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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4365-4369 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.2078 Incidence of Metastatic Nonseminomatous Germ Cell Tumor Outside the Boundaries of a Modified Postchemotherapy Retroperitoneal Lymph Node Dissection
From the Department of Urology and Medical Oncology, 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
Introduction Modified template retroperitoneal lymph node dissections (RPLND) have become increasing applied in the postchemotherapy (PC) setting. We evaluated our experience with PC-RPLND to determine the incidence of disease extending outside the boundaries of a modified PC-RPLND. Patients and Methods From 1989 through 2003, a total of 532 men underwent PC-RPLND for metastatic nonseminomatous germ cell tumor (NSGCT). Of these, 269 (51%) had either viable germ cell tumor (GCT) or teratoma present in the RPLND specimen. After Institutional Review Board approval, clinical and pathologic data were obtained from our prospective surgical database. The incidence of retroperitoneal disease outside the boundaries of five modified templates was reported for the presence of viable GCT or teratoma. Results Of the 269 patients with viable GCT or teratoma, 20 to 86 (7% to 32%) patients had evidence of extratemplate retroperitoneal disease, depending on the boundaries of the modified template. There was no difference in the histologic distribution for patients with disease confined to or outside of the modified templates. Despite the absence of preoperative radiographic evidence of disease outside the boundaries of the Testicular Tumor Study Group template, the incidence of extratemplate metastasis for men with residual retroperitoneal masses less than 1, 1 to 2, 2 to 5, and more than 5 cm was two of 24 (8%), seven of 38 (18%), 27 of 92 (29%), and 14 of 55 (25%), respectively. Conclusion Our data suggest a bilateral RPLND is a prudent approach for the management of men with metastatic NSGCT after chemotherapy, given that at least 7% to 32% of men will have teratoma or viable GCT outside the boundaries of a modified template.
Testicular cancer is the most common malignancy in men 20 to 35 years of age and accounts for approximately 1% of all male malignancies. Through the appropriate use of clinical trials, effective treatment paradigms have been developed for the management of all stages of testicular cancer. Most men presenting with advanced metastatic nonseminomatous germ cell tumor (NSGCT) are managed with cisplatin-based chemotherapy followed by postchemotherapy (PC) surgery. This multidisciplinary approach to the management of germ cell tumors of the testis has resulted in survival rates of greater than 90% overall.1 After postchemotherapy retroperitoneal lymph node dissection (PC-RPLND), residual viable GCT and teratoma are present in approximately 15% and 40% of patients, respectively.2 Traditionally, bilateral infrahilar RPLND templates have been recommended for patients undergoing PC-RPLND to maximize oncologic efficacy. This approach however, may be associated with significant ejaculatory morbidity due to interruption of the sympathetic nerves and hypogastric plexus. In an effort to reduce retrograde ejaculation, modified unilateral templates limiting contralateral dissection were proposed based on anatomic nodal mapping studies done by Ray et al,3 Donohue et al,4 and Weissbach and Boedefeld.5 Numerous modified templates have been proposed and are used for both open and laparoscopic RPLND.5-9 These templates originally were described for men with clinical stage I NSGCT undergoing a primary RPLND. However, in recent years, several groups have implemented the use of modified templates in the PC setting.10,11 Unfortunately, these studies lack sufficient follow-up to determine if oncologic efficacy is equivalent. This is especially important given that an inadequately controlled retroperitoneum remains the most common site for late relapse. We analyzed the anatomic nodal mapping data for men found to have viable GCT or teratoma at the time of PC-RPLND to determine the incidence of retroperitoneal disease outside the boundaries of five published modified templates.
From 1989 to 2003, a total of 532 men underwent PC-RPLND for metastatic NSGCT after induction or second-line chemotherapy at our institution. Patients treated for late relapse and those requiring reoperative retroperitoneal surgery were excluded from our study. Retroperitoneal viable germ cell tumor (GCT) or teratoma was present in 269 patients (51%) and these patients constitute our study cohort. This study was approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center. Clinical and pathologic data were obtained from our prospective surgical database. PC-RPLND was performed with therapeutic intent and anatomic nodal regions were sent individually for pathologic analysis. These noted regions were labeled as paracaval, precaval, interaortocaval, preaortic, para-aortic, ipsilateral iliac, contralateral iliac, and gonadal vein. For each patient, the anatomic nodal region pathologic findings were reported individually. A full bilateral dissection was performed in 204 men (76%), and a modified template dissection was performed in 65 men (24%). We analyzed the anatomic distribution of disease in our cohort and applied these findings to five modified templates described in the literature to determine the incidence of disease outside of each template (Table 1; Fig 1). The three open templates studied are those described by the Testicular Tumor Study Group (TTSG),5 Indiana University (Indiana),6 and Memorial Sloan-Kettering Cancer Institute,7 and for laparoscopic RPLND, those used at the University of Innsbruck (Innsbruck)8 and Johns Hopkins University.9 The anatomic limits of the TTSG and Innsbruck modified templates are identical; therefore, data are reported only for the TTSG template. Disease outside the template was defined as a retroperitoneal nodal region with viable GCT or teratoma not included in the template.
When the TTSG modified template was used as a representative template, the incidence of extratemplate disease was reported for preoperative clinical parameters. The International Germ Cell Cancer Collaborative Group risk classification was assigned before induction chemotherapy. In a minority of select patients with elevated tumor markers after induction and salvage chemotherapy regimens, a PC-RPLND was performed. Prechemotherapy and PC nodal size was determined by measuring the transverse diameter of the largest retroperitoneal mass on computed tomography (CT) imaging as determined from the radiology report. On CT imaging, the presence of retroperitoneal disease outside the anatomic boundaries of the TTSG modified template was noted from the radiologist's report. Statistical analyses were performed using SPSS software, version 11.0 (SPSS Inc, Chicago, IL).  2 analysis was use to evaluate binary variables, and a P value less than .05 was considered statistically significant.
Of the 532 patients in our series, the retroperitoneal histology was fibrosis in 263 patients (49%), teratoma alone in 210 patients (40%), and viable GCT in 59 patients (11%). Overall, teratomatous elements were present in 235 patients (44%). Patients with the histology finding of fibrosis (n = 263) were excluded from our analyses. Table 2 lists the clinical and pathologic parameters of patients with viable GCT or teratoma at PC-RPLND (n = 269). The median prechemotherapy and PC retroperitoneal nodal size was 4.5 cm (interquartile [IQ] range, 2.8 to 8.0 cm) and 3.0 cm (IQ range, 1.5 to 5.4 cm), respectively. A select group of 43 patients underwent a PC-RPLND in the presence of positive serum tumor markers after induction and salvage chemotherapy regimens. At PC-RPLND, 34 patients had an  -fetoprotein level  15 ng/mL and 11 patients had a human chorionic gonadotropin level 2 mIU/mL. The median follow-up for survivors was 45 months (IQ range, 20 to 81 months).
Table 3 lists the incidence of extratemplate disease, the retroperitoneal histology, and the anatomic locations of extratemplate disease for each of the four modified templates in men with viable GCT or teratoma (n = 269) at PC-RPLND. The incidence of retroperitoneal extratemplate disease for men with viable GCT or teratoma ranged from 7% to 32%, depending on the anatomic limits of the modified template. For left-sided primary tumors, the most common sites of extratemplate disease were the interaortocaval, precaval, and paracaval regions. For right-sided primary tumors, the most common sites of extratemplate disease were the para-aortic and preaortic regions. By including the interaortocaval, precaval, and paracaval nodes for a left-sided template, and the preaortic and para-aortic nodes for a right-sided template, the incidence of extratemplate disease would be reduced to 4%. There was no significant difference in the distribution of retroperitoneal histology for disease confined to the template and disease outside the template.
Table 4 lists the incidence of extratemplate retroperitoneal disease for the TTSG template according to several clinical parameters. Patients who initially presented with extra-retroperitoneal metastasis (clinical stage III) had a higher incidence of extratemplate disease compared with patients with disease localized to the retroperitoneum at initial diagnosis (48% v 23%). For men undergoing PC-RPLND with a PC radiographically normal retroperitoneum (nodal size < 1 cm), the incidence of extratemplate disease was 14% and increased to 25% for men with residual retroperitoneal masses more than 5 cm. For patients with no radiographic evidence of disease outside the boundaries of the TTSG template, the incidence of extratemplate metastasis for men with residual intratemplate retroperitoneal masses less than 1, 1 to 2, 2 to 5, and more than 5 cm was two of 24 (8%), seven of 38 (18%), 27 of 92 (29%), and 14 of 55 (25%), respectively.
Bilateral infrahilar RPLND templates are recommended for patients undergoing PC-RPLND to maximize oncologic efficacy. However, this approach has been associated with significant ejaculatory morbidity and sexual dysfunction. In an effort to reduce rates of retrograde ejaculation, modified unilateral templates limiting contralateral dissection were proposed based on anatomic nodal mapping studies done by Ray et al,3 Donohue et al,4 and Weissbach and Boedefeld.5 These anatomic mapping studies have marked limitations. First, these studies have limited postoperative follow-up to evaluate for retroperitoneal recurrences. Second, surgical and/or pathologic sample error may underestimate the true incidence of disease. Lastly, many of patients in these studies received adjuvant chemotherapy; therefore, the true incidence of regional disease is unknown. Despite the inherent flaws of these mapping studies, several groups have examined the role of modified templates for select patients undergoing PC-RPLND.10,11 Our data suggest that at least 7% to 32% of patients with residual viable GCT or teratoma at PC-RPLND will have disease outside the boundaries of a modified template. Our study represents the lowest incidence of extratemplate disease, given that approximately 25% of men did not undergo a bilateral PC-RPLND. Furthermore, although our median follow-up was 45 months, additional extratemplate relapses may be identified with longer follow-up. The incidence of extratemplate retroperitoneal disease ranged from 11% to 32% for left-sided modified templates and from 4% to 32% for right-sided modified templates. Modified templates with more restrictive anatomic limits of dissection were associated with a higher incidence of extratemplate disease. The most common sites of extratemplate disease for left-sided templates were the interaortocaval, precaval, and paracaval regions. For right-sided modified templates, the most common sites of extratemplate disease were the para-aortic and preaortic regions. This has profound implications, given that several investigators have recommended performing modified template RPLND in the PC setting.10,11 Therefore, modified templates may place patients at risk for both early as well as late relapse. Steiner et al11 reported the outcomes of patients undergoing a modified (TTSG) template PC-RPLND in patients with stage II NSGCT who had disease restricted to the ipsilateral template and reported a 94% preservation of ejaculation. Unfortunately, with a median follow-up of 70 months, three recurrences were observed, two of which were late relapses, and one recurred within the boundaries of a bilateral infrahilar template. When applying the template used in this study to our cohort of patients, 30% of patients with viable GCT or teratoma had extratemplate disease, despite the presence of preoperative disease restricted to the ipsilateral template on CT imaging. Furthermore, approximately 80% of men with extratemplate disease have teratomatous elements that may not become clinically manifest for years. Previously, several groups have reported that even with a normal PC retroperitoneum on CT imaging, 20% to 30% will have viable GCT or teratoma, demonstrating that the retroperitoneum remains difficult to accurately stage in the PC setting.12,13 In our series, 14% of patients had extratemplate disease (TTSG template), despite the presence of normal PC CT imaging of the retroperitoneum (retroperitoneal nodes < 1 cm). Furthermore, for patients with no radiographic evidence of disease outside the boundaries of the TTSG template, the incidence of extratemplate retroperitoneal metastasis for men with residual intratemplate retroperitoneal masses less than 1, 1 to 2, 2 to 5, and more than 5 cm was two of 24 (8%), seven of 38 (18%), 27 of 92 (29%), and 14 of 55 (25%), respectively. In our current study, approximately 80% of the patients with extratemplate retroperitoneal disease had teratomatous elements and 20% had viable GCT. There are significant potential implications of unresected extratemplate retroperitoneal disease. These patients may be at an increased risk for both early and late relapse. By definition, relapses after initial chemotherapy are chemotherapy resistant and salvage therapy may be less effective at the time of relapse.14 In addition, although teratoma is histologically mature, it is biologically unpredictable, and has a capacity for local growth and transformation into somatic malignancies such as sarcoma or carcinoma, and may contribute to the development of late relapse.15,16 The uncontrolled retroperitoneum is the most common site for late relapse, with approximately 50% to 80% of late relapses occurring in the retroperitoneum.17,18 The survival rate after late relapse tends to be poor, with approximately 30% to 50% of patients remaining disease free.15,17,18 Furthermore, several investigators have demonstrated that men requiring reoperative surgery for a retroperitoneal recurrence after PC-RPLND have an inferior survival.14,19 Therefore, our data suggest that a bilateral PC-RPLND is the prudent management for men with metastatic NSGCT after risk-appropriate chemotherapy. With the advent of the nerve-sparing technique, more than 95% of men undergoing a primary bilateral infrahilar RPLND for clinical stage I NSGCT will have successful preservation of ejaculatory function.20 The implementation of these techniques in the PC setting has obviated the necessity for modified templates in these patients, allowing maximal therapeutic efficacy while minimizing morbidity. We believe that successful preservation of ejaculatory function can be obtained by using a nerve-sparing technique in the PC setting with maximal oncologic efficacy by reducing the potential risk of relapse from unresected disease in extratemplate sites.
The author(s) indicated no potential conflicts of interest.
Conception and design: Brett S. Carver, Bobby Shayegan, Scott Eggener, Robert J. Motzer, George J. Bosl, Joel Sheinfeld Administrative support: Joel Sheinfeld Provision of study materials or patients: Brett S. Carver, Joel Sheinfeld Collection and assembly of data: Brett S. Carver, Bobby Shayegan, Jason Stasi Data analysis and interpretation: Brett S. Carver, Scott Eggener, Robert J. Motzer, George J. Bosl, Joel Sheinfeld Manuscript writing: Brett S. Carver, Joel Sheinfeld Final approval of manuscript: Brett S. Carver, Bobby Shayegan, Scott Eggener, Jason Stasi, Robert J. Motzer, George J. Bosl, Joel Sheinfeld
Supported in part by the Craig Tifford Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bosl G, Bajorin D, Sheinfeld J, et al (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, JB Lippincott, 2000, pp 1491-1518 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. Ray B, Hajdu SI, Whitmore WF Jr: Proceedings: Distribution of retroperitoneal lymph node metastases in testicular germinal tumors. Cancer 33:340-348, 1974[CrossRef][Medline] 4. Donohue JP, Zachary JM, Maynard BR: Distribution of nodal metastases in nonseminomatous testis cancer. J Urol 128:315-320, 1982[Medline] 5. Weissbach L, Boedefeld EA: Localization of solitary and multiple metastases in stage II nonseminomatous testis tumor as basis for a modified staging lymph node dissection in stage I. J Urol 138:77-82, 1987[Medline] 6. Donohue JP, Thornhill JA, Foster RS, et al: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): Modifications of technique and impact on ejaculation. J Urol 149:237-243, 1993[Medline] 7. Sheinfeld J, Herr HW: Role of surgery in management of germ cell tumor. Semin Oncol 25:203-209, 1998[Medline] 8. Janetschek G, Reissigl A, Peschel R, et al: Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous testicular tumor. Urology 44:382-391, 1994[CrossRef][Medline] 9. Nelson JB, Chen RN, Bishoff JT, et al: Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular tumors. Urology 54:1064-1067, 1999[CrossRef][Medline] 10. Beck SD, Foster RS, Bihrle R, et al: Is full bilateral retroperitoneal lymph node dissection (RPLND) always necessary for postchemotherapy residual tumor? Cancer [e-pub Jul 30, 2007] 11. Steiner H, Peschel R, Muller T, et al: Postchemotherapy retroperitoneal lymph node dissection (RPLND): Is full bilateral resection always necessary? J Urol AUA 2006 (abstr 592) 12. Fosså SD, Qvist H, Stenwig AE, et al: Is postchemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses? J Clin Oncol 10:569-573, 1992 13. Carver BS, Bianco FJ, Shayegan B, et al: Predicting Teratoma in the retroperitoneum for men undergoing post-chemotherapy retroperitoneal lymph node dissection. J Urol 176:100-103, 2006[CrossRef][Medline] 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. 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 16. Carver BS, Shayegan B, Serio A, et al: Long-term clinical outcome following post-chemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 25:1033-1037, 2007 17. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract] 18. 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] 19. Donohue JP, Leviovitch I, Foster RS, et al: Integration of surgery and systemic therapy: Results and principles of integration. Semin Urol Oncol 16:65-71, 1998[Medline] 20. Jewett MA, Kong YS, Goldberg SD, et al: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 139:1220-1224, 1988[Medline] Submitted February 8, 2007; accepted May 11, 2007.
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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
