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Anterior mediastinal lesions

Antonio D’andrilli, Erino Angelo Rendina and Federico Venuta

The mediastinum is a virtual three-dimensional space located between the lungs, above the diaphragm, posteriorly to the sternum, and anteriorly to the spine. The thoracic inlet (or outlet) is open toward the neck. Due to its complexity, the great number of anatomical structures and the list of disorders that may affect them, the mediastinum is classically divided into compartments. The classification is extremely useful to drive a differential diagnosis for a given mediastinal mass. The classical anatomical classification of the mediastinum reports four compartments: anterior, superior, middle, and posterior. The anterior and the superior compartments are often unified in a single region (the anterosuperior compartment) since most of the disorders affecting one of them usually involve, or might involve, the other. The anterior compartment is bounded anteriorly by the posterior aspect of the sternum and posteriorly by the pericardium. The superior compartment is that territory above an imaginary line drawn from the sternomanubrial junction and the inferior border of the fourth thoracic vertebra. The union of these two regions corresponds to what Shields called the “prevascular zone.” ¹ This space contains mediastinal fat, the thymus, and lymph nodes. Since germ cell tumors can arise within this region, germ cell remnants are theoretically assumed to be present; however, they are seldom found in a nonneoplastic state. In addition, ectopic parathyroids are occasionally found, sometimes embedded within the thymus. Also, it is in these compartments that the thyroid gland can descend as a retrosternal goiter.

The most common tumors in this region are thymoma, lymphoma, germ cell tumor, and parathyroid adenoma.

THYMOMA

Tumors of the thymus gland are known as “thymomas.” Although these lesions are relatively rare, they account more than 50% overall making them the most common anterior mediastinal masses. ² , ³ They can present both as small, round, encapsulated lesions or huge infiltrating masses involving the surrounding structures. Calcifications can be found in approximately 10%-20% of the cases.

Thymomas are often associated with a variety of parathymic syndromes. The most frequent is myasthenia gravis (MG), which has been reported in up to 45% of these patients. The presence of this condition in association with an anterior mediastinal mass is usually pathognomonic for a thymoma.

Although thymoma may occur at all ages, this disease is more frequent in those aged between 40 and 70 years. Patients with MG tend to be slightly younger, with a peak between 30 and 60 years. Only 10%-15% of the patients with MG are found to have thymoma. ⁴

Therefore, in adult patients with MG and a typical presentation on computed tomography (CT) scan, the diagnosis of thymoma appears very likely. In such cases, a biopsy to confirm diagnosis is generally considered not necessary and surgical resection based on clinical findings is justified when feasible without induction therapy.

At younger ages, without MG, if the mediastinal lesion has no typical radiographic features, histological confirmation is required, particularly for large infiltrating masses.

Fine needle or core biopsy should be preferred as a first step; however, these procedures frequently yield insufficient material, with subsequent need for surgical sampling through anterior mediastinotomy or (more rarely) thoracoscopy. The average sensitivity of needle biopsy has been reported as high as 60% compared with approximately 90% of surgical approach; however, the ability to accurately determine the exact histology of thymoma on a limited biopsy has been reported as low. ⁵

Management of stage I and II thymic tumors

Surgical resection is the gold standard of thymoma treatment, resulting in high overall and disease-free survival rates in patients with stage I and II disease.

In a review including a series with more than 100 patients, Detterbeck and Parsons reported 5-year survival rates ranging from 80% to 100% after resection of stage I thymoma, with an average rate of 91%. ⁴ An average 5-year survival of 80% was reported for stage II thymoma, with a higher variability in results among the series (range 42%-100%). Average overall 10-year survival rates were 87% (range 75%-100%) for stage I and 67% for stage II. The average recurrence rate was 3% after resection of stage I tumor and 11% for stage II thymoma.

Complete resection is the norm and is expected for stage I tumors. For stage II lesions an average complete resection rate of 87% has been reported, but wide variation among different studies exists. ⁶

Recommendation for total thymectomy is made even when the thymoma involves only a limited portion of the gland, although no definitive evidence has been demonstrated to support this recommendation.

PREOPERATIVE ASSESSMENT FOR THYMOMA

1. The tumor usually is first detected on a chest radiograph. The extent of the tumor can be well evaluated by conventional chest CT and magnetic resonance imaging (MRI). An exact histological diagnosis is very important to differentiate thymomas from other malignant thymic tumors, especially when the lesion appears to be locally invasive. CTguided biopsy, anterior mediastinotomy, or rarely a thoracotomy is used for this purpose. (See Figure 9.1.)

ANESTHESIA FOR THYMOMA

If airway compromise is present, awake endotracheal intubation should be considered. Otherwise, general anesthesia can be induced in the usual manner. A double lumen endotracheal tube is indicated for procedures where a partial lung resection may be indicated. Central venous pressure should be carefully monitored if the venous return is impaired. A thoracic epidural catheter is placed for intraoperative and postoperative pain management. In cases of MG, the anesthesia should be managed accordingly with careful attention paid to the appropriate use of neuromuscular blocking agents.

OPERATION FOR THYMOMA

Preparation for tumor resection

1. An extended total thymectomy, including the tumor in conjunction with resection of any invaded adjacent structure, is the ultimate goal. The anterior mediastinum is entered through a full median sternotomy. The intact part of the thymus is first dissected along with pericardium if involved. When the mediastinal pleura is invaded by the tumor, the pleura is incised and taken with the specimen. If invasion into the lung is present, partial resection is performed with a linear stapler. Thus, the thymus and the tumor can be freed from the surrounding structures, except for the SVC and brachiocephalic veins if they are involved. The right and left brachiocephalic veins should be dissected sufficiently distal to the tumor invading site and encircled with cotton umbilical tape. The SVC is also mobilized and encircled with tape, either inside or outside the pericardium, depending on the extent of tumor invasion to the SVC. The azygos vein above the pulmonary hilum and the internal mammary vein are separated and divided between the ligatures. The phrenic nerve is sacrificed if absolutely necessary to achieve a complete resection. (See Figure 9.2.)

Reconstruction of the left brachiocephalic vein and the superior vena cava

1. In general, reconstruction is first performed between the left brachiocephalic vein and the right atrium, followed by reconstruction between the right brachiocephalic vein and the SVC. After heparin sodium is intravenously administered, the left brachiocephalic vein is occluded distally with an atraumatic vascular clamp and ligated proximally, and then divided. An anastomosis between the distal stump of the left brachiocephalic vein and the appendage of the right atrium is performed using a ringed Gore-Tex 8.0 mm graft secured with a 5-0 monofilament polypropylene suture by a simple continuous technique. (See Figure 9.3 a and b.)
   
2. The right brachiocephalic vein is occluded distally and the SVC proximally, and both veins are divided on the tumor side. Thus, the thymus, including the tumor, is completely removed. The SVC is reconstructed in the same manner as the left brachiocephalic vein using a ringed Gore-Tex 10.0 mm graft. Some surgeons believe that one brachiocephalic vein is adequate to return blood from the upper half of the body to the heart. Reconstruction of the right brachiocephalic vein can be abandoned without major complications, except for transient swelling in the right upper extremity. In this instance, effort should be made to leave the azygos vein intact. (See Figure 9.4.)

Complications

Major complications are rarely encountered. Occlusion of the graft, particularly that used for the left brachiocephalic vein, sometimes occurs, because it is long and could be compressed by the sternum and ascending aorta. When both veins are reconstructed, however, occlusion of only one graft may not cause a problem. Postoperative respiratory failure may be related to the severity of the associated MG and complicated if the phrenic nerve was sacrificed. As patients with MG have a relatively early stage thymoma, this ominous combination is quite rare.

OUTCOME FOR THYMOMA

The clinical staging system for thymomas devised by Masaoka, which is based on the local extension of the tumor, has been shown to best reflect the prognosis, and the significance of staging by this system has been validated by several other institutions. ⁷ A brief description of Masaoka’s criteria is presented in Table 9.1.

Among 194 consecutively treated patients with thymoma who underwent a complete resection or subtotal resection at our institution, the 10-year and 20-year survival rates were, respectively, 99% and 90% for stage I disease, 94% and 90% for stage II tumors, 88% and 56% for stage III disease, 30% and 15% for stage IVA lesions, and 0% and 0% for stage IVB tumors. ⁸ In addition, the 10-year and 20-year survival rates for patients with stage III disease were, respectively, 97% and 75% when no involvement of the great vessels was present, and 70% and 29% when these vessels were involved. Thus, involvement of the great vessels was the single independent prognostic factor in patients with stage III disease, by multivariate analysis.

The TNM [tumor node metastasis] Classification of Malignant Tumors staging system has been also proposed for thymoma with limited acceptance, particularly because prognosis and treatment strategies for this tumor are mainly influenced by the T status, which is well described by the Masaoka system, while mediastinal node involvement (N factor) has a minor significance.

Pathologic classification has been reported as an additional factor potentially influencing prognosis and it should be considered for tumor management. ⁹

The World Health Organization (WHO) classification was originally proposed in 1999 and it is now the most widely adopted. ¹⁰ This system has several similarities to the previously used Müller-Hermelink classification ¹¹ and recognizes six different types of thymic tumor (see Table 9.2): A, AB, B1, B2, B3, and C.

However, although currently considered the most detailed pathologic system, its clinical relevance in predicting long-term outcome and guiding clinical management is controversial. Studies assessing its prognostic significance by multivariate analysis generally indicate the WHO pathologic category to be an independent prognostic factor, although clinical stage always represents the most significant factor for prognosis. ¹² There is general evidence that histologic type C is related to worse survival, and that type B3 is predictive of intermediate survival, while no clear correlation with prognosis has been defined for other subtypes due to conflicting and nonhomogeneous results across studies. ⁷

ADJUVANT THERAPY

Only limited data are available in the literature to assess the role of adjuvant therapy after resection of early stage (I and II) thymoma. Little or no role has been generally reported for adjuvant chemotherapy at this stage.

In two large retrospective studies, Ströbel et al. and Singhal et al. showed no evidence of increased survival rates with adjuvant RT in completely resected and margin-negative stage I and II thymomas. ¹³ , ¹⁴ Based on the findings of these two studies one could conclude that no additional treatment is required if a complete resection of early stage thymoma is accomplished.

In the largest published series, of 1320 patients with thymoma from 115 centers, Kondo and Monden showed that prophylactic mediastinal radiotherapy was not effective in preventing recurrences in patients with radically resected stage II and III thymomas. ¹⁵

Management of stage III thymic tumors

Thymic tumors invading the surrounding structures such as the pericardium, great vessels (SVC, innominate veins and arteries, aorta, and pulmonary artery), lung, diaphragm, and chest wall are classified as Masaoka stage III. These tumors often provide a major surgical challenge, mainly due to the need for extended resections and even complex reconstructive procedures.

The brachiocephalic veins, SVC, lung, pericardium, right atrium, and diaphragm can be safely resected with or without reconstruction increasing the complete resection rate. ¹⁶ – ¹⁸ Also, resection and reconstruction of the aorta and the main pulmonary artery may be indicated in selected cases to achieve complete resection. ¹⁹

Extended and technically demanding operations can be justified at this stage, since, if complete tumor removal is accomplished, survival rates can be achieved that are comparable to those of patients with stage I and II disease. ²⁰

Regnard and colleagues ²¹ reported a 75% 10-year survival rate after radical resection of stage III thymoma.

Since these tumors have been documented to be chemoresponsive, attempts have been made in recent years to increase their resectability rate by the administration of preoperative induction chemotherapy. ²⁰ , ²²

An average recurrence rate of 26% was reported from literature data of stage III patients treated between 1980 and 2002. ²³ The average 5-year survival of stage III tumor patients was 78% after induction chemotherapy plus surgery, compared with 65% after surgery alone. ²³ However, most series using induction chemotherapy have excluded patients with thymic carcinoma, while series of resection alone have generally included these patients.

Management of stage IV thymic tumors

Current treatment strategies for Masaoka stage IV thymic tumors include different strategies for stage IVA and IVB. Stage IVA tumors presenting with pleural or pericardial dissemination are generally treated by a multimodal approach including surgery, chemotherapy, and sometimes radiotherapy. ²⁴ At stage IVB, chemotherapy is the recommended treatment without surgical resection though resection. has been considered in selected cases. ²⁵

Chemotherapy has been promoted for stage IVA, usually as an induction agent but also in an adjuvant fashion in association with resection with the aim of increasing progression-free survival.

Several surgical options have been proposed: partial or complete pleurectomy associated with thymectomy or, in selected cases, pleuropneumonectomy. ²⁶ Pleurectomy is a viable option allowing encouraging long-term survival (43% at 5 years) when associated with either induction or adjuvant chemotherapy. ²⁷ Pleuropneumonectomy has been proposed as a possible option in selected cases with extensive and confluent pleural disease invading the lung and precluding gross tumor removal with pleurectomy. ²⁶ Although this approach may look excessively aggressive, the biologic behavior of this tumor that usually is consistent with long-term survival even in the presence of recurrence seems to support the rationale for such an operation. Induction chemotherapy is generally administered to improve results. Irradiation has been beneficial in an adjuvant setting.

Residual microscopic or macroscopic infiltration after resection of stage IV thymoma is a frequent finding regardless of the surgical option that has been adopted. Some additional local treatments have been therefore experimentally proposed for these patients.

LYMPHOMA OF THE MEDIASTINUM

Many histologic subtypes of lymphoma can arise in the chest, but only few of these present with isolated mediastinal localization. Those with potential primary mediastinal presentation include: Hodgkin lymphoma, large B-cell lymphoma, lymphoblastic lymphoma, and pulmonary mucosa-associated lymphoid tissue lymphoma. Although marked geographic variability is reported in the incidence of lymphoma subtypes, Hodgkin lymphoma generally represents about 10%-15% of the total number of new cases, with stable numbers over the last decade, while non-Hodgkin lymphoma subtypes account for about 85%-90%, with a progressive increase over the last years. ²⁸

Clinical presentation may be similar among different subtypes, as most of these neoplasms generally appear as large invasive anterior mediastinal masses with possible involvement of the surrounding structures.

Possible symptoms are attributable to compression from the enlarging neoplasm and can include chest pain, cough, dyspnea, wheezing, stridor, dysphagia, and signs referable to superior vena cava syndrome. Pericardial effusion is sometimes present and can be occasionally responsible for cardiac tamponade. Asymptomatic presentation is infrequentbut is more frequently observed in patients with Hodgkin lymphoma and large B-cell lymphoma as opposed to other types.

Surgery has a limited role in the management of lymphoma, since the treatment is almost exclusively based on chemotherapy with or without radiotherapy. Thus, surgery usually plays only a diagnostic role, as adequate tissue sampling is crucial for a precise histological definition and subsequent treatment.

Correct histological diagnosis can sometimes be achieved by less invasive approaches such as percutaneous fine needle aspiration (FNA) or core biopsy (generally under CT guidance) or by more invasive surgical procedures for biopsy, including anterior mediastinotomy, mediastinoscopy, and videothoracoscopy. ²⁹ , ³⁰

Surgical biopsy

Although more invasive than percutaneous procedures, surgical approaches, including anterior mediastinotomy, mediastinoscopy, and videothoracoscopy, certainly represent the most effective diagnostic options for patients with mediastinal lymphoma. These techniques establish definitively a specific histologic diagnosis and provide adequate tissue for phenotyping avoiding more extended surgical approaches such as thoracotomy and sternotomy. ³⁰

Anterior mediastinotomy is the most commonly used procedure for lesions presenting in a retrosternal location. We reported the possibility of safely and effectively performing a biopsy using this approach under local anesthesia. ³¹

Mediastinoscopy is the procedure of choice when the tumor is present in the paratracheal or subcarinal region. Videothoracoscopy may also be a valid alternative.

GERM CELL TUMORS

Germ cell tumors, though exceedingly rare, represent 10%-20% of all anterior mediastinal masses. These tumors comprise three histologic categories: (1) mature teratoma, (2) seminomatous germ cell tumor, and (2) nonseminomatous germ cell tumor. ³² A specific staging classification has been proposed for these tumors ³³ (see Table 9.3).

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