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Tumors of the Mediastinum^*

^* From the Departments of Internal Medicine (Dr. Duwe) and Pulmonary, Allergy, and Critical Care Medicine (Drs. Sterman and Musani), Hospital of the University of Pennsylvania, Philadelphia, PA.

Correspondence to: Ali I. Musani, MD, Assistant Professor, Pulmonary, Allergy and Critical Care Medicine, Associate Director, Interventional Pulmonology Program, Hospital of the University of Pennsylvania, Philadelphia, PA 19104; e-mail: amusani{at}mail.med.upenn.edu

	Abstract

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
Tumors of the mediastinum represent a wide diversity of disease states. The location and composition of a mass is critical to narrowing the differential diagnosis. The most common causes of an anterior mediastinal mass include the following: thymoma; teratoma; thyroid disease; and lymphoma. Masses of the middle mediastinum are typically congenital cysts, including foregut and pericardial cysts, while those that arise in the posterior mediastinum are often neurogenic tumors. The clinical sequelae of mediastinal masses can range from being asymptomatic to producing symptoms of cough, chest pain, and dyspnea. This article will review the anatomy of the mediastinum as well as the different clinical, radiographic, and prognostic features, and therapeutic options of the most commonly encountered masses.

Key Words: bronchogenic • cysts • enterogenous • germ cell tumor • goiter • lymphoma • mediastinum • neuroblastoma • neurogenic tumor • pericardial • teratoma • thyroid • thymoma

	Introduction

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
The mediastinum is demarcated by the pleural cavities laterally, the thoracic inlet superiorly, and the diaphragm inferiorly. It is further compartmentalized into anterior, middle, and posterior divisions based on structural landmarks seen on the lateral radiograph. This has important implications for diagnosing suspected masses¹ (Table 1 ). The anterior mediastinum contains the thymus, fat, and lymph nodes. The middle mediastinum contains the heart, pericardium, ascending and transverse aorta, brachiocephalic veins, trachea, bronchi, and lymph nodes, while the posterior mediastinum consists of the descending thoracic aorta, esophagus, azygous vein, autonomic ganglia and nerves, thoracic lymph nodes, and fat.

The most common symptoms at presentation were as follows: cough (60%); chest pain (30%); fevers/chills (20%); and dyspnea (16%). Most symptoms can be categorized into the following two groups: localizing symptoms (Table 2 ); and systemic symptoms (Table 3 ). Localizing symptoms are secondary to tumor invasion. Common localizing symptoms include respiratory compromise; dysphagia; paralysis of the limbs, diaphragm, and vocal cords; Horner syndrome; and superior vena cava syndrome.⁴ Systemic symptoms are typically due to the release of excess hormones, antibodies, or cytokines. A classic example is hypercalcemia, which is caused by a parathyroid adenoma.

Although nuclear scans and biochemical studies can be used to further characterize a lesion, tissue diagnosis is almost always required. If a mass is likely to be benign after initial workup, it can be removed surgically without biopsy. Otherwise, a diagnostic biopsy specimen can be obtained by transthoracic or transbronchial needle aspiration, mediastinoscopy, anterior mediastinotomy, or video-assisted thoracic surgery, depending on the anatomic location and radiographic appearance of the lesion.

	Tumors of the Anterior Mediastinum

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
Thymoma
Thymomas are the most common neoplasm of the anterior mediastinum with an incidence of 0.15 cases per 100,000.⁶⁷⁸⁹ Although rare in children, thymomas represent 20% of anterior mediastinal neoplasms in adults.¹⁰¹¹

Thymomas as a group have a wide spectrum of histologic diversity and are classified based on cell type predominance as lymphocytic, epithelial, or spindle cell variants. There is a strong association between histologic subtype and invasiveness as well as prognosis.¹²¹³¹⁴ As a result, the World Health Organization¹⁵ devised a new classification system to group thymomas based on cytologic differences, which may be helpful in determining treatment regimens and predicting survival (Table 4 ).

The Masaoka clinical staging system is based on the degree of invasion of the tumor through the capsule into the surrounding structures, which has important implications for prognosis²¹ (Table 5 ). In the study by Okumura et al,¹² the Masaoka staging system was shown to be useful as an independent predictor of survival in patients with thymoma.

Myasthenia gravis is most frequent in women and is associated with thymoma. Symptoms include diploplia, ptosis, dysphagia, weakness, and fatigue. Thirty percent to 50% of patients with thymomas have myasthenia gravis, compared to 10 to 15% of patients with myasthenia gravis who have a thymoma.²⁴²⁵ Pathogenesis is thought to occur via myloid cell lineages derived from the thymus that recognize antigens on the neuromuscular junction producing autoantibodies.²⁶ These autoantibodies bind to acetylcholine receptors of the neuromuscular junction, causing muscle fatigue.²⁶ Thymectomy can alleviate symptoms; however, this benefit is often delayed for months after surgery. Given the association between thymoma and myasthenia gravis, the serum anti-acetylcholine receptor antibody level should be measured in all patients with a suspected thymoma to rule out myasthenia gravis before surgery.²⁷²⁸

Hypogammaglobulinemia and pure RBC aplasia are present in 10% and 5% of patients with a thymoma, respectively.⁷ Good syndrome is diagnosed in patients with a thymoma and combined B-cell/T-cell immunodeficiency.²⁹ Thymoma is also associated with various other autoimmune disorders, such as systemic lupus erythematosus, polymyositis, and myocarditis.³⁷¹⁸³⁰

Thymomas appear on a chest radiograph as a well-defined lobulated mass in the anterosuperior mediastinum, typically anterior to the aortic root.⁷¹⁸ Further evaluation with contrast-enhanced thoracic CT scanning usually reveals an encapsulated, well-defined, soft-tissue mass, often with hemorrhage, necrosis, or cyst formation³¹ (Fig 1 ). They can also appear predominantly cystic with a nodular component.³²

View larger version (97K): [in this window] [in a new window] [Download PPT slide]   Figure 1. A 36-year-old man with an invasive thymoma. A contrast-enhanced CT scan shows a heterogenous high-attenuated solid upper portion (arrow) with a small calcification in the left anterior aspect of the main pulmonary artery.

Surgical resection remains the standard of care for both noninvasive and invasive thymomas as it provides the best prognosis. Adjunctive chemotherapy and radiation treatment is used for locally invasive or metastatic disease, or inoperable tumors. Additionally, although it is commonly accepted that resection alone is sufficient treatment for stage I disease, there is no consensus regarding the role for postoperative radiation therapy in patients with stage II disease.³⁵

According to Curran et al,³⁶ of 117 patients, postoperative radiotherapy showed no survival benefit for those patients with stage I disease but did for patients with stage II and III disease. The 5-year mediastinal relapse rate for patients with stage II or III disease treated with surgery alone was 53%, while patients who received treatment with total resection and radiotherapy experienced no relapses. A smaller retrospective study by Eralp et al³⁷ of 36 patients with stage II or III disease also showed a benefit for postoperative radiation therapy. While these studies had positive results, other institutional reviews³⁵³⁸ have shown no benefit to postoperative radiotherapy. A larger randomized controlled trial would be useful to assess the benefit of postoperative radiation therapy in patients with stage II thymomas.

Thymoma is generally responsive to chemotherapy as well. In locally invasive or bulky disease, preoperative cisplatin-based chemotherapy, with or without postoperative radiotherapy, may offer the best prognosis.³⁹ Kim et al⁴⁰ examined 23 patients with locally advanced, unresectable disease who underwent three courses of induction chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and prednisone. The 7-year disease-free and overall survival rates were 77% and 79%, respectively.⁴⁰

Other chemotherapeutic agents and regimens are less efficacious. Thus, these alternative regimens should only be used in patients who cannot tolerate cisplatin and doxorubicin or as second-line therapy in those who have relapsed.⁴¹

The following features are associated with poor prognosis: metastasis; large tumor size (ie, > 10 cm); tracheal or vascular compression; age < 30 years; epithelial or mixed histology; and the presence of a hematologic paraneoplastic syndrome.⁴² As the above prognostic factors suggest, both histologic subtype and disease stage appear to be important in predicting survival. Currently, stage is used principally to guide treatment; however, controversy regarding the use of chemotherapy and radiation therapy in patients with different stages of thymoma may reflect that histologic subtype ought to play an important role in determining which treatment modalities are most appropriate. The creation of the World Health Organization classification system for thymoma in 1999 has given further insight into the potential importance of histologic subtype on prognosis; however, the Masaoka staging system is still currently used to stratify 5-year survival rates (Table 5).

Thymic Carcinoma
Thymic carcinomas are a heterogeneous group of aggressive, invasive epithelial malignancies.³ Their incidence is rare, occurring predominantly in middle-aged men. Most patients present with cough, shortness of breath, and chest pain.⁴³ Fatigue, weight loss, and anorexia are common, while superior vena cava syndrome and cardiac tamponade have been described.⁴⁴⁴⁵⁴⁶

Histologically, thymic carcinomas are large, firm, infiltrating masses with areas of cystic change and necrosis. They are classified as low grade or high grade, with squamous cell-like and lymphoepithelioma-like variants being the most common cell types.⁴⁷ In contrast to thymomas, thymic carcinomas are cytologically malignant, with typical features of cellular necrosis, atypia, and mitoses.⁴⁴ Radiographically, thymic carcinomas are heterogeneous with necrosis and calcifications (Fig 2 ) and can be associated with pleural and pericardial effusions.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   Figure 2. A 46-year-old man with a thymic carcinoma. A contrast-enhanced CT scan shows a necrotic mass with an irregularly shaped enhancing wall in the right anterior mediastinum.

Yoh et al⁵¹ examined 18 patients with thymic carcinomas. Patients with unresectable disease were treated with cisplatin, vincristine, doxorubicin, and etoposide. The overall response rate was 42% with 1-year and 2-year survival rates of 80% and 56%, respectively.⁵¹ Superior to previous chemotherapeutic regimens, the regimen of cisplatin, vincristine, doxorubicin, and etoposide warrants additional study by a randomized controlled trial for its use in the treatment of thymic carcinoma.

Thymic Carcinoid
Thymic carcinoid is a malignant tumor, which is histologically similar to carcinoid tumors found at other sites. Its highest incidence is in the fourth and fifth decades of life.⁴⁴ Thymic carcinoid is associated with Cushing syndrome and multiple endocrine neoplasia syndrome.⁷ According to a prospective study of patients with endocrine neoplasia syndrome type 1 by Gibil et al,⁵² thymic carcinoid developed in 8% of patients.

Thymic carcinoid presents as a large, lobulated, invasive mass of the anterior mediastinum with or without hemorrhage and necrosis.⁵³ Metastasis is common, with spread to regional lymph nodes as well as distant metastasis developing in two thirds of patients.⁵³ The treatment is complete surgical resection. For a locally invasive tumor, radiotherapy and chemotherapy are used despite minimal effect.⁵³⁵⁴ The prognosis of these tumors is poor but difficult to assess. In a retrospective study by Tiffet et al,⁵⁵ there was no association between prognosis and histologic features.

Thymolipoma and Nonneoplastic Thymic Cysts
Thymolipoma is a rare, benign, slowly growing tumor of the thymus gland that occurs in young adults of both sexes.² CT scans and MRI studies show a characteristic fat density. The treatment of choice is surgical excision.

Thymic cysts are rare tumors of unclear etiology. They can be congenital or acquired, and are associated with inflammation or with an inflammatory neoplasm, such as Hodgkin disease (HD).⁵⁶ Congenital thymic cysts are remnants of the thymopharyngeal duct.⁵⁷ Inflammatory cysts probably arise from an inflamed thymic parenchyma. Radiographically, they appear as simple homogenous cysts (Fig 3 ). Microscopically, thymic cysts may be identical to cystic thymic neoplasms. Thus, thorough sampling and examination are essential.⁵⁸ Surgical excision is curative.

View larger version (102K): [in this window] [in a new window] [Download PPT slide]   Figure 3. A 30-year-old woman with a unilocular thymic cyst. A contrast-enhanced CT scan shows a homogeneous cystic mass with a partially enhanced wall (arrows).

	Mediastinal GCTs

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

GCTs are classified into the following three groups based on cell type: benign teratomas; seminomas; and embryonal tumors. The embryonal tumors, also called malignant teratomas or nonseminomatous GCTS, are diverse and include choriocarcinomas, yolk sac carcinomas, embryonal carcinomas, and teratocarcinomas.⁶² These tumors often produce serologic markers such as -fetal protein (AFP) and human chorionic gonadotropin (hCG), which can be useful in the diagnostic evaluation.²

Mediastinal Teratomas (Benign)
Consisting of tissue from at least two of the three primitive germ layers, benign teratomas are the most common mediastinal GCT.⁶³ Ectodermal tissues, which usually predominate, include skin, hair, sweat glands, and tooth-like structures. Mesodermal tissues, such as fat, cartilage, bone, and smooth muscle are less common, as are endodermal structures like respiratory and intestinal epithelium.⁶⁴ The majority of mediastinal teratomas are mature teratomas that are histologically well-defined and benign.⁶³ If a teratoma contains fetal tissue or neuroendocrine tissue, it is defined as immature and malignant. In children, the prognosis is favorable, but it can often recur or metastasize.⁶⁵

Most patients are completely asymptomatic. Like other mediastinal masses, presenting symptoms include cough, dyspnea, and chest pain. Digestive enzymes secreted by intestinal mucosa or pancreatic tissue found in the teratoma can lead to the rupture of the bronchi, pleura, pericardium, or lung.² A rare result of a ruptured mediastinal teratoma is the expectoration of hair or sebum.⁶⁶⁶⁷ Mature teratomas do have the potential in rare circumstances to undergo malignant transformation into a variety of malignancies. Reports⁶⁸ of rhabdomyosarcoma, adenocarcinoma, leukemia, and anaplastic small cell tumors have all been identified as arising from mature or immature teratomas.

Benign teratomas are well-defined, round, or lobulated masses when seen on a chest radiograph. Up to 26% are calcified, as they often have elements of bone or teeth.⁶⁹ CT scanning and MRI are used to assess resectability (Fig 4 ), and may identify sebaceous elements and fat, supporting the diagnosis.⁷⁰⁷¹ Complete surgical resection is the treatment of choice; however, subtotal resection can relieve symptoms. Adjunctive chemotherapy may be useful after subtotal resection.⁷²

View larger version (87K): [in this window] [in a new window] [Download PPT slide]   Figure 4. A 16-year-old male patient with a mature cystic teratoma. A contrast-enhanced CT scan shows a multilocular cystic mass in the left anterior mediastinum. Histologic examination revealed a mature cystic teratoma with foreign-body reaction and dystrophic calcification.

Radiographically, seminomas are bulky, lobulated, homogenous masses. Local invasion is rare, but metastasis to lymph nodes and bone does occur.² CT and gallium scanning is used to evaluate the extent of disease.⁷⁵

Seminomas are uniquely sensitive to radiation therapy. In a study by Bush et al⁷⁶ of 13 patients with localized disease who were treated with external beam radiation, the 10-year disease-free survival rate was 54%, with an actuarial survival rate of 69%. There is, however, debate as to the role of chemotherapy and surgical resection. A retrospective study by Bokemeyer et al⁷⁷ showed that chemotherapy alone led to a 90% 5-year disease-free survival rate and that additional radiation offered only a slight survival advantage, while patients treated with just radiation initially had a much higher rate of disease recurrence. In patients with locally advanced disease, the preferred treatment includes chemotherapy followed by the surgical resection of residual disease.⁷⁸

Mediastinal Nonseminomatous GCTs
Nonseminomatous malignant GCTs comprise a heterogeneous group of masses that includes embryonal cell carcinomas, endodermal thymus tumors, choriocarcinomas, yolk sac tumors, and mixed GCTs with multiple cellular components. These tumors are often symptomatic and malignant, and predominantly affect young men.² In addition, they can be associated with hematologic malignancies, and 20% of patients have Kleinfelter syndrome.⁷⁹⁸⁰

At diagnosis, 85% of patients are symptomatic, which includes complaints of chest pain, hemoptysis, cough, fever, or weight loss. Gynecomastia can develop as a result of ß-hCG secretion from certain tumor types.⁶²⁸¹

These tumors are large, irregularly shaped, with areas of central necrosis, hemorrhage, or cyst formation⁸² (Fig 5 ). Measuring AFP and ß-hCG levels is important in making the diagnosis. An elevated AFP level is suggestive of an endodermal sinus tumor or embryonal carcinoma and is sufficient, in the presence of a mediastinal mass, to establish the diagnosis.⁶²⁸¹

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Figure 5. A 59-year-old man with a nonseminatous malignant GCT. A contrast-enhanced CT scan shows a heterogeneous low-attenuating anterior mediastinal mass compressing the pulmonary artery.

Mediastinal Goiter
In patients undergoing thyroidectomy, the incidence of mediastinal goiter is 1 to 15%.⁸⁶ Most goiters are euthyroid and are found incidentally during a physical examination. Radiographically, mediastinal goiters are encapsulated, lobulated, heterogeneous tumors.² A classic finding on a CT scan is continuity of the cervical and mediastinal components of the thyroid. If the goiter contains functional thyroid tissue, then scintigraphy with a radioactive isotope of iodine can be diagnostic.²

Surgical resection is recommended since these lesions are not usually amenable to needle biopsy, and malignancy develops in a significant number. Nearly all substernal goiters can be removed easily through a cervical incision minimizing surgical morbidity.⁸⁷

Mediastinal Parathyroid Adenoma
The mediastinum is the most common location at which an ectopic parathyroid tumor may develop. Overall, 20% of parathyroid adenomas develop in the mediastinum, with 80% occurring in the anterior mediastinum.⁸⁸

These tumors are encapsulated, round, and usually < 3 cm in size, so that they may not be identified on a CT scan. Thus, MRI or nuclear scans with ^99mTc and ²⁰¹TI are more effective for the diagnosis of parathyroid adenomas.⁸⁹ Surgical resection is curative.

	Primary Mediastinal Lymphoma

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
Primary mediastinal lymphoma is a rare entity comprising only 10% of lymphomas in the mediastinum. Lymphoma usually occurs in the anterior mediastinum and is part of more widespread disease. HD represents approximately 50 to 70% of mediastinal lymphomas, while non-Hodgkin lymphoma comprises 15 to 25%.⁹⁰⁹¹ The three most common types of mediastinal lymphoma include nodular sclerosing HD, large B-cell lymphoma, and lymphoblastic lymphoma.²

HD
HD has an incidence of approximately 2 to 4 cases per 100,000 people per year, with a bimodal distribution of incidence peaking in young adulthood and again after age 50 years.⁹² For mediastinal-predominant disease, prevalence peaks in young women during the third decade of life, while it is unaffected by age in men.⁹³ HD is divided into four subtypes, including nodular sclerosing, lymphocyte-rich, mixed cellularity, and lymphocyte depleted HD, with the nodular sclerosing subtype representing more than two thirds of cases.⁹⁴

Most patients experience constitutional symptoms (B symptoms), including fevers, night sweats, and weight loss. For patients with mediastinal involvement, cough, dyspnea, chest pain, pleural effusions, and superior vena cava syndrome may occur.⁹³

The presence of Reed-Sternberg cells are pathognomonic of HD. These cells contain bilobed nuclei containing prominent eosinophilic nuclei. The classic immunohistochemical profile is biomarker positivity for CD15 and CD30 cells.⁹⁵

The chest radiograph finding is abnormal in up to 76% of patients with HD, often showing enlargement of the prevascular and paratracheal nodes.⁹⁶⁹⁷⁹⁸ A CT scan examination is usually sufficient to identify lymphoma; however, in certain circumstances, such as after radiation treatment, MRI may be better in distinguishing scars from residual disease⁹⁶ (Fig 6 ). A positron emission tomography scan may also be useful in staging and following disease progression.⁹⁹

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   Figure 6. A 39-year-old man with nodular sclerosis HD. A contrast-enhanced CT scan shows an anterior mediastinal mass in which the central portion is cystic (black arrow). The right paratracheal lymph node is enlarged (white arrow).

Patients who relapse may benefit from a bone marrow transplant (BMT), while those who have had a good response to standard-dose second-line chemotherapy benefit the most.¹⁰³ For patients with HD, autologous BMT is superior to allogeneic BMT since the relapse rate for both is similar, and the nonrelapse mortality rate is 48% for patients who have undergone allogeneic BMT and 27% for those who have undergone autologous BMT.¹⁰⁴

Patients with stage I and II HD have cure rates of > 90%. Patients with stage IIIA HD have a cure rate of 30 to 90% with standard treatment. Stage IIIB HD offers a cure rate of 60 to 70%, while stage IV HD has a cure rate of 50 to 60% (2,101). Among patients with advanced disease, a prognostic index was created by the International Prognostic Factor Project on Advanced Hodgkin’s Disease that was based on the total number of unfavorable features from among seven potential features found at diagnosis, as follows: serum albumin level, < 4 g/dL (or 40 g/L); hemoglobin level, < 10.5 g/dL (105 g/L); male gender; age > 45 years; stage IV disease; WBC count, 15,000 cells/µL; and lymphocyte count, < 600/µL and/or < 8% of the WBC count.¹⁰⁵

Non-Hodgkin Lymphoma
Although there are many classes and grades of non-Hodgkin lymphoma, lymphoblastic lymphoma and large B-cell lymphoma are the most common subtypes to affect the mediastinum.¹⁰⁶ The overall incidence of non-Hodgkin lymphoma is greatest in white men with a mean age of 55 years.¹⁰⁶ However, the mean ages of presentation for lymphoblastic lymphoma and primary large B-cell lymphoma are 28 and 30 to 35 years, respectively.¹⁰⁶¹⁰⁷

Lymphoblastic lymphoma is highly aggressive, arising from thymic lymphocytes.¹⁰⁸ Common symptoms include cough, wheezing, shortness of breath, superior vena cava syndrome, cardiac tamponade, or tracheal obstruction, and can involve the mediastinum, bone marrow, CNS, skin, or gonads.¹⁰⁸ It is often confused with T-cell acute lymphoblastic leukemia (ALL) because bone marrow involvement with blasts is relatively common.¹⁰⁹¹¹⁰

Primary mediastinal B-cell lymphoma is a diffuse large B-cell lymphoma derived from the thymus. Common symptoms at presentation include chest pain, cough, dysphasia, superior vena cava syndrome, phrenic nerve palsy, and hoarseness.¹⁰⁷ The involvement of extrathoracic structures and bone marrow is less common at presentation than for lymphoblastic lymphoma. However, on the recurrence of disease, involvement of the liver, kidneys, and brain can occur.¹¹¹¹¹²

Computer tomography scanning is used to characterize the lesion and to determine the extent of invasion. The middle and posterior mediastinal nodes are involved more often than the anterior ones.² Tissue diagnosis should be obtained before treatment. Flow cytometry and cytogenetic analysis can be used to help render a definitive diagnosis.¹¹³

Treatment for mediastinal non-Hodgkin lymphoma depends on the stage, histologic subtype, and extent of the disease. For lymphomblastic lymphoma, the treatment regimens are often similar to ALL due to its propensity to involve the marrow. Treatment with intensive chemotherapy programs with maintenance-phase chemotherapy is superior to short-term chemotherapy without a maintenance phase. In a study by Kobayashi et al,¹¹⁴ patients with ALL and those with lymphoblastic lymphoma who received short-term chemotherapy had a cure rate of 78% but a relapse rate of 72% with only a 7% 7-year survival rate. Intrathecal chemotherapy is also necessary to prevent CNS relapse. CNS irradiation is often part of prophylactic treatment to prevent CNS recurrence, while mediastinal irradiation has been used as well. Many patients go on to relapse even after treatment. As a result, BMT is a commonly employed treatment for patients with lymphoblastic lymphoma. Levine et al¹¹⁵ demonstrated in a retrospective analysis of 204 patients with lymphoblastic lymphoma who had been treated with either allogeneic or autologous BMT that although there were fewer relapses at 5 years with allogeneic BMT (relapse rate, 46% vs 56%, respectively), the incidence of treatment-related mortality in patients who underwent allogeneic BMT made the overall survival benefit insignificant.

Patients with primary mediastinal B-cell lymphoma can be treated with conventional chemotherapy; however, there may be an additional benefit to treatment with high-dose chemotherapy and involved-field radiation.¹⁰⁷¹¹⁶ Currently, if patients fail to have a full response to standard chemotherapy, high-dose chemotherapy and/or radiation therapy are considered. After relapse, many patients are treated with high-dose chemotherapy and autologous BMT.¹⁰⁷

	Tumors of the Middle Mediastinum

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
Mediastinal Cysts
Mediastinal cysts comprise 12 to 20% of mediastinal masses and are found in the middle compartment of the mediastinum.^117118119 Despite a similar incidence, children are more often symptomatic at presentation due to compression on the surrounding structures.¹²⁰ The most common type of mediastinal cyst are foregut cysts, which are derived as an embryonic abnormality, with enterogenous cysts (50 to 70%) and bronchogenic cysts (7 to 15%) being the most common subtypes.²

Bronchogenic Cysts
Bronchogenic cysts are formed during embryonic development as an anomalous budding of the laryngotracheal groove.¹²¹ These cysts are lined with ciliated, pseudostratified, columnar epithelium, and contain bronchial glands and cartilaginous plates.² Approximately 40% of bronchogenic cysts are symptomatic resulting in cough, dyspnea, or chest pain.¹²¹

Radiographically, bronchogenic cysts can be identified on plain radiographs (Fig 7 a) but are best defined by CT scanning. These cysts are well-defined round masses with a homogenous density similar to water; however, some bronchogenic cysts are mucoid and can give the impression of being a solid mass.¹²⁰ Bronchogenic cysts are nonenhancing, and, when there is a direct communication with the tracheobronchial tree, air-fluid levels may be seen.¹²² MRI can differentiate the lesion from other masses (Fig 7, bottom, B, 8 ).

View larger version (67K): [in this window] [in a new window] [Download PPT slide]   Figure 7. Top, A: a 49-year-old man with a bronchogenic cyst. A chest radiograph shows a rounded mass (arrow) that displaces the right primary bronchus superiorly. Bottom, B: a 49-year-old man with a bronchogenic cyst. A sagittal T1-weighted magnetic resonance image shows a high-signal intensity cyst with a fluid-fluid level due to infection (arrow).

View larger version (93K): [in this window] [in a new window] [Download PPT slide]   Figure 8. A 37-year-old woman with a bronchogenic cyst. A coronal T1-weighted magnetic resonance image shows a cyst with high-signal intensity contents (arrow).

Enterogenous Cysts
Enterogenous cysts arise from the dorsal foregut and are lined by squamous or enteric (alimentary) epithelium and may contain gastric or pancreatic tissue. Esophageal duplication cysts are located in or are attached to the esophageal wall. Twelve percent of patients with esophageal duplication cysts have associated malformations, mostly of the GI tract.¹²⁴

Symptoms of enterogenous cysts are similar to those of other mediastinal cysts. They are often asymptomatic, but if they contain gastric or pancreatic mucosa, there is the added risk of hemorrhage or rupture of the cyst from mucosal secretions. Radiographically, it can be difficult to distinguish these from bronchogenic cysts, although they are more often calcified (Fig 9 ). The presence of cartilage suggests the presence of a bronchogenic cyst.¹²¹ Most cysts should be surgically excised, and video-assisted thoracic surgery is the treatment of choice.¹²⁵

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figure 9. A 10-year-old female patient with a duplication cyst. A contrasted-enhanced CT scan shows a thin-walled water-attenuation cyst adjacent to the esophagus (arrow).

Pericardial Cysts
Pericardial cysts are part of a larger group of mesothelial cysts. They form as a result of a persistent parietal recess during embryogenesis.¹²¹ They are estimated to occur in 1 of 100,000 people. Although most are congenital, a few cases of acquired pericardial cysts do exist. They are often asymptomatic and are identified in the fourth to fifth decade of life. Rarely, cardiac compression may occur, causing hemodynamic compromise.⁹⁵ Radiographically, pericardial cysts are well-marginated spherical or tear drop-shaped masses that characteristically abut the heart, anterior chest wall, and diaphragm.² The most common location of pericardial cysts is at the right cardiophrenic angle (70%), followed by the left cardiophrenic angle (22%).¹²⁸ On CT scans, these masses appear as unilocular and nonenhancing (Fig 10, 11 ). As with most mediastinal cysts, surgical removal is the treatment of choice, although clinically asymptomatic patients may be observed without intervention.

View larger version (96K): [in this window] [in a new window] [Download PPT slide]   Figure 10. A 37-year-old man with a pericardial cyst. A contrast-enhanced CT scan shows a thin-walled water-attenuation cyst (arrow).

View larger version (111K): [in this window] [in a new window] [Download PPT slide]   Figure 11. A 54-year-old woman with a pericardial cyst. A contrast-enhanced CT scan shows a large thin-walled cystic mass at the level of the aortic arch (black arrow). The innominate vein is compressed by this mass (white arrow).

	Tumors of the Posterior Mediastinum

TOP Abstract Introduction Tumors of the Anterior... Mediastinal GCTs Primary Mediastinal Lymphoma Tumors of the Middle... Tumors of the Posterior... Malignant Tumors of Nerve... References

 
Neurogenic Tumors
Neurogenic tumors are derived from tissue of the neural crest, including cells of the peripheral, autonomic, and paraganglionic nervous systems. Ninety-five percent of posterior mediastinal masses arise in the intercostal nerve rami or the sympathetic chain region.¹³³ They are classified on the basis of cell type and comprise approximately 12 to 21% of all mediastinal masses, although 95% occur in the posterior compartment.¹³⁴ Seventy percent to 80% of neurogenic tumors are benign, and nearly half are asymptomatic; however, they can occasionally cause compressive or neurologic symptoms.^133135136

Nerve Sheath Tumors
These benign, slowly growing tumors comprise 40 to 65% of neurogenic mediastinal masses. Neurilemomas or schwannomas constitute 75% of this group of masses. These tumors are firm, encapsulated masses consisting of Schwann cells. Neurofibromas are nonencapsulated, soft, and friable, and are associated with Von Recklinghausen neurofibromatosis.¹³⁷¹³⁸ They are often asymptomatic and are discovered incidentally.

Radiographically, nerve sheath tumors are sharply marginated spherical masses. Being adjacent to the spine, they can cause erosion and deformity of the ribs and ventral bodies as they increase in size. Low attenuation on CT scans can indicate hypocellularity, cystic changes, hemorrhage, or the presence of lipid within myelin.² Ten percent of these tumors grow through the intervertebral foramina and create a dumbbell appearance on radiographs.¹³⁹ MRI is used to rule out intraspinal extension.

The surgery of choice for removal of these tumors is thoroscopy, or thorocotomy when the former is not an option.¹³³¹³⁴ For tumors invading the vertebral body or foramina, en bloc resection can be achieved.¹⁴⁰ There may be a role for postoperative chemotherapy or radiation therapy when total resection is not possible. Postoperative complications include Horner syndrome, partial sympathectomy, recurrent laryngeal nerve damage, and paraplegia.¹³⁴

	Malignant Tumors of Nerve Sheath Origin

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Malignant nerve sheath tumors are spindle cell sarcomas of the posterior mediastinum, and include malignant neurofibromas, malignant schwannomas, and neurogenic fibrosarcomas. They affect men and women equally in the third to fifth decade of life and are closely associated with neurofibromatosis, with a 5% risk of sarcomatous degeneration.¹⁴¹ Pain and nerve deficits are common. Complete surgical resection is the optimal treatment, but, in patients with unresectable tumors, adjuvant chemotherapy and radiation are options.

Autonomic Ganglionic Tumors
Tumors of the autonomic nervous system arise from neuronal cells rather than from the nerve sheath. They form a continuum ranging from benign encapsulated ganglioneuroma to aggressive malignant nonencapsulated neuroblastoma. Derived from embryologic origins, these tumors arise in the adrenal glands or in the sympathetic ganglia. However, ganglioneuromas and ganglioneuroblastomas arise mostly in the sympathetic ganglia of the posterior mediastinum.¹⁴² Fifty percent of neuroblastomas arise in the adrenal glands and up to 30% in the mediastinum.¹⁴²¹⁴³

Ganglioneuroma:
Ganglioneuromas are benign tumors composed of one or more mature ganglionic cells. Arising from the nerve ganglion cells, they are the most benign and differentiated of the autonomic ganglionic tumors.¹⁴⁴ Most patients are asymptomatic and receive diagnoses in the second or third decade of life.¹⁴⁵ Radiographically, the tumors are oblong and well-marginated, occurring along the anterolateral aspect of the spine and spanning three to five vertebrae¹⁴⁵ (Fig 12 ). CT scanning is not particularly helpful as the mass can be homogenous or heterogeneous. Complete surgical resection is ideal.¹⁴⁶

View larger version (79K): [in this window] [in a new window] [Download PPT slide]   Figure 12. A 20-year-old woman with a posterior mediastinal ganglioneuroma. Top, A: a contrast-enhanced CT scan image that shows a mass with mixed attenuation and calcifications. Bottom, B: acoronal T2-weighted magnetic resonance image that shows an 8-cm mass with heterogeneous signal intensity.

Neuroblastoma:
Neuroblastoma is a disease of young children, with 95% occurring in patients < 5 years of age.¹⁴³¹⁴⁸ Neuroblastomas are highly aggressive and readily metastasizing tumors that are composed of small round cells arranged in sheets or pseudorosettes.¹⁴⁹ They are nonencapsulated lesions, often exhibiting hemorrhage, necrosis, or cystic degeneration. Symptoms include pain, neurologic deficits, Horner syndrome, respiratory distress, and ataxia.¹⁴⁸¹⁴⁹ Neuroblastomas have the highest propensity of any tumors in its class to produce vasoactive substances that can cause hypertension, flushing, and diarrhea.¹⁴²

Grossly, these tumors appear as an elongated paraspinous mass, sometimes impinging on adjacent structures and causing skeletal damage.¹⁵⁰¹⁵¹ On CT scans, 80% of these tumors have calcification.¹⁵¹ As with all neurogenic tumors, MRI is useful to determine the extent of intraspinal involvement.¹⁴⁶ Radionuclide imaging with ¹²³I metaiodobenzylguanide can also be used to detect primary and metastatic disease.¹⁵²

Treatment for neuroblastoma depends primarily on the stage of disease (Table 7 ). Treatment for limited-stage disease is surgical resection. For patients with stage I disease, resection is usually curative. For patients with partially resectable stage II and III disease, treatment includes postoperative chemotherapy and radiation. For patients with stage IV disease, there is much controversy over the role of surgery; however, some studies¹⁵³ have suggested that delayed surgery after initial treatment with chemotherapy and radiation results in a better outcome than initial surgical intervention. In addition, there are ongoing studies looking at the role of radioactive ¹³¹I metaiodobenzylguanide therapy in combination with chemotherapy in patients with advanced-stage disease.¹⁵⁴ Poor prognostic factors in neuroblastoma include large tumor size, poorly differentiated cell type, advanced stage, extrathoracic origin, and presentation in an elderly patient.¹³⁸

	Acknowledgements

 
We thank the following people for their contributions: Jin Mo Goo, MD, Department of Radiology, Seoul National University College of Medicine, for the contribution of Figures 123456and 11, which were originally published in the Journal of Computed Assisted Tomography in 2003; Mi-Young Jeung, MD, Department of Radiology, University of Strasbourg, for the contribution of Figures 678910, which were originally published in Radiographics in 2002; Allen Forsythe, MD, for the contribution of Figure 12, which was published in Radiographics in 2004. It was only through their contributions that we were able to produce this study.

	Footnotes

 
Abbreviations: AFP = -fetal protein; ALL = acute lymphoblastic leukemia; BMT = bone marrow transplant; GCT = germ cell tumor; hCG = human chorionic gonadotropin; HD = Hodgkin disease

Received for publication December 6, 2004. Accepted for publication April 1, 2005.

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