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1 A Multidisciplinary Approach to Primary Nonseminomatous Germ Cell Tumo~s of the Mediastinurn P. H. Kay, F.R.C.S., F. C. Wells, F.R.C.S., and P. Goldstraw, F.R.C.S. ABSTRACT The introduction of cis-platinum-based chemotherapy has dramatically improved the prognosis for patients with primary nonseminomatous germ cell tumors of the mediastinum. Since 1978, 12 male patients (mean age, 29 years) have been seen with a large mediastinal mass, normal testes, and abnormal testicular tumor markers. Eleven patients had raised a-fetoprotein levels (median, 1,300 &L; normal, less than 10 pg/l), and 3 had elevated levels of the beta fraction of human chorionic gonadotropin (median, 8,OOO IWL; normal, less than 5 IU/ L). Two patients were treated by primary surgical intervention followed by chemotherapy. Ten patients were treated with primary chemotherapy (cis-platinum, vinblaatine sulfate or etoposide, and bleomycin sulfate), and this was followed by timed surgical excision of the tumor mass in 7. Six (60%) patients responded to primary chemotherapy with normalization of tumor markers. In this group there was 1 postoperative death and 1 recurrence. The 4 remaining patients are alive and free from disease at a mean of five years. Of the 4 patients with persistently elevated tumor markers, 2 died within six months, 1 is alive with recurrence, and 1 is lost to follow-up at three months. Patients whose tumor markers return to normal after cisplatinum-based chemotherapy have a good long-term prognosis following radical surgery. If the tumor markers remain elevated, the prognosis is poor. Most germ cell tumors arise in the testes. Indeed, only 1 to 2% of these tumors arise in extragonadal sites [l]. The most common extragonadal sites are the mediastinum [2] and the retroperitoneum [3]; rarely tumors are found in the pineal [4] and presacral[5] areas. Within the mediastinum, primary germ cell tumors can be further subdivided into "seminomatous" and "nonseminomatous" elements. The latter comprise embryonal teratoma, teratocarcinoma, chorioncarcinoma, and endodermal sinus tumors. This distinction has important therapeutic and prognostic implications [6]. Patients with pure seminomas are effectively treated with radiotherapy. Indeed, 75% of 72 patients with seminomas in a combined series [7-131 extending from 1964 to 1978 had long-term, disease-free remission [ 131. Conversely, nonseminomatous tumors From Brompton Hospital, London, England. Accepted for publication Mar 30, Address reprint requests to Mr. Goldstraw, Brompton Hospital, Fulham Rd, London, England SW3 6HP. are radioresistant and have tended to have a poor prognosis. Only 3% of 63 patients with such tumors in the same combined series [7-131 survived longer than sixteen months. The introduction of chemotherapy in 1960 for advanced testicular tumors met with only limited success [14]. Thereafter, numerous developments have taken place, culminating in the cis-diaminodichloroplatinum, vinblastine sulfate, and bleomycin sulfate (PVB) regimen introduced by Einhorn and Donohue [15] in This same chemotherapeutic regimen has been shown to have dramatic effects on extragonadal germ cell tumors ( Material and Methods Since 1978, 12 male patients with primary mediastinal nonseminomatous germ cell tumors have been admitted under the care of one of us (P. G.). The mean age of the patients was 29 years (range, 23 to 37 years). Eight patients were seen initially with chest pain and 4, with a nonproductive cough and dyspnea. Five of the patients had generalized symptoms of weakness and lethargy. Gynecomastia was observed in 3 patients. One patient had evidence of superior vena cava obstruction. All patients had normal testes on clinical examination. This was confirmed by testicular ultrasound in 6 patients. Combined chest roentgenography and computed tomography showed an anterior mediastinal mass in all patients. In 7, there was direct extension of the tumor mass into the lungs, and in 1, the tumor extended into the thoracic inlet. Three patients had pulmonary metastases, 1 of whom also had pelvic metastases. In 1 patient, axillary and cervical glands were involved with tumor. Tumor markers were elevated in all patients (Fig 1). Eleven patients had raised serum a-fetoprotein levels (median, 1,300 pg/l; range, 25 to 40,000 pg/l; normal, less than 10 p,g/l). Serum human chorionic gonadotropin (HCG) (beta fraction) levels were elevated in 3 patients (median, 8,000 IUL; range, 24 to 24,330 IUL; normal, less than 5 WL). The 1 patient with a normal serum a-fetoprotein level (7 p@) had a gross elevation of the serum beta fraction of HCG (24,330 IUk). Initially a clinical diagnosis was made on the basis of a young male patient with a large anterior mediastinal mass, raised testicular tumor markers, and normal testes. A tissue diagnosis was made by thoracotomy in 6 patients, anterior mediastinotomy in 4, cervical mediastinoscopy in 1 patient, and needle biopsy in 1. Histological examination revealed 7 pure malignant teratomas, Ann Thorac Surg 44: , Dec 1987

2 579 Kay et al: Primary Nonseminomatous Germ Cell Tumors of Mediastinurn Pre Post Post Pre Treatment Treatment a a2 & 24 8 X Qa al v1 M 3 tumor marker status after chemotherapy. The overall results are summarized in the Table and Figure 2. Primary Surgery An attempt was made to excise the tumor in 4 patients. Two of them (Patients 5 and 6) were considered to have inoperable disease and subsequently received chemotherapy. They are considered later. One patient (Patient 1) underwent resection of the mediastinal mass and right lower lobectomy. Initially tumor markers returned to normal, but a relapse occurred at nine months when the patient was found to have local recurrence. This was treated with cisplatinum-based chemotherapy [15]. The patient remains alive and well seven years later. Patient 2 had thymectomy and left upper lobectomy, following which the tumor markers returned to normal. He then underwent six courses of PVB chemotherapy [15]. The patient returned to his country of origin at nine months and has been lost to follow-up. 'atient 0 number number Fig 1. Effect of primary treatment on tumor markers. (a FP = a-fetoprotein; p HCG = beta fraction of human chorionic gonadotropin.) malignant teratomas with seminomatous elements, 2 endodermal sinus tumors, and 1 choriocarcinoma. Follow-up Three patients died during follow-up. The current status of 7 of the surviving patients was ascertained in February, Two patients returned to their country of origin shortly after treatment and are lost to follow-up. Results The results are presented in terms of the primary method of treatment, and are analyzed in terms of Prima y Chemotherapy Ten patients were treated with primary chemotherapy. In 4, the classic PVl3 regimen of Einhorn and Donohue [15] was used [19]. In 6 of the more recent patients, etoposide (VP ) was substituted for vinblastine [20]. In 6 patients (Patients 3 through 8), chemotherapy resulted in the tumor markers returning to normal, but in 4 (Patients 9 through 12), the markers remained persistently elevated. The effect of chemotherapy as shown in the chest roentgenogram and computed tomographic scan is shown in Figures 3 and 4. Seven patients, 5 with normal tumor markers, then underwent resection of the residual tumor. This was performed through a median sternotomy in 5 patients and a right lateral thoracotomy in 2. In all patients, the dissection was exacting and the resection was extensive, frequently involving sacrifice of the pericardium, one or occasionally both phrenic nerves, and the innominate Survival in ReZation to Normalization of Tumor Markers by Primary Treatment Method Patient Primary Markers Secondary No. Treatment Normalized Treatment Outcome 1 Surgery Yes Chemotherapy Alive at 7 yr 2 Surgery Yes Chemotherapy Lost to follow-up at 9 mo 3 Chemotherapy Yes Surgery Postop death 4 Chemotherapy Yes Surgery Alive at 4 yr 5 Chemotherapy Yes surgery Alive at 5 yr 6 Chemotherapy Yes Surgery Alive at 4 yr 7 Chemotherapy Yes Surgery Recurrence at 6 mo 8 Chemotherapy Yes None Alive at 6 yr 9 Chemotherapy No None Died at 6 mo 10 Chemotherapy No Surgery Died at 3 mo 11 Chemotherapy No Surgery Recurrence at 1 yr 12 Chemotherapy No None Lost to follow-up at 3 mo

580 The Annals of Thoracic Surgery Vol 44 No 6 December 1987 1 relanse 2 c m l e t e resectton 4 surgery 12cases > 1 Lost to foliw-ud 2

(a & w = alive and / 5 reslduol moss exctsed wall restdual mass+ 1 WSt-OP o t w 6 years + 2 early deoths 1 aiive wlth recurrent dlsease 1 Lost

3 580 The Annals of Thoracic Surgery Vol 44 No 6 December relanse 2 c m l e t e resectton 4 surgery 12cases > 1 Lost to foliw-ud 2 Irresectoble 6 markers nomllsed I 8 ChmtheraDY 4 markers obnoml Fig 2. Summary of results. (a & w = alive and / 5 reslduol moss exctsed wall restdual mass+ 1 WSt-OP o t w 6 years + 2 early deoths 1 aiive wlth recurrent dlsease 1 Lost to f0llw-w well.) A B Fig 3. Chest roentgenograms (A) before and (B)after chemotherapy. A Fig 4. Computed tomographic scan (A) w o r e and (B)after chemotherapy. deoth 3 a L w 4 years 1 recurrent dlsmse B

581 Kay et al: Primary Nonseminomatous Germ Cell Tumors of Mediastinum vein. A plane of cleavage was developed around the tumor, which permitted it to be "stripped off" the raw surface of the lung.

4 581 Kay et al: Primary Nonseminomatous Germ Cell Tumors of Mediastinum vein. A plane of cleavage was developed around the tumor, which permitted it to be "stripped off" the raw surface of the lung. Despite the extensive nature of the resection, it is gratifying that chemotherapy facilitated tumor removal in 2 patients (Patients 5 and 6) whose disease has been declared "inoperable" at a previous thoracotomy. Macroscopic clearance of the tumor was achieved in 5 patients; the other 2 (Patients 7 and 11) had multiple bilateral pulmonary metastases. Normal Tumor Markers Six patients had normal tumor markers after chemotherapy. Five of them (Patients 3 through 7) underwent surgical intervention as a secondary procedure. Macroscopic clearance of the tumor was achieved in 4 (Patients 3 through 6), including the 2 (Patients 5 and 6) whose tumor had been described as inoperable prior to chemotherapy. In this group of 4 patients undergoing "curative" resection, there was 1 death (Patient 3), which was attributed to respiratory failure due to a combination of bleomycin lung toxicity and sacrifice of both phrenic nerves. The 3 surviving patients are alive four, four, and five years postoperatively and have negative tumor markers. Patient 7 had resection of the mediastinal mass and sampling of pulmonary metastases. These proved to contain active tumor. The tumor markers have subsequently relapsed and remain elevated despite secondline chemotherapy and radiotherapy. Computed tomography shows an increase in the size of the tumor metastases. In 1 patient (Patient B), the original tumor was detected at an early stage on a routine chest roentgenogram for asthma surveillance. Following chemotherapy, the tumor shrank to a tiny mass, which has remained static on serial computed tomograms. The patient has not undergone operation and remains well with normal tumor markers six years after primary chemotherapy. Abnormal Tumor Markers In 4 patients (Patients 9 through 12), the tumor markers remained abnormal. Two of these patients died within six months, one (Patient 9) of local disease and the other (Patient 10) of secondary deposits within the brain following removal of the mediastinal primary. Patient 11 had an extremely stormy postoperative course because of the development of an Aspergillus empyema. He has subsequently received radiotherapy and remains alive, albeit with persistently raised tumor markers at one year. Patient 12 returned to his country of origin shortly after primary chemotherapy followed by radiotherapy, and has been lost to follow-up. Survival The 4 patients who continue to have negative markers following primary chemotherapy (Patients 4 through 6 and 8), with or without surgical intervention, have a mean survival of five years. There is no definite evidence of survival beyond one year in patients who remain marker positive. Comment Nonseminomatous germ cell tumors of the mediastinum represent a group of tumors at the more aggressive end of the spectrum of tumors, ranging from benign teratoma to the rapidly fatal endodermal sinus tumor. It has been argued that these tumors represent- metastases from an occult testicular primary. However, Luna and Valenzuela-Tamariz [21] found evidence of this in only 5% of their patients at postmortem examination. A more plausible explanation is that extragonadal germ cell tumors arise from the primordial germ cells that have failed to complete their migration from the urogenital ridge to the gonads during embryogenesis [21, 221. Patients with active nonseminomatous germ cell tumors are unusual in that the tumors elaborate one or both of two proteins: a-fetoprotein and the beta fraction of HCG. These may be detected in the serum and are useful in monitoring tumor activity and response to therapy [23, 241. Our results confirm previous reports [ of improved survival following cis-platinum-based chemotherapy. Six (60%) of the patients responded to primary chemotherapy. This is similar to the 67% response reported by Hainsworth and colleagues [17] and the 56% response obtained by Feun and co-workers However, in the latter series, the response was short-lived, the mean duration being a mere two months. Furthermore, Economou and associates [13] had only 3 longterm survivors among 17 patients. It is noteworthy that these were the 3 patients who underwent surgical resection of the residual tumor mass. The improved survival of our patients strengthens the argument for timed radical excision of the tumor in patients who respond to primary chemotherapy. This approach has also been used by Parker and colleagues [26]; in a group of 8 patients treated similarly to ours, 3 patients died early and 5 were long-term survivors. The present study also defines the role of surgery in the management of patients with primary nonseminomatous germ cell tumors of the mediastinum. Surgical intervention appears to have little value as a primary treatment method, as 2 of the 4 patients in which it was attempted were found to have inoperable disease and 1 patient had recurrence shortly after operation. Surgery does, however, appear to be beneficial in patients whose tumor is responsive to chemotherapy. Though we have no direct evidence that removal of the unstable residual tumor mass does prolong survival, this may be inferred from the case of 1 patient (Patient 7) whose tumor markers returned to normal after chemotherapy and who subsequently suffered relapse in an area of incomplete tumor removal. This combined approach of radical surgery following primary chemotherapy has also been successfully used by Hendry and colleagues [27] in patients with nonseminomatous germ cell tumors of the testis. Their re-

582 The Annals of Thoracic Surgery Vol 44 No 6 December 1987 sults are analogous to ours: good long-term survival in patients with normal tumor markers and no evidence of residual disease.

5 582 The Annals of Thoracic Surgery Vol 44 No 6 December 1987 sults are analogous to ours: good long-term survival in patients with normal tumor markers and no evidence of residual disease. Conversely, the prognosis was poor when markers remained elevated or active disease was present in the resected specimen. Patients whose tumors are resistant to the cisplatinum-based primary chemotherapy pose a difficult management problem. Surgical intervention was clearly ineffective in 2 patients (Patients 10 and ll), and there is no evidence that radiotherapy or second-line chemotherapy prolonged survival. In summary, this report describes the evolution of a philosophy of management of primary nonseminomatous germ cell tumors of the mediastinum. Its main features are as follows: A high index of suspicion for the diagnosis should be maintained in young male patients with normal testes, large anterior mediastinal masses, and abnormal levels of a-fetoprotein or the beta fraction of HCG. The primary treatment method should be cisplatinum-based combination chemotherapy. Patients whose tumor markers return to normal have a good long-term prognosis following radical surgery. Patients whose tumor markers remain elevated after chemotherapy have a poor prognosis, and attempts to salvage them by radical surgery are futile. We thank our oncology colleagues Prof. M. Peckham, Dr. S. Spiro, and Dr. J. Tobias for their cooperation in this multidisciplinary approach. We also thank Dr. J. Husband for the roentgenograms and computed tomograms, and the photographic department of the Royal Marsden Hospital for their reproduction. References 1. Collins D, Pugh R Classification and frequency of testicular tumours. Br J Urol 36:Suppl 1:11, Friedman N: The comparative morphogenesis of extragenital and gonadal teratoid tumors. Cancer 4265, Veraguth P, Maellard G, Macgee W Retroperitoneal seminomas without evidence of primary growth. Oncology 24193, Friedman N: Germinoma of the pineal: its identity with germinoma ( seminoma ) of the testis. Cancer Res 7;363, Lisco H: Malignant tumors developing in sacrococcygeal teratoma. Ann Surg 115:378, Hajdu S Pathology of germ cell tumors of the testis. Semin Oncol 6:14, Johnson D, Laneri J, Mountain C, Luna M: Extragonadal germ cell tumors. Surgery 73:85, Martini M, Golbey R, Hajdu S, et al: Primary mediastinal germ cell tumors. Cancer 33:763, Oberman H, Libcke J: Malignant germinal neoplasms of the mediastinum. Cancer 17498, Pecondo J, Libshitz H Mediastinal extragonadal germ cell tumors. Urology 11:369, Pochter M, Lattes R Germinal tumors of the mediastinum: a clinico-pathological study of adult teratomas, teratocarcinomas, choriocarcinomas and seminomas. Chest 45:301, Walden P, Woods R, Fox B, Bagshawe K: Primary mediastinal trophoblastic teratomas. Thorax 32:752, Economou J, Trump D, Cormack-Holmes E, Eggleston J: Management of primary germ cell tumors of the mediastinum. J Thorac Cardiovasc Surg 83643, Li M, Whitmore W, Golbey R, Grabstald H: Effects of combined drug therapy on metastatic cancer of the testis. JAMA , Einhom L, Donohue J: Cis diamminodichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87293, Reynolds T, Yagoda A, Vugrin D, Golbey R Chemotherapy of mediastinal germ cell tumors. Semin Oncol6113, Hainsworth J, Einhorn L, Williams S, et al: Advanced extragonadal germ cell tumors: successful treatment with combination chemotherapy. Ann Intern Med 977, Vogelzang NJ, Raghavan D, Anderson RW, et al: Mediastinal nonseminomatous germ cell tumors: the role of combined modality therapy. Ann Thorac Surg 33:333, Peckham M, Barrett A, McElwain T, et al: Non-seminoma germ cell tumours (malignant teratoma) of the testis: results of treatment and an analysis of prognostic factors. Br J Urol 53362, Peckham M, Barrett A, Liew K, et al: The treatment of metastatic germ cell testicular tumours with bleomycin, etoposide and cisplatinum (BEP). Br J Cancer 47613, Luna M, Valenzuela-Tamariz J: Germ cell tumors of the mediastinum: post mortem findings. Am J Clin Path01 65:450, Steinmetz W, Hays R Primary seminoma of the mediastinum: report of a case with an unusual site of metastasis and review of the literature. Am J Roentgen01 86:669, Javadpour N: The value of biologic markers in the diagnosis and treatment of testicular cancer. Semin Oncol637, Stepanas A, Samaan N, Schultz P, Hologe P: Endocrine studies in testicular tumor patients with and without gynecomastia: a report of 45 cases. Cancer 41:369, Feun L, Samson M, Stephens R Vinblastine (VBL), bleomycin (Bleo), cis-diamminodichloroplatinum (DDP) in disseminated extragonadal germ cell tumors. Cancer , Parker D, Holford C, Begart R, et al: Effective treatment for mediastinal teratoma. Thorax 38:897, Hendry W, Goldstraw P, Husband J, et al: Elective delayed excision of bulky para aortic lymph node metastases in advanced non-seminoma germ cell tumours of the testis. Br J Urol53:648, 1981

Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy

Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy Nicholas J. Vogelzang, M.D., Derek Raghavan, M.B., B.S., Robert W. Anderson, M.D., Juan Rosai, M.D., Seymour H. Levitt,