Tumors of the Mediastinum*

By Duwe, Beau V; Sterman, Daniel H; Musani, Ali I

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. (CHEST 2005; 128:2893-2909)

Keywords: bronchogenic; cysts; enterogenous; germ cell tumor; goiter; lymphoma; mediastinum; neuroblastoma; neurogenic tumor; pericardial; teratoma; thyroid; thymoma

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

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 likelihood of malignancy is influenced primarily by the following three factors: mass location; patient age; and the presence or absence of symptoms. Although more than two thirds of mediastinal tumors are benign, masses in the anterior compartment are more likely to be malignant.2 In the study by Davis et al3 of 400 patients with mediastinal masses, malignancy was seen in 59%, 29%, and 16%, respectively, of anterior, middle, and posterior mediastinal masses. Age is an important predictor of malignancy as well with many of the lymphomas and germ cell rumors (GCTs) presenting between the second and fourth decade of life. Last, symptomatic patients are more likely to have a malignancy. In Davis et al,3 85% of patients with a malignancy were symptomatic at presentation, compared to 46% of patients with benign neoplasms.

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; Homer 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.

The initial workup of a suspected mediastinal mass involves obtaining posteroanterior and lateral chest radiographs. This can provide information pertaining to the size, anatomic location, density, and composition of the mass (Table 1). CT scanning is used to further characterize mediastinal masses and their relationship to surrounding structures as well as to identify cystic, vascular, and soft-tissue structures.4 In rare circumstances, fluoroscopy, barium swallow, angiograph, CT angiography, and three-dimensional reconstruction may provide additional information. The role of MRI is primarily in ruling out or evaluating a neurogenic tumor.5 MRI is also valuable to evaluate the extent of vascular invasion or cardiac involvement.

Table 1-Differential Diagnosis of a Mediastinal Mass by Anatomic Location*

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

Thymoma

Thymomas are the most common neoplasm of the anterior mediastinum with an incidence of 0.15 cases per 100,000.6-9 Although rare in children, thymomas represent 20% of anterior mediastinal neoplasms in adults.10,11

Table 2-Localizing Symptoms secondary to Tumor Invasion of Surrounding Structures*

Table 4-World Health Organization Classification of Thymomas*

Table 3-Systemic Syndromes secondary to Primary Mediastinal Tumors and Cysts*

Thymomas as a group have a wide spectrum of histologie 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.12- 14 As a result, the World Health Organization15 devised a new classification system to group thymomas based on cytologie differences, which may be helpful in determining treatment regimens and predicting survival (Table 4).

Most thymomas are solid tumors, but up to one third may have components that are necrotic, hemorrhagic, or cystic.7,16 Thirty- four percent of thymomas invade through their own capsules, extending into surrounding structures.8,17-20 Likewise, transdiaphragmatic extension into the abdomen and metastasis into the ipsilateral pleura and pericardium can occur,7,9,18 although lymphogenous and hematogenous spread is rare.16,17

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.

Typically, a thymoma is an incidental finding on a chest radiograph.10,22,23 One third of patients manifest symptoms of chest pain, cough, or dyspnea related to tumor compression or invasion.16 Metastasis is uncommon; however, parathymic syndromes, which include myasthenia gravis, hypogammaglobulinemia, and pure RBC aplasia, may develop.17

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.24,25 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 antiacetylcholine receptor antibody level should be measured in all patients with a suspected thymoma to rule out myasthenia gravis before surgery.27,28

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.3,7,18,30

Thymomas appear on a chest radiograph as a well-defined lobulated mass in the anterosuperior mediastinum, typically anterior to the aortic root.7,18 Further evaluation with contrast-enhanced thoracic CT scanning usually reveals an encapsulated, welldefined, soft- tissue mass, often with hemorrhage, necrosis, or cyst formation31 (Fig 1). They can also appear predominantly cystic with a nodular component.32

Table 5-Masaoka Staging System of Thymoma*

Surgical excision can be used for diagnosis; however, the sensitivity of ultrasonography and C]T scanguided fine-needle aspiration is increasing. Anderson and colleagues33 reported a success rate of 95% using ultrasonographically guided fine-needle aspiration. The success of fine-needle aspiration is operator- dependent and contingent on the skill of the immunohistologist. Thus, the results in the study by Anderson et al33 may overstate the true success of preoperative diagnosis. Tissue diagnosis may occur simultaneously with total resection of the mass if a thymoma is strongly suspected on the basis of clinical and radiologic evidence.34

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 c\ommonly 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 reviews35-38 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 its 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

FIGURE 1. A 36-year-old man with an invasive thymoma. A contrast- enhanced CT scan shows a heterogenons high-attenuated solid upper portion (arrow) with a small calcification in the left anterior aspect of the main pulmonary artery.

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

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.44-46

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.

Treatment and prognosis depend on the cancer stage and grade. The Masaoka staging system used for thymomas is not useful as a prognostic tool in thymic carcinoma.48 Morphologic features that portend a poor prognosis include the following: infiltration of the tumor margin; absence of a lobular growth pattern; presence of high- grade atypia and necrosis; and > 10 mitoses per high-power field.21 Complete surgical resection is the treatment of choice and can be curative.49 Chemotherapy and radiation therapy have roles in treating unresectable tumors.36,40,50

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.

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.

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.53,54 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.

MEDIASTINAL GCTs

Mediastinal GCTs are derived from primitive germ cells that fail to migrate completely during early embryonic development.59-61 GCTs are found in young adults and represent 15% of anterior mediastinal masses found in adults.2 Malignant GCTs are more common (> 90%) in men. A mediastinal GCT should prompt a search for a primary gonadal malignancy.

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).

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 α-fetal protein (AFP) and human chorionic gonadotropin (hCG), which can be useful in the diagnostic evaluation.2

Mediastical Teratomas (Benign)

Consisting of tissue from at least two of the three pnmitive 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.66,67 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.70,71 Complete surgical resection is the treatment of choice; however, subtotal resection can relieve symptoms. Adjunctive chemotherapy may be useful after subtotal resection.72

FIGURE 4. A 16-year-old male patient with a mature cystic teratoma. A contrast-enhanced CT scan showsa multilocular cystic mass in the left anterior mediastinum. Histologie examination revealed a mature cystic teratoma with foreign-body reaction and dystrophic calcification.

Mediastinal Seminoma

Primary mediastinal seminomas, although uncommon, comprise 25 to 50% of malignant mediastinal GCTs occurring most frequently in men ages 20 to 40 years. Patients present with dyspnea, substernal pain, weakness, cough, fever, gynecomastia, or weight loss. Because of the tumor location, about 10% of patients present with superior vena cava syndrome.73 However, tumors can grow 20 to 30 cm before symptoms develop.74

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.79,80

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 β-hCG secretion from certain tumor types.62,81

These tumors are large, irregularly shaped, with areas of central necrosis, hemorrhage, or cyst formation82 (Fig 5). Measuring AFP and β-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.62,81

Chemotherapy with bleomycin, etoposide, and cisplatin is the current standard of care for patients with nonseminomatous malignant GCTs.83 Following chemotherapy,

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, tabulated, 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

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.

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

PRIMARY MEDIASTINAL LYMPHOMA

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%.90,91 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.96-98 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

Still widely used is the Ann Arbor staging system for HD. This system has important implications for determining prognosis and types of treatment (Table 6). In 1989, the Ann Arbor staging system was modified at a meeting in Cotswold, England, to separate out patients with bulky disease due to its prognostic significance.

The treatment of HD is separated into the treatment of early- stage disease (ie, stage I and II disease) and late-stage disease (ie, stage III and IV disease). Based on the Cotswold modifications, early-stage disease can be further subclassified into favorable and unfavorable, depending on the degree of tumor burden. For patients with favorable stage I or II disease, extended-field radiation alone used to be the standard of care. Hagenbeek et al100 conducted a randomized controlled trial in which 762 patients with favorable stage I or II HD were randomized to receive either combination therapy with six cycles of epirubicin, bleomycin, vinblastine, and prednisone, and involved field radiation, or to receive subtotal nodal irradiation alone. The complete remission rate was similar among patients in both groups, while the relapse rate was significantly higher in the radiation-alone group.100 Thus, the use of combined involved-field radiation and chemotherapy is quickly becoming the standard of care. For patients with stage I or II HD with bulky tumors, treatment consists of chemotherapy followed by radiation.101 Patients with stage III or IV HD are treated primarily with chemotherapy. Canellos et al102 showed that ABVD was superior to MOPP in preventing relapse.

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).

Table 6-Ann Arbor Staging System With Cotswold Modifications for HD*

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, 45 years; stage IV disease; WBC count, > 15,000 cells/L; and lymphocyte count,

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 medi\astinum.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.106,107

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.109,110

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.111,112

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, histologie 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.107,116 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

Mediastinal Cysts

Mediastinal cysts comprise 12 to 20% of mediastinal masses and are found in the middle compartment of the mediastinum.117-119 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 7a) 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).

Tissue is often required to make a definitive diagnosis of a bronchogenic cyst. This can be accomplished by tracheobronchial, endoscopic, or thoroscopic needle aspiration. Most bronchogenic cysts are removed surgically or are drained by needle aspiration. The treatment of asymptomatic cysts is controversial as surgery is not without risk, yet these cysts can grow to cause symptoms in the future.123

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

FIGURE 7. Top, A: a 49-year-old man with a bronehogenic 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 bronehogenic cyst. A sagittal T1-weighted magnetic resonance image shows a high-signal intensity cyst with a fluid-fluid level due to infection (arrow).

FIGURE 8. A 37-year-old woman with a brochogenic cyst. A coronal T1-weighted magnetic resonance image shows a cyst with high-signal intensity contents (arrow).

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 videoassisted thoracic surgery is the treatment of choice.125

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).

Neuroenteric Cysts

Neuroenteric cysts are characterized by the presence of both enteric and neural tissue in surgical specimens.126 Most of these cysts form in the posterior mediastinum above the level of the main carina. The close association of the foregut and notochord during embryogenesis possibly explains this anatomic location. Neuroenteric cysts are associated with multiple vertebral anomalies, such as scoliosis, spina bifida, hemivertebra, and vertebral fusion. Almost all are discovered by age 1 years due to symptoms from tracheobronchial compression.2 Neurologic symptoms may be caused by intraspinal extension. Complete surgical excision is curative.127

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.

Lymphangiomas

Lymphangiomas are rare congenital abnormalities of the lymphatic vessels. Typically, they are isolated solitary masses, but they can be more widespread or associated with chromosomal abnormalities.129 These lesions are benign in nature and are found in the cervical region 75% of the time. In 10% of cases, the cysts extend into the mediastinum and are associated with chylothorax and hemangiomas.129 Although these tumors are commonly identified in children before the age of 2 years, when the mass is isolated to the mediastinum it is often not identified until it has gotten large enough to cause compressive symptoms.130 Such symptoms include chest pain, cough, mid dyspnea. Radiographically, these lesions appear cystic and can be confused with pericardial cysts, although lymphangiomas are more likely to have a loculated appearance.130 The use of lymphangiographic contrast media combined with CT scanning can also differentiate these lesions.129 Total resection is optimal; however, in cases complicated by chylothorax, there is some evidence suggesting that additional radiotherapy may be of some benefit.131 Lymphangiomatosis seen in young women is typically a more progressive form of disease in which multiple tumors are found and invade multiple organ structures, including the lung, heart, and bone.132

FIGURE 10. A 37-year-old man with a pericardial cyst. A contrastenhanced CT scan shows a thin-walled water-attenuation cyst (arrow).

TUMORS OF THE POSTERIOR MEDIASTINUM

Neurogenic Tumors

Neurogenic tumors \are derived from tissue of the neural crest, including cells of the peripheral, autonomie, 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.133,135,136

Nerve Sheath Tumors

These benign, slowly growing tumors comprise 40 to 05% of neurogenic mediastinal masses. Neurilemomas or schwunnomas 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.137,138 They are often asymptomatic and are discovered incidentally.

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).

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.133,134 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

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.142,143

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

Ganglioneuroblastoma: Ganglioneuroblastomas have histologic features of both ganglioneuromas and neuroblastomas. They are the least common type of neurogenic tumor. Prognosis depends on histologic appearance.2 Both sexes are equally affected in the first decade of life.147 Symptoms may arise due to large tumor size, intraspinal extension, and metastasis. Staging is similar to that for neuroblastoma, as described in the following section.

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

Grossly, these tumors appear as an elongated paraspinous mass, sometimes impinging on adjacent structures and causing skeletal damage.150,151 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

Table 7-Staging of Neuroblastoma and Ganglioneuroblastomas*

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

ACKNOWLEDGMENT: 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 1 to 6 and 11, which were originally published in the Journal of Computed Assisted Tomography in 2003; MiYoung Jeung, MD, Department of Radiology, University of Strasbourg, for the contribution of Figures 6 to 10, 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.

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

REFERENCES

1 Fraser RS, Par JAP, Fraser RG, et al. The normal chest. In: Fraser RS, Pare JAP, Fraser RG, et al, eds. Synopsis of diseases of the chest. 2nd ed. Philadelphia, PA: WB Saunders, 1994; 1-116

2 Strollo DC, Rosado-de-Christenson ML, Jett JR, et al. Primary mediastinal tumors: Part 1. Tumors of the anterior mediastinum. Chest 1997; 112:511

3 Davis RD Jr, Newland Oldham H Jr, Sabiston DC fr. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 1987; 44:229-237

4 Silverman NA, Sabiston DC Jr. Mediastinal masses. Surg Clin North Am 1980; 60:757-777

5 Grillo HC, Ojemann RG, Scunnell JG, et al. Combined approach to “dumbbell’ intrathoracic and intraspinal neurogenic tumors. Ann Thorac Surg 1983; 36:402-407

6 Wychulis AR, Payne WS, Clagett OT, et al. Surgical treatment of mediastinal tumors. J Thorac Cardiovasc Surg 1972; 62:379-391

7 Rosai J, Levine GD. Tumors of the thymus. In: Firminger HI, ed. Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology, 1976; 34-212

8 Lattes R. Thymoma and other tumors of the thymus: an analysis of 107 cases. Cancer 1962; 15:1224-1260

9 Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003; 105:546-551

10 Mullen B, Richardson JD. Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg 1986; 42:338-345

11 Gerein AN, Srivastava SP, Burgess J. Thymoma: a ten-year review. Am J Surg 1978; 136:49-53

12 Okumura M, Ohta M, Tateyama H, et al. The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 2002; 94:624-632

13 Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2003; 126:1134-1140

14 Lardinois D, Rechsteiner R, Lang RH, et al. Prognostic relevance of Masaoka and Muller-Hermelink classification in patients with thymic tumors. Ann Thorac Surg 2000; 69:1550-1555

15 Wilkins EW Jr, Edmunds L Jr, Castleman B. Cases of thymoma of the Massachusetts General Hospital. J Thorac Cardiovasc Surg 1966; 52:322-330

16 Lewis JE, Wick MR, Scheithauer BW, e\t al. Thymoma: a clinicopathologic review. Cancer 1987; 60:2727-2743

17 Verstandig AG, Epstein DM, Miller WT, et al. Thymoma-report of 71 cases and a review. Crit Rev Diagn Imaging 1992; 33:201-230

18 Zerhouni EA, Scott WW, Baker RR, et al. Invasive thymomas: diagnosis and evaluation by CT. J Comput Assist Tomogr 1982; 6:92- 100

19 Yokoi K, Miyazawa N, Mori K, et al. Invasive thymoma with intracaval growth into right atrium. Ann Thorac Surg 1992; 53:507- 509

20 Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981; 48:2485-2492

21 Shamji F, Pearson FG, Todd TR, et al. Results of surgical treatment for thymoma. J Thorac Cardiovasc Surg 1984; 87:4.3-47

22 Cohen DJ, Ronnigan LD, Graeber GM, et al. Management of patients with malignant thymoma. J Thorac Cardiovasc Surg 1984; 87:301-307

23 Laurent E, Latrabe V, Lecesne R, et al. Mediastinal masses: diagnostic approach. Eur Radiol 1998; 8:1148-1159

24 Osserman KE, Genkins G. Studies in myasthenia gravis: review of a 20-year experience in over 1200 patients. Mt Sinai J Med 1971; 38:497-537

25 Marx A, Muller-Hermelink HK, Strobel P. The role of thymomas in the development of myastheniu gravis. Ann N Y Acad Sci 2003; 998:223-236

26 Drachmnan DB. Myasthenia gravis. N Engl J Med 1994; 330:1797- 1810

27 Lennon VA, Jones G, Howard F, et al. Auto antibodies to acetylcholine receptors in myasthenia gravis. N Engl J Med 1983; 308:402-403

28 Howard FM Jr, Lennon VA, Finley J, et al. Clinical correlation of antibodies that bind, block or modulate human acetylcholine receptors in myasthenia gravis. Ann N Y Acad Sci 1987; 505:526-538

29 Souadjian JV, Enriquez P, Silver-stein MN, et al. The spectrum of diseases associated with thymoma. Arch Intern Med 1974; 134:374- 379

30 Kelleher P, Misbah SA. What is Good’s syndrome? Immunological abnormalities in patients with thymoma. J Clin Pathol 2003; 56:12- 16

31 Kim JH, Goo JM, Lee HJ, et al. Cystic tumors in the anterior mediastinum: radiologic-pathological correlation. J Comput Assist Tomogr 2003; 27:714-723

32 Rosado de Christenson ML, Galobardes J, Moran CA. Thymoma: radiologic-pathologic correlation. Radiographies 1992; 12:151-168

33 Anderson T, Lindgren PG, Elvin A. Ultrasound guided tumor biopsy in the anterior mediastinum. Acta Radiol 1992; 33:310-311

34 Morgenthaler TI, Brown LR, Colby TV, et al. Symposium on intrathoracic neoplasms: part IX. Mayo Clin Proc 1993; 68:1110-1123

35 Singhal S, Shrager JB, Rosenthal DI, et al. Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 2003; 76:1635-1641

36 Curran WJ Jr, Kornstein MJ, Brooks JJ, et al. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988; 6:1722-1727

37 Eralp Y, Aydiner A, Kizir A, et al. Resectable thymoma: treatment outcome and prognostic factors in the late adolescent and adult age group. Cancer Invest 2003; 21:737-743

38 Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995; 60:908-913

39 Thomas CR, Wright CD, Loehrer PJ. Thymoma. J Clin Oncol 1999; 17:2280-2289

40 Kim ES, Putnam JB, Komaki R, et al. Phase 11 study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004; 44:339-379

41 Daniele O, Fornasiero A. Ifosfamide in thymic neoplasms. Oncology 2003; 65:44-45

42 Gamondes JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment oi thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991; 5:124-131

43 Hernandex-Ilizaliturri FJ, Tan D, Cipolla D, et al. Multimodality therapy for thymic carcinoma (TCA): results of a 30- year single-institution experience. Am J Clin Oncol 2004; 27:68-72

44 Truoug LD, Mody DR, Cagle PT, et al. Thymic carcinoma: a clinicopathologic study of 13 cases. Am J Surg Pathol 1990; 14:151- 166

45 Tamura Y, Kuroiwa T, Doi A, et al. Thymic carcinoma presenting as cranial metastasis with intradural and extracranial extension: case report. Neurosurgery 2004; 54:209-211

46 Yaqub A, Munn NJ, Wolfer RS. Thymic carcinoma presenting as cardiac tamponade. South Med J 2004; 97:212-213

47 Suster S, Rosai J. Thymic carcinoma: a clinicopathologic study of 60 cases. Cancer 1991; 67:1025-1032

48 Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 1998; 115:303-338

49 Ritter JH, Wick MR. Primary carcinoma of the thymus gland. Semin Diagn Pathol 1999; 16:18-31

50 Loehrer PJ, Kim KM, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma. J Clin Oncol 1994; 12:1164-1168

51 Yoh K, Goto K, Ishii G, et al. Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide is an effective treatment for advanced thymic carcinoma. Cancer 2003; 98:920-931

52 Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2003; 88:1066-1081

53 Wick MR, Bernatz PE, Camey JA, et al. Primaiy mcdiastinal carcinoid tumors. Am J Surg Pathol 1982; 6:195-205

54 Economopoulos GC, Lewis JW Jr, Lee MW, et al. Carcinoid tumors of the thymus. Ann Thorac Surg 1990; 50:58-61

55 Tiffet O, Nicholson AG, Ladas G, et al. A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus. Chest 2003; 124:141-146

56 Graeber GM, Thompson LD, Cohen DJ, et al. Cystic lesions of the thymus. J Thorac Cardiovasc Surg 1984; 87:295-300

57 Indeglia RA, Shea MA, Grage TB. Congenital cysts of the thymus gland. Arch Surg 1967; 94:149-152

58 Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive process. Am J Surg Pathol 1991; 15:388-398

59 Parker D, Holford CP, Begent RH. Effective treatment for malignant mediastinal teratoma. Thorax 1983; 38:897-902

60 Bohle A, Studor UK, Sonntag RW, et al. Primary or secondary extragonadal germ cell tumor? J Urol 1986; 135:939-943

61 Recondo J, Libshitz HI. Mediastinal extragonadal germ cell rumors. Urology 1978; 11:369-375

62 Javadpour N. Significance of elevated serum alpha fetoprotein (AFP) in seminoma. Cancer 1980; 45:2166-2168

63 Nichols CR. Mediastinal germ cell tumors: clinical features and biologic correlates. Chest 1991; 99:472-479

64 Crussi-Gonzalez F. Extragonadal teratomas. In: Hartmann WH, ed. Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology, 1982; 77-94

65 Carter C, Bibro MC, Touloukian RJ. Benign clinical behavior of immature mediastinal teratoma in infancy and childhood. Cancer 1982; 49:398-402

66 Adebonojo SA, Nicola ML. Teratoid tumors of the mediastinum. Am Surg 1976; 42:361-365

67 Thompson DP, Moore TC. Acute thoracic distress in childhood due to spontaneous rupture of large mediastinal teratoma. J Pediatr Surg 1969; 4:416-423

68 Donadio AC, Motzer Rf, Bajorin DF, et al. Chemotherapy for teratoma with malignant transformation. J Clin Oncol 2003; 21:4285- 4291

69 Lewis BD, Hurt RD, Payne WS, et al. Benign teratoma of the mediastinum. J Thorac Cardiovasc Surg 1983; 86:727-731

70 Graeber GM, Shriver CD, Albur RA, et al. The use of computed tomography in the evaluation of mediastinal rumors. J Thorac Cardiovasc Surg 1986; 91:662-666

71 Moeller KH, Rosado-de-Christenson ML, Templeton DA. Mediastinal mature teratoma: imaging features. AJR Am J Roentgenol 1997; 169:985-990

72 Arai K, Ohta S, Suzuki M, et al. Primary immature mediastinal teratoma in adulthood. Eur J Surg Oncol 1997; 23: 64-67

73 Polansky SM, Barwick KW, Revie CE. Primary mediastinal seminoma. AJR Am J Roentgenol 1979; 132:17-21

74 Hainsworth J. Diagnosis, staging, and clinical characteristics of the patient with mediastinal germ cell carcinoma. Chest Surg Clin N Am 2002; 12:665-672

75 Hosono M, Machida K, Honda N, et al. Intense Ga-67 accumulation in pure primary mediastinal seminomas. Clin Nucl Med 2003; 28:25-28

76 Bush SE, Martinez A, Bagshaw MA. Primary mediastinal seminoma. Cancer 1981; 48:1877-1882

77 Bokemeyer C, Droz JP, Horwich A, et al. Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome. Cancer 2001; 91:1394-1401

78 Bukowski RM, Wolf M, Kulander BG, et al. Alternating combination chemotherapy in patients with extragonadal germ cell tumors: a Southwest Oncology Croup study. Cancer 1993; 71:2631-2638

79 Dexeus FH, Logothetis CJ, Chong C, et al. Genetic abnormalities in men with germ cell tumors. J Urol 1988; 140: 80-84

80 Nichols CR, Hoffman R, Einhorn HI, et al. Hematologic malignancies associated with primary mediastinal germ cell tumors. Ann Intern Med 1985; 102:603-609

81 Hori K, Uematsu K, Yasoshima H, et al. Testieular seminoma with human chorionic gonadotropin production. Pathol Int 1997; 47:592-599

82 Lee KS, Im JG, Han CH, et al. Malignant primary germ cell tumors of the mediastinum: CT features. AJR Am J Roentgenol 1989; 153:947-951

83 Wright C, Kesler K. Surgical techniques and outcomes for primary nonseminomatous germ cell tumors. Chest Surg Clin N Am 2002; 12:707-715

84 Walsh GL, Taylor GD, Nesbitt JC, et al. Intensive chemotherapy and radical resections for primary non-seminomatous mediastinal germ cell tumors. Ann Thorac Surg 2000; 69:337-343

85 International Germ Cell Consensus Classification. A prognostic factor-based staging system for metastatic germ cell cancers: International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15:594-603

86 Kathic M, Wang C, Grille H. Substernal goiter. Ami Thorac Surg 1985; 39:391-399

87 Allo MD, Thompson NW. Rationale for the operative management of substernal goiters. Surgery 1983; 94:969-977

88 Clark O. Mediastinal parathyroid tumors. Arch Surg 1988; 123:1096-1100

89 Oates E. Improved parathyroid scintigraphywith Tc 99m MIBI, a superior radio tracer. Appl Radiol 1994; 23:37-40

90 Strickler JG, Kurtin PJ. Mediastinal lymphoma. Semin Diagn Pathol 1991; 8:2-13

91 Liechtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal lymphoma in adults. Am J Med 1980; 68:509-514

92 Cartwright R, Brincker H, Carli PM, et al. The rise in incidence of lymphomas in Europe. Eur J Cancer 1999; 35:627-633

93 Vaeth JM, Moskowitz SA, Green JP. Mediastinal Hodgkin’s disease. AJR Am J Roentgenol 1976; 126:123-126

94 Yung L, Linch D. Hodgkin’s lymphoma. Lancet 2003; 361:943-951

95 Kornstein MJ, DeBlois, et al. Pathology of the thymus and mediastinum. 1st ed. Philadelphia, PA: WB Saunders, 1995

96 Costello P, Jochelson M. Lymphoma of the mediastinum and lung. In: Taveras JM, Ferrucci JT, eds. Radiology: diagnosis, imaging, intervention (vol 1). Philadelphia, PA: Lippincott-Raven 1996; 1-13

97 Keller AR, Kaplan US, Lukes RJ, et al. Correlation of histopathology with other prognostic indicators in Hodgkin’s disease. Cancer 1968; 22:487-499

98 Castellino RA, Blank N, Hoppe RT, et al. Hodgkin disease: contributions of chest CT in the initial staging evaluation. Radiology 1986; 160:603-605

99 Schiepers C. Filmont JE. Czeruin J. PET for staging of Hodgkin’s disease and non-Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging 2003; 30(suppl):S82-S88

100 Hagenbeek A, Garde P, Noordijk E, et al. Prognostic factor tailored treatment of early stage Hodgkin’s disease: results from a prospective randomized phase III clinical trial of 762 patients [abstract]. Blood 1997; 90:585

101 DeVita VT, Maack PM, Harris NL. Hodgkin’s disease. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia, PA: Lippincott-Raven, 1997; 2242- 2283

102 Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992; 327: 1478-1484

103 Moskowitz C. An update on the management of relapsed and primary refractory Hodgkin’s disease. Semin Oncol 2004; 31:54-59

104 Hale GA, Phillips GL. Allogeneic stem cell transplantation for the non-Hodgkin’s lymphomas and Hodgkin’s disease. Cancer Treat Rev 2000; 26:411-427

105 Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 1998; 339:1506-1514

106 Sutcliff SB. Primary mediastinal malignant lymphoma. Seinin Thorac Cardiovasc Surg 1992; 4:55-67

107 van Besien K, Kelta M, Bahaguna P. Primary mediastinal B- cell lymphoma: a review of pathology and management. J Clin Oncol 2001; 19:1855-1864

108 Thomas DA, Kantarjian H. Lymphoblastic lymphoma. Heinatol Oncol Clin North Am 2001; 15:51-95

109 Murphy S. Childhood non-Hodgkin’s lymphoma. N Engl J Med 1978; 299:1446-1148

110 Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980; 7:332-339

111 Kirn D, Mauch P, Shaffer K, et al. Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients. J Clin Oncol 1993; 11:1336-1343

112 Lazzarino M, Orlandi E, Paulli M, et al. Primary mediastinal B-cell lymphoma with sclerosis: an aggressive tumor with distinctive clinical and pathologic features. J Clin Oncol 1993; 11:2306-2313

113 Cheson BD. Hodgkin’s disease and the Non-Hodgkin’s lymphomas. In: Lenhard RE Jr, Osteen RT, Gansler T, eds. Clinical Oncol. Atlanta, GA: American Cancer Society 2001; 497-516

114 Kobayashi T, Tobinai K, Shimoyama M, et al. Long-term follow up results of adult patients with acute lymphocytic leukemia or lymphoblastic lymphoma treated with short-term, alternating non- cross-resistant chemotherapy. Jpn J Clin Oncol 1999; 29:340-348

115 Levine JE, Harris RE, Loberiza JO, et al. A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 2003; 101:2476-2482

116 Aviles A, Garcia EL, Fernandez R, et al. Combined therapy in the treatment of primary mediastinal B-cell lymphoma: conventional versus escalated chemotherapy. Ann Hematol 2002; 81:368-373

117 Pun YW, Moreno BR, Prieto VJ, et al. Multicenter experience of video-assisted thoracic surgery to treat mediastinal cysts and tumors. Archivos de Bronconeumologia 2002; 38:410-414

118 Wychulis AR, Payne WS, Clagett OT, et al. Surgical treatment of mediastinal tumors: a 40 year experience. J Thorac Cardiovasc Surg 1971; 62:379-392

119 Whooley BP, Urschel JD, Antkowiak JG, et al. Primary tumors of the mediastinum. J Surg Oncol 1999; 70:95-99

120 Ahrens B, Wit J, Schinitt M, et al. Symptomatic bronchogenic cyst in a six mouth old infant: case report and review of the literature. J Thorac Cardiovasc Surg 2001; 122:1021-1023

121 Takeda S, Miyoshi S, Minami M, et al. Clinical spectrum of mediastinal cysts. Chest 2003; 124:125-132

122 Crapo JD, Glassroth J, Karlinsky J, et al. Baum’s textbook of pulmonary diseases. Philadelphia, PA: Lippincott Williams & Wilkins, 2004; 883-912

123 Kumar A, Aggarwal S, Halder S, et al. Thorascopic excision of mediastinal bronchogenic cyst: a case report and review of literature. Ind J Chest Dis Allied Sci 2003; 45:199-201

124 O’Neill JA. Fo