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Mediastinal Tumors
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Mediastinal Tumors Christopher Hazzard, Andrew Kaufman, and Raja Flores
SUMMARY OF KEY POINTS • Knowledge of the anatomy of the mediastinum is critical to establishing the differential diagnosis and choosing the best diagnostic and therapeutic interventions. • A wide variety of possible etiologies must be considered including solid and lymphatic malignancies, benign cysts, and benign neoplasms. • Computed tomography (CT) and magnetic resonance imaging (MRI) are essential tools for the diagnosis and planning of surgical approach and choice of surgical technique. • Thymoma and lymphoma are common anterior mediastinal masses in adults. Lymphoma and benign cysts are the most common middle mediastinal lesions. Neurogenic tumors are seen only in the posterior mediastinum. • Vital visceral, vascular, and neurologic structures exist in the mediastinum, and precise surgical technique is paramount to avoid complications. • Surgical resection of benign cysts should be reserved for bronchogenic or esophageal cysts; pericardial cysts do not warrant invasive tissue sampling or removal. • Bronchogenic and esophageal cysts can acquire significant adhesions to surrounding structures, making minimally invasive resection challenging in some patients. • Electrocautery should be used with caution near the spinal foramina to avoid central nervous system injury. • Known complications from surgery include phrenic nerve injury and paralysis, chyle leak, bronchial or esophageal perforation, and bleeding.
The mediastinum is the region of the thorax between the pleural cavities, commonly described in three compartments: anterior, visceral or middle, and posterior. The anterior mediastinum contains the thymus, lymph nodes, connective tissue, and fat. The visceral mediastinum contains the heart and its vasculature within the pericardium, trachea and proximal bronchi, esophagus, thoracic duct, lymph nodes, and the vagus, phrenic, and recurrent laryngeal nerves. The posterior mediastinum contains the sympathetic chain and proximal intercostal arteries, veins, and nerves. The differential diagnosis for a mediastinal mass is influenced by its anatomic position (Table 54.1).1 Mediastinal masses are often asymptomatic and present as an incidental finding during workup, surveillance, or screening for an unrelated condition. Malignant disease is more likely to be symptomatic.2 Symptoms resulting from local compression and invasion include superior vena cava syndrome, dyspnea, dysphagia, hoarseness, cardiac tamponade, and Horner syndrome. Systemic symptoms may occur because of endocrine tumor activity or fever, chills, and weight loss associated with malignancy (Table 54.2).1 Certain syndromes have commonly associated tumors and symptoms, including myasthenia gravis and anterior mass with
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thymoma or café-au-lait spots and posterior mass with von Recklinghausen neurofibromatosis. The most common anterior mediastinal masses in adults are thymoma, germ cell tumor (GCT), lymphoma, and displaced thyroid. In the visceral compartment, the most common mass is lymphadenopathy associated with metastatic disease. Other visceral masses are usually congenital cysts. Most posterior masses are neurogenic tumors.3 CT can provide information about the size, density, and anatomic relationship of mediastinal masses. Intravenous contrast medium used with CT will usually assist in the definition of mediastinal masses. MRI of the mediastinum is hindered by cardiac and respiratory motion artifacts. MRI of mediastinal masses is normally reserved for assessing intraspinal involvement of paravertebral tumors.4
GERM CELL TUMORS Extragonadal GCTs result from errors in cell migration during embryogenesis (Fig. 54.1). These tumors are most commonly found in the mediastinum, where they account for 15% of anterior mediastinal masses in adults.5 Most mediastinal GCTs present in the second through fourth decade of life. Approximately 85% of mediastinal GCTs are benign and occur at similar rates in men and women;6 however, 90% of malignant GCTs occur in men. With malignant GCTs, scrotal ultrasound is necessary to detect possible primary gonadal tumors. Histologically, there are three types of GCTs: benign teratoma, seminoma, and nonseminomatous GCT (NSGCT).3
Benign Teratoma Benign teratomas are composed of multiple germ cell layers, and are also referred to as mature teratomas. These teratomas may contain any type of tissue, including teeth, hair, bone, cartilage, and occasionally higher order structures. Although many patients will be asymptomatic, benign teratomas have the capacity to compress, erode, rupture, and fistulize into surrounding structures.7 Rarely, these benign tumors undergo malignant transformation.8 Elevated serum levels of beta-human chorionic gonadotropin (beta-hCG) or alpha-fetoprotein (AFP) may indicate malignant GCT. Total surgical excision of benign teratoma is recommended. The treatment approach for benign teratomas can vary and has included median sternotomy and lateral thoracotomy. The preferred treatment, particularly with GCTs, is the hemiclamshell approach, which is a unilateral extension into the hemithorax. For large masses with bilateral extension, a clamshell incision (a combined upper median sternotomy and anterior thoracotomy) provides excellent exposure. Benign teratomas are often adjacently adherent, which can make dissection challenging, and total resection is not always possible. However, postsurgical prognosis is excellent, even with incomplete excision.7 There is no indication for chemotherapy or radiotherapy.
Seminoma Seminomas occur almost exclusively in men and usually present in the third to fourth decade of life. Seminomas often grow quite large before discovery, and metastatic disease is present in 60%
CHAPTER 54 Mediastinal Tumors
to 70% of cases.9 The serum AFP level is normal in pure seminoma and the beta-hCG level can be elevated in some patients. An elevated AFP level implies a nonseminomatous component, but workup and treatment should be the same as for NSGCTs; however, a CT-guided needle biopsy should be considered over surgical biopsy.10,11 Because of the prevalence of systemic disease, treatment with radiotherapy alone is associated with significantly lower progression-free survival compared with that associated with bleomycin, etoposide, and cisplatin chemotherapy.12 Even TABLE 54.1 Differential Diagnosis of Mediastinal Mass by Compartment1 Anterior
Middle
Posterior
Thymoma Teratoma, seminoma Lymphoma Carcinoma Parathyroid adenoma Intrathoracic goiter Lipoma Lymphangioma Aortic aneurysm
Lymphoma Pericardial cyst Bronchogenic cyst Metastatic cyst Systemic granuloma
Neurogenic tumor Bronchogenic cyst Enteric cyst Xanthogranuloma Diaphragmatic hernia Meningocele Paravertebral abscess
TABLE 54.2 Systemic Symptoms of Mediastinal Tumors1 Syndrome
Tumor
Myasthenia gravis, red Thymoma blood cell aplasia, hypogammaglobulinemia, Good syndrome, Whipple disease, megaesophagus, myocarditis Multiple endocrine adenomatosis, Carcinoid, thymoma Cushing syndrome Hypertension Pheochromocytoma, ganglioneuroma, chemodectoma Diarrhea Ganglioneuroma Hypercalcemia Parathyroid adenoma, lymphoma Thyrotoxicosis Intrathoracic goiter Hypoglycemia Mesothelioma, teratoma, fibrosarcoma, neurosarcoma Osteoarthropathy Neurofibroma, neurilemoma, mesothelioma Vertebral abnormalities Enteric cysts Fever of unknown origin Lymphoma Alcohol-induced pain Hodgkin lymphoma Opsomyoclonus Neuroblastoma
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in the case of a residual mass, there is little, if any, role for surgical interventions.9
Nonseminomatous Germ Cell Tumor NSGCTs can include embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, or a mixed histology. Primary mediastinal NSGCT appears to be biologically distinct from testicular NSGCT and is associated with a poor prognosis.13 Primary mediastinal NSGCTs grow rapidly and metastatic disease is found in 80% of patients.14 Overall survival after multimodality treatment is 40% to 50%. Hematologic malignancies present with NSGCT in 6% of cases, most commonly in patients with acute megakaryoblastic leukemia, and myelodysplastic syndrome is the most common.15 The serum AFP level is elevated in 80% of patients and the beta-hCG level is elevated in 30% to 35%. Substantial elevation of tumor marker levels can preclude biopsy.12 However, if biopsy is performed, fine-needle aspiration can be ambiguous and is discouraged in favor of core-needle biopsy or anterior mediastinotomy.16 The standard treatment for NSGCT is four courses of bleomycin, etoposide, and cisplatin; ifosfamide has been recommended over bleomycin to avoid pulmonary complications prior to surgical resection.12 Residual mass after chemotherapy should be surgically resected, regardless of the serum marker levels; the prognosis is poor for patients with unresectable residual masses. When active germ cell cancer is present in the surgical specimen, two additional courses of chemotherapy should be given. Patients who have no residual tumor should be followed closely with history and physical examination, determination of serum markers, and CT. Patients who have disease recurrence have a particularly poor prognosis, although a small number of patients may benefit from salvage chemotherapy.13 A 20% survival rate following surgical resection for relapsed primary mediastinal NSGCT has also been reported.17
LYMPHOMA Lymphomas represent a variety of hematologic neoplasms. Proper management of lymphoma depends on subtyping and staging. Approximately 15% of mediastinal masses are lymphomas, typically in the anterior or middle compartment (Fig. 54.2). About 90% of mediastinal lymphomas represent disseminated disease, and one-third are Hodgkin lymphomas. Most patients present with some combination of systemic B symptoms, and symptoms associated with local compression.18 Positron emission tomography is frequently used to stage and monitor the progress of lymphoma.19
Hodgkin Lymphoma Mediastinal involvement occurs in as many as two-thirds of Hodgkin lymphoma. Diagnosis typically requires tissue quantities only obtainable by surgical biopsy. Typically, video-assisted thoracoscopy (VATS) or anterior mediastinotomy will yield definitive samples; however, mediastinoscopy is not always sufficient.
Fig. 54.1. Anterior mediastinal germ cell tumor with extension into the left hemithorax.
Fig. 54.2. Lymphoma in the anterior mediastinum.
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SECTION X Other Thoracic Malignancies
CD15- and CD30-positive Reed-Sternberg cells, which are diagnostic for Hodgkin lymphoma, can be difficult to identify in a small biopsy.18 Disease is staged according to the Ann Arbor Staging System;20 early-stage Hodgkin lymphoma is treated with chemoradiation therapy and late-stage disease is treated with chemotherapy only.21
Non-Hodgkin Lymphoma Large B-cell lymphoma and lymphoblastic lymphoma are the most common forms of non-Hodgkin lymphoma of the mediastinum. As in Hodgkin lymphoma, a sizable biopsy sample is often required for diagnosis. However, lymphoblastic lymphoma is usually first identified in bone marrow and peripheral blood; thus a mediastinal biopsy is not necessary. Lymphoblastic lymphoma is particularly aggressive, and treatment with chemotherapy and possible bone marrow transplant should not be delayed by staging procedures. Large B-cell lymphoma is treated with chemotherapy, and some centers also use radiotherapy for the treatment of B-cell lymphoma and lymphoblastic lymphoma.18
NEUROGENIC TUMORS Approximately three-quarters of posterior mediastinal tumors are neurogenic (Fig. 54.3). These neurogenic tumors arise from the sympathetic chain or intercostal rami, and they most commonly take the forms of nerve sheath tumors (schwannoma and neurofibroma). Nearly all neurogenic tumors are benign, and approximately 30% of neurofibromas are associated with von Recklinghausen disease. Neurogenic tumors may erode osseous structures; this contributes to the development of an intraspinal (dumbbell) extension. MRI is essential if intraspinal involvement is suspected, as failure to recognize involvement can result in devastating spinal cord injury during attempted excision; resection of intraspinal tumor requires neurosurgical expertise. Simple nerve sheath tumors, whether benign or malignant, should be surgically resected, and a VATS approach is usually sufficient. Relative contraindications for complete resection include a mass greater than 6 cm and spinal artery involvement. Chemotherapy and radiotherapy may be used when complete resection is not possible.4
BENIGN CYSTIC MASSES Bronchogenic Cysts Bronchogenic cysts arise from errors in embryonic budding of the tracheobronchial tree (Fig. 54.4); they are the most
Fig. 54.3. Paravertebral mass typical of neurogenic tumors.
common mediastinal cysts and are frequently found behind the carina. The majority of bronchogenic cysts are discovered before the onset of symptoms, but most do eventually cause symptoms. Bronchogenic cysts can cause local compression and erosion and may become infected.22 Resection of asymptomatic cysts can be controversial, but because of their potential to cause later complications and the favorable outcomes from early surgical intervention, VATS or mediastinoscopic resection is recommended.22–24
Esophageal Cysts Esophageal cysts, also called esophageal duplications, arise in a similar manner as bronchogenic cysts. Like bronchogenic cysts, esophageal cysts can also cause local compression and may become infected. There is also risk of hemorrhage and rupture into the esophagus or airways. VATS excision is recommended, with care taken to minimize disruption of the esophageal muscularis.22
Pericardial Cysts Pericardial cysts are mesothelium-derived and in close proximity to the pericardium. Pericardial cysts are typically benign and require no intervention. However, a growing pericardial cyst can cause hemodynamic compromise, and excision should be performed for symptomatic patients.25 VATS is recommended, if feasible.
SUBSTERNAL GOITER Goiters are enlargements of the thyroid and are deemed substernal when more than half of the gland extends inferior to the sternal notch (Fig. 54.5). Substernal goiters are the most common superior mediastinal tumors, usually found in the anterior mediastinum; however, 10% to 15% of substernal goiters are found in the posterior compartment.26 The most common symptoms of substernal goiters are caused by local compression and include dyspnea, cough, and hoarseness. Approximately 25% of patients will be asymptomatic. A palpable thyroid is present in 88% of patients, and 16% of patients have hyperthyroidism.27 Serum levels of thyroid-stimulating hormone, free T4, and total T3 can be useful in the diagnosis and detection of subclinical hyperthyroidism.28 Spirometry can assess the extent of airway compression and may identify abnormalities in asymptomatic patients. CT is used to determine the extent and position of the goiter. Although malignancy is possible, needle biopsy is not indicated, as the malignant focus may be missed and its presence does not alter the operative indication.29 Presence of substernal goiter is itself an indication for resection. Further enlargement worsens compression-associated symptoms and can complicate surgical
Fig. 54.4. Bronchogenic cyst in the visceral mediastinum.
CHAPTER 54 Mediastinal Tumors
treatment that would otherwise be associated with low postoperative morbidity.27 Total thyroidectomy is recommended and can usually be accomplished by a collar incision. When the extent of thoracic involvement does not permit resection by a collar incision, possible approaches include manubrial split, sternotomy, and thoracotomy. Postoperative complications are infrequent and include hypoparathyroidism and recurrent laryngeal nerves paralysis.29
PARATHYROID ADENOMA Primary hyperparathyroidism is most commonly a result of adenoma of the parathyroid glands (Fig. 54.6). Approximately 22% of parathyroid adenomas are found in a mediastinal parathyroid gland.30 Resection of the tumor is curative in nearly every case.31 The preferred surgical approach is minimally invasive and relies on precise preoperative localization. The mainstay of parathyroid adenoma localization is technetium-99m sestamibi scintigraphy; when combined with three-dimensional single-photon emission CT, the sensitivity and specificity are high.32 Ultrasound is often used to complement other modalities. Localization has no diagnostic role and is used only for preoperative planning in biochemically proven cases. Most mediastinal parathyroid tumors can be resected transcervically, and videomediastinoscopy may be useful in difficult cases. VATS has also been used for the resection of parathyroid adenomas, but precise localization is particularly important with this approach. Intraoperative monitoring of the parathyroid hormone level is used to confirm systemic cure.33
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SURGICAL APPROACH The appropriate surgical approach depends on the nature and position of the lesion within the mediastinum. A minimally invasive approach is often possible for uninvolved benign masses. More aggressive exposure is used for large and/or malignant tumors, for which complete resection is crucial and dissection is potentially challenging. Access to small anterior midline tumors is commonly approached by a median sternotomy, with the patient in the supine position with the arms tucked to the side. In this position, the mediastinal vasculature, left and right hemithoraces, and lung hila are well exposed; however, exposure of the left lower lobe and posterior aspect of the lungs is poor. In some cases, a partial sternum-sparing approach will allow for sufficient exposure, such as a manubrial split for superior mediastinal mass. A collar incision may also provide sufficient access to the superior mediastinum if the mass can be accessed through the neck. For large tumors extending into either of the hemithoraces, a hemiclamshell incision provides good exposure.37 The patient should be placed in the supine position, with a longitudinal roll
LEIOMYOMA Leiomyoma in the mediastinum usually arises from the esophagus or large vessels (Fig. 54.7). Primary mediastinal leiomyoma not associated with adjacent organs is exceedingly rare.34 These lesions are firm and well circumscribed, and symptoms are typically due to local compression. Complete excision is the definitive treatment;35 esophageal leiomyoma is treated using VATS enucleation.36
Fig. 54.6. Parathyroid adenoma in the superior anterior mediastinum.
Fig. 54.5. Substernal goiter in the superior mediastinum.
Fig. 54.7. Leiomyoma of the thoracic esophagus.
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elevating the thoracotomy side by 30 degrees and the arms tucked to the side. The ipsilateral lung may be collapsed to allow for anatomic resection of involved lobes, if necessary, and access to the posterolateral aspect of the tumor. If the tumor has substantial cervical extension, the upper sternotomy may be extended superiorly along the anterior border of the sternocleidomastoid.38 This approach exposes the carotid and jugular vessels if vascular dissection is necessary. Rarely, resection of the subclavian vessels will be needed for a GCT. In these cases, a so-called trap door incision, created by extending the upper sternotomy along the superior margin of the clavicle, will allow for appropriate exposure. Excision of the medial third of the clavicle may also assist in exposure of the tumor. A large tumor that extends into both right and left hemithoraces may be resected through a bilateral clamshell incision, with the patient in the supine position and the arms abducted or flexed over the forehead. A curvilinear incision should be made along the inframammary crease from the right to left anterior axillary lines for access to the fourth intercostal space; the mammary vessels are then ligated, and the sternum is divided transversally. Retraction is provided by two Finochietto retractors. An upper sternal split may be made in the event that an initial clamshell approach provides inadequate exposure of the superior mediastinum.
CONCLUSION The mediastinum is dense with multiple organ systems, and the tumors thereof are equally varied. Appropriate management and surgical approach require careful assessment of each case. Indications for chemotherapy, radiotherapy, and surgical treatment of mediastinal GCTs vary according to the histologic subtypes. Surgical exposure of large mediastinal GCTs is often best approached by hemiclamshell or bilateral clamshell incision. Lymphoma of the mediastinum is usually a disseminated disease. Surgical biopsy provides sufficient tissue for diagnosis, but treatment is nonsurgical and based on the subtype and stage. Posterior masses are typically neurogenic tumors. MRI is essential for assessment of intraspinal involvement. Small uninvolved neurogenic tumors should be treated by VATS. Congenital cystic masses of the bronchial tree and esophagus should be resected
by minimally invasive approach. Resection of pericardial cysts is reserved for symptomatic patients. A substernal goiter is an indication for total thyroidectomy. A collar incision is often sufficient, but more involved goiters can require a sternal split. Parathyroid adenomas causing primary hyperparathyroidism should be resected with a minimally invasive approach. Precise preoperative localization of parathyroid adenoma is crucial to successful resection. Leiomyomas are typically of the esophagus or large vessels and should be excised.
KEY REFERENCES 2. Davis Jr RD, Oldham Jr HN, Sabiston Jr DC. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management, and results. Ann Thorac Surg. 1987;44(3):229–237. 6. Mullen B, Richardson JD. Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg. 1986;42(3):338–345. 12. Albany C, Einhorn LH. Extragonadal germ cell tumors: clinical presentation and management. Curr Opin Oncol. 2013;25(3):261–265. 14. McNamee CJ. Malignant primary anterior mediastinal tumors. In: Sugarbaker DJ, Bueno R, Krasna MJ, Mentzer SJ, Zellos L, eds. Adult Chest Surgery. New York, NY: McGraw-Hill; 2009:1154–1158. 16. Alam N, Flores R. Management of mediastinal tumors not of thymic origin. In: Pass HP, Carbone DP, Johnson DH, et al., eds. Principles and Practice of Lung Cancer. 4th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. 18. Smith S, van Besien K. Diagnosis and treatment of mediastinal lymphomas. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2379–2387. 22. Ferraro P, Martin J, Duranceau ACH. Foregut cysts of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2009:2519–2538. 36. Vallböhmer D, Hölscher AH, Brabender J, Bollschweiler E, Gutschow C. Thoracoscopic enucleation of esophageal leiomyomas: a feasible and safe procedure. Endoscopy. 2007;39(12):1097–1099. 37. Bains MS, Ginsberg RJ, Jones 2nd WG, et al. The clamshell incision: an improved approach to bilateral pulmonary and mediastinal tumor. Ann Thorac Surg. 1994;58(1):30–32. discussion 33.
See Expertconsult.com for full list of references.
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1. Crapo JD, Glassroth J, Karlinsky J, et al. Baum’s Textbook of Pulmonary Diseases. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:883–912. 2. Davis Jr RD, Oldham Jr HN, Sabiston Jr DC. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management, and results. Ann Thorac Surg. 1987;44(3):229–237. 3. Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest. 2005;128(4):2893–2909. 4. Reynolds M, Shields TW. Benign and malignant neurogenic tumors of the mediastinum in children and adults. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2415–2439. 5. Strollo DC, Rosado de Christenson ML, Jett JR. Primary mediastinal tumors. Part 1: tumors of the anterior mediastinum. Chest. 1997;112(2):511–522. 6. Mullen B, Richardson JD. Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg. 1986;42(3):338–345. 7. Allen MS, Trastek VF, Pairolero PC. Benign germ cell tumors of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2389–2395. 8. Kim HJ, Kim HR. Naturally occurring mediastinal teratoma with malignant transformation in an adult male. Korean J Thorac Cardiovasc Surg. 2013;46(4):305–308. 9. Rice DC, Moran CA, Dabal RJ, Wood DE. Primary seminomas of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2397–2402. 10. Chhieng DC, Lin O, Moran CA, et al. Fine-needle aspiration biopsy of nonteratomatous germ cell tumors of the mediastinum. Am J Clin Pathol. 2002;118(3):418–424. 11. Kwon MS. Aspiration cytology of mediastinal seminoma: report of a case with emphasis on the diagnostic role of aspiration cytology, cell block and immunocytochemistry. Acta Cytol. 2005;49(6):669–672. 12. Albany C, Einhorn LH. Extragonadal germ cell tumors: clinical presentation and management. Curr Opin Oncol. 2013;25(3):261–265. 13. Hainsworth JD, Greco FA. Nonseminomatous malignant germ cell tumors of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2403–2409. 14. McNamee CJ. Malignant primary anterior mediastinal tumors. In: Sugarbaker DJ, Bueno R, Krasna MJ, Mentzer SJ, Zellos L, eds. Adult Chest Surgery. New York, NY: McGraw-Hill; 2009:1154–1158. 15. Hartmann JT, Nichols CR, Droz JP, et al. Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst. 2000;92(1):54–61. 16. Alam N, Flores R. Management of mediastinal tumors not of thymic origin. In: Pass HP, Carbone DP, Johnson DH, et al., eds. Principles and Practice of Lung Cancer. 4th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. 17. Radaideh SM, Cook VC, Kesler KA, Einhorn LH. Outcome following resection for patients with primary mediastinal nonseminomatous germ-cell tumors and rising serum tumor markers post-chemotherapy. Ann Oncol. 2010;21(4):804–807. 18. Smith S, van Besien K. Diagnosis and treatment of mediastinal lymphomas. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2379–2387.
19. Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007;110(10):3507–3516. 20. Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 1971;31(11):1860–1861. 21. Gobbi PG, Ferreri AJM, Ponzoni M, Levis A. Hodgkin lymphoma. Crit Rev Oncol Hematol. 2013;85(2):216–237. 22. Ferraro P, Martin J, Duranceau ACH. Foregut cysts of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2009:2519-2538. 23. Fievet L, D’Journo XB, Guys JM, Thomas PA, De Lagausie P. Bronchogenic cyst: best time for surgery? Ann Thorac Surg. 2012; 94(5):1695–1699. 24. Granato F, Luzzi L, Voltolini L, Gotti G. Video-assisted mediastinoscopic resection of two bronchogenic cysts: a novel approach. Interact Cardiovasc Thorac Surg. 2010;11(3):335–336. 25. Song J, Costic JT, Seinfeld FI, Laub GW. Thoracoscopic resection of unusual symptomatic pericardial cysts. J Laparoendosc Adv Surg Tech A. 2002;12(2):135–137. 26. White ML, Doherty GM, Gauger PG. Evidence-based surgical management of substernal goiter. World J Surg. 2008;32(7):1285–1300. 27. Erbil Y, Bozbora A, Barbaros U, et al. Surgical management of substernal goiters: clinical experience of 170 cases. Surg Today. 2004;34(9):732–736. 28. Rieu M, Bekka S, Sambor B, Berrod JL, Fombeur JP. Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre. Clin Endocrinol (Oxf). 1993;39(1): 67–71. 29. Farivar AS, Lukanich JM. Resection of substernal goiter. In: Sugarbaker DJ, Bueno R, Krasna MJ, Mentzer SJ, Zellos L, eds. Adult Chest Surgery. New York, NY: McGraw-Hill; 2009:1108–1114. 30. Clark OH. Mediastinal parathyroid tumors. Arch Surg. 1988;123(9):1096–1100. 31. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg. 2002;235(5):665–670. discussion 670–672. 32. Kunstman JW, Kirsch JD, Mahajan A, Udelsman R. Parathyroid localization and implications for clinical management. J Clin Endocrinol Metab. 2013;98(3):902–912. 33. Gopaldas RR, Rice DC, Bondeson A-G, Thompson NW. Mediastinal parathyroid tumors. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009: 2499–2510. 34. Fang HK, Sundaresan S. Unusual mediastinal tumors. In: Pearson FG, Cooper JD, Deslauriers J, et al., eds. Thoracic Surgery. 2nd ed. New York, NY: Churchill Livingstone; 2002:1739–1748. 35. Shields TW, Robinson PG. Mesenchymal tumors of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2473–2497. 36. Vallböhmer D, Hölscher AH, Brabender J, Bollschweiler E, Gutschow C. Thoracoscopic enucleation of esophageal leiomyomas: a feasible and safe procedure. Endoscopy. 2007;39(12):1097–1099. 37. Bains MS, Ginsberg RJ, Jones 2nd WG, et al. The clamshell incision: an improved approach to bilateral pulmonary and mediastinal tumor. Ann Thorac Surg. 1994;58(1):30–32. discussion 33. 38. Rusca M, Carbognani P, Bobbio P. The modified “hemi-clamshell” approach for tumors of the cervicothoracic junction. Ann Thorac Surg. 2000;69(6):1961–1963.
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Mediastinal Tumors Christopher Hazzard, Andrew Kaufman, and Raja Flores
SUMMARY OF KEY POINTS • Knowledge of the anatomy of the mediastinum is critical to establishing the differential diagnosis and choosing the best diagnostic and therapeutic interventions. • A wide variety of possible etiologies must be considered including solid and lymphatic malignancies, benign cysts, and benign neoplasms. • Computed tomography (CT) and magnetic resonance imaging (MRI) are essential tools for the diagnosis and planning of surgical approach and choice of surgical technique. • Thymoma and lymphoma are common anterior mediastinal masses in adults. Lymphoma and benign cysts are the most common middle mediastinal lesions. Neurogenic tumors are seen only in the posterior mediastinum. • Vital visceral, vascular, and neurologic structures exist in the mediastinum, and precise surgical technique is paramount to avoid complications. • Surgical resection of benign cysts should be reserved for bronchogenic or esophageal cysts; pericardial cysts do not warrant invasive tissue sampling or removal. • Bronchogenic and esophageal cysts can acquire significant adhesions to surrounding structures, making minimally invasive resection challenging in some patients. • Electrocautery should be used with caution near the spinal foramina to avoid central nervous system injury. • Known complications from surgery include phrenic nerve injury and paralysis, chyle leak, bronchial or esophageal perforation, and bleeding.
The mediastinum is the region of the thorax between the pleural cavities, commonly described in three compartments: anterior, visceral or middle, and posterior. The anterior mediastinum contains the thymus, lymph nodes, connective tissue, and fat. The visceral mediastinum contains the heart and its vasculature within the pericardium, trachea and proximal bronchi, esophagus, thoracic duct, lymph nodes, and the vagus, phrenic, and recurrent laryngeal nerves. The posterior mediastinum contains the sympathetic chain and proximal intercostal arteries, veins, and nerves. The differential diagnosis for a mediastinal mass is influenced by its anatomic position (Table 54.1).1 Mediastinal masses are often asymptomatic and present as an incidental finding during workup, surveillance, or screening for an unrelated condition. Malignant disease is more likely to be symptomatic.2 Symptoms resulting from local compression and invasion include superior vena cava syndrome, dyspnea, dysphagia, hoarseness, cardiac tamponade, and Horner syndrome. Systemic symptoms may occur because of endocrine tumor activity or fever, chills, and weight loss associated with malignancy (Table 54.2).1 Certain syndromes have commonly associated tumors and symptoms, including myasthenia gravis and anterior mass with
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thymoma or café-au-lait spots and posterior mass with von Recklinghausen neurofibromatosis. The most common anterior mediastinal masses in adults are thymoma, germ cell tumor (GCT), lymphoma, and displaced thyroid. In the visceral compartment, the most common mass is lymphadenopathy associated with metastatic disease. Other visceral masses are usually congenital cysts. Most posterior masses are neurogenic tumors.3 CT can provide information about the size, density, and anatomic relationship of mediastinal masses. Intravenous contrast medium used with CT will usually assist in the definition of mediastinal masses. MRI of the mediastinum is hindered by cardiac and respiratory motion artifacts. MRI of mediastinal masses is normally reserved for assessing intraspinal involvement of paravertebral tumors.4
GERM CELL TUMORS Extragonadal GCTs result from errors in cell migration during embryogenesis (Fig. 54.1). These tumors are most commonly found in the mediastinum, where they account for 15% of anterior mediastinal masses in adults.5 Most mediastinal GCTs present in the second through fourth decade of life. Approximately 85% of mediastinal GCTs are benign and occur at similar rates in men and women;6 however, 90% of malignant GCTs occur in men. With malignant GCTs, scrotal ultrasound is necessary to detect possible primary gonadal tumors. Histologically, there are three types of GCTs: benign teratoma, seminoma, and nonseminomatous GCT (NSGCT).3
Benign Teratoma Benign teratomas are composed of multiple germ cell layers, and are also referred to as mature teratomas. These teratomas may contain any type of tissue, including teeth, hair, bone, cartilage, and occasionally higher order structures. Although many patients will be asymptomatic, benign teratomas have the capacity to compress, erode, rupture, and fistulize into surrounding structures.7 Rarely, these benign tumors undergo malignant transformation.8 Elevated serum levels of beta-human chorionic gonadotropin (beta-hCG) or alpha-fetoprotein (AFP) may indicate malignant GCT. Total surgical excision of benign teratoma is recommended. The treatment approach for benign teratomas can vary and has included median sternotomy and lateral thoracotomy. The preferred treatment, particularly with GCTs, is the hemiclamshell approach, which is a unilateral extension into the hemithorax. For large masses with bilateral extension, a clamshell incision (a combined upper median sternotomy and anterior thoracotomy) provides excellent exposure. Benign teratomas are often adjacently adherent, which can make dissection challenging, and total resection is not always possible. However, postsurgical prognosis is excellent, even with incomplete excision.7 There is no indication for chemotherapy or radiotherapy.
Seminoma Seminomas occur almost exclusively in men and usually present in the third to fourth decade of life. Seminomas often grow quite large before discovery, and metastatic disease is present in 60%
CHAPTER 54 Mediastinal Tumors
to 70% of cases.9 The serum AFP level is normal in pure seminoma and the beta-hCG level can be elevated in some patients. An elevated AFP level implies a nonseminomatous component, but workup and treatment should be the same as for NSGCTs; however, a CT-guided needle biopsy should be considered over surgical biopsy.10,11 Because of the prevalence of systemic disease, treatment with radiotherapy alone is associated with significantly lower progression-free survival compared with that associated with bleomycin, etoposide, and cisplatin chemotherapy.12 Even TABLE 54.1 Differential Diagnosis of Mediastinal Mass by Compartment1 Anterior
Middle
Posterior
Thymoma Teratoma, seminoma Lymphoma Carcinoma Parathyroid adenoma Intrathoracic goiter Lipoma Lymphangioma Aortic aneurysm
Lymphoma Pericardial cyst Bronchogenic cyst Metastatic cyst Systemic granuloma
Neurogenic tumor Bronchogenic cyst Enteric cyst Xanthogranuloma Diaphragmatic hernia Meningocele Paravertebral abscess
TABLE 54.2 Systemic Symptoms of Mediastinal Tumors1 Syndrome
Tumor
Myasthenia gravis, red Thymoma blood cell aplasia, hypogammaglobulinemia, Good syndrome, Whipple disease, megaesophagus, myocarditis Multiple endocrine adenomatosis, Carcinoid, thymoma Cushing syndrome Hypertension Pheochromocytoma, ganglioneuroma, chemodectoma Diarrhea Ganglioneuroma Hypercalcemia Parathyroid adenoma, lymphoma Thyrotoxicosis Intrathoracic goiter Hypoglycemia Mesothelioma, teratoma, fibrosarcoma, neurosarcoma Osteoarthropathy Neurofibroma, neurilemoma, mesothelioma Vertebral abnormalities Enteric cysts Fever of unknown origin Lymphoma Alcohol-induced pain Hodgkin lymphoma Opsomyoclonus Neuroblastoma
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in the case of a residual mass, there is little, if any, role for surgical interventions.9
Nonseminomatous Germ Cell Tumor NSGCTs can include embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, or a mixed histology. Primary mediastinal NSGCT appears to be biologically distinct from testicular NSGCT and is associated with a poor prognosis.13 Primary mediastinal NSGCTs grow rapidly and metastatic disease is found in 80% of patients.14 Overall survival after multimodality treatment is 40% to 50%. Hematologic malignancies present with NSGCT in 6% of cases, most commonly in patients with acute megakaryoblastic leukemia, and myelodysplastic syndrome is the most common.15 The serum AFP level is elevated in 80% of patients and the beta-hCG level is elevated in 30% to 35%. Substantial elevation of tumor marker levels can preclude biopsy.12 However, if biopsy is performed, fine-needle aspiration can be ambiguous and is discouraged in favor of core-needle biopsy or anterior mediastinotomy.16 The standard treatment for NSGCT is four courses of bleomycin, etoposide, and cisplatin; ifosfamide has been recommended over bleomycin to avoid pulmonary complications prior to surgical resection.12 Residual mass after chemotherapy should be surgically resected, regardless of the serum marker levels; the prognosis is poor for patients with unresectable residual masses. When active germ cell cancer is present in the surgical specimen, two additional courses of chemotherapy should be given. Patients who have no residual tumor should be followed closely with history and physical examination, determination of serum markers, and CT. Patients who have disease recurrence have a particularly poor prognosis, although a small number of patients may benefit from salvage chemotherapy.13 A 20% survival rate following surgical resection for relapsed primary mediastinal NSGCT has also been reported.17
LYMPHOMA Lymphomas represent a variety of hematologic neoplasms. Proper management of lymphoma depends on subtyping and staging. Approximately 15% of mediastinal masses are lymphomas, typically in the anterior or middle compartment (Fig. 54.2). About 90% of mediastinal lymphomas represent disseminated disease, and one-third are Hodgkin lymphomas. Most patients present with some combination of systemic B symptoms, and symptoms associated with local compression.18 Positron emission tomography is frequently used to stage and monitor the progress of lymphoma.19
Hodgkin Lymphoma Mediastinal involvement occurs in as many as two-thirds of Hodgkin lymphoma. Diagnosis typically requires tissue quantities only obtainable by surgical biopsy. Typically, video-assisted thoracoscopy (VATS) or anterior mediastinotomy will yield definitive samples; however, mediastinoscopy is not always sufficient.
Fig. 54.1. Anterior mediastinal germ cell tumor with extension into the left hemithorax.
Fig. 54.2. Lymphoma in the anterior mediastinum.
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SECTION X Other Thoracic Malignancies
CD15- and CD30-positive Reed-Sternberg cells, which are diagnostic for Hodgkin lymphoma, can be difficult to identify in a small biopsy.18 Disease is staged according to the Ann Arbor Staging System;20 early-stage Hodgkin lymphoma is treated with chemoradiation therapy and late-stage disease is treated with chemotherapy only.21
Non-Hodgkin Lymphoma Large B-cell lymphoma and lymphoblastic lymphoma are the most common forms of non-Hodgkin lymphoma of the mediastinum. As in Hodgkin lymphoma, a sizable biopsy sample is often required for diagnosis. However, lymphoblastic lymphoma is usually first identified in bone marrow and peripheral blood; thus a mediastinal biopsy is not necessary. Lymphoblastic lymphoma is particularly aggressive, and treatment with chemotherapy and possible bone marrow transplant should not be delayed by staging procedures. Large B-cell lymphoma is treated with chemotherapy, and some centers also use radiotherapy for the treatment of B-cell lymphoma and lymphoblastic lymphoma.18
NEUROGENIC TUMORS Approximately three-quarters of posterior mediastinal tumors are neurogenic (Fig. 54.3). These neurogenic tumors arise from the sympathetic chain or intercostal rami, and they most commonly take the forms of nerve sheath tumors (schwannoma and neurofibroma). Nearly all neurogenic tumors are benign, and approximately 30% of neurofibromas are associated with von Recklinghausen disease. Neurogenic tumors may erode osseous structures; this contributes to the development of an intraspinal (dumbbell) extension. MRI is essential if intraspinal involvement is suspected, as failure to recognize involvement can result in devastating spinal cord injury during attempted excision; resection of intraspinal tumor requires neurosurgical expertise. Simple nerve sheath tumors, whether benign or malignant, should be surgically resected, and a VATS approach is usually sufficient. Relative contraindications for complete resection include a mass greater than 6 cm and spinal artery involvement. Chemotherapy and radiotherapy may be used when complete resection is not possible.4
BENIGN CYSTIC MASSES Bronchogenic Cysts Bronchogenic cysts arise from errors in embryonic budding of the tracheobronchial tree (Fig. 54.4); they are the most
Fig. 54.3. Paravertebral mass typical of neurogenic tumors.
common mediastinal cysts and are frequently found behind the carina. The majority of bronchogenic cysts are discovered before the onset of symptoms, but most do eventually cause symptoms. Bronchogenic cysts can cause local compression and erosion and may become infected.22 Resection of asymptomatic cysts can be controversial, but because of their potential to cause later complications and the favorable outcomes from early surgical intervention, VATS or mediastinoscopic resection is recommended.22–24
Esophageal Cysts Esophageal cysts, also called esophageal duplications, arise in a similar manner as bronchogenic cysts. Like bronchogenic cysts, esophageal cysts can also cause local compression and may become infected. There is also risk of hemorrhage and rupture into the esophagus or airways. VATS excision is recommended, with care taken to minimize disruption of the esophageal muscularis.22
Pericardial Cysts Pericardial cysts are mesothelium-derived and in close proximity to the pericardium. Pericardial cysts are typically benign and require no intervention. However, a growing pericardial cyst can cause hemodynamic compromise, and excision should be performed for symptomatic patients.25 VATS is recommended, if feasible.
SUBSTERNAL GOITER Goiters are enlargements of the thyroid and are deemed substernal when more than half of the gland extends inferior to the sternal notch (Fig. 54.5). Substernal goiters are the most common superior mediastinal tumors, usually found in the anterior mediastinum; however, 10% to 15% of substernal goiters are found in the posterior compartment.26 The most common symptoms of substernal goiters are caused by local compression and include dyspnea, cough, and hoarseness. Approximately 25% of patients will be asymptomatic. A palpable thyroid is present in 88% of patients, and 16% of patients have hyperthyroidism.27 Serum levels of thyroid-stimulating hormone, free T4, and total T3 can be useful in the diagnosis and detection of subclinical hyperthyroidism.28 Spirometry can assess the extent of airway compression and may identify abnormalities in asymptomatic patients. CT is used to determine the extent and position of the goiter. Although malignancy is possible, needle biopsy is not indicated, as the malignant focus may be missed and its presence does not alter the operative indication.29 Presence of substernal goiter is itself an indication for resection. Further enlargement worsens compression-associated symptoms and can complicate surgical
Fig. 54.4. Bronchogenic cyst in the visceral mediastinum.
CHAPTER 54 Mediastinal Tumors
treatment that would otherwise be associated with low postoperative morbidity.27 Total thyroidectomy is recommended and can usually be accomplished by a collar incision. When the extent of thoracic involvement does not permit resection by a collar incision, possible approaches include manubrial split, sternotomy, and thoracotomy. Postoperative complications are infrequent and include hypoparathyroidism and recurrent laryngeal nerves paralysis.29
PARATHYROID ADENOMA Primary hyperparathyroidism is most commonly a result of adenoma of the parathyroid glands (Fig. 54.6). Approximately 22% of parathyroid adenomas are found in a mediastinal parathyroid gland.30 Resection of the tumor is curative in nearly every case.31 The preferred surgical approach is minimally invasive and relies on precise preoperative localization. The mainstay of parathyroid adenoma localization is technetium-99m sestamibi scintigraphy; when combined with three-dimensional single-photon emission CT, the sensitivity and specificity are high.32 Ultrasound is often used to complement other modalities. Localization has no diagnostic role and is used only for preoperative planning in biochemically proven cases. Most mediastinal parathyroid tumors can be resected transcervically, and videomediastinoscopy may be useful in difficult cases. VATS has also been used for the resection of parathyroid adenomas, but precise localization is particularly important with this approach. Intraoperative monitoring of the parathyroid hormone level is used to confirm systemic cure.33
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SURGICAL APPROACH The appropriate surgical approach depends on the nature and position of the lesion within the mediastinum. A minimally invasive approach is often possible for uninvolved benign masses. More aggressive exposure is used for large and/or malignant tumors, for which complete resection is crucial and dissection is potentially challenging. Access to small anterior midline tumors is commonly approached by a median sternotomy, with the patient in the supine position with the arms tucked to the side. In this position, the mediastinal vasculature, left and right hemithoraces, and lung hila are well exposed; however, exposure of the left lower lobe and posterior aspect of the lungs is poor. In some cases, a partial sternum-sparing approach will allow for sufficient exposure, such as a manubrial split for superior mediastinal mass. A collar incision may also provide sufficient access to the superior mediastinum if the mass can be accessed through the neck. For large tumors extending into either of the hemithoraces, a hemiclamshell incision provides good exposure.37 The patient should be placed in the supine position, with a longitudinal roll
LEIOMYOMA Leiomyoma in the mediastinum usually arises from the esophagus or large vessels (Fig. 54.7). Primary mediastinal leiomyoma not associated with adjacent organs is exceedingly rare.34 These lesions are firm and well circumscribed, and symptoms are typically due to local compression. Complete excision is the definitive treatment;35 esophageal leiomyoma is treated using VATS enucleation.36
Fig. 54.6. Parathyroid adenoma in the superior anterior mediastinum.
Fig. 54.5. Substernal goiter in the superior mediastinum.
Fig. 54.7. Leiomyoma of the thoracic esophagus.
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elevating the thoracotomy side by 30 degrees and the arms tucked to the side. The ipsilateral lung may be collapsed to allow for anatomic resection of involved lobes, if necessary, and access to the posterolateral aspect of the tumor. If the tumor has substantial cervical extension, the upper sternotomy may be extended superiorly along the anterior border of the sternocleidomastoid.38 This approach exposes the carotid and jugular vessels if vascular dissection is necessary. Rarely, resection of the subclavian vessels will be needed for a GCT. In these cases, a so-called trap door incision, created by extending the upper sternotomy along the superior margin of the clavicle, will allow for appropriate exposure. Excision of the medial third of the clavicle may also assist in exposure of the tumor. A large tumor that extends into both right and left hemithoraces may be resected through a bilateral clamshell incision, with the patient in the supine position and the arms abducted or flexed over the forehead. A curvilinear incision should be made along the inframammary crease from the right to left anterior axillary lines for access to the fourth intercostal space; the mammary vessels are then ligated, and the sternum is divided transversally. Retraction is provided by two Finochietto retractors. An upper sternal split may be made in the event that an initial clamshell approach provides inadequate exposure of the superior mediastinum.
CONCLUSION The mediastinum is dense with multiple organ systems, and the tumors thereof are equally varied. Appropriate management and surgical approach require careful assessment of each case. Indications for chemotherapy, radiotherapy, and surgical treatment of mediastinal GCTs vary according to the histologic subtypes. Surgical exposure of large mediastinal GCTs is often best approached by hemiclamshell or bilateral clamshell incision. Lymphoma of the mediastinum is usually a disseminated disease. Surgical biopsy provides sufficient tissue for diagnosis, but treatment is nonsurgical and based on the subtype and stage. Posterior masses are typically neurogenic tumors. MRI is essential for assessment of intraspinal involvement. Small uninvolved neurogenic tumors should be treated by VATS. Congenital cystic masses of the bronchial tree and esophagus should be resected
by minimally invasive approach. Resection of pericardial cysts is reserved for symptomatic patients. A substernal goiter is an indication for total thyroidectomy. A collar incision is often sufficient, but more involved goiters can require a sternal split. Parathyroid adenomas causing primary hyperparathyroidism should be resected with a minimally invasive approach. Precise preoperative localization of parathyroid adenoma is crucial to successful resection. Leiomyomas are typically of the esophagus or large vessels and should be excised.
KEY REFERENCES 2. Davis Jr RD, Oldham Jr HN, Sabiston Jr DC. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management, and results. Ann Thorac Surg. 1987;44(3):229–237. 6. Mullen B, Richardson JD. Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg. 1986;42(3):338–345. 12. Albany C, Einhorn LH. Extragonadal germ cell tumors: clinical presentation and management. Curr Opin Oncol. 2013;25(3):261–265. 14. McNamee CJ. Malignant primary anterior mediastinal tumors. In: Sugarbaker DJ, Bueno R, Krasna MJ, Mentzer SJ, Zellos L, eds. Adult Chest Surgery. New York, NY: McGraw-Hill; 2009:1154–1158. 16. Alam N, Flores R. Management of mediastinal tumors not of thymic origin. In: Pass HP, Carbone DP, Johnson DH, et al., eds. Principles and Practice of Lung Cancer. 4th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. 18. Smith S, van Besien K. Diagnosis and treatment of mediastinal lymphomas. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2379–2387. 22. Ferraro P, Martin J, Duranceau ACH. Foregut cysts of the mediastinum. In: Shields TW, Lociciero J, Reed CE, Feins RH, eds. General Thoracic Surgery. 7th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2009:2519–2538. 36. Vallböhmer D, Hölscher AH, Brabender J, Bollschweiler E, Gutschow C. Thoracoscopic enucleation of esophageal leiomyomas: a feasible and safe procedure. Endoscopy. 2007;39(12):1097–1099. 37. Bains MS, Ginsberg RJ, Jones 2nd WG, et al. The clamshell incision: an improved approach to bilateral pulmonary and mediastinal tumor. Ann Thorac Surg. 1994;58(1):30–32. discussion 33.
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