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© 2002 American Society for Clinical Oncology Extragonadal Germ Cell Tumors of the Mediastinum and Retroperitoneum: Results From an International AnalysisByFrom the Tuebingen University Medical Center II, Tuebingen; Klinikum Großhadern, Munich; Virchow Klinikum, Berlin; and University of Halle, Halle, Germany; Oregon Health Sciences University, Portland, OR; Centre Léon-Berard, Groupe d’Etude des Tumeurs Urologiques et Genitales, Lyon, France; Royal Marsden Hospital, Sutton, United Kingdom; Norwegian Radium Hospital, Oslo, Norway; Kaiser Franz Josef Spital, Vienna, Austria; and Indiana University, Indianapolis, IN. Address reprint requests to C. Bokemeyer, MD, Department of Hematology/Oncology/Immunology, UKT-University Medical Center II, Eberhard-Karls-University, Otfried-Mueller-Str 10, 72076 Tuebingen, Germany; email: carsten.bokemeyer{at}med.uni-tuebingen.de
PURPOSE: To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies. PATIENTS AND METHODS: Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology. RESULTS: After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P = .0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy. CONCLUSION: Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.
MALE GERM CELL tumors (GCTs) predominantly arise from the testis. However, a small subset of 2% to 5% is of extragonadal origin.1 These extragonadal GCTs (EGCTs) histologically contain the same components as their gonadal counterparts, but they are found in the midline of the body and there is no gonadal mass detectable by palpation or high-resolution ultrasonography. It was hypothesized that EGCTs are either a consequence of a mismigration of germ cells along the urogenital ridge during embryogenesis2 or they may result from germ cells that are distributed physiologically to the liver, bone marrow, and brain in order to provide regular functions or convey hematologic or immunologic information.3 Testicular and EGCTs also share similar serologic features such as secretion of the tumor markers alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (ß-HCG). The characteristic genetic abnormality that is found in both EGCTs and gonadal GCTs is an isochromosome i(12p).4 Although it may be possible that regression of a primary testicular tumor, with or without residual scarring, occurs and its metastases might be diagnosed as an EGCT, it is generally accepted that EGCTs represent the malignant transformation of germinal elements without a gonadal focus. Supporting this hypothesis, specific syndromes such as the association between mediastinal nonseminoma and Klinefelter syndrome as well as the frequent development of hematologic malignancies have been observed only in patients with EGCTs.5-7 The introduction of cisplatin-based combination chemotherapy regimens along with aggressive postchemotherapy surgery has substantially improved the prognosis of patients with metastatic testicular GCTs.8 However, limited data are available regarding the clinical course of patients with EGCTs and the outcome after cisplatin-based chemotherapy in this specific disease. This report adds information from a large database investigating patients with EGCTs from 11 European and American cancer centers. All patients were treated during a recent time period where modern cisplatin-based combination chemotherapy regimens were generally available, thus allowing analysis of the prognosis of this patient cohort when treated according to currently available strategies.
Data Collection We evaluated the medical records of 635 EGCT patients treated at 11 cancer centers in the United States and Europe between 1975 and 1996. An EGCT was defined as the absence of testicular abnormalities on physical examination and ultrasonography. In case of abnormalities, biopsy was performed to exclude invasive testicular germ cell cancer. Testicular intraepithelial neoplasia (TIN) or a scar found at biopsy was not a cause for exclusion from study. For all living patients, the status as of February 1999 was obtained. The contributing centers were as follows: Indiana University, Indianapolis, IN (n = 216; time period, 1989 through 1996); Hannover University Medical School, Hannover, and Eberhard-Karls-University Medical Center II, Tuebingen, Germany (n = 101; time period, 1978 through 1995); Institute Gustave-Roussy, Villejuif, Centre Léon-Berard, Lyon, and the Groupe d’Etude des Tumeurs Urologiques et Genitales, France (n = 93; time period, 1975 through 1996); Royal Marsden Hospital, Sutton, United Kingdom (n = 65; time period, 1979 through 1994); Klinikum Großhadern, Munich, Germany (n = 63; time period, 1979 through 1996); Norwegian Radium Hospital, Oslo, Norway (n = 48; time period, 1980 through 1995); Virchow-Klinikum, Berlin, Germany (n = 30; time period, 1987 through 1994); and Kaiser-Franz-Josef Spital, Vienna, Austria (n = 19; time period, 1975 through 1996). For data collection, a standardized questionnaire was sent to each center and completed by one of the coinvestigators. All patients’ data were obtained in an anonymous manner. Detailed information on patient characteristics such as location and histology of primary tumor; extent of disease including serum tumor marker concentrations of ß-HCG, AFP, and lactate dehydrogenase; history of testicular abnormalities, diagnostic methods, treatment, and response; and follow-up period and data on metachronous testicular cancer (MTC) and second cancers were acquired. All histopathologic slides of these cases were reviewed by each center’s pathology department. Patients were classified to have a nonseminomatous GCT if an elevation of serum AFP greater than 10 ng/mL or serum ß-HCG greater than 100 ng/mL was found even when histopathologic examination revealed pure seminoma. Tumor response was classified as follows: complete remission (CR) was defined as a complete disappearance of all clinical, radiologic, and biochemical evidence of disease with normalization of ß-HCG and/or AFP and/or lactate dehydrogenase for at least a 1-month duration. A partial response was defined as a decrease of  50% of the sum of the products of perpendicular diameters of measurable disease lasting for at least 1 month. If elevated markers were the only evidence of disease, a decrease of 90% was required for a partial response. Progressive disease was defined as either residual lesions increasing in size or occurrence of new lesions and/or elevation of tumor markers at repeated controls. Duration of follow-up and survival were calculated on the basis of the date of diagnosis of the EGCT until the date of last contact, if the patient was still alive, or the date of death.
Statistical Analysis The numbers of cases of leukemia, MTC, and second nongerminal solid tumors in the study group were compared with 5-year age-group–specific data of the cancer registry of Saarland, Germany. This population-based cancer registry covers the federal state of Saarland located in the southwest of Germany. Results were standardized on the basis of age and follow-up duration (patient-years at risk) and expressed using a standardized incidence ratio (SIR) with the associated 95% confidence interval (CI) calculated on the assumption of a Poisson distribution.7,11,12
Patient Characteristics Individual data on 635 patients with a median age of 30 years (range, 14 to 79 years) were assessable for this analysis. Three hundred forty-one patients (54%) had a primary mediastinal EGCT, and 283 patients (45%) had a primary retroperitoneal EGCT. One patient (0.16%) was found to have only primary cervical lymph node involvement. In addition, 10 patients (1.6%) had widespread pulmonary disease, both midline retroperitoneal and mediastinal, and therefore the location of the primary tumor could not be specified. Their clinical and demographic features are listed in Tables 1 and 2. One hundred four patients with a pure seminomatous EGCT were identified, representing 16% of the 635 EGCT patients in the database, whereas 524 patients (83%) had a nonseminomatous EGCT. Histology was not specified in seven patients.
Clinical Presentation and Diagnostic Procedures In patients with mediastinal EGCTs, the most common symptoms at presentation were dyspnea (25%), chest pain (23%), and cough (17%), followed by fever (13%), weight loss (11%), vena cava occlusion syndrome and fatigue/weakness (6% each), and pain at other locations except the chest (5%). Less frequent symptoms were chest wall or cervical mass (2%), and hemoptysis, hoarseness, nausea, or dysphagia (1% each). Abdominal (29%) and back pain (14%) were the two most common presenting symptoms among the 283 patients with retroperitoneal GCTs. Less frequent symptoms were weight loss (9%), fever/night sweats (8%), venous thrombosis (9%), a palpable abdominal (6%) or cervical mass (4%), scrotal edema/hydrocele (5%), gynecomastia and dyspnea (3% each), fatigue, pain, nausea, or venous thrombosis (2% each), dysphagia, obstipation, cough, and hemoptysis (1% each), and hematuria (0.3%). The initial diagnosis was achieved by a combination of computed scans, radiographs, sonograms, and determination of tumor markers in 93% of patients. In 13 patients (2%), a primary tumor resection was performed, and in 30 patients (5%), a biopsy of the lesion was performed as the initial diagnostic procedure. In 65 patients, the tumor marker findings were considered sufficient to classify the lesion as extragonadal nonseminoma without histologic confirmation, and in the remaining 570 patients, cytologic or histopathologic diagnosis was gained before the start of treatment.
Medical History in EGCT Patients In 71 patients (11%), testicular biopsies were performed before or shortly after the start of treatment for EGCT (time interval since diagnosis, 0.4 months; range, -5.0 to 3.0 months). Twenty-six patients underwent bilateral biopsies. Sixty patients (85%) who underwent testicular biopsy had a retroperitoneal EGCT, and 11 patients (16%) had a mediastinal EGCT. Histopathologic results in 65 available patients revealed normal testicular histology in 35 cases (49%), Sertoli cell only syndrome in two patients (3%), and atrophic or fibrotic testis in 22 patients (31%). In six patients (9%), TIN was evident, four cases in retroperitoneal EGCT and two cases in mediastinal tumors.
MTC in EGCT Patients
Second Nongerminal Malignancies There were no cases of treatment-related leukemia observed in the 611 patients who had received cisplatin-based chemotherapy. These leukemias are distinguished from primary mediastinal EGCT-associated hematologic disorders by the time interval of occurrence (5 to 7 years after the application of alkylating agents; > 2 years after topoisomerase-II inhibitors), evidence of preceding preleukemic myelodysplasia, phenotype according to French-American-British classification (M1/M2 or M4/M5), and characteristic translocations (long arm of chromosome 11 [11q23] after etoposide; involvement of 5 or 7 in 60% to 90% after treatment with alkylating agents). In contrast, hematologic disorders associated with mediastinal germ cell tumors seem to have no consistent cytogenetic abnormalities. In this series, 17 of the 287 patients with mediastinal nonseminomatous EGCTs developed hematologic disorders within a short time interval of 6 months (range, 0 to 47 months) after the diagnosis. These disorders were mainly acute megakaryoblastic leukemia (n = 5) and myelodysplasia with abnormal megakaryocytes (n = 5). Cytogenetic analyses available in 13 patients revealed the GCT marker chromosome i(12p) in leukemic blasts from 38% of these patients. Other karyotypic abnormalities included trisomy 8 in two of 13 patients (15%) and Klinefelter syndrome (XXY) in one patient (8%). The statistical risk for developing hematologic disorders was markedly increased in patients with primary mediastinal nonseminomatous EGCTs (SIR, 250; 95% CI, 140 to 405). The prognosis of these patients was dismal, with a median survival time of only 5 months (range, 0 to 16 months) after the diagnosis of the hematologic disorder.
Treatment and Clinical Outcome of EGCT Patients
Mediastinal nonseminoma. Two hundred eighty-seven (55%) of 524 nonseminomatous EGCT patients had a primary mediastinal location. One hundred forty-five patients (51%) did not have any additional metastatic sites, 97 patients (34%) had one, and 45 patients (16%) had two or more additional lesions. Treatment consisted of chemotherapy in 278 patients (98%). Four patients each received primary mediastinal irradiation (range, 45 to 60 Gy) or underwent primary resection of mediastinal teratoma (1.4% each). Mainly conventional cisplatin-based combination regimens were used (Table 2). Overall, 64% of patients (95% CI, 58% to 70%) responded favorably to treatment (CR, n = 54 [19%]; tumor marker normalized PR, n = 124 [45%]). One hundred forty-three patients (49%) underwent secondary resections of residual tumor masses after chemotherapy (thoracic surgery, n = 121; retroperitoneal surgery, n = 4; combined thoracic and abdominal operation ± resection of liver metastases, n = 18) yielding viable tumor in 49 (34%) and non-GCT elements in two patients (1.4%), mature teratoma in 37 (26%), and necrotic tissue in 53 patients (37%) (nonassessable, n = 2). The calculated 5-year OS and PFS rates were 45% and 44%, respectively. OS is shown in Fig 1B. Retroperitoneal nonseminoma. These patients represent 43% of all nonseminomas. They frequently had metastatic involvement at two or more different sites (n = 109 patients [48%]). A retroperitoneal mass alone was found in 55 patients (24%). Two hundred twenty-three patients (98%) were treated with primary chemotherapy. Two patients underwent primary resection of retroperitoneal tumor alone (0.9%) (irradiation alone, n = 1). The ORR for all patients was 68% (95% CI, 62% to 75% [149 of 218 assessable patients]) including 61 patients (28%) rated as CR. One hundred one patients (45%) underwent secondary surgery of residual tumor masses (retroperitoneal surgery, n = 85; thoracic surgery, n = 8; combined thoracic and abdominal operation, n = 4; resection of liver metastases, n = 3; neck dissection, n = 1) after completion of chemotherapy. Histopathologic examination of resected tumor masses revealed viable undifferentiated tumor in 23 patients (25%), mature teratoma in 37 (16%), and necrotic tissue in 54 patients (59%) (nonassessable, n = 9). The calculated 5-year OS and PFS rates for patients with retroperitoneal nonseminoma were 62% and 45%, respectively. OS is shown in Fig 1B.
Salvage Chemotherapy in Patients With Relapsed Nonseminoma The median follow-up period from the start of salvage chemotherapy for all relapsed patients was 11 months (range, 1 to 159 months) and 45 months (range, 6 to 157 months) for surviving patients. Only 27 (19%) of 142 patients are alive without evidence of disease after salvage chemotherapy. Eighteen (30%) of 61 patients with retroperitoneal tumors have become free of disease, in contrast to only nine (8%) of 79 patients with mediastinal EGCTs (P = .01).
Multivariate Analysis on Prognostic Factors for Survival in EGCT
This report describes the presenting clinical features, treatment outcome, and selected biologic aspects of 635 consecutive adult patients with retroperitoneal and mediastinal EGCTs treated with platinum-based chemotherapy at 11 cancer centers. As expected, most patients had symptomatic disease at the time of diagnosis with dyspnea, chest pain, and cough as well as back or abdominal pain being the most common symptoms at presentation for mediastinal and retroperitoneal EGCT location, respectively. Overall, extragonadal seminoma is a rare disease. Most previous reports included only five to 10 patients and thus do not enable the analysis of treatment strategies and prognostic factors. In the present series, 104 patients with pure seminomas have been identified, with mediastinal and retroperitoneal primary tumors being equally distributed. This is in contrast to earlier observations that reported the mediastinal location to be more common.13,14 Because seminomas grow slowly and produce few symptoms, most tumors have been found bulky at presentation. The median size was 5 cm for mediastinal and 7 cm for retroperitoneal tumors. Interestingly, patients with mediastinal seminoma were diagnosed at a median age of 33 years (range, 18 to 65 years), whereas patients with retroperitoneal primary tumors tended to be 8 years older (41 years; range, 23 to 70 years). The current series demonstrates that no significant differences in PFS and OS exist between patients with mediastinal and retroperitoneal seminoma location. The analysis of treatment strategies revealed a lower probability for PFS for patients treated with radiotherapy compared with those receiving chemotherapy. In patients with metastatic testicular seminoma and abdominal lymph nodes greater than 5 cm at initial diagnosis, a relapse rate of approximately 20% to 30% after radiation therapy alone has been reported.15,16 This is in accordance with the high relapse rate observed with radiotherapy alone in patients with bulky extragonadal seminoma. Retrospective analyses by other authors have also indicated that initial radiotherapy might reduce the overall likelihood for cure in advanced seminoma. Therefore, primary chemotherapy has widely replaced radiotherapy as initial treatment in patients with mediastinal or bulky retroperitoneal seminoma.17-19 Outside of clinical trials, the treatment for patients with good or intermediate prognosis gonadal or extragonadal seminoma according to the International Germ Cell Cancer Collaborative Group (IGCCCG) criteria20 consists of three or four cycles of cisplatin-based chemotherapy. Our results confirm the favorable treatment outcome achieved with primary chemotherapy in patients with extragonadal seminoma, yielding an ORR of 92%, and an OS rate of 88% after 5 years of follow-up. Resection of postchemotherapy residual masses in 25 patients demonstrated a high probability for necrosis in patients with extragonadal seminoma. Only two patients (8%) had either vital seminoma or mature teratoma found at resection. The presence of teratoma in a resected residual mass may indicate the initial presence of nonseminomatous elements in this patient. The observed results in terms of treatment outcome support the conclusion that no distinction has to be made between patients with gonadal and those with extragonadal seminoma.21 Although the principles of management of patients with nonseminomatous EGCTs parallel those of metastatic testicular GCTs, these patients clearly have a worse prognosis compared with their gonadal counterparts within the same prognostic IGCCCG group or compared with patients with seminomas at any location. In particular, patients with mediastinal nonseminomatous EGCTs revealed inferior survival rates. Twenty years ago, in these patients, a survival rate of 3% was published.22 With the incorporation of cisplatin into chemotherapy regimens, retrospective analysis yielded ORR in the range of 40% to 80%, resulting in a survival rate of approximately 30%.19,23-28 Two prospective series based on 31 and 41 patients reported a long-term survival of more than 50% after cisplatin-based chemotherapy plus surgery.29,30 Our experience in 284 assessable patients with primary mediastinal location revealed a long-term survival rate of 48%. Thus, survival rates seem to have improved over the years, maybe because of better chemotherapeutic regimens in combination with aggressive postchemotherapy surgery of residual masses, and now approach the rate achieved in the subgroup of patients with so-called poor prognosis disease according to the IGCCCG classification,20 which includes patients with metastatic testicular GCTs and nonpulmonary visceral metastases in liver, bone, or the CNS or with highly elevated tumor markers. Half of the patients in the current series have undergone a multidisciplinary treatment approach including aggressive postchemotherapy surgery. As in patients with metastatic gonadal GCTs, radical surgical resection of all residual mass after first-line chemotherapy is indicated in EGCT patients whenever technically possible, either as a one-stage or as a sequential procedure.29,31-34 Patients with nonseminomatous retroperitoneal EGCTs within the same IGCCCG category also have a clinical outcome between that of patients with metastatic gonadal tumors and those with primary mediastinal tumors. The results of the present series confirmed the inferior prognosis of retroperitoneal EGCT patients compared with their gonadal counterparts. Patients fulfilling "poor" prognosis criteria had a 59% 5-year survival rate; however, in patients with either "good" or "intermediate" prognosis disease, a survival rate of 61% was observed, which is clearly lower than that expected according to the IGCCCG classification. Thus, it seems to be worthwhile to treat those patients with four cycles of cisplatin-based combination chemotherapy or consider them alternatively as candidates for experimental protocols. Postchemotherapy dissection in cases of residual masses is recommended to improve treatment results. Table 4 compares the results of chemotherapy, the rate of relapse, and the 5-year PFS and OS rate among the different categories of EGCT, including mediastinal seminoma, retroperitoneal seminoma, mediastinal nonseminoma, and retroperitoneal nonseminoma.
Although metastatic testicular cancer is one of the few solid tumors in the adult for which salvage chemotherapy still offers a curative chance, the results with salvage treatment—even including high-dose chemotherapy—in nonseminomatous EGCTs have been disappointing. It seems that more than 90% of patients with relapsed mediastinal nonseminoma are unable to obtain a durable, complete remission.35,36 Long-term OS reported for a small number of cases in the literature ranged from 0% to 27%.27,37-40 Data from the present series on 142 patients with relapsed nonseminomatous EGCTs confirm that only patients with primary retroperitoneal tumors achieved a long-term salvage rate comparable to patients with relapsed metastatic gonadal GCTs. The prognosis of patients with mediastinal EGCTs at relapse was clearly inferior, with a salvage rate of less than 10%. Primary mediastinal tumor and resistance to cisplatin-based induction chemotherapy were identified as significant prognostic indicators for long-term outcome. Thus, surgical resection plays an important role in the salvage treatment and might even be beneficial in selected patients with elevated tumor markers when no further effective chemotherapy is available.41,42 Overall, no elevated risk for the development of solid nongerminal tumors was found.43 On the other hand, about 70 cases with hematologic disorders in EGCT patients have been described in the literature since 1985.5,7 These cases occurred exclusively in patients with primary mediastinal EGCTs and were mainly disorders of the megakaryocyte lineage. The interval between the diagnosis of GCT and of the hematologic disorder was usually short, and a substantial number of patients had a simultaneous onset of both EGCT and leukemia. This hematologic malignancy had a very aggressive clinical course, with patients either dying before treatment, not responding to antileukemic therapy, or achieving remissions of very short duration. On the basis of the cytogenetic findings—ie, high incidence of i(12p) in leukemic blasts—and the short time interval from GCT to leukemia, it has been postulated that the hematologic malignancy and the mediastinal GCT arise from a common progenitor cell.7,44 The incidence rate of leukemia in 287 patients with mediastinal nonseminomatous EGCTs included in this series was 6% (95% CI, 3.5% to 9.3%).7 MTCs have occurred in EGCT patients despite the three to four cycles of platinum-based chemotherapy in all 16 patients affected. With one exception, all cases presented with retroperitoneally located EGCTs, but for the first time an elevated standard incidence ratio for MTC has also been observed in mediastinal EGCTs. MTCs were predominantly of seminomatous histology, despite the fact that the initial EGCTs were almost all of nonseminomatous histology. Although this risk translates to a 10% chance of developing MTC over a 10-year period, there was no mortality observed in those patients with subsequent MTC. All patients have been treated successfully, indicating that close follow-up is very relevant in curatively treatable patients with EGCTs.45 In addition, more than 30 cases of Klinefelter syndrome in patients with mediastinal GCTs and at least 10 cases in patients with extragonadal GCTs in other locations have been reported.6 In smaller series, the estimated frequency was 8% to 18% in patients with mediastinal EGCTs.46 This investigation, based on over 600 patients, however, revealed a lower frequency, maybe because of the elimination of a selection bias, which is often seen in single case reports from specialized centers. This investigation of 635 patients has allowed the identification of prognostic factors on the basis of the large number of patients included: negative predictors for both PFS and OS were the presence of liver and CNS metastases, a primary mediastinal location, and nonseminomatous histology. The elevation of ß-HCG and bone metastases indicated an inferior OS, and the presence of lung metastases an inferior PFS. With the above-mentioned exception of ß-HCG concentrations, no other tumor marker revealed statistical significance for either PFS or OS regardless of their consideration as absolute values in serum, elevation or nonelevation, or grouping according to the IGCCCG criteria. Overall, the 5-year survival rate for patients with EGCT varies from 45% for patients with nonseminomatous mediastinal EGCT to 90% for patients with seminomatous mediastinal and retroperitoneal EGCT. In patients with primary retroperitoneal nonseminomatous EGCT, an intermediate long-term cure rate of 50% to 65% can be expected after cisplatin-based chemotherapy and radical surgery of residual tumor masses.
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
