the neural foramen, where it widens the foramen but does not truly extend into the spinal canal. Such tumors still may be resected solely via a thoracic approach, taking care not to avulse the nerve root and injure the spinal cord by using meticulous dissection and control of any incised dura to prevent cerebrospinal fluid leak.56 For true dumbbell tumors with intraspinal extension, some have advocated removal of the intraspinal portion via laminectomy for immediate decompression of the spinal cord and relief of symptoms, followed by resection of the intrathoracic portion as a second procedure.57,58 Grillo and colleagues removed dumbbell tumors via a single posterolateral thoracotomy with a "hockey-stick" extension that extended vertically over the middle of the spinous processes.59 The vertical aspect of the skin incision traversed 5 cm superior and inferior to the level of the involved foramen, and thus a skin flap was created to access the desired site of thoracotomy superior to the level of the horizontal skin incision. In a recent report, this technique was used without significant morbidity, and the order of the thoracotomy and intrathoracic tumor mobilization and laminectomy or hemilaminectomy for the intraspinal resection was not fixed. Rather, it depended on surgeon preference.31 In general, a full laminectomy is not necessary to mobilize a unilaterally oriented tumor60 (Fig. 138-4). Whether a single incision or combined chest and back approach is used, the goal of obtaining a complete resection with minimal risk of bleeding and cerebrospinal fluid leak is paramount.

Figure 138-4.

 

Approach for dumbbell tumors. A. Hemilaminectomy (black arrow). B. Resection of intraspinal component of tumor prior to thoracic approach.

 

In the last 15 years, video-assisted thoracic surgery has been used to resect posterior mediastinal neurogenic tumors.56,61–63 The need to convert to thoracotomy has been reported to range from 4% to 17%.61–63 Although the operative time is longer, the advantages of the thoracoscopic approach include quicker recovery, as evidenced by a shorter length of stay and quicker return to work.64 A prospective trial comparing the two techniques has not been done.

The camera and port sites are similar to those used for standard thoracoscopic lung resection (Fig. 138-5). The videoscope generally is introduced into the chest in the seventh interspace in the middle to posterior axillary line. A port is placed anteriorly to retract the lung away from the paravertebral space. One or two additional ports then are placed for dissection, with the locations determined by the level of the tumor. The resected tumor is removed in a specimen bag to avoid contamination of the port site. This technique has been used for resection of dumbbell tumors as well, in conjunction with a spinal approach either before or after the thoracic dissection.65,66 More recently, reports have described successful robotic thoracoscopic resection of neurogenic tumors.67,68

Figure 138-5.

 

Ideal port placement for access to posterior mediastinal compartment.

POSTOPERATIVE MANAGEMENT

Patients undergoing neurogenic tumor resection are managed similarly to any patient who has undergone thoracotomy or thoracoscopy. Chest drains are removed early (i.e., on the day of surgery or postoperative day 1) based on output and reexpansion of the lung. Patients are extubated in the OR, and early mobilization is advocated. The performance of a hemilaminectomy in patients with dumbbell tumors should not dissuade this practice. Diet may be resumed in short order as tolerated. Analgesia is diverged via patient-controlled analgesia devices or orally in video-assisted thoracic surgery patients.

The management of patients with paragangliomas warrants special attention to heart rate and blood pressure because doses of pharmacologic agents may be reduced or withdrawn preoperatively. For example, because of its prolonged half-life, the dose of the alpha blocker phenoxybenzamine usually is reduced immediately prior to surgery to prevent postoperative hypotension. Although beta blockers may be continued through the perioperative period for cardioprotective effects, the dose likewise may be reduced.

COMPLICATIONS

Hemorrhage requiring spinal cord decompression has been described.2,54 Postoperative assessment after resection of a neurogenic tumor should include a detailed neurologic examination, even with a purely thoracic (i.e., nondumbbell) tumor resection. Of note, the preoperative physical assessment also should document the neurologic examination in detail to distinguish preoperative deficits from the untoward sequelae of resection.

Management of the dura when tumor invades the neural foramen requires meticulous dissection and attention to the possibility of a dural leak. A cerebrospinal fluid leak into the chest, necessitating a pleural drain, can add to the already negative intrathoracic pressures of inspiration and may be difficult to manage conservatively. Thus the sleeve on the nerve root should be controlled with a hemoclip or suture before the proximal margin of resection is divided. Intraoperatively, if any cerebrospinal fluid is detected, further application of suture, clips, fibrin glue, or a fascial patch may be used to control the leak.56 In the immediate postoperative interval, chest drains are placed on water seal as opposed to suction. In some patients, a lumbar drain can be used to reduce the potential flow gradient of cerebrospinal fluid into the pleural space.56 If the dural leak is noted postoperatively, reoperation and laminectomy will be required occasionally to close the dural defect.5

Other complications are related to the extent of resection, and these possibilities should be conveyed when obtaining the preoperative informed consent. Depending on the scope of the intended resection, these may include recurrent nerve palsy (vagus), Horner's syndrome (sympathetic chain), neuralgia/paresthesia/hypesthesia/neuropraxia (nerve root, brachial plexus), and dyspnea (lung, phrenic nerve).1–3,5

Other complications, such as wound infection, atelectasis, postthoracotomy or postthoracoscopic port neuralgia, and chylothorax, are managed with standard measures.

SUMMARY

Most thoracic neurogenic tumors are found in the posterior mediastinum, and most posterior mediastinal neoplasms are neurogenic in origin. Adequate preoperative workup includes elucidation of any functional symptoms or symptoms of local invasion. The radiologic workup must definitively assess for neural foraminal and spinal canal involvement by tumor, which could change the approach from solely thoracic to a combined spinal and thoracic procedure with involvement of a neurosurgical team. Most adult neurogenic tumors are benign, and surgical resection affords excellent survival and freedom from recurrence in most cases.

EDITOR'S COMMENT

The management of presumed neurogenic tumors requires an appreciation of statistical likelihood—the vast majority of these lesions are benign—and a vigilance for low frequency events. In the elderly patient with comorbidities, the statistical likelihood of benignity is a prudent rationale for surveillance. Alternatively, an otherwise healthy patient may warrant careful consideration of low frequency events such as malignant neurogenic tumors, foraminal involvement, and unexpected malignant diagnoses (e.g., mesothelioma, thymic implant, etc.).

–SJM

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