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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 “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.
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.
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 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.
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 dissection-sparing 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.
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.
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.
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 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.
An aggressive surgical approach after cisplatin-based chemotherapy can result in long-term survival even in patients with persistent nonseminomatous germ cell and/or nongerm cell cancer and is warranted in these otherwise young and healthy patients.
Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: Final analysis of an intergroup trial.