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Originally published as JCO Early Release 10.1200/JCO.2005.05.4791 on January 29 2007 © 2007 American Society of Clinical Oncology. Long-Term Clinical Outcome After Postchemotherapy Retroperitoneal Lymph Node Dissection in Men With Residual Teratoma
From the Department of Urology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to Brett S. Carver, MD, Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, 353 E 68th St, New York, NY 10021; e-mail: carverb{at}mskcc.org
Purpose The histologic finding of teratoma occurs in approximately 40% of all postchemotherapy retroperitoneal lymph node dissections (PC-RPLND). We evaluated patients at our institution undergoing initial PC-RPLND for teratoma to determine their clinical outcome. Patients and Methods We identified 210 patients from 1989 to 2003 with nonseminomatous germ cell tumors (NSGCT) who underwent initial PC-RPLND and were found to have only teratoma in the retroperitoneum. Clinical and pathologic information was obtained from our prospective surgical database, and clinical outcome was reported. Results Of the 210 patients in our series, 192 (92%) received only induction chemotherapy, and 18 (9%) required additional chemotherapy regimens. PC-RPLND pathology revealed mature teratoma in 178 patients (85%), immature teratoma in 15 patients (7%), and teratoma with malignant transformation in 17 patients (8%). With a median follow-up time for survivors of 37 months, disease recurred in 30 patients. The probability of remaining free of disease recurrence at 5 and 10 years was 83% and 80%, respectively. Of the 30 patients with disease recurrence, 10 (33%) had recurrence with teratoma, five (17%) had recurrence with teratoma with malignant transformation, and 15 (50%) had recurrence with viable germ cell tumor. On multivariable analysis, residual mass size and International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification were predictors of disease recurrence (P < .0005 and = .001, respectively). Conclusion PC-RPLND remains critical in the management of patients with NSGCT. Patients found to have teratoma at PC-RPLND have a 10-year probability of freedom from recurrence of 80%. The size of the residual mass and IGCCCG risk classification were significant predictors of disease recurrence.
The successful multidisciplinary approach for the management of nonseminomatous germ cell tumors (NSGCT) has resulted in survival rates of greater than 90% overall.1 After induction chemotherapy for metastatic NSGCT, approximately 40% of patients undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) will have teratoma in their retroperitoneum, and an additional 10% to 15% of patients will have viable germ cell tumor (GCT).2-5 Teratoma, although histologically mature, is biologically unpredictable, with a capacity for local growth or transformation into somatic malignancies such as sarcoma or carcinoma. The incidence of malignant transformation is approximately 3% to 6% in men undergoing PC-RPLND after induction chemotherapy but increases to 12% to 18% in men undergoing reoperative PC-RPLND and in men experiencing late relapse.6,7 Relapse rates with viable GCT or teratomatous elements after postchemotherapy resection of teratoma range from 6% to 39%.8-11 Although the majority of relapses occur within the first 2 years of follow-up, Sonneveld et al11 reported a long disease-free interval of 31 months in patients who experienced relapse with teratoma or teratoma with malignant transformation. Late recurrences with teratoma and malignant transformation have been reported and account for approximately 25% and 14% of all late relapses, respectively.7,12,13 An inadequately controlled retroperitoneum is the most common site of late relapse, and it has been reported that recurrence of teratoma may be related to the completeness of the initial postchemotherapy surgical resection.12 We evaluated men undergoing initial PC-RPLND at our institution after induction or second-line chemotherapy who were found to have teratomatous elements in the retroperitoneum to determine their long-term clinical outcome. Additionally, we evaluated clinical variables to determine predictors for disease recurrence.
From 1989 to 2003, a total of 532 men underwent initial PC-RPLND after induction or second-line chemotherapy at our institution as part of the multidisciplinary management of metastatic NSGCT. Of these, 210 men (40%) were found to have only teratomatous elements in the retroperitoneal nodal specimen after complete surgical resection. Teratoma was defined as the presence of mature teratoma, immature teratoma, or teratoma with malignant transformation in the resected specimen. Patients undergoing redo-PC-RPLND and patients with late relapse were not included in this study because previous studies have demonstrated that these patients may be at a higher risk of relapse and progression independent of tumor histology.7,14 This study was approved by the institutional review board at Memorial Sloan-Kettering Cancer Center (New York, NY). Clinical and pathologic data were obtained from our prospective surgical database. The International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification was assigned before induction chemotherapy.15 Patterns of relapse and subsequent therapies are reported during follow-up according to IGCCCG risk classification and retroperitoneal histology. In addition, histologic findings at the time of relapse are reported. Retroperitoneal nodal size before and after chemotherapy was determined by the transverse diameter of the largest mass on computed tomography imaging. Long-term clinical outcome is reported using the Kaplan-Meier method for disease recurrence and disease-specific survival. Differences in survival probabilities were assessed using the log-rank test. Cox proportional hazards regression was used to univariately evaluate variables that may predict for disease recurrence. Variables that were significant at the P = .05 level in univariate analyses were entered in a multivariable Cox regression model. For our analysis, postchemotherapy alpha-fetoprotein levels were entered as a continuous variable, whereas human chorionic gonadotropin (hCG) levels were transformed into a categoric variable (normal for hCG < 2.0 U v elevated for hCG > 2.0 U).
Statistical analysis was performed using STATA 8.2 (STATA Corp, College Station, TX). P
Of the 210 patients with only teratomatous elements at PC-RPLND, 192 (91%) received only induction chemotherapy, and 18 (9%) required multiple chemotherapy regimens for persistently elevated serum tumor markers after induction chemotherapy. Patients were classified based on the IGCCCG risk criteria, with good-, intermediate-, and poor-risk disease in 146 patients (70%), 33 patients (16%), and 31 patients (14%), respectively. Postchemotherapy retroperitoneal histology revealed mature teratoma in 178 patients (85%), immature teratoma in 15 patients (7%), and teratoma with malignant transformation in 17 patients (8%). Pre-RPLND patient characteristics are listed in Table 1. The median pre- and postchemotherapy retroperitoneal nodal sizes were 4.0 cm (interquartile [IQ] range, 2.5 to 7.0 cm) and 3.0 cm (IQ range, 1.5 to 5.3 cm), respectively. Overall, serum tumor markers were elevated in 18 patients at the time of PC-RPLND. The median serum alpha-fetoprotein level before PC-RPLND was 3.0 ng/mL (IQ range, 1.9 to 4.9 ng/mL).
Five patients (2%) had progressive viable GCT outside the retroperitoneum after PC-RPLND and were never rendered clinically disease free with surgery; therefore, these patients were excluded from the disease recurrence analyses. With a median follow-up time for survivors of 37 months (IQ range, 14 to 64 months), disease recurrence was noted in 30 patients. Twenty-four patients (80%) experienced relapse within the first 2 years of follow-up, and six patients experienced relapse beyond 2 years. Of the 30 men who experienced a recurrence, 10 (33%) had relapse with mature/immature teratoma, five (17%) had relapse with teratoma with malignant transformation, and 15 (50%) had relapse with viable GCT. The 5- and 10-year probabilities of freedom of recurrence were 83% (95% CI, 76% to 88%) and 80% (95% CI, 70% to 87%), respectively. The histologies of the relapse according to the initial retroperitoneal histology and IGCCCG risk classification are listed in Table 2. Of the 193 patients with mature/immature teratoma, 24 experienced relapse after PC-RPLND, and two experienced relapse with teratoma with malignant transformation. For men relapsing with only teratomatous histology, sites of relapse were retrocrural in seven, pulmonary in four, liver in one, pelvis in one, neck in one, and para-aortic/hilar in one. For men relapsing with viable GCT, sites of relapse were pulmonary in five, liver in four, suprahilar in four, brain in three, neck in one, and elevated markers alone in two. Only one patient suffered an in-field recurrence.
The probability of freedom from recurrence according to IGCCCG risk classification, retroperitoneal histology, and size of the residual mass is shown in Figure 1. The 5-year probabilities of freedom from recurrence for patients with good, intermediate, and poor IGCCCG risk were 91% (95% CI, 84% to 95%), 70% (95% CI, 49% to 84%), and 62% (95% CI, 38% to 79%), respectively (P = .01). Patients with good risk had the highest probability of freedom from recurrence, and patients with intermediate and poor risk were comparable (P = .7). Patients with teratoma with malignant transformation had a significantly lower 5-year probability of freedom from recurrence when compared with men with mature/immature teratoma (54%; 95% CI, 25% to 77% v 86%; 95% CI, 78% to 90%, respectively; P = .001). Patients with residual masses of less than 2 cm, 2 to 5 cm, and  5 cm had 5-year probabilities of freedom from recurrence of 94% (95% CI, 76% to 99%), 91% (95% CI, 82% to 96%), and 59% (95% CI, 42% to 72%), respectively (P < .0005).
On univariate analysis, higher pre- and postchemotherapy retroperitoneal nodal size, intermediate or poor IGCCCG risk classification, and the presence of malignant transformation were significant predictors for increased risk of disease recurrence (Table 3). Of note, the histologic finding of immature teratoma at PC-RPLND was not a predictor of disease recurrence when compared with men with mature teratomatous histology. Because patients with intermediate and poor risk disease were at comparable risk of recurrence on univariate analysis, we grouped them together and compared them against patients with good risk in the multivariable model. We included postchemotherapy retroperitoneal nodal size, but not prechemotherapy retroperitoneal nodal size, in the multivariable model because of the high correlation (0.79) between those two predictors. On multivariable analysis, larger postchemotherapy retroperitoneal nodal size and intermediate or poor IGCCCG risk classification remained significant predictors of disease recurrence, and presence of malignant transformation showed a trend for increased risk of disease recurrence (Table 3).
With a median follow-up time for survivors of 38 months (IQ range, 17 to 69 months), 10 patients were dead of disease. Overall, the 5- and 10-year probabilities of disease-specific survival were 94% (95% CI, 88% to 97%) and 92% (95% CI, 85% to 96%), respectively. For patients initially experiencing relapse with teratoma, viable GCT, and malignant transformation, one of 10 men, three of 15 men, and three of five men, respectively, were dead of disease at last follow-up.
Teratomatous elements are present in the retroperitoneum in approximately 40% of men undergoing PC-RPLND for metastatic NSGCT.2-5 Despite the histologically benign nature of teratoma, there are significant advantages to complete resection. Unresected teratoma may grow, obstruct, or invade adjacent structures. Additionally, there is the risk of malignant transformation to non–germ cell malignant elements such as sarcoma or carcinoma. In our series, teratoma with malignant transformation was present in 3% of patients overall and represented 8% of patients with teratoma only. Lastly, teratoma may result in late relapses. The finding of residual teratoma in the retroperitoneum after chemotherapy has been assumed to be a favorable prognostic factor. However, several series have reported a high frequency of recurrences. Loehrer et al10 reported on 51 patients who had surgical resections of teratoma after cisplatin-based chemotherapy. Twenty patients (39%) experienced relapse with either histologically proven teratoma (10 patients) or viable GCT (10 patients). Sonneveld et al11 reported on 51 patients with retroperitoneal teratoma after chemotherapy for NSGCT. In their series, nine patients experienced a relapse, with growing mature teratoma in 56%, teratoma with malignant transformation in 33%, and viable GCT in 11%. Our current series represents a contemporary cohort of 210 patients with teratomatous elements in the retroperitoneum at PC-RPLND and, to our knowledge, is the largest series in the literature reporting on long-term outcomes. Overall, relapse occurred in 30 patients, and the 10-year probability of freedom from recurrence was 80%. Of our patients who experienced relapse, 50% relapsed with teratomatous elements, and 50% relapsed with viable GCT. For patients experiencing relapse after resection of teratoma, 17% had relapse with malignant transformation. The histologic finding of teratoma with malignant transformation in the postchemotherapy RPLND specimen has been associated with a poor prognosis.6,16,17 Comiter et al16 reported on 21 patients undergoing therapy for teratoma with malignant transformation, and with a median follow-up time of 50 months, 17 patients experienced relapse. Motzer et al6 reported on 46 patients with malignant transformation managed with chemotherapy and/or surgical resection. With a median follow-up of 34 months, 25 patients remained disease free. In our current series, the presence of malignant transformation in the resected mass was associated with a higher probability of disease recurrence. Additionally, for those patients who experienced relapse with malignant transformation, three of five men died of disease. Because teratoma with malignant transformation is generally resistant to standard chemotherapy, complete surgical resection, particularly of a solitary site, remains the treatment of choice. Donadio et al17 reported on 10 patients with malignant transformation who received chemotherapy tailored to the histology of the malignant cell type. In this series, seven patients achieved a partial response to chemotherapy, and three patients achieved durable long-term survival. Therefore, chemotherapy regimens should be administered based on the histology of the malignant transformation, although prognosis is still guarded. Because patients with postchemotherapy residual teratoma are at risk for recurrence with viable GCT as well as teratomatous elements, appropriate clinical follow-up should incorporate routine physical examination, measurement of serum tumor markers, and radiologic imaging. In an effort to establish appropriate clinical follow-up protocols and potentially identify patients who would benefit from adjuvant therapy, previous investigators have evaluated variables predicting for disease recurrence in men with teratoma after chemotherapy for metastatic NSGCT. Loehrer et al10 reported that, on univariate analysis, initial tumor burden, malignant transformation in the resected specimen, and the site of residual disease (mediastinum) predicted for disease relapse after postchemotherapy resection of residual teratoma. Additionally, it has been shown that recurrence of teratoma is related to the completeness of the surgical resection.12 Our current study demonstrates that increasing postchemotherapy retroperitoneal nodal size and intermediate or poor IGCCCG risk classification were independent predictors of disease recurrence after complete resection of teratoma. Patients with intermediate or poor risk classification and those with large residual masses (> 5 cm) are at a high risk of recurrence (5-year probability of freedom from recurrence, 70%, 62%, and 59%, respectively). Although the histologic finding of teratoma with malignant transformation was not a significant predictor of disease recurrence in our multivariable analysis, these patients have a guarded prognosis, with a 5-year probability of freedom from progression of 54%. Nevertheless, our low in-field recurrence rate highlights the importance of complete surgical resection for men undergoing PC-RPLND for residual teratoma, and every effort should be made to control the retroperitoneum after chemotherapy. Furthermore, clinical follow-up should be guided according to the risk of relapse after PC-RPLND for teratoma, such that patients with a high risk of disease recurrence should undergo more frequent surveillance with physical examination, serum tumor markers, and periodic abdominal and chest imaging. We currently recommend computed tomography imaging of the abdomen on an annual basis, although we are currently evaluating whether this should be performed more frequently in patients at an increased risk for relapse. For men who experience relapse after postchemotherapy resection of teratoma, treatment should be tailored according to the probable histology of the relapse. For patients experiencing relapse with a solitary site of disease and normal serum tumor markers, primary surgical resection is the preferred therapy. Patients who have multiple sites of disease and those with elevated serum tumor markers should receive appropriate chemotherapy tailored to the histology of the relapse followed by surgical resection of any residual masses. With this approach, the majority of patients experiencing relapse with teratoma or viable GCT are rendered disease free. In our current series, 21 of 25 men were rendered disease free after relapse with teratoma or viable GCT. Patients experiencing relapse with malignant transformation continue to have a guarded prognosis, and in our series, three of five of these patients ultimately died of disease. Our study has several important implications for the management and follow-up of patients who have undergone postchemotherapy resection of teratoma. It is the first study to incorporate the IGCCCG risk classification in the outcome analysis of resected teratoma. The initial IGCCCG risk classification and postchemotherapy retroperitoneal nodal size are adverse predictors of disease recurrence. Although it is still possible that these factors are interrelated, the observations have broad implications for patient counseling and the establishment of follow-up protocols based on postoperative risk assessment. After complete resection of residual teratoma, the 10-year probabilities of freedom from recurrence and disease-specific survival are 80% and 92%, respectively, highlighting the importance of continued careful vigilance, particularly in patients with adverse prognostic features. Most relapses occurred outside the retroperitoneum, confirming the importance of meticulous surgery and the need for careful monitoring of extraretroperitoneal sites. Furthermore, 29% of patients with teratoma had a residual retroperitoneal mass less than 2 cm, demonstrating that the retroperitoneum remains difficult to stage clinically. We have demonstrated an excellent clinical outcome for men undergoing PC-RPLND for residual masses less than 2 cm (5-year probability of freedom from recurrence, 94%), justifying an aggressive surgical approach for all patients with NSGCT who achieve marker-negative status after chemotherapy. Therefore, we recommend that complete surgical resection be the treatment of choice for patients with residual teratoma.
The authors indicated no potential conflicts of interest.
Conception and design: Brett S. Carver, Bobby Shayegan, George J. Bosl, Joel Sheinfeld Administrative support: Robert J. Motzer, George J. Bosl, Joel Sheinfeld Collection and assembly of data: Brett S. Carver, Bobby Shayegan Data analysis and interpretation: Brett S. Carver, Angel Serio Manuscript writing: Brett S. Carver Final approval of manuscript: Brett S. Carver, Bobby Shayegan, Angel Serio, Robert J. Motzer, George J. Bosl, Joel Sheinfeld
published online ahead of print at www.jco.org on January 29, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Sheinfeld J, Herr HW: Role of surgery in management of germ cell tumor. Semin Oncol 25:203-209, 1998[Medline] 2. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 8:1683-1694, 1990[Abstract] 3. Steyerberg EW, Keizer HJ, Fossa SD, et al: Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: Multivariate analysis of individual patient data from six study groups. J Clin Oncol 13:1177-1187, 1995[Abstract] 4. Aass N, Klepp O, Cavallin-Stahl E, et al: Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: A multicenter experience. J Clin Oncol 9:818-826, 1991[Abstract] 5. Fossa SD, Qvist H, Stenwig AE, et al: Is post-chemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses? J Clin Oncol 10:569-573, 1992 6. Motzer RJ, Amsterdam A, Prieto V, et al: Teratoma with malignant transformation: Diverse malignant histologies arising in men with germ cell tumors. J Urol 159:133-138, 1998[CrossRef][Medline] 7. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract] 8. Donohue JP, Roth LM, Zachary JM, et al: Cytoreductive surgery for metastatic testis cancer: Tissue analysis of retroperitoneal masses after chemotherapy. J Urol 127:1111-1114, 1982[Medline] 9. Fossa SD, Aass N, Ous S, et al: Histology of tumor residuals following chemotherapy in patients with advanced nonseminomatous testicular cancer. J Urol 142:1239-1242, 1989[Medline] 10. Loehrer PJ, Hui S, Clark S, et al: Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: A clinicopathological correlation. J Urol 135:1183-1189, 1986[Medline] 11. Sonneveld DJ, Sleifer DT, Koops HS, et al: Mature teratoma identified after post-chemotherapy surgery in patients with disseminated nonseminomatous testicular germ cell tumors. Cancer 82:1343-1351, 1998[CrossRef][Medline] 12. Dieckmann KP, Albers P, Classen J, et al: Late relapse of testicular germ cell neoplasms: A descriptive analysis of 122 cases. J Urol 173:824-829, 2005[CrossRef][Medline] 13. George DW, Foster RS, Hromas RA, et al: Update on late relapse of germ cell tumor: A clinical and molecular analysis. J Clin Oncol 21:113-122, 2003 14. McKiernan JM, Motzer RJ, Bajorin DF, et al: Reoperative retroperitoneal surgery for nonseminomatous germ cell tumor: Clinical presentation, patterns of recurrence, and outcome. Urology 62:732-736, 2003[CrossRef][Medline] 15. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594-603, 1997 16. Comiter CV, Kibel AS, Richie JP, et al: Prognostic features of teratomas with malignant transformation: A clinicopathological study of 21 cases. J Urol 159:859-863, 1998[CrossRef][Medline] 17. Donadio AC, Motzer RJ, Bajorin DF, et al: Chemotherapy for teratoma with malignant transformation. J Clin Oncol 21:4285-4291, 2003 Submitted December 26, 2005; accepted June 12, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05 was considered statistically significant, and hazard ratios with 95% CIs were reported for our Cox regression model. 
