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Ann Thorac Surg 2008;85:379-384. doi:10.1016/j.athoracsur.2007.09.011
© 2008 The Society of Thoracic Surgeons
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Right arrow Mediastinum

Original Articles: General Thoracic

Surgical Treatment of Malignant Mediastinal Nonseminomatous Germ Cell Tumor

Chang Hyun Kang, MDa,*, Young Tae Kim, MDa, Sang-Hoon Jheon, MDb, Sook-whan Sung, MDb, Joo Hyun Kim, MDa

a Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University Hospital, Xenotransplantation Research Center, Clinical Research Institute, Seoul National University College of Medicine, Seoul, South Korea
b Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea

Accepted for publication September 10, 2007.

* Address correspondence to Dr Kang, Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28 Yongon-dong, Chongro-gu, Seoul, 110-744, South Korea (Email: chkang{at}snu.ac.kr).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The aim of this study was to evaluate the role of surgical treatment for mediastinal nonseminomatous germ cell tumors (MNSGCT) and identify the factors of long-term survival.

Methods: A retrospective review of the medical records of patients with primary MNSGCT who registered at our institute between 1988 and 2005 was performed. Of 29 patients who presented with primary MNSGCT, 21 patients (72.4%) underwent curative resection and were included in this study.

Results: All patients were male and symptomatic at presentation. Mean patient age was 24.4 years (range, 9 to 53 years). Three different regimens were used for preoperative chemotherapy, and 14 patients (66.7%) achieved partial response, 4 (19.0%) had stable disease, and 2 (9.5%) had progressive disease. Complete en bloc excision was possible in 16 patients (76.2%). The most common cause of incomplete resection was great vessel invasion (n = 3). Concomitantly resected organs were lung in 13 patients (61.9%) and superior vena cava in 5 (23.8%). Viable germ cell tumor was identified in pathology specimens in 12 (57.1%), total necrosis in 7 (33.3%), and remnant teratoma in 2 (9.5%). Five-year overall and disease-free survivals were 63.6% and 61.1%. Risk factors for poor overall survival by multivariate analysis were β-human chorionic gonadotrophin (β-HCG) elevation at initial diagnosis (p = 0.02) and incomplete resection (p = 0.002).

Conclusions: Surgical resection of MNSGCT after chemotherapy showed favorable long-term survival. Complete resection should be performed to achieve long-term survival. An elevated β-HCG level at initial diagnosis was associated with a poor prognosis despite multimodality therapy.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Malignant mediastinal germ cell tumor is a rare disease and represents only 1% to 4% of all mediastinal tumors. Gonadal germ cell tumor is generally the most common germ cell tumor type and constitutes 90% of germ cell tumors, whereas the mediastinum is the second most frequently affected area ahead of other extragonadal areas, which include retroperitoneum, the sacrococcygeal area, and the central nervous system [1].

Mediastinal nonseminomatous germ cell tumor (MNSGCT) shares several features with its gonadal counterpart, which shows similar serologic expressions of tumor markers and characteristic genetic abnormalities [2]. However, MNSGCT also has features that differentiate it from gonadal nonseminomatous germ cell tumor, such as an association with Klinefelter syndrome [3] and the frequent development of a hematologic malignancy [4].

The most striking difference between mediastinal and gonadal nonseminomatous germ cell tumor concerns prognoses. Overall 5-year survival in MNSGCT is about 40%, which is much lower than in gonadal nonseminomatous germ cell tumor and is a unique feature of MNSGCT [5, 6]. After the introduction of cisplatin-based chemotherapy, followed by surgical resection, survival in cases of MNSGCT improved dramatically, and this multimodality treatment has become the standard treatment for MNSGCT. Studies on the surgical treatment of MNSGCT are infrequent [7–12], however, because of the low incidence of the disease. This study reviewed the clinical features and treatment results of MNSGCT at a single institute to identify factors associated with long-term survival.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patients
A retrospective review of medical records was performed on patients who underwent surgical resection for MNSGCT between 1988 and 2005. Inclusion criteria were (1) anterior mediastinal nonseminomatous germ cell tumor, (2) no evidence of germ cell tumor in the testis, (3) a diagnosis of MNSGCT by marker study or biopsy, and (4) curative resection. During the study period, 29 patients were diagnosed with MNSGCT at Seoul National University Hospital. Surgical resection was not performed in 8 patients because of disease progression during chemotherapy in 7 and complete remission after chemotherapy in 1; thus, 21 consecutive patients who underwent surgical resection were included. This study was approved by the Institutional Review Board at our hospital in December 2006, which waived the need of patient consent.

Routine evaluations performed in the 21 patients included chest and abdominal computed tomography (CT) scan, testis sonography, and tumor marker study, including serum levels for {alpha}-fetoprotein ({alpha}-FP) and β-human chorionic gonadotrophin (β-HCG). The cutoff values were 20 ng/mL for {alpha}-FP and 10 µIU/mL for β-HCG.

Pretreatment pathologic diagnoses were confirmed in 16 patients (76.2%) by percutaneous needle biopsy or surgical biopsy. Biopsy was not performed in the other 5 patients, and imaging studies and serum tumor marker studies were used to make the preoperative diagnoses.

Preoperative chemotherapy was administered to 20 patients, and surgical extirpation of residual mediastinal mass was performed within 3 months of chemotherapy. The remaining single patient underwent surgical resection without preoperative chemotherapy. En bloc resection, including an adjacent organ, was attempted in all patients; however, extensive tumor involvement prohibited complete resection in 3 patients. Patients who showed viable tumor cells in a postresection pathology specimen received postoperative chemotherapy.

The patients were followed up by attending surgeons or medical oncologists at an interval of 3 months. Chest roentgenograms and serum marker tests including {alpha}-FP and β-HCG were performed at every appointment. A routine chest CT scan was done annually.

Statistical Analysis
Continuous variables are expressed as means ± standard deviation. The Kaplan-Meier method was used to determine overall and recurrence-free survivals. Univariate analysis was performed using the log-rank test. Multiple categoric and continuous variables included in the univariate analysis were age, pathologic diagnosis at initial presentation, accompanying metastatic disease, elevated {alpha}-FP concentrations at diagnosis, elevated β-HCG concentrations at diagnosis, chemotherapy regimen, response to chemotherapy, completeness of resection, superior vena cava resection, lung resection, viable germ cell tumor by postresection pathology findings, size of primary tumor at resection (>10 cm), need of postoperative chemotherapy, and persistent elevation of serum tumor marker concentration after surgical treatment. Multivariate analysis was performed using the Cox proportional hazard model. All factors with a value of p < 0.05 by univariate analysis were included in the multivariate analysis. Statistical significance was accepted at the p < 0.05 level. Statistical analyses were performed using SPSS 11.0 software (SPSS Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
All the patients were male with a mean age of 24.4 years (range, 9 to 53 years). All patients were symptomatic at diagnosis, and the most frequent symptoms were cough in 9 (42.9%) and dyspnea in 8 (38.1%). Extramediastinal disease was present in 5 patients (23.8%), all of whom had metastasis to the lung. Klinefelter syndrome was identified in 2 patients (9.5%). Tumor marker concentrations, including {alpha}-FP and β-HCG, are summarized in Table 1. Elevated {alpha}-FP or β-HCG concentrations were identified in 95.2% and 33.3% of patients at the initial diagnosis.


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  		Table 1 Tumor Marker Concentrations at Diagnosis, Operation, and Follow-up
 
Three chemotherapy regimens were used for first-line chemotherapy: bleomycin, etoposide, and cisplatin (BEP); etoposide, ifosfamide, and cisplatin (VIP); and cisplatin, vinblastine, and bleomycin (cis-VAB). The cis-VAB regimen was exclusively used for children. BEP was used in 9 patients (42.9%), VIP in 9 (42.9%), and cis-VAB in 2 (9.5%). The mean number of chemotherapy regimen cycles delivered was 4.1 ± 0.9 (range, 2 to 6 cycles).

Tumor responsiveness after chemotherapy was evaluated by determining tumor marker levels and by chest CT. Partial response was identified in 14 (66.7%), stable disease in 4 (19.0%), and progressive disease in 2 (9.5%) by chest CT. Changes in tumor marker concentrations are listed in Table 1. The interval between chemotherapy and operation was 31.6 ± 10.7 days (range, 10 to 61 days). Second-line chemotherapy was necessary in 3 patients (14.3%).

Surgical resection was performed by median sternotomy in all patients. Concomitantly resected organs were the superior vena cava in 5 patients (23.8%) and lung in 13 (61.9%), and the phrenic nerve was scarified in 6 (28.6%). Complete resection without residual tumor was possible in 16 (76.2%). Gross residual tumor (R2 resection) remained in 4 patients and microscopic residual tumor (R1 resection) in 1. Great vessel invasions (aorta or main pulmonary artery) were the causes of incomplete resection in 3 patients.

One patient who presented with a huge mediastinal choriocarcinoma and multiple metastatic lesions in both lung fields underwent en bloc mass excision and left pneumonectomy due to extensive left hilar structure invasion; however, a residual metastatic lesion in the right lung could not be resected. R1 resection was performed in a patient who underwent primary operation without preoperative chemotherapy. There was no difference in the complete resection rate between chemotherapy regimens (77.8% in BEP regimen and 77.8% in VIP regimen). Complete resection was possible in the two children who received cis-VAB regimen.

Operative mortality occurred in 2 patients (9.5%), one because of postoperative sepsis and airway bleeding in the other. Postoperative morbidity occurred in 3 patients (14.3%), with 1 patient each with postoperative bleeding, chylothorax, and persistent chest tube drainage for more than a week. Persistent elevation of tumor markers after operation was found in 6 patients (28.6%), of which 5 had {alpha}-FP elevations and 1 had β-HCG elevation. Only 1 patient (6.7%) of those who underwent complete resection showed persistent elevation of tumor marker; however, in the patients with incomplete resection, 4 patients (66.7%) showed elevated tumor marker. The difference was statistically significant (p = 0.011).

Postoperative pathology examinations revealed residual viable germ cell tumor in 12 patients (57.1%), total necrosis in 7 (33.3%), and remnant teratoma in 2 (9.5%). The most common MNSGCT cell type was endodermal sinus tumor (42.9%). Tumor cell types for all patients are listed in Table 2.


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  		Table 2 Cell Types of Mediastinal Nonseminomatous Germ Cell Tumors
 
The mean follow-up period was 46.2 months (range, 3 to 186 months), and there was no follow-up loss. Tumors recurred in 7 patients during follow-up, of which 5 died and 2 remain alive, and 12 patients were free of disease after surgical resection. Overall 5-year survival was 63.6%, and 5-year disease-free survival was 61.1%.

Univariate analysis was performed on the 14 variables described earlier to identify predictors of overall survival. The statistically significant variables were serologic diagnosis without tissue confirmation and the urgent initiation of chemotherapy (p = 0.01), elevated β-HCG concentration at presentation (p = 0.025), progressive disease during chemotherapy (p = 0.007), incomplete resection (p = 0.001), and elevated tumor markers after operation (p = 0.004). Multivariate analysis identified an elevated β-HCG concentration at presentation (odds ratio [OR], 9.2, 95% confidence interval [CI], 0.98 to 87.3; p = 0.02) and incomplete resection (OR, 32.6; 95% CI, 3.5 to 302.0; p = 0.002) as independent prognostic factors of overall survival (Table 3).


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  		Table 3 Univariate and Multivariate Analysis for the Risk Factors of Overall Survival
 
Only 2 of the 7 patients who presented with an elevated β-HCG concentration at presentation remain alive without recurrence (Fig 1), and all patients in the incomplete resection group died (Fig 2). Median survival in the incomplete resection group was 6 months postoperatively (range, 3 to 19 months). Normalization of tumor markers before operation did not influence the overall survival significantly. The patients with normal tumor marker levels after chemotherapy had a 5-year survival rate of 71.3%, and the rate those with persistent elevated tumor marker level was 53.3%. The differences between the two patient groups were not statistically significant.


Figure 1
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  		Fig 1. Survival difference between patients with normal (solid line) vs elevated β-human chorionic gonadotrophin (BHCG) levels (dashed line).

 

Figure 2
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  		Fig 2. Survival difference between patients with complete (solid line) vs incomplete (dashed line) resection.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Two theories have been proposed to explain the development of MNSGCT. One is that mediastinal germ cell tumors originate from germ cells that mismigrate during embryogenesis, and the other theory is that they originate from germ cells that are widely distributed during embryogenesis. Both theories could explain the central location of germ cell tumors in mediastinum, retroperitoneum, sacrococcygeal area, and in central nervous system [6].

Patients with MNSGCT are classified as a poor prognosis subgroup in the international germ cell consensus classification [13]. Several causes of this unfavorable prognosis have been suggested, one of which is the bulky presentation of MNSGCT that makes complete surgical resection impossible in patients with advanced-stage disease [14]. The different histology of MNSGCT could also influence prognosis. Pure yolk sac and pure choriocarcinoma occur frequently among MNSGCTs but are rarely found among primary testicular tumors [15].

Some authors have insisted that the presence of a yolk sac element indicated reduced sensitivity to cisplatin [14, 16], and although chemo-responsiveness according to histology type is debatable, it is usually accepted that MNSGCTs are not as chemosensitive as other germ cell tumors [17]. For example, MNSGCTs more frequently require resection of residual malignancy to attain complete remission than gonadal germ cell tumors [8, 18].

In the present study, only 1 patient (3.5%) achieved complete remission after chemotherapy, and 31% of patients showed progressive disease during chemotherapy. Most of these patients died despite operation or intensive second-line chemotherapy. In particular, no patient with residual tumor after operation survived irrespective of adjuvant treatment, including chemotherapy and radiotherapy. These findings suggest that the chemoresistant nature of MNSGCT has an effect on prognosis.

Originally, surgical treatment was the first treatment modality implemented for MNSGCT, but overall survival rates were dismal despite aggressive surgical resection [9]. Kesler and colleagues [10] reported that 85% to 95% of nonseminomatous germ cell tumors have metastasized to at least one site at presentation, which suggests that isolated local control treatment is contraindicated for patients with a nonseminomatous germ cell tumor. After the introduction of cisplatin-based chemotherapy, the recommendation of primary surgical resection for MNSGCT was rescinded.

Takeda and colleagues [19] reported a median survival for surgical resection of 7.6 months and for multimodality therapy of 58.3 months. This chemotherapeutic approach has dramatically improved nonseminomatous germ cell tumor treatment results. Single-modality chemotherapy is insufficient for the treatment of MNSGCT, however, because complete remission after chemotherapy is rare due to the bulky nature of the disease and its tendencies to progress and recur after remission. Unfortunately, second-line chemotherapy and autologous bone marrow transplantation both returned poor results after first line-chemotherapy failure; fewer than 10% of patients are expected to survive long-term after second-line treatment [18, 20].

The current standard treatment in MNSGCT is chemotherapy combined with postchemotherapy residual mass excision. In addition, to removing residual tumor, surgical resection enables the sensitivity of the tumor to chemotherapeutic regimens to be evaluated and provides the opportunity to administer additional chemotherapy if viable cancer remains in resected specimens. Vuky and colleagues [11] reported a high frequency of viable tumor in resected specimens and emphasized the importance of the integral role of surgical treatment after chemotherapy. They reported that 57% of patients showed viable germ cell tumor despite tumor marker normalization.

In most cases, surgery is technically challenging. Dense fibrous adhesion and invasion of surrounding structures are usually found during exploration, and great vessel invasion often makes complete excision impossible. In the present study, complete resection was not possible in 5 patients, and the most common cause was great vessel invasion, which included the aorta and main pulmonary artery. It has been suggested that partial response to chemotherapy or partial resection of residual mass results in subsequent rapid disease progression [21], which concurs with our finding of a median survival period of only 6 months in patients with incomplete resection. Therefore, complete resection must be the surgical objective in every case. Most other series have also shown significantly better survivals for patients in whom complete resection has been achieved [7].

Total resection includes en bloc resection of primary lesion and the complete excision of metastatic lesions, and if technically feasible, radical surgical resection of all residual mass should be performed. Moreover, to achieve complete resection, a preoperative evaluation of resectability is mandatory. In the present study, complete resection was not possible in patients with progressive disease that did not respond to chemotherapy by chest CT scan or according to tumor marker studies.

The role of salvage surgery in chemoresistant patients is still debatable. It may have a role in selected patient groups, but we did not have such a case in the present study. Moreover, responsive but nevertheless elevated tumor marker concentrations were not found to influence surgical resectability.

The blood concentrations of tumor markers are a significant prognostic factor, which is well documented in the international germ cell consensus classification [13], and high levels of {alpha}-FP, β-HCG, and lactate dehydrogenase are associated with poor long-term survival. In addition, viable germ cells in resected specimens are also an important prognostic factor. Preoperative evaluations of residual tumor viability were traditionally assessed using tumor markers, and sustained tumor marker elevations after chemotherapy represent residual chemoresistant viable germ cells in the mediastinal mass.

The value of surgical treatment set against a background of elevated tumor marker levels is debatable. Second-line chemotherapy was tried and operation was delayed until tumor marker normalization by Walsh and colleagues [12]. Kesler and colleagues [10] reported that an elevated {alpha}-FP after first-line chemotherapy is a risk factor of poor overall survival. Others have reported that elevated tumor marker levels by themselves neither contraindicate surgical resection nor constitute a prognostic factor after surgical resection [11, 22]. These reports indicate that the presence of elevated serum tumor markers at resection does not alter outcome if residual disease is completely resected.

In the present study, the absolute preoperative levels of tumor markers did not indicate the need for surgical intervention, and surgical resectability was decided according to disease extent as evaluated by imaging studies. However, we did identify the prechemotherapy β-HCG concentration as an independent prognostic factor. The poor prognosis of high β-HCG tumors has been previously documented [6, 23], but without statistical support. In the present study, tumors with high β-HCG levels responded poorly to chemotherapy. Of 7 patients with an elevated β-HCG level, 2 patients showed progressive disease during chemotherapy and 6 had viable germ cells in resected specimens.

In summary, during a 17-year period, we treated 21 surgical cases of MNSGCT, which constituted 72.4% of all MNSGCT cases treated in our hospital during the study period. Surgical resection after chemotherapy was feasible in most of these patients, and overall survivals were favorable. However, it is evident that to achieve long-term survival, complete resection must be the surgical target. Elevated β-HCG levels in the blood were found to portend a poor prognosis and attenuated responsiveness to chemotherapy.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
Financial support for this study was provided by the Lung Cancer Research Fund of the Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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