The anterior mediastinum represents the second most

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1 Technique of Mediastinal Germ Cell Tumor Resection Kenneth A. Kesler, MD The anterior mediastinum represents the second most common site of germ cell tumor origin. Nonseminomatous germ cell cancers not only comprise the main category of the malignant germ cell tumors arising in the mediastinum (PMNSGCT) but also the most challenging from both oncologic and surgical standpoints. Although histologically similar to their more commonly occurring testicular counterparts, PMNSGCT have an overall worse prognosis and therefore have been categorized as poor risk along with other subsets of testicular nonseminomatous germ cell tumors. The majority of PMNSGCTs occur in males 20 to 40 years of age. Most patients present symptomatic secondary to a rapidly growing anterior mediastinal mass. Computed tomographic (CT) scans typically demonstrate a large heterogeneous mass. Local invasion into lung, great vein, and pericardium is common and even direct cardiac chamber/proximal great artery involvement can occasionally be present. Associated pericardial and pleural effusions are also common but typically not malignant in nature. For any young adult male presenting with a mass in the anterior mediastinal compartment, obtaining serum tumor markers (STMs), alpha-fetoprotein, and human chorionic gonadotropin is an essential component of clinical evaluation as significant elevation of either STM is diagnostic for PMNSGCT. Biopsy in these cases is not only unnecessary but can be misleading due to sampling error within these typically large and heterogeneous neoplasms. We believe biopsy confirmation is only necessary in rare PMNSGCT patients presenting with normal STMs or patients with minor elevations of human chorionic gonadotropin, which can be present in pure seminomatous germ cell cancer. Histologically, these neoplasms comprise at least one nonseminomatous germ cell cancer subtype (yolk sac cancer, embryonal carcinoma, or choriocarcinoma in order of frequency), and frequently are mixed with some form of pathologic teratoma ranging from mature teratoma to teratoma with immature elements ( stromal aytpia ), and finally, to frank malignant degeneration of teratoma into the so-called Department of Surgery, Cardiothoracic Division, Indiana University School of Medicine, Indianapolis, Indiana. Address reprint requests to Kenneth A. Kesler, MD, Indiana University Department of Surgery, Cardiothoracic Division, Barnhill Drive EH #215, Indianapolis, IN kkesler@iupui.edu nongerm cell cancer (sarcomas and epithelial carcinomas). Chest and abdominal CT scans are standard imaging tests for staging with other radiologic studies including positron emission tomography scan and central nervous system magnetic resonance imaging obtained on an individual basis. Gated magnetic resonance imaging or echocardiogram can be helpful to determine the presence of great vessel or cardiac involvement; however, invasion may be subtle and only apparent at the time of postchemotherapy surgical resection. We therefore have cardiopulmonary bypass capabilities available for these cases. After diagnosis and staging, surgical resection for PMNSGCT as initial therapy will rarely achieve local control and does not treat metastatic disease, present in 20 to 25% of cases. Appropriate therapy typically begins with cisplatin-based chemotherapy. Over the past 3 years we have utilized etoposide, ifosfamide, and cisplatin (VIP) for combination chemotherapy to eliminate the possibility of pulmonary toxicity with bleomycin before a major thoracic surgical procedure. 1 Following chemotherapy, there is typically resolution of pleural and pericardial effusions and a significant decrease in STMs. There is also typically a reduction in tumor dimensions. However, a residual mediastinal mass (RM) is still invariably present and pathologically contains complete tumor necrosis only in a distinct minority of cases. Therefore, teratoma, persistent nonseminomatous germ cell cancer, or degenerative nongerm cell cancer is pathologically present in most RMs for which surgery is indicated. Optimally STMs normalize and surgery is planned after adequate functional and hematologic recovery, which usually occurs between 4 and 6 weeks following completion of chemotherapy. Although prechemotherapy STMs are highly sensitive and specific to establish a diagnosis of PMNSGCT, unfortunately, postchemotherapy STMs notoriously lack predictive value for either residual malignant or benign pathologic conditions. Additionally, second-line chemotherapy has a very poor response rate for PMNSGCT refractory to first-line therapy. 2 It has therefore been our policy over the past decade to recommend surgery for patients deemed operable after first-line chemotherapy with persistently elevated or even rising STMs. In this same regard, resection of the RM must proceed carefully with frozen section control of close surgical margins even in patients with normal preoperative (postchemotherapy) STMs as up to a third of patients with /09/$-see front matter 2009 Elsevier Inc. All rights reserved. doi: /j.optechstcvs

2 56 K.A. Kesler normal STMs will pathologically demonstrate malignant elements (germ cell or nongerm cell cancers). Occasionally PMNSGCT patients will demonstrate the so-called growing teratoma syndrome with paradoxical growth of a mediastinal mass associated with a rapid decrease of STMs during chemotherapy. Chemotherapy should be discontinued and surgery undertaken if feasible in these situations. Of note, however, although teratoma is pathologically identified in many of these cases, over 50% of patients presenting for surgery at our institution with this clinical scenario have pathologically demonstrated areas of degenerative nongerm cell cancer or occasionally persistent nonseminomatous germ cell cancer in the RM. Surgery The basic premise of our surgical approach involves a complete en-bloc removal of the RM, thymus, and surrounding involved structures. Surgery for PMNSGCT is technically demanding as preoperative chemotherapy renders surrounding mediastinal tissues fibrotic, obscuring normal anatomic planes. The effectiveness of cisplatin-based chemotherapy for germ cell cancer, however, also usually results in extensive tumor necrosis, which is more marked around the periphery. This finding usually allows a complete resection, which minimizes operative morbidity by preserving critical structures that abut but are not densely adherent to nor directly involved with the RM, such lung, great veins, phrenic nerves, and occasionally, cardiac chambers where the pericardial barrier has been violated. In general, we believe aggressively removing all visible residual disease but balancing dissectionsparing critical structures with liberal frozen section analysis is warranted. This approach has allowed resection of virtually all RMs, including extremely large RMs, with tumor-free margins. Although all PMNSGCT arise in the anterior mediastinal compartment, the exact location, size, and degree of adjacent organ involvement of postchemotherapy masses are extremely variable. The most critical initial decision therefore is the determination of the surgical approach. A median sternotomy, bilateral anterior thoracotomy with transverse sternotomy (or the so-called clamshell incision), or anteriolateral thoracotomy is chosen to optimize dissection around critical structures anticipated to be encountered at the time of surgery. Based on cases referred to our institution, we currently utilize sternotomy and clam approaches with approximate equal frequency and thoracotomy somewhat less often.

3 Mediastinal germ cell tumor resection 57 Operative Technique Figure 1 (A) CT of patient who underwent a sternotomy approach to remove a moderate-sized RM after chemotherapy. Note the RM is substernal with no extension toward either pulmonary hilum, which makes sternotomy the approach of choice. (B) Standard sternotomy approach to this residual mass. Only en-bloc removal of the thymus and pericardium was required in this case.

4 58 K.A. Kesler Figure 2 (A) CT of a patient who underwent a sternotomy approach to remove a moderate-sized RM after chemotherapy. Note extension into the right pulmonary hilum in addition to the substernal component. (B) With the use of sternal retractors used to mobilize internal thoracic arteries for coronary bypass procedures and instruments designed for minimally invasive pulmonary surgery, en-bloc pulmonary resection can be accomplished through this approach. In this case, extension into the pulmonary hilum precluded wedge resection. En-bloc right upper and middle lobectomies and pericardectomy with resection of the right phrenic nerve resection were required. Although a clamshell approach could have been utilized in this patient, the sternotomy approach facilitated recovery. The sternotomy approach also provided better exposure to the anterior compartment as compared with a thoracotomy approach.

5 Mediastinal germ cell tumor resection 59 Figure 3 (A) CT of a patient who underwent a clamshell approach to remove a large RM after chemotherapy. Note a large substernal component and significant extension into the left pleural space with effacement of pulmonary hilum. (B) Patient positioning is supine with both arms crossed, padded, and then secured to an ether screen above the head. In this case, the incision extended from the right mid clavicular line to the leftward mid axillary line. En-bloc left bracheocephalic vein, left upper lobectomy, and pericardectomy was required based on intraoperative findings.

6 60 K.A. Kesler

7 Mediastinal germ cell tumor resection 61 Figure 5 Although many RMs abut the parietal pleura, we have encountered chest wall/sternal involvement, requiring en-bloc resection in only 3 of 176 total PMNSGCT patients surgically treated at our institution to date. For most cases where the CT scan shows the RM to abut the chest wall, however, there is no evidence of frank chest wall/sternal involvement, and we begin with an extrapleural dissection until it can be determined that the RM does or does not involve the parietal pleura. The pleural space is entered at any point if the RM is found not to be adherent. If the RM is adherent, then at least a 1-cm rim of visibly normal parietal pleura is removed en bloc with a frozen section of the pleural margin. From this point, given the variability in the location, size, and degree of adjacent organ involvement of postchemotherapy masses, unfortunately there is no consistent step-by-step surgical routine. In general, however, a surgical strategy proceeding from the most easy to the most difficult works best. We typically begin by dissecting adherent lung tissue from the RM, particularly if this involves lysis of filamentous adhesions or stapled wedge resection, removing a rim of lung parenchyma more densely adherent to the RM. Stapled wedge resection is facilitated by passage of a red rubber catheter between the RM and pulmonary hilum for elevation and lateral retraction of the lung parenchyma before stapler division. Invasion of the RM into a significant amount of pulmonary parenchyma or pulmonary hilum usually requires formal anatomic resection, which can be done at this point or after further dissection. In our institution s experience, over half of the PMNSGCT patients require some form of en-bloc pulmonary resection. Formal lobectomy has been required in approximately one-third of patients, wedge resection in 20%, and total pneumonectomy in 5% of cases. 4 Figure 4 CT of two patients who underwent a right (A) and left (B) thoracotomy approach to remove moderate-sized RMs after chemotherapy. Note no substernal component to the RM in either patient. (C) The patient is positioned in the normal lateral decubitus position and then slightly rotated outward. Padding and then securing the ipsilateral arm to an ether screen can improve exposure to the anterior chest. Critical structures anticipated during dissection in these types of cases are the pulmonary hilum and phrenic nerves bilaterally. The superior vena cava will additionally be encountered during dissection of the rightward mass and the vagus nerve with its recurrent branch will be encountered on the left. The pericardium is usually a successful barrier to tumor involvement of the ascending aorta by the right-sided RMs and main pulmonary artery by the left-sided RMs; however, provisions to surgically remove portions of these great arteries including the availability of cardiopulmonary bypass for cases of RM involvement should be made.

8 62 K.A. Kesler Figure 6 We typically proceed with dissection of uninvolved tissues superior and inferior to the RM. The thymic horns are rarely involved and can be easily mobilized from the neck. Below, the pericardial fat is mobilized along with uninvolved contiguous thymic tissue to within 1 cm of the RM. Typically the RM is densely adherent to the pericardium. As there is little downside to pericardectomy, no attempt is made to separate the RM from the pericardium and the pericardium is removed en bloc with a 1-cm tumor-free margin. Inspection of underlying cardiac structures including determination if the RM has transgressed the pericardial barrier is made at this time. Occasionally inflammatory adhesions to the epicardial surface are present and can be lysed with frozen section control. Division of the pericardium around the inferior aspect of the RM may also facilitate dissection around more critical structures such as great veins and phrenic nerves. Many pericardial defects are of no consequence. Pericardial reconstruction should be performed, however, by using either fenestrated permanent thinwalled prosthesis or absorbable mesh prosthesis, where any possibility of cardiac herniation exists. v. vein.

9 Mediastinal germ cell tumor resection 63 Figure 7 Many RMs are in proximity to the left bracheocephalic vein. Although an attempt is made to spare the left bracheocephalic vein with frozen section control where there is no radiographic or visible evidence of frank invasion, if the RM is found to be densely adherent to the left bracheocephalic vein, then en-bloc removal without reconstruction is warranted as there is typically only minor and temporary left upper extremity venous insufficiency in these cases. If both bracheocephalic veins and the superior vena cava (SVC) are removed en bloc with the RM, which in our experience has been necessary in approximately 10% of cases, we prefer unilateral right bracheocephalic to SVC reconstruction utilizing an externally stented polytetrafluoroethylene vascular prosthesis. Care must be taken to avoid injury to the right phrenic nerve if it has been preserved during clamping of the right bracheocephalic vein and SVC. The proximal anastomosis is done first, followed by the distal anastomosis after the prosthesis is cut to length by using 5-0 polytetrafluoroethylene suture. Although somewhat more difficult than left bracheocephalic reconstruction, we believe that the straight, short, and downward course of a right bracheocephalic to SVC vascular prosthesis along with a higher venous flow if the left bracheocephalic vein is not reconstructed will promote patency. We have reconstructed partial SVC defects with a patch of autologous pericardium. n. nerve; SVC superior vena cava; v. vein.

10 64 K.A. Kesler Figure 8 One phrenic nerve is almost always found in close proximity to the RM. When there is clear evidence of frank unilateral phrenic nerve invasion with preoperative CT evidence of diaphragmatic paralysis, early en-bloc phrenic nerve resection will then facilitate the remaining dissection including exposure to hilar structures. More commonly, the ability to spare or the necessity to remove a phrenic nerve in close proximity to the RM can only be determined at the time of surgery however. In these cases, phrenic nerve dissection is best deferred until the later stages of the surgical procedure. The pericardiophrenic fat can be densely adherent to the RM and at times inperceivably blends into the fibrotic soft tissue surrounding the RM. In these cases an attempt at freeing the phrenic nerve with frozen section control can be challenging but minimizes short- and long-term morbidity. When a sternotomy approach has been utilized, we prefer using a standard sternal retractor during periphrenic nerve dissection as opposed to internal thoracic artery retractors with medial retraction on the tumor mass to expose the pericardiophrenic structures. The phrenic nerve is initially identified superiorly and inferiorly to the area abutting the RM. Careful blunt dissection with the tip of a clamp or cold blade of an electrocautery unit can facilitate developing a plane between the phrenic nerve and RM when there is dense peritumoral fibrosis without neural invasion, controlling pericardiophrenic branch vessels with surgical clips when encountered. En-bloc phrenic nerve resection has been required in almost one-third of our surgical cases. Bilateral phrenic nerve removal has never been necessary in our experience and should be avoided at all costs. Diaphragmatic plication is performed after removal of the RM only if an ipsilateral lobectomy or pneumonectomy is not required with phrenic nerve resection. n. nerve. Cardiopulmonary Bypass Cardiopulmonary bypass has been required in approximately 5% of our cases. Most of these patients required excision and patch repair of the right atrial free wall; however, we have had two patients who underwent patch repair of the main pulmonary artery. These excisions and repairs can usually be performed with normothermic cardiopulmonary bypass using bicaval venous cannulation, allowing the heart to beat empty with control of the coronary sinus return through a cardiotomy sucker when necessary. Metastatectomy When required, the timing of pulmonary metastastectomy is individualized based on several factors including the surgical approach to the RM, the magnitude of pulmonary resection required to remove the RM, and the magnitude of pulmonary resection required for metastastectomy. Pulmonary metastatectomy is usually accomplished at the time of surgery to remove the RM; however, we do not hesitate to stage pulmonary metastatectomy after recovery if deemed prudent. Finally, approximately 10% of patients in our surgical series have undergone staged extrathoracic metastatectomy for either synchronous or metachronous metastases to other organs including bone, cervical lymph node, and central nervous system. Conclusions PMNSGCT represent a challenging group of malignant germ cell tumors and survival outcome is dependant on both successful chemotherapy and surgery to remove residual disease when

11 Mediastinal germ cell tumor resection 65 feasible. New chemotherapy strategies, which reduce the incidence of persistent nonseminomatous germ cell and/or nongerm cell cancer, need continued investigation. Although overall survival is inferior to nonseminomatous germ cell tumors of testicular origin, favorable subsets with pathologic evidence of either complete tumor necrosis or teratoma in the resected residual disease have been identified. 3 An aggressive surgical approach after cisplatin-based chemotherapy can result in longterm survival even in patients with persistent nonseminomatous germ cell and/or nongerm cell cancer and is warranted in these otherwise young and healthy patients. References 1. Hinton S, Catalano P, Einhorn L, et al: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: Final analysis of an intergroup trial. Cancer 97: , Kruter LE, Kesler KA, Yu M, et al: The predictive value of serum tumor markers for pathologic findings of residual mediastinal masses after chemotherapy for primary mediastinal nonseminomatous germ cell tumors. Proc ASCO 15S:5087, Kesler KA, Rieger KM, Einhorn L, et al: A 25-year single institution experience with surgery for primary mediastinal nonseminomatous germ cell tumors. Ann Thorac Surg 85: , 2008