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 162-1). 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 162-2). 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
|ORIGIN||TUMOR||BENIGN||MALIGNANT||ASSOCIATED BIOLOGICAL ACTIVITY|
|Granular cell tumor||X||X|
|Malignant peripheral nerve sheath tumor||X||Insulin-releasing substance|
|Ganglion cell||Ganglioneuroma||X||Catecholamines, vasoactive intestinal polypeptide (VIP)|
|Intercostal nerve||Primitive neuroectodermal tumor||X|
|TUMOR||ALSO KNOWN AS|
|Neurilemmoma||Schwannoma, neurilemmoma, 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 (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.3 The epidemiology of neurogenic tumors depends primarily on whether the patient is an adult or a child. Although one-third of mediastinal tumors diagnosed and treated in children are neurogenic, the incidence is only 12% to 14% in adults.7,8 Adults also have a lower rate of malignancy (5%–10% in adults compared with 40%–60% in children) (Fig. 162-1).1,7 The most common neurogenic tumors in adults arise from the nerve sheath (e.g., neurilemmoma and neurofibroma), whereas in pediatric populations the cells of origin are the ganglia (e.g., ganglioneuroma and neuroblastoma) (Table 162-3).1,9,10
|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|
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.3 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.
Benign nerve sheath tumors have an excellent prognosis, with negligible rates of local recurrence after complete resection.2,11,12 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% to 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.13 von Recklinghausen disease also may be associated with ganglion cells tumors, neurilemmoma, and malignant peripheral nerve sheath tumors, with the incidence of malignancy severalfold higher than that of the general population.2,5,11 In cases of malignant peripheral nerve sheath tumors, von Recklinghausen disease confers a worse prognosis.5,13 Postoperative radiation has been used to obtain local control of malignant peripheral nerve sheath tumors, but the efficacy of this strategy remains unproved.1,2,12 There is no effective adjunctive cytotoxic chemotherapy.1,2,5,12 Recent advances in targeted therapies have yielded promising results using bevacizumab and erlotinib for vestibular schwannoma in the setting of neurofibromatosis type 2.14–17 Whether this may translate to the adjuvant or palliative setting for mediastinal peripheral nerve sheath tumors remains to be seen however.
Granular cell tumors are found rarely in the posterior mediastinum.18 Such tumors are thought to arise from the Schwann cell and can be found throughout the body.19 Few granular cell tumors are malignant (2%–3%).20 Complete surgical resection is the treatment of choice. Absent a total resection, the local recurrence rate may be as high as 20%.18
Neuroblastoma is a tumor that is seen rarely in adults. Most cases are diagnosed in children under 5 years of age.4 The International Neuroblastoma Staging System has established disease stages that span from local tumor growth to lymph node involvement and distant metastasis.21 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.9,22 A 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.23 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.24
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.22,25 A recent report on children with thoracic ganglion cell tumors noted that with an age <1 year, nearly all (92%) had neuroblastomas, whereas with age ≥1 year, ganglioneuroblastomas and neuroblastomas were found in near-equal distribution (39% and 37%), with a significant number of ganglioneuroma as well (24%).26 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.22 The 5-year survival of posterior mediastinal ganglioneuroblastoma has been reported to be as high as 88%, which exceeds survival with neuroblastoma.27 Surgical resection of ganglioneuroma should be curative for this benign tumor.
Paraganglion cell tumors can be functioning or nonfunctioning, and either type has the possibility of being malignant or benign.28–31 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.30 Surgical resection is the standard treatment, with en bloc resection of involved structures, if possible.
Neurogenic tumors exhibit bioactivity. This feature, along with immunohistochemistry, can be harnessed for diagnostic purposes (see Table 162-1). 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.28 Adults with neurogenic tumors, however, generally are asymptomatic. As few as 16% to 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.5 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 syndrome), bioactivity (e.g., catecholamine, vasoactive intestinal peptide, or insulin-releasing substance production), or associated syndromes (e.g., von Recklinghausen and neurofibromas). Rarely, evidence of cord compression from tumor extension within the spinal canal may be detected by history and physical examination.32
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 involvement (Fig. 162-2).33 Features such as enhancement and homogeneity of density on CT scan can help differentiate different types of neurogenic tumors.34–36 A tumor size greater than 10 cm has been correlated with malignancy, as well as the findings of pleural effusion and significant mediastinal displacement.5 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.33 In 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 later) 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.37 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. 162-3). This practice has been advocated as part of the preoperative workup to minimize spinal cord ischemia during resection.38 Finally, the tumor bioactivity may be targeted with radiologic modalities such as [123I]meta-iodobenzylguanidine (MIBG) scanning, which detects neuroblastomas or functioning paragangliomas.39 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.40 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.41 In the case of the more common neurilemmomas and neurofibromas, however, standard PET scanning has not been found to very specific or sensitive and thus would not be recommended for a standard workup.42–44
CT and MRI appearance of neurogenic tumors. A. Neurilemmoma (white arrow) clearly not invading the neural foramen (black arrow) on CT scan. B. Neurilemmoma (white arrow) in closer proximity to neural foramen on CT scan. C. Neurilemmoma (dotted white outline) invading neural foramen (black arrow) on CT scan. D. Neurilemmoma (white arrow) in proximity to neural foramen (black arrow) but not extending into it on T1-weighted MRI.