While thymomas are rare epithelial tumors, they represent the most common type of neoplasm in the mediastinum and they account for 45% of anterior mediastinal tumors. These tumors occur with equal frequency in men and women, and are often detected during the fourth to seventh decade of life.16,17
Although most patients are asymptomatic, approximately one-third of them experience chest pain, coughing, dyspnea, and chest tightness. If the tumor invades the phrenic nerve, patients may present with shortness of breath either because of a paralyzed hemidiaphragm or a pleural effusion.18 Approximately 60% of thymomas are associated with various systemic or paraneoplastic disorders, such as myasthenia gravis, hypogammaglobulinemia, and red cell aplasia. Myasthenia gravis exhibits in 30% to 60% of patients with thymomas, whereas only 5% to 15% of patients with myasthenia gravis have thymomas. The presence or absence of myasthenia gravis has no impact on the clinical outcome of thymomas patients. However, thymectomies can alleviate the myasthenia gravis symptoms in most of cases.19-23 On CT imaging, thymomas typically appear as homogenously encapsulated masses with smooth contours. Certain findings, such as encasement of mediastinal structures, infiltration of fat planes, irregular interface between the mass and lung parenchyma, and vascular involvement are referred to as “advanced-stage of thymomas.” On occasion, pleural and multiple lung metastases could be found by initial imaging presentation.24
To date, Masaoka schema and the subsequent Koga-modified Masaoka staging system (Table 65-2) remains the most commonly used classification.20,25 This staging system takes into account the gross presence or absence of invasion into adjacent structures as identified at the time of surgery. This schema is able to show a stepwise decline of survival curves in association with the advance of clinical stages. The World Health Organization (WHO) devised a classification system in 1999 and 2004 to categorize thymomas based on cytologic differences.26 Two major types of thymomas were identified and they were separated based on whether the epithelial cells showed a spindle/oval shape (designated type A) or if they showed a round and epithelioid appearance (designated type B). Tumors showing a combination of these two cell types are designated as type AB. In general, the type A thymomas are referred as medullary thymomas and have the best clinical outcome. Type AB thymomas are mixed foci showing both features of type A and B, and an intermediate prognosis. Type B thymomas are referred to as the cortical type of thymomas and they are associated with poor prognosis. Type B thymomas can be further divided into three subtypes: B1, B2, and B3 based on the lymphocyte infiltration and presence of atypical epithelial cells. Type C thymomas are regarded as thymic carcinomas. After comparison of the proportions of thymoma histologic types by Masaoka stage, it showed that type A, AB, and B1 thymomas were significantly more frequent in stage I and II. Conversely, type B2 and B3 thymomas were significantly more frequent in stages III and IV, and they are expected to show a “high risk” for early recurrence and poor prognosis.27-30 The WHO histologic systems can be used in combination with a Masaoka-type staging system to provide more precise prognostic information.
Masaoka Staging System and WHO Classification for thymomas
|Favorite Table|Download (.pdf) TABLE 65-2:
Masaoka Staging System and WHO Classification for thymomas
|Modified Masaoka Staging Systema ||WHO (2004) Classificationb |
|Stage ||Definition ||10-Year Survival (%)c ||Type ||Histologic Definition ||10-Year Survival (%)c |
|I ||Macroscopically completely encapsulated and micropapillary no capsular invasion ||99 ||A ||Spindle cell, medullary ||97 |
|IIa ||Microscopic invasion into capsule || ||AB ||Mixed ||95 |
|IIb ||Macroscopic invasion into surrounding fatty tissue or mediastinal pleura or pericardium ||94 ||B1 ||Lymphocyte-rich, cortical predominantly ||92 |
|III ||Macroscopic invasion into neighboring organ (i.e., pericardium, great vessels, or lung) ||88 ||B2 ||Cortical ||81 |
|IVa ||Pleural or pericardial dissemination ||30 ||B3 ||Epithelial-rich ||62 |
|IVb ||Lymphogenous or hematogenous metastasis ||0 ||C ||Well-differentiated thymic carcinoma ||29 |
Currently, surgery is the mainstay of thymoma treatment and a complete resection leads to the best prognosis. Complete resection rates are achieved in 47% and 26% of stage III and IV cases, respectively, compared to 100% and 85% in stage I and II cases, respectively.31 With regards to resectability, if advanced thymomas did not invade adjacent structures, surgery should be initially undertaken with the aim of complete removal of the tumor with free resection margins. However, if a tumor had invaded into great vessels or other vital organs, patients should be reassessed for surgery after neoadjuvant chemoradiation therapy.32 There are several surgical approaches developed to remove the thymic thymoma. In general, a median sternotomy provides excellent exposure to the tumor as well as the great vessels. Minimally invasive surgery is recommended for small size and early stage thymomas, with or without myasthenia gravis.33-35 Regardless of the surgical approaches chosen, the major goal is the removal of the entire tumor and thymus without spillage.
Operative mortality rates ranges from 0% to 5% and mostly due to myasthenic crises. Preoperative adjustment of medication and plasmapheresis are indicated for the patient who presents with severe myasthenia gravis symptoms. The 5-year survival rate is 89% to 100%, 59% to 75%, 34% to 71%, and 0% to 53% in stage I, II, III, and IV, respectively. The Masaoka stage and completeness of resection are the most commonly cited prognostic factors in thymoma. In stage III thymomas, involvement of great vessels and the WHO classification (type A vs. B2 or B3) are also independent prognostic factors.29,36,37
Until now, the role of debulking surgery in advanced thymoma was controversial. However, debulking surgery can protect the adjacent organs from irradiation toxicity by reducing the adjuvant radiotherapy field. Therefore, debulking surgery should be considered for patients with advanced stage thymomas who require extensive radiotherapy.32,38 Currently, routine adjuvant radiotherapy is not recommended for stage I and II thymomas because of their low (5%) local recurrence rate. Adjuvant radiotherapy is indicated for patients with macroscopic capsular invasion, WHO type B thymomas, and tumor adherent to the pericardium. For patients whose tumors were incompletely resected and had gross residual disease, postoperative radiotherapy may achieve a local control effect. Adjuvant chemotherapy is also necessary to eradicate the microscopic metastasis in the distant sites. A combination of adjuvant chemotherapy and radiotherapy is recommended for stage III and IV thymoma patients after surgery. If patients who are medically unfit for surgery or with a technically unresectable tumor, definitive chemotherapy concurrent with, or sequential to, radiation therapy would be an option of treatment. Local recurrence or limited pleural metastasis can occur after primary surgery. A redo operation is recommended or there is data to support a survival advantage. Otherwise, definitive chemoradiation therapy may be a better option for patients with systemic and distant metastatic recurrence.
Insights of tumor biology and oncogenic pathway are needed to develop novel strategies for thymoma treatment. Somatostatin (SST) receptors had been identified to be highly expressed in the thymus of thymoma patients.39 Octreotide, which is an octapeptide SST analog with a high affinity for SST receptors, in a phase II Trial from the Eastern Cooperative Oncology Group (ECOG) demonstrated an overall response rate of 32% when combined with prednisone in 38 stage III and IV thymic tumors.40 Moreover, larger phase III studies are warranted to confirm these results. Another new treatment approach involves the use of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. The EGFR is overexpressed in 71% of thymomas, especially in stage III and IV tumors. However, current phase II results showed a low response rate to the use of EGFR tyrosine kinase inhibitors in thymic tumors.41,42
Thymic carcinomas account for almost 15% of thymic epithelial tumors and patients have a mean age of 50 years.43 Unlike thymomas, most thymic carcinomas are locally invasive and frequently metastasize to regional lymph nodes and distant sites at initial diagnosis.27 The typical radiological appearance of a thymic carcinoma is a bulky, poorly defined, and heterogeneous mass that is associated with pleural and pericardial effusion. Effective therapies for thymic carcinomas require a multimodality approach that includes induction therapy, surgery, and adjuvant therapy. The prognosis of thymic carcinomas is worse than the prognosis of thymomas. Primary neuroendocrine tumors of the thymus are very rare and included in the thymic carcinoma group according to the 2004 WHO classification of tumors. Recent international multicenter retrospective study showed those aggressive characteristics with a poor prognosis due to the high incidence of recurrence after surgery.44
Mediastinal lymphoma is more common in children than in adults. It accounts for nearly 50% of mediastinal tumors in children as opposed to just 20% in adult patients. Both Hodgkin and non-Hodgkin lymphoma can appear as a mediastinal mass, however, Hodgkin lymphoma represents 75% of mediastinal lymphoma cases.1 The typical imaging appearance of Hodgkin lymphoma is a large anterior heterogeneous mass involving the thymus and the neck lymph nodes. Non-Hodgkin lymphomas are more commonly detected in younger children and frequently involve the subcarinal, posterior mediastinal, and intra-abdominal lymph nodes.45
If a mediastinal lymphoma is suspected, surgical approaches to obtain a sufficient sample tissue for a precise diagnosis is warranted (see previous discussion). The treatment of mediastinal lymphomas consist of chemotherapy with or without radiotherapy. Surgical resection does not play a role in the treatment of mediastinal lymphomas.
Primary mediastinal GCTs compose 15% of anterior mediastinal masses in adults and they occur most frequently in males. Since 50% of mediastinal GCTs will coexist with testicular and retroperitoneal GCTs, patients with mediastinal GCTs should be carefully evaluated for extrathoracic lesions.46,47 Primary mediastinal GCTs have a peak age of incidence between 20 and 35 years and they are categorized into three cell types: mature teratomas, seminomas, and nonseminomatous GCTs. Although mature teratomas occur with equal frequency between men and women, malignant GCTs are much more common in men (>90%).48
Mature mediastinal teratomas are the most common type of mediastinal GCTs. They are composed of two to three primitive germinal layers. Ectodermal tissues include skin, hair, and tooth-like structures. Mesodermal tissues include fat, cartilage, bone, and smooth muscle. Endodermal tissues include respiratory and intestinal epithelium, and pancreatic tissue. Mature teratomas are usually benign and most often occur in adolescents. If a teratoma contains fetal tissue, it is considered immature teratoma and represents a greater malignant potential.49
Most patients with mature teratomas are asymptomatic. Cough, chest pain, or dyspnea may occur as a result of local compression during the growth of the tumor. The expectoration of hair (trichoptysis) is rare. The imaging studies typically demonstrate a well-circumscribed and heterogeneous mass with soft tissue, fat, fluid, and calcium. If a teratoma is suspected by CT image, excision of the tumor without a preoperative biopsy is the primary treatment. Both median sternotomy and VATS approach can achieve the goal of curative-intent resection with low rates of recurrence.50
Seminomas compose 25% to 40% of primary malignant mediastinal GCTs. The peak incidence is in the third decade of life and more than 90% of seminomas occur in men.51,52 They are slow-growing tumors and they exhibit few symptoms, which explain why most tumors are bulky at presentation. Substernal chest pain, dyspnea, and coughing are the most common symptoms. Gynecomastia and SVC syndrome may also accompany with seminoma. Approximately 10% of patients with seminomas may have a mild increase of β-hCG level (<1000 IU/L), but never an increased level of AFP. On CT scans, they are large, lobulated, and well-circumscribed masses with homogenous attenuation. Although seminomas are highly sensitive to chemotherapy and radiation therapy, current evidence demonstrates that the chemotherapy provides the best clinical outcome (88% of 5-year survival rate). Chemotherapy has widely replaced radiotherapy as the initial treatment in patients with mediastinal advanced seminomas.53,54
Nonseminomatous GCTs represent heterogeneous tumors that include yolk sac tumors, embryonal carcinomas, choriocarcinomas, immature teratomas, teratocarcinomas, and mixed GCTs. Much like seminomas, they occur predominantly in men and have a peak incidence in the third and fourth decades of life.55 Nonseminomatous GCTs are associated with hematologic malignancies and Klinefelter syndrome (47XXY).56,57 In addition to the local symptoms of chest pain, dyspnea, and coughing, nonseminomatous GCTs are more likely to present with systemic symptoms of fever, chills, and weight loss. Most patients have an increased AFP or a highly elevated β-hCG level (>1000 IU/L). Cisplatin-based chemotherapy is the standard primary treatment. Salvage surgery for the residual tumor is suggested after initial chemotherapy. Even with multimodality therapy, nonseminomatous GCTs carry a worse prognosis with a 5-year overall survival rate of 40% to 60%.54,58
Substernal Thyroid Goiter
Substernal goiters are found in 3% to 20% of all thyroid goiter operations. Most are asymptomatic, but some patients may present with dyspnea, dysphagia, dysphonia, or SVC syndrome.59 Often, the chest radiography shows deviation of the trachea. The classic appearance on a CT scan is a multinodular goiter and continuity of the cervical and mediastinal components of the thyroid gland. Radiographically, substernal goiters are encapsulated, lobulated, and heterogeneous tumors. Radioactive iodine ablation has a low success rate for substernal goiters, therefore total thyroidectomy is the treatment of choice. Nearly all substernal goiters can be removed through a transcervical approach (collar incision) without the need of sternotomy. If greater exposure becomes necessary, a partial sternal split is usually sufficient; a full sternotomy should be avoided. Identification of recurrent laryngeal nerve during surgery can prevent postoperative vocal cord paresis or paralysis. In addition, patients with goiters larger than 200 g and those with tracheal compression on preoperative imaging were more likely to have postoperative tracheomalacia and a compromised airway.60