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Ann Thorac Surg 1998;66:1709-1714
© 1998 The Society of Thoracic Surgeons

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Original articles: general thoracic

Pulmonary metastasectomy for testicular germ cell tumors: A 28-year experience

^a Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
^b Genitourinary Oncology Service, Division of Solid Tumor Oncology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Address reprint requests to Dr Ginsberg, Division of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, C-881, New York, NY 10021
e-mail: (GinsbergR{at}mskcc.org)

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusions References

 
Background. The role of surgery in patients with pulmonary metastatic germ cell tumors has been evolving since the 1970s. To evaluate the results of pulmonary resection, we reviewed our 28-year experience.

Methods. Between July 1967 and May 1995, 157 patients with testicular germ cell tumors underwent pulmonary resections for suspected metastases. Their clinical and pathological data were reviewed. Kaplan-Meier and Cox regression models were used to analyze prognostic factors for survival after resection of metastatic disease.

Results. All patients were male with median age of 27 years (range 15–65). Complete resection was accomplished in 155 (99%) patients. Viable carcinoma was present in 44% (70) of the patients. Forty-one (26%) patients had metastases to other sites after pulmonary metastasectomy. The overall actuarial survival 5 years after pulmonary resection was 68% for the entire group and 82% for patients diagnosed after 1985. On multivariate analysis, the adverse prognostic factors were metastases to nonpulmonary visceral sites (p = 0.0069) and the presence of viable carcinoma in the resected specimen (p < 0.0001).

Conclusions. With current chemotherapy regimens, almost 85% of the patients with testicular germ cell tumors undergoing complete resection of their pulmonary metastases can be expected to achieve long-term survival.

	Introduction

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Germ cell tumors (GCT) are uncommon neoplasms accounting for 1% of all cancers, but are the most common malignancy in young adult males between the ages of 15 and 35 years [1]. Ninety percent of these tumors arise from the testes. The current annual incidence of GCT is approximately 5 cases per 100,000. While the incidence of GCT has been steadily increasing, the mortality rate from GCT has declined [2] which has been attributed to the advent of an effective multimodality approach consisting primarily of cisplatin-based chemotherapy and surgery. The prognosis of patients with GCT, including those patients with distant metastatic spread (most commonly lung [3]), is excellent. Surgical resection of residual disease after chemotherapy plays an important adjunctive role in the management of germ cell tumors. We report our experience with pulmonary metastasectomy and its role in the multimodality therapy of GCT.

	Material and methods

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Between July 1967 and May 1995, 2,138 patients with newly diagnosed GCT were seen at the Memorial Sloan-Kettering Cancer Center. One thousand eight hundred patients had testicular primaries. Approximately 30% of these patients developed intrathoracic lesions. During this time period, 168 patients with testicular GCT had radiographic evidence of intrathoracic abnormalities after chemotherapy and underwent thoracic exploration with either diagnostic or therapeutic intentions. We excluded patients who had mediastinal disease and identified 157 patients with intrathoracic lesions limited to the lungs who are the subjects of this study. Operative indications were as follows: patients who had (1) complete serologic response with residual pulmonary lesions, (2) evidence of persistent intrathoracic disease with elevated tumor markers despite a full course of chemotherapy, or (3) lesions which did not respond or progressed while on chemotherapy. Complete clinical and pathologic data were reviewed. Serum tumor markers, -fetoprotein (AFP) and human chorionic gonadotropin (HCG), were recorded if obtained within 3 weeks before their surgery. Clinical outcome was measured from the time of the first thoracic operation to the date of the first recurrence and to the date of either the last follow-up or death. Categories at the time of the last follow-up were no evidence of disease, alive with disease, died of other causes, and died of disease.

All statistical analyses were performed using SPSS 6.1 for Windows (SPSS Inc, Chicago, IL). The Kaplan-Meier and Cox regression methods were used to analyze prognostic factors for survival after resection of metastatic disease. A p value of less than 0.05 was regarded as statistically significant.

Diagnosis
All patients were male. Their ages ranged from 15 to 65 years, with a median of 27 years. Ninety-seven percent of the testicular primary tumors (n = 153) were nonseminomas. Forty-nine patients had pure embryonal cell carcinoma which accounted for almost one third of all histologies, 46 had a mixed pattern, 34 had teratocarcinomas, and 24 had mature teratomas (Table 1).

Treatment
All 157 patients in this review had undergone an inguinal orchiectomy for their primary testicular lesion and 153 patients were then treated with systemic chemotherapy. Of these, 143 patients received cisplatin-based chemotherapy. Four patients received only external radiation to the retroperitoneum and inguinal regions after orchiectomy. In addition to chemotherapy, 85 patients underwent retroperitoneal lymph node dissections, 25 of which were performed either concurrently with their pulmonary resections or during the same hospital stay. Nineteen patients had disease involving other organs and local control was obtained before undergoing pulmonary resection. The remaining 138 patients had hematogenous spread limited to the lung.

One hundred two patients had serum tumor markers assessed within 3 weeks before their surgery. The serology was normal in 94 patients. Eight patients had elevated serum tumor markers defined by AFP > 15 ng/mL, HCG > 2 ng/mL or 2.2 mIU/mL. Viable tumor in the resected specimens was found in 5 (63%) of 8 patients with positive serologies compared with only 11 (12%) of 94 patients with normal serum tumor markers.

The operative approach at the initial thoracotomy was unilateral in 104 patients and bilateral in the remainder either by a median sternotomy (n = 20), clamshell (n = 22), or staged bilateral thoracotomies (n = 11). Conservation of pulmonary parenchyma when possible was the rule reflected by the fact that most resections were confined to wedge excisions (n = 141). Fourteen patients had a lobectomy and 2 patients required a pneumonectomy. All patients underwent resection with curative intent except for 2 patients who were found to have unsuspected mediastinal disease in addition to their pulmonary lesions. There was one postoperative death secondary to pneumonia. Ten patients had complications after surgery, the most common being prolonged air leaks (n = 5). Other complications included one aortic injury, one partial esophageal tear, one stroke, and two septic complications. The overall mortality rate was 0.6% and morbidity rate 6%.

	Results

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Histology
Histologic examination of the resected pulmonary specimens revealed viable tumor in 70 patients, necrosis/fibrosis in 47 patients, and mature teratoma in 40 patients. Sixty-three patients (40%) had histology from their resected pulmonary lesions that agreed with the histology from their testicular primary (Table 1). Interestingly, mature teratoma in the resected pulmonary lesions was found in 7 patients who had pure embryonal carcinoma in their primary histology. Of the 25 patients who underwent RPLN dissection and pulmonary resection either simultaneously or during the same hospital stay, 6 (24%) had discordant pathologies between the pulmonary and retroperitoneal specimens.

Recurrence
Seventy-three patients remained disease free after their first thoracic operation and 58 patients developed recurrences with the majority being located in the lungs. Nonpulmonary visceral sites of recurrence included brain, retroperitoneum, neck, liver, and other sites (Table 2). Seventy-four percent of patients (n = 43) who had recurrence of disease did so within 1 year (median, 5 months). Thirty-three patients (58%) who had recurrences and both patients who had unresectable disease died.

View larger version (11K): [in this window] [in a new window]   Fig 1. Overall survival of patients after pulmonary resection.

Serum tumor markers within 3 weeks of surgery were recorded in 102 patients. Five (62%) of 8 patients with positive serologies and 75 (80%) of 94 patients with negative serologies were alive without disease with a median follow-up time of 82 months and 46 months, respectively (p = 0.21).

Patients with residual viable tumor had a significantly worse prognosis when compared with patients who had findings of necrosis/fibrosis or mature teratoma. Overall 10-year survival for patients with viable carcinoma was 43% compared with 86% and 84% for patients with necrosis/fibrosis and mature teratoma, respectively (p < 0.0001) (Fig 2).

View larger version (17K): [in this window] [in a new window]   Fig 2. Overall survival according to histology of resected specimens.

View larger version (13K): [in this window] [in a new window]   Fig 3. Overall survival according to metastatic sites involved.

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusions References

The role of pulmonary metastasectomy in the treatment of testicular GCT has been evolving with the introduction of cisplatin to chemotherapy regimens in the mid-1970s. Further advances were made in the mid-1980s with the introduction of new technology, better detection methods, and treatment protocols. The improvements in the overall survival of patients undergoing pulmonary resection for their metastatic lesions reflects these periods. In the pre-cisplatin era (1967–1974), the 5-year survival rate for patients after pulmonary resection was 41%. After cisplatin was introduced and became a standard component in the medical treatment of patients with metastatic disease, the 5-year survival rate improved to 65%. Patients diagnosed after 1985 had a 5-year survival rate of 82% (p < 0.0001) (Fig 4). This latter improvement is most likely due to stage migration [4].

View larger version (16K): [in this window] [in a new window]   Fig 4. Overall survival of patients according to year of primary diagnosis.

Several studies have attempted to predict the histology of the residual lesions preoperatively in order to spare those patients with benign pathology from operation [7, 12–15]. Various predictor factors have been assessed including size of lesion before and after chemotherapy, histology of primary tumor, tumor markers, findings on computed tomographic scan, and most recently positron emission tomography scan. None have demonstrated a reliability in predicting preoperatively which masses contain necrosis/fibrosis, mature teratoma, or viable malignant tumor. When the pathologies between the retroperitoneal residual thoracic masses were compared, there were discordant findings ranging from 25% to 46% [11, 16–18]. In our study, 6 of 27 patients had dissimilar pathologies for a discordant rate of 22%. Therefore, pathologic findings from one site cannot be reliably used to predict the histology of another site. It is unclear however, whether or not resection of all lesions is necessary. Watchful waiting may be another option.

Traditionally, patients with elevated serum markers, indicative of persistent disease were believed to be unresectable and not considered for surgical resection. However, a few studies have demonstrated the potential for cure with salvage surgery in a select group of patients. Patients who were most likely to benefit from pulmonary resection of chemoresistant disease had lesions which were limited to one site and completely resectable. In a study by Murphy and colleagues, 3 of 4 patients with disease limited to the lung parenchyma and 1 of 2 patients with mediastinal nodal disease only, had no evidence of disease with a minimal follow-up time of 31 months [19]. In another report by Wood and colleagues [20], 3 patients with lung metastases and 1 with mediastinal disease were resected. Two were free of disease 16 months later. Eight patients in our study had persistently elevated serum tumor markers after chemotherapy prior to undergoing pulmonary resection. Five were alive without evidence of disease, 3 of whom are considered to be cured with follow-up times greater than 15 years. While the number of patients in this group is too small to draw definitive conclusions, long-term disease free status is possible with salvage surgery.

The other significant prognostic factor of outcome in our study was involvement of extrathoracic sites other than the retroperitoneum. It is generally recognized that the lung and retroperitoneum are favorable sites for metastases whereas nonpulmonary visceral metastases predict poor prognosis. Various staging systems including one proposed by the International Germ Cell Cancer Collaborative Group have designated patients with non-pulmonary visceral metastases as being in the poor risk category [21]. In their study, the presence of liver, bone, brain, or other nonpulmonary visceral metastases were each associated with 5-year survival rates below 50%. When grouped together, patients with any nonlung visceral metastases had an overall 5-year survival rate of 41% compared with 83% for patients who had disease limited to the lung or retroperitoneum. In our study, 125 patients had metastatic disease limited to either the lungs alone or lungs and retroperitoneum. The 5-year survival rate in this group was 77%. The remaining 43 patients who had involvement at sites other than lungs or retroperitoneum had a significantly lower 5-year survival rate of 40% (Fig 3).

Our current treatment of good-risk GCT patients with pulmonary metastases consists initially of combination cisplatin-based chemotherapy [22, 23]. Of the patients who relapse from a complete remission, fewer than 25% can be salvaged by ifosfamide and cisplatin-based regimens [24]. A significant number of patients with pulmonary metastases manifest residual radiographic abnormalities in the lung despite normal markers after chemotherapy. Because there is no reliable method of predicting the histology of the residual lesions, surgical resection of all sites of metastatic disease is indicated in this select group of patients.

Postoperative management depends on the pathology of all resected masses. No further treatment is warranted with pathological confirmation of fibrosis/necrosis and mature teratomas. Approximately 90% of these patients will be cured with resection alone. The identification of viable malignant tumor in any resected lesion necessitates further treatment with chemotherapy [6]. Sixty to 70% of patients are cured with this approach. The 30% of patients who fail treatment have a poor prognosis and should be considered for experimental high-dose chemotherapy trials or other innovative treatment strategies. Salvage surgery should only be considered for the very rare patients with persistently elevated serum tumor markers after a full course of chemotherapy who have resectable metastases limited to the lung.

	Conclusions

Top Abstract Introduction Material and methods Results Comment Conclusions References

 
Currently, patients with testicular germ cell tumors undergoing complete resection of pulmonary metastases after cisplatin-based chemotherapy are expected to achieve long-term survival. Patients with nonpulmonary metastases, persistently elevated tumors markers, or viable tumor at the time of thoracotomy have a worse prognosis. Pulmonary resection has an important role in salvage surgery for patients with chemorefractory tumors and in identifying those patients with persisting viable tumor requiring further treatment.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): David Liu Amir Abolhoda Michael E. Burt Nael Martini Manjit S. Bains Robert J. Downey Valerie W. Rusch Robert J. Ginsberg Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, D. Articles by Ginsberg, R. J. Search for Related Content PubMed PubMed Citation Articles by Liu, D. Articles by Ginsberg, R. J.