The anatomy of the three mediastinal compartments is outlined and reviewed in Chapters 155 and 161. The anterior compartment differs from the middle and posterior compartments in that it has a higher rate of malignant tumors. In a study of over 400 patients with primary mediastinal tumors, malignancy was identified in 59% of anterior compartment tumors as compared with only 29% for middle compartment and 16% for posterior compartment tumors in adults.1,2 Malignancy is also dependent on age and the presence of symptoms. Children are more likely to develop lymphoma or malignant neurogenic tumors.3 The presence of symptoms foretells malignant disease in 85% of patients, while only 46% of patients with symptoms have benign disease.1,4 Posterior compartment mediastinal tumors are described in Chapter 162 and the middle mediastinal compartment is described in Chapter 161.
The three primary malignant mediastinal tumors that commonly occur in the anterior compartment are thymic tumors, GCTs, and lymphomas (Fig. 163-1). Each of these tumors can be further divided into subtypes, each possessing a unique tumor biology which influences treatment and outcomes. Mesenchymal tumors are uncommon, comprising less than 10% of anterior mediastinal tumors, and can be divided into tumors of vascular origin, lymphatic origin, or tumors of connective tissue origin.5
The three primary malignant tumors that occur in the anterior compartment are thymoma, seminoma, and lymphoma. Clamshell incisions (A) and median sternotomy (B) provide access for wide surgical margins.
Thymoma and Thymic Tumors
Thymic tumors are the most frequently identified primary mediastinal tumor in adults and although they originate in the anterior mediastinum they may invade other neighboring structures or cavities. Thymic tumors are pathologically subclassified as noninvasive (encapsulated) thymomas, invasive thymomas, thymic carcinomas, and neuroendocrine thymic tumors. Of these thymic tumors, noninvasive thymomas are defined by encapsulation, without involvement of other surrounding structures. Invasive thymomas may ostensibly possess benign appearing features on histologic examination but they may also demonstrate malignant properties with invasion past the capsule into contiguous structures.6 This extracapsular invasion can occur irrespective of size, such that at least 30% of thymomas may demonstrate invasion of surrounding mediastinal fat.6,7 It has likewise been recognized that “noninvasive” thymoma pathology does not necessarily predict a “benign” clinical outcome. Stage I thymomas (i.e., well-encapsulated tumors without invasion) have been found to recur and metastasize, although these recurrences are usually indolent.8 Thymic cancers do not possess the bland histologic features of thymoma; they demonstrate cellular atypia, mitoses, and necrosis and lack the organoid features of a normal thymus gland.9–11 Neuroendocrine tumors of the thymus are rare; the most common histologic type is carcinoid tumors (typical and atypical). These thymic neuroendocrine tumors carry a worse prognosis as compared to carcinoid tumors of the lung.12
Clinically, thymomas may be associated with paraneoplastic syndromes. Myasthenia gravis is the most common parathymic syndrome, occurring in 45% of thymoma patients (range 10%–67%), followed by pure red blood cell aplasia (2%–5%) and hypogammaglobulinemia (2%–5%).13 These tumors are also known to be associated with other neuromuscular syndromes, hematologic syndromes, autoimmune disorders, endocrine disorders, as well as immunodeficiency syndromes.7 While prognosis is variable for the majority of these parathymic syndromes, symptoms of myasthenia gravis may improve postthymectomy for thymoma. However the neuromuscular improvement is not to the same extent that is observed in patients with thymic hyperplasia suggesting the possibility of a different pathway for antibody production with thymoma as compared to hyperplasia.14
The classification of thymomas is geared to prognosis and is based on extent of tumor invasiveness and tumor histology. Two different staging schemes have been proposed to accommodate both of these systems. I. Currently, the Masaoka staging system is used most widely for clinical staging (Table 163-1). This staging classification emphasizes a correlation between the extent of tumor involvement/invasion and prognosis. However, it is primarily based on local or distant extracapsular invasion and does not include the complex histology of thymic tumors, which many believe is relevant for determining overall clinical prognosis. To this end, a World Health Organization (WHO) classification (Table 163-2) was created.15–18 This classification includes all thymic tumors, and differentiates thymomas according to separate morphology.19 Each subsequent subtype in this classification (ranging from A to B3) demonstrates increasing abnormal histology of epithelial cells in proportion to lymphocytes with preserved organoid features, which is correlated with survival. Type C thymic tumors (thymic carcinoma) in comparison to thymomas demonstrate cytologic features of malignancy, a lack of encapsulation, and adherence to, or invasion of, mediastinal structures. These tumors fail to recapitulate the normal thymus tissue and may resemble malignant neoplasms from other organs.20
Table 163-1Masaoka Thymoma Staging System ||Download (.pdf) Table 163-1Masaoka Thymoma Staging System
|Stage I ||Encapsulated tumor without gross or microscopic capsular invasion |
|Stage IIA ||Macroscopic invasion into surrounding mediastinal fat or pleura |
|Stage IIB ||Microscopic capsular involvement |
|Stage III ||Gross invasion of neighboring organs |
|Stage IVA ||Pleural or pericardial spread |
|Stage IVB ||Lymphatic or hematogenous metastases |
Table 163-2World Health Organization Classification of Thymoma ||Download (.pdf) Table 163-2World Health Organization Classification of Thymoma
|A (medullary) ||Thymoma with spindle or oval epithelial cells with little nuclear atypia and few lymphocytes. |
|AB (mixed) ||Thymoma with features of A mixed with lymphocytes. |
|B1 (organoid) ||Thymoma that resembles the normal functioning thymus with cortical and medullary areas. |
|B2 (cortical) ||Thymoma with plump epithelial cells among a large population of lymphocytes. |
|B3 (epithelial) ||Thymoma with epithelial cells with a round or polygonal shape with mild atypia in a sheetlike growth. They are admixed with a minor component of lymphocytes. |
|C (carcinoma) ||Thymic tumor with obvious atypia and features that do not resemble thymus tissues. These tumors lack immature lymphocytes; if any are present, they are mature and mixed with plasma cells. |
The prognosis for these tumors depends on three interrelated parameters: histologic features (i.e., WHO classification), staging (i.e., Masaoka classification), and the completeness of resection.18 These three factors determine the invasiveness and metastatic potential of these tumors. Lymphatic or hematogenous involvement of these tumors is uncommon; however, local recurrence can occur, even for encapsulated tumors without capsular invasion after resection.13 Long-term survival for thymoma has been directly related to stage, extent of resection, and histology.21
As part of the initial evaluation, thymic tumors require a complete chest and upper abdomen computed tomography (CT) scan to delineate the full extent of disease. The CT attenuation (fat attenuation vs. water attenuation) as well as the calcification and contrast pattern may be helpful to discriminate between the different anterior mediastinal tumors.22 Positron emission tomography (PET) is not an obligatory investigation for this malignancy but may serve in difficult situations to discriminate thymic hyperplasia from thymic tumors and may also help to confirm metastatic disease.23,24 Magnetic resonance imaging (MRI) is primarily useful with large tumors to identify the anatomy and possible invasion of vascular structures which may be distorted by tumor bulk. Preoperative biopsy has long been debated regarding its usefulness in the assessment of thymic tumors. Biopsy is considered unnecessary, particularly when there is substantial evidence of a parathymic syndrome, if the tumor is considered small (and possibly well encapsulated), and there is little likelihood of a competing diagnosis (e.g., germ cell tumor, lymphoma). In all other instances, a preoperative biopsy is helpful to determine appropriate therapy for the mediastinal tumor. Preoperative pathology has been found to be most useful in the differentiation between thymic tumors and lymphoma particularly because the latter is usually treated non-surgically.13 Practical experience has demonstrated that biopsy tract seeding following thymic biopsy is a rather rare phenomenon. However, this does not address the practical concern of conversion of a Masaoka stage I thymoma to a Masaoka stage II thymoma by extrinsic capsular needle invasion.
In the preoperative investigation of an anterior mediastinal mass, patients with clinically suspected thymic tumors should be assessed for myasthenic signs and symptoms. If myasthenia gravis is suspected, an assay for antiacetylcholine receptor antibody titer will be diagnostic and will help to obviate the need for a preoperative biopsy. If the diagnosis is still unclear, all male patients should undergo a testicular examination, as well as serology for alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-HCG), to help exclude the possibility of a malignant germ cell tumor. If the diagnosis is still elusive, biopsy is mandatory.
With respect to surgical resection, the surgical literature is divided between those who recommend traditional sternotomy with removal of both the tumor and its surrounding tissue to prevent local recurrence from microscopic invasion, and those who advocate a sternal-sparing procedure (i.e., thoracoscopic approach).8,25 The perioperative considerations and surgical techniques for these different approaches are discussed in Chapters 159 and 160. Transcervical thymectomy is not an option for patients with thymomas or thymic tumors (Chapter 158); it is reserved specifically for patients with thymic hyperplasia or nonthymomatous thymic conditions.26 Thoracoscopic approaches may be used for small (<4 cm), well-encapsulated thymomas and thymic cysts, but are not recommended for bulky or invasive thymomas or thymic tumors.8,27 Large (>4 cm) or invasive thymomas (i.e., stage II or higher) may require a transsternal approach to help facilitate exposure and completeness of resection. In the preoperative setting, it may often be difficult to determine whether a small thymoma has an invasive component. Invasiveness may be predicted clinically or radiographically, based on the association of myasthenia gravis (primarily associated with B1, B2, and B3 thymomas), presence of calcifications, or a flat or irregular surface, as compared with a round or oval shape (as seen with encapsulated thymomas).19 If invasion of surrounding structures is suspected, a transsternal radical thymectomy is recommended to decrease the local recurrence rate as well as to avoid future concerns as to the value of a re-do procedure for microscopic disease.
Complete thymus resection is the procedure of choice for thymomas with Masaoka stages I and II, as well as limited stage III cases. It is recommended that patients with more extensive thymomas (e.g., stages III and IVa) with obvious invasion or intrathoracic spread should undergo neoadjuvant chemotherapy, followed by complete surgical resection. Thymomas are chemosensitive, with objective response rates of 67% to 100%, and complete response rates of 33% (range 7%–57%). Complete surgical resection following induction chemotherapy yields response rates of 69% to 92%, although results likely depend on surgical expertise.28 Some centers advocate induction chemotherapy protocols for thymomas >5 cm, and as treatment for locally recurrent thymomas prior to reoperation.29
Thymomas are also largely radiosensitive, and postoperative radiation therapy is increasingly utilized, particularly for locally advanced thymic tumors (e.g., stages II and III). Postoperative radiation was historically reserved for incomplete resections, but is now recommended by most large centers, particularly for stages II and III thymomas, even when resection is deemed complete.30 The present available data, however, does not support improvement in survival or overall recurrence, but does suggest that mediastinal recurrence may be reduced.31 Thus, radiation therapy immediately following resection for these tumors is reasonable, as is treatment for recurrences not amenable to reresection. Long-term surveillance is mandatory given the indolent biology of these tumors.
Chemotherapy is the primary modality for treatment of stage IV thymomas. Select patients with stage IVa thymomas, however, should be treated with neoadjuvant chemotherapy, followed by complete resection of all clinically evident disease. This has resulted in significantly improved 5-year and 10-year survivals (78% and 65%, respectively) for stage IVa patients.32 However, for resection to be “complete,” all pericardial and pleural implants should be widely excised, sometimes requiring pleurectomy, as well as lung resection (extrapleural pneumonectomy), in addition to thymectomy. Patients with evidence of extrathoracic disease (e.g., stage IVb) are not considered surgical candidates and are best treated with maintenance chemotherapy protocols. There is no established role for radiation therapy for stage IV disease.
Thymic carcinomas (WHO type C) are not associated with parathymic syndromes, but instead cause symptoms of local compression or invasion. These tumors are markedly aggressive and invasive. Most are either squamous cell carcinomas or are lymphoepithelioma-like carcinomas. Roughly, about two-thirds of thymic carcinomas are high grade, and one-third are low grade. The low-grade thymic carcinomas are usually well localized, whereas the high-grade types are usually found to have extensive spread, at presentation.9 While there is no established protocol for treatment of thymic carcinomas, most authors advocate a trimodality approach, including neoadjuvant chemoradiation followed by complete surgical resection.33 Complete surgical resection can only be performed in one-third of patients, and survival is markedly better for low-grade thymic carcinomas.5,13 Prognosis is poor for patients with nodal involvement, with a distant metastasis, with high-grade histology, or those with an incomplete resection.34
Thymic neuroendocrine tumors are rare, accounting for fewer than 5% of anterior mediastinal tumors. They can be further subdivided into typical thymic carcinoids (low-grade), atypical thymic carcinoids (intermediate-grade), and thymic small-cell carcinomas (high-grade).35 Collectively, they are all aggressive tumors compared with neuroendocrine tumors in other locations. Fifty percent of patients with a thymic carcinoid have an endocrine abnormality (e.g., Cushing syndrome or multiple endocrine neoplasia [MEN] syndrome). Expression of the carcinoid syndrome is, however, very rare.35 Complete surgical resection, if possible, is the desired approach, because thymic carcinoids respond poorly to adjuvant therapy. Surgical debulking for extensive thymic carcinoids is warranted in selected cases, as this may help to palliate symptoms and prolong survival.36 Octreotide therapy has also been shown to help palliate symptoms, particularly if the thymic carcinoid is associated with an endocrine syndrome. Thymic small-cell carcinomas are exceedingly rare, but likewise are aggressive, and are usually found to have extensive metastases on presentation. Surgery should only be offered for those with limited disease, or those who demonstrate a significant clinical response after induction therapy. Overall prognosis and survival is poor.35