There are relatively few malignant primary mediastinal tumors. However, the ability to distinguish one from another is important for the determination of tumor-specific treatment protocols, as well as tumor-specific outcomes. These tumors commonly occur in younger patients and often cause symptoms of acute hemodynamic embarrassment owing to compression of neighboring structures. A priori strategies and experience are essential in the management of these tumors.

ANATOMY AND PATHOLOGY

The mediastinum is divided into three compartments, as discussed in Chapter 137. Malignant posterior compartment mediastinal tumors are described in Chapter 138. Primary malignant mediastinal tumors tend to occur in the anterior compartment as compared with the middle compartment, which is occupied primarily by benign cysts. Malignant involvement of the middle compartment of the mediastinum occurs chiefly as a consequence of metastatic involvement of mediastinal nodes from pulmonary or esophageal cancers. Malignant mesenchymal tumors are rare, representing fewer than 5% of all primary malignant mediastinal tumors, and may occur in all compartments.¹ Most of these tumors are vascular or lymphatic sarcomas. All benefit from excisional surgery with the possibility of adjuvant therapies.¹

There are three primary malignant tumors that occur in the anterior compartment, and these constitute most of the malignant mediastinal tumors (Fig. 139-1). Each tumor type possesses unique biologic properties that separate it from the other anterior mediastinal tumors. In addition, each tumor type may have intratumoral diversity.

THYMOMA

Thymomas often occur in association with parathymic syndromes. Myasthenia gravis is the most common syndrome, occurring in 45% of patients (range 10–67%), followed by pure red blood cell aplasia (2–5%) and hypogammaglobulinemia (2–5%).² These tumors also may be associated with immune-modulated disorders, affecting either the neuromuscular or hematologic systems, as well as with other autoimmune, endocrine, and miscellaneous disorders.³

Thymic tumors are classified as noninvasive, invasive, thymic carcinoma, and neuroendocrine tumors of the thymus. Thymomas often demonstrate benign features on histologic examination. Invasiveness often is determined by histologic criteria demonstrating extracapsular invasion. This can occur irrespective of size, such that at least 30% of thymomas have invasion of the mediastinal fat.^3,4 The bland cytologic nature of these tumors has led some authors to refer to noninvasive thymomas as "benign thymomas." However, even stage I thymomas (i.e., encapsulated tumors without invasion) may recur and metastasize.⁵ These recurrences may be indolent; however, this behavior is a malignant characteristic that decries the nomenclature of thymoma.²

Clinical staging is helpful to determine the invasive nature of these tumors. The Masaoka staging system is the one used most widely (Table 139-1). Difficulties with the morphologic separation of these tumors and the prognostic significance of the separation of the Masaoka staging classification has led to the creation of a new World Health Organization classification^2,6–9 (Table 139-2). The value of this classification is that it includes all thymic tumors, including thymic cancers, and it separates organotypic (thymus-like) tumors from thymic cancers.¹⁰

The prognosis for these tumors depends on three interdependent parameters: histologic features, staging, and the status of resection (complete or incomplete).⁹ These three factors are used to gauge the invasive 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.² Long-term survival for thymoma has been directly related to stage, extent of resection, and histology.¹¹

The invasive nature of thymomas that allows for local recurrence (even for encapsulated early-stage thymomas) creates a surgical dilemma as to the route of excision for small thymomas that have no evidence of local invasion. It is this characteristic that gives physicians a reason to pause concerning the decision to perform a preoperative biopsy (capsular invasion occurs with tumor biopsy) and causes surgeons to reconsider sternal-sparing procedures for thymoma excision. Practical experience has demonstrated that tract seeding does not occur following thymic biopsies. However, in general, clinical acumen aided by evidence of parathymic syndromes may obviate the need for a preoperative biopsy. Definitive biopsy is needed to differentiate these tumors from lymphomas or to determine if preoperative neoadjuvant therapy is needed.²

With respect to the route of excision, the surgical literature is divided between those who espouse a sternotomy with removal of both the tumor and surrounding tissue to prevent local recurrence from microscopic invasion and those who advocate for a sternal-sparing procedure.^5,12 Invasiveness may be predicted based on the association of myasthenia gravis (primarily associated with B₁, B₂, and B₃ thymomas), calcifications, or a flat or irregular surface as compared with a round or oval shape.¹⁰ It is possible that the removal of small thymomas that do not display associated immune-modulated disorders and are small (<3 cm) and encapsulated may suffice with limited video-assisted thoracic surgery (VATS) incisions, such as for thymic hyperplasia.⁵

Extensive thymomas (e.g., stages III and IV) with obvious invasion are chemosensitive, with objective responses of 67–100% and complete responses of 33% (range 7–57%). Complete surgical resection following induction chemotherapy yields response rates of 69–92%, although results likely depend on surgical expertise.¹³ Thymomas are moderately radiosensitive. Most authors also would provide local radiotherapy as multimodality therapy for these locally advanced tumors.

The addition of postoperative radiotherapy for completely resected stage II or III thymoma is controversial in that overall recurrence is not reduced; however, mediastinal recurrence may be reduced.¹⁴ Thus radiation immediately following resection for these tumors is reasonable, as is surveillance with radiation reserved for recurrences not amenable to reresection. Long-term surveillance is mandatory given the indolent nature of these tumors.

Thymic cancers are not associated with parathymic syndromes but instead cause symptoms of local compression or invasion. These tumors are markedly aggressive and invasive. Most are squamous cell carcinomas, and the minority are lymphoepithelial-like. They may be associated with a translocation of chromosomes 15 and 19. Complete surgical resection can be performed in only a third of patients, and survival is better for low-grade tumors.^1,2

Thymic neuroendocrine tumors (formerly thymic carcinoids) are rare. They account for fewer than 5% of anterior mediastinal tumors. These are aggressive tumors compared with neuroendocrine tumors in other locations. Fifty percent of patients have endocrine abnormalities (e.g., Cushing's syndrome or multiple endocrine adenomatosis (MEA) syndrome). Rarely, however, is there expression of the carcinoid syndrome. Complete surgical resection, if possible, is the desired approach because these tumors respond poorly to adjuvant therapy. Consideration of radionuclide therapy for somatostatin receptor-positive tumors may improve survival.¹

PRIMARY GERM CELL TUMORS OF THE MEDIASTINUM

Germ cell tumors of the mediastinum are thought to arise from an embryogenic error during the migration of stems cells to the gonads. They account for 50–75% of extragonadal tumors and for 10–15% of primary mediastinal masses.³ They also account for 10–15% of anterior mediastinal masses. They are divided into four categories:

1. Teratoma with benign clinical course. These tumors may present as immature or mature lesions. The mature teratoma presents in prepubertal and postpubertal patients. A tumor is defined as mature if it has fewer than 50% immature elements. The immature form is found only in prepubescent patients.^3,15

2. Malignant teratoma. Malignant teratomas generally have more than 50% immature elements. They present in postpubescent patients. The malignant teratomas include germ cell tumor, sarcoma, and mixed tumors.

3. Seminoma. These tumors are the most frequent malignant germ cell tumors.

4. Nonseminomatous germ cell tumors of the mediastinum. As with seminomas, most postpubertal malignant mediastinal germ cell tumors occur in males.^1,16

Benign and Malignant Teratomas

Benign prepubertal teratomas do not show any sex predilection. Postpubertal teratomas may occur equally in either sex or they have a slight female preponderance.^1,17 These tumors were described in Chapter 137. Surgical resection of these tumors is often complicated because the tumor adheres to adjacent structures. Tumors with immature elements found after resection should be considered for treatment with adjuvant chemotherapy and/or irradiation if the patient is postpubescent, as should teratomas in which more than 50% of the tumor is composed of immature elements.¹⁵

Teratomas may develop additional malignant elements from germ cell elements, which may be detected by the isochrome 12p marker. However, other malignant cell lines can develop from immature elements, of which the most common is sarcoma. These tumors are notoriously resistant to the usual chemotherapy regimens.¹⁶ The presence of a malignant germ cell line in a teratoma is associated with a recurrence rate of 25%. However, if the malignant element is a sarcoma (commonly rhabdosarcoma or angiosarcoma), the prognosis is grave, and recurrence is common. Adjuvant treatment after resection in cases of malignant sarcomatous transformation should be directed against the recurrence of the sarcomatous element.^15,16

Mediastinal Seminomas and Nonseminomatous Germ Cell Tumors

Mediastinal seminomas may contain elements of thymic tissue, suggesting the thymus as a primary site of origin. These tumors rarely secrete identifying hormones. A biopsy (CT-guided core or minimal surgical incision) is required to establish their identity. Immunohistochemistry will help to further identify and differentiate these tumors if nonseminomatous elements are present.¹⁶ Occasionally, they may be associated with elevated beta-human chorionic gonadotropin but not alpha-fetoprotein. They often metastasize (60–70%), often to lymph nodes. However, despite their metastatic potential, they have a very favorable prognosis (88% 5-year survival), akin to gonadal seminomas, when treated with chemotherapy or radiotherapy for local disease.^1,3

Mediastinal seminomas and germ cell tumors may demonstrate histologic and morphologic features as well as chemosensitivity similar to testicular germ cell tumors. However, the nonseminomatous germ cell tumors (NSGCTs) demonstrate a clinical course and biologic behavior pattern associated with markedly inferior prognosis compared with gonadal germ cell tumors.^16,18–20 The salient divergent points between malignant mediastinal and testicular germ cell tumors are the inferior sensitivity of mediastinal NSGCTs to chemotherapy and the treatment of tumors with elevated tumor markers after chemotherapy. Attempts to deal with the inferior chemosensitivity of mediastinal NSGCTs have included dose escalation and intensive chemotherapy regimens with peripheral stem cell transplantation.^19–21

Surgical resection of testicular NSGCT is indicated for residual masses with normalized serum tumor markers, patients with a late relapse, or for desperation salvage resections. Mediastinal NSGTC tumors, however, that relapse following chemotherapy have poor response to salvage chemotherapy, unlike testicular tumors. Furthermore, the presence of elevated serum tumor markers after chemotherapy does not reflect the status of residual viable tumor. However, elevated serum tumor markers after chemotherapy and, in particular, viable tumor after resection are adverse prognostic markers.^19,20,22 A large series of mediastinal NSGCTs has shown that in postchemotherapy treated tumors, elevated serum tumor markers occur in 28% of patients with benign tumors, 44% of patients with persistent germ cell tumors, and 66% of patients with malignant non-germ cell cancers.¹⁹ Expectations of postchemotherapy pathology for mediastinal NSGCTs include necrosis (25.5%), teratoma (34%), and persistent germ cell tumor (31.4%).

MEDIASTINAL LYMPHOMA

Mediastinal lymphoma commonly occurs as a manifestation of systemic disease; however, in 5% of cases the mediastinum is the only site of disease occurrence. Primary mediastinal lymphoma is derived from thymic lymphocytes. Commonly, if the thymic lymphocytes develop into lymphoma, they devolve into Hodgkin disease; however, they also may degenerate into non-Hodgkin B-cell lymphoma or lymphoblastic lymphoma. Mediastinal lymphoma accounts for 20% of mediastinal tumors in adults and 50% of mediastinal tumors in children. These tumors may occur in any compartment, but typically, Hodgkin lymphoma has a predilection for the anterior mediastinum. These tumors are well described by Priola and colleagues,³ Macchiarini and Ostertag,¹ and Savage.²³ The diagnosis is often achieved by CT-guided core biopsy. Surgery is required only for CT biopsy failures or to diagnose residual masses after chemotherapy.

Hodgkin Lymphoma

Hodgkin lymphoma exhibits a bimodal distribution (adolescence and early adulthood). It is commonly discovered as an asymptomatic radiographic finding. The most common variant is the nodular sclerosing type. The disease has a predilection for young women. Patients with early-stage disease require radiation and chemotherapy and have an excellent prognosis.

Non-Hodgkin Lymphoma

Patients with non-Hodgkin lymphoma present with diffuse disease. Eighty-five percent of patients present with advanced disease and systemic symptoms. Prognosis depends on histology rather than extent of disease. It has a predilection for young woman who present with rapidly growing masses and acute symptoms. Infiltration of the superior vena cava and neighboring organs is common. In comparison with diffuse B-cell lymphoma, primary mediastinal B-cell lymphoma lacks immunoglobulin production. Treatment consists of multidrug chemotherapy with the addition of rituximab; autologous stem cell transplantation also may reduce recurrences. Treatment failures occur in the first 6–12 months; recurrences after 2 years are rare.

Residual masses after chemotherapy are diagnostic challenges as to whether they harbor fibrosis or active lymphoma. Consolidative radiotherapy has been used as a preventive measure. However, it is unclear as to its effectiveness in preventing relapses, and there is a concern about the long-term toxicity of mediastinal irradiation. Common diagnostic methods for dealing with residual masses are gallium or PET scans as inferences of disease relapse or surgical biopsies for confirmation.

Lymphoblastic Lymphoma

Lymphoblastic lymphoma is often an aggressive tumor. It occurs typically in adolescent males. It is the most common mediastinal lymphoma of children. This high-grade malignancy requires high-dose intensive chemotherapy.

Surgery for removal of mediastinal tumors other than lymphoma may be accomplished by several means. Minimal-access surgery (i.e., sternal-sparing surgery), as outlined in Chapter 137, may be used for early-stage encapsulated thymomas. The intrinsic concern with this approach is the potential for local recurrence. Sternal splitting procedures with the addition of cardiopulmonary bypass and possibly major vessel resection and reconstruction also may be used, that is, vertical sternotomy, clamshell procedures, or a Dartevelle procedure with trapdoor extension as needed (see Fig. 139-1). Finally, mediastinal tumors may be approached by posterior thoracotomy.

EDITOR'S COMMENT

Almost all patients with large mediastinal tumors—in the >8 cm range—will benefit from a multimodality approach. A critical surgical task is to help establish an accurate histologic diagnosis and facilitate treatment planning, a task complicated by cell type heterogeneity within many mediastinal tumors. Ample biopsies and a preliminary identification of "lesional tissue" by pathologists during the operation are essential for an accurate diagnosis.

–SJM

REFERENCES