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The indication for postchemotherapy lymph node dissection in clinical stage IS nonseminomatous germ cell tumor†
Article first published online: 2 JAN 2008
Copyright © 2008 American Cancer Society
Volume 112, Issue 4, pages 800–805, 15 February 2008
How to Cite
Dash, A., Carver, B. S., Stasi, J., Bajorin, D. F., Motzer, R. J., Bosl, G. J. and Sheinfeld, J. (2008), The indication for postchemotherapy lymph node dissection in clinical stage IS nonseminomatous germ cell tumor. Cancer, 112: 800–805. doi: 10.1002/cncr.23233
Presented in part at the 2006 Annual Meeting of the American Urologic Association, Atlanta, Georgia, May 20–25, 2006.
- Issue published online: 1 FEB 2008
- Article first published online: 2 JAN 2008
- Manuscript Accepted: 10 SEP 2007
- Manuscript Revised: 8 AUG 2007
- Manuscript Received: 30 MAY 2007
- Craig Tifford Foundation
- Tina and Richard V. Carolan Foundation
- National Institutes of Health. Grant Number: T32-82088
- retroperitoneal lymph node dissection;
- germ cell tumor;
The initial management of patients with clinical stage IS (cIS) nonseminomatous germ cell tumor (NSGCT) has evolved from primary retroperitoneal lymph node dissection (RPLND) to induction chemotherapy. The objectives of the current study were to determine the clinical outcome, patterns of relapse, and incidence of teratoma in the retroperitoneum for men with cIS NSGCT.
Between 1988 and 2004, 24 patients with cIS stage NSGCT were evaluated and treated at Memorial Sloan-Kettering Cancer Center. Clinical and pathologic data were obtained from the institutional prospective database. Seven patients underwent primary RPLND, and 17 patients received induction chemotherapy as initial management. Clinical outcomes, patterns of relapse, and pathologic findings were reported.
Six of the 7 patients who underwent primary RPLND had viable germ cell tumor (GCT) present. Four of those patients did not receive adjuvant chemotherapy, and all experienced systemic relapse. Of the 17 patients who received induction chemotherapy, 3 patients underwent elective postchemotherapy RPLND (PC-RPLND), and 14 patients were followed expectantly. Four patients who were followed expectantly relapsed in the retroperitoneum and underwent PC-RPLND. Of the 7 patients who underwent PC-RPLND, 1 patient had fibrosis (14%), but 6 patients (86%) had teratoma, including 1 patient who also had a viable GCT in the retroperitoneum. Overall, the incidence of teratoma or viable GCT in the retroperitoneum after chemotherapy was 43% (6 of 14 patients). At a median follow-up of 35 months, 23 men remained alive, and 1 man had died of disease.
The current data suggest that patients with cIS stage NSGCT will benefit from adjuvant PC-RPLND. Cancer 2008. © 2008 American Cancer Society.
The incorporation of serum tumor markers (STMs) into the American Joint Committee on Cancer staging system is unique to the staging of testis cancer. Clinical stage IS (cIS) nonseminomatous germ cell tumor (NSGCT) is defined by the presence of persistently elevated STMs after orchiectomy without detectable radiographic evidence of metastatic disease. The initial management of patients with cIS NSGCT has evolved from primary retroperitoneal lymph node dissection (RPLND) to induction chemotherapy followed by surveillance.1–3 This policy change was based on the high rate of systemic relapse in men after primary RPLND, demonstrating the high likelihood of occult, systemic, micrometastatic disease. The 2 previous studies addressing the outcome after management of cIS NSGCT demonstrated a 37% and 100% relapse rate after primary RPLND.1, 3 Currently, the initial management of patients with cIS NSGCT is International Germ Cell Consensus Classification Group (IGCCCG) risk-appropriate induction chemotherapy followed by surveillance if STMs normalize after chemotherapy and the retroperitoneum remains normal.4
Emerging data suggest that complete control of the retroperitoneum is critical for the successful management of metastatic NSGCT. The uncontrolled retroperitoneum predisposes patients to both early as well as late relapses.5 After induction chemotherapy for clinical stage II (cII) and clinical stage III (cIII) NSGCT, between 10% and 40% of patients have viable germ cell tumor (GCT) or teratoma in the retroperitoneum at postchemotherapy RPLND (PC-RPLND), respectively.6–9 Furthermore, approximately 20% of men who undergo PC-RPLND who have a normal postchemotherapy retroperitoneum on computed tomography (CT) imaging (≤10 mm) will harbor retroperitoneal, viable GCT or teratoma.7, 10, 11 The likelihood of teratoma in the retroperitoneum depends on the presence or absence of teratoma in the primary tumor and the degree of shrinkage of the retroperitoneal adenopathy.12, 13 Teratoma is dangerous, because it is chemorefractory and has the potential for continued growth, malignant transformation, and predisposition for late relapse. Consequently, control of the retroperitoneum is critical.
To our knowledge, no previous study has assessed the outcome of patients with cIS disease who were treated initially with induction chemotherapy. The objective of our study was to determine the patterns of relapse, clinical outcome, and incidence of teratoma in the retroperitoneum for men with cIS NSGCT.
MATERIALS AND METHODS
After Institutional Review Board approval, we identified 30 patients with cIS NSGCT of the testis who were evaluated at our institution between 1988 and 2004. Of these patients, 24 had complete initial staging information reviewed at our institution confirming the diagnosis of cIS NSGCT and constituted our study cohort. The remaining 6 patients with cIS NSGCT were excluded from the study, because initial clinical and radiologic information was not available for review, and these patients initially were diagnosed and managed at outside institutions. Patients were clinically staged as cIS either if the serum α-fetoprotein (AFP) level was >15 ng/mL, or if the serum β-human chorionic gonadotropin (β-HCG) level was >2.2 U/mL without appropriate decline after orchiectomy, and if neither physical examination nor radiographic imaging revealed any detectable metastatic disease. A radiographic “normal retroperitoneum” was defined as no detectable retroperitoneal lymph nodes that measured >1 cm on CT imaging. Clinical and pathologic data were obtained from our prospective testicular cancer database. We reviewed the pathologic findings from the orchiectomy specimens and from those patients who underwent RPLND. We report on the patterns of relapse and clinical outcome. All patients who underwent chemotherapy were classified as good risk by the IGCCCG classification.14 Of the 24 patients identified, 7 underwent primary RPLND, all of which were performed before 1994, and 17 patients were managed initially with induction chemotherapy. Although primary RPLND is not the current standard of care for the management of cIS NSGCT, we elected to include patients undergoing primary RPLND in this study to demonstrate the incidence and histology of retroperitoneal disease in our cohort. Routine follow-up included clinic visits approximately monthly in Year 1, every second month in Year 2, every third month in Year 3, every fourth month in Year 4, every 6 months in Year 5, and annually thereafter. At each visit, a history, physical examination, chest x-ray, and STM evaluations were performed. A baseline abdominal CT scan after RPLND was obtained 6 months after RPLND and annually thereafter if teratoma was present. Patients who underwent induction chemotherapy were followed by serial CT scans.
A Fisher exact test analysis was performed to determine the association of teratoma in the orchiectomy specimen with the finding of teratoma in the retroperitoneum. All statistical analyses were performed using SPSS software (version 11.0; Chicago, Ill), and P values <.05 were considered statistically significant.
All 24 primary tumors had embryonal carcinoma, 12 patients (50%) had elements of yolk sac tumor, and 10 patients (42%) had teratoma present. Thirteen of 24 patients (43%) had lymphovascular invasion present in the orchiectomy specimen (Table 1).
|Characteristic||No. of patients (%)|
|Pathologic feature (histology nonexclusive), n = 24|
|Embryonal carcinoma||24 (100)|
|Yolk sac||16 (67)|
|Lymphovascular invasion||20 (83)|
|Primary RPLND, n = 7|
|Elevated βHCG||1 (14)|
|Elevated AFP||7 (100)|
|Both elevated||1 (14)|
|Follow-up [range], mo||119 [33–145]|
|Chemotherapy as initial therapy, n = 17|
|Elevated βHCG||12 (50)|
|Elevated AFP||11 (46)|
|Both elevated||6 (25)|
|Follow-up [range], mo||24 [15–63]|
Seven patients underwent primary RPLND (Fig. 1). All 7 patients had an elevated AFP level (the median AFP level was 54.0 ng/mL) at presentation, whereas 1 patient also had an elevated β-HCG level before surgery (Table 1). The median follow-up in these patients was 119 months (interquartile range [IQ], 33–145 months). Of the 7 patients who underwent primary RPLND, 1 patient had a negative histology, and the remaining 6 patients had viable GCT in the retroperitoneum, including 2 patients with teratomatous elements present in the resected specimen (Table 2). The 3 patients who received adjuvant chemotherapy with 2 cycles of etoposide and cisplatin (EP) remained free of disease (NED), whereas all 4 patients who were followed expectantly relapsed systemically, including 1 patient who ultimately died of progressive disease. For 3 of the 4 patients who did not receive adjuvant chemotherapy, STMs did not normalize after primary RPLND.
|Histology (Nonexclusive)||No. of patients (%)|
|Primary RPLND, n = 7||PC-RPLND, n = 7|
|Viable GCT||6 (86)||1 (14)|
|Any teratoma||2 (29)||6 (86)|
|Teratoma only||—||5 (71)|
|Fibrosis/negative||1 (14)||1 (14)|
Seventeen patients received induction chemotherapy as initial management (Fig. 2). The β-HCG was elevated in 12 patients, the AFP was elevated in 11 patients before chemotherapy, and both AFP and β-HCG were elevated in 6 patients (Table 1). The median AFP was 27.6 ng/mL (IQ, 5.5–58.6 ng/mL), and the median β-HCG was 24.6 ng/mL (0.75–55 ng/mL). The median follow-up in these patients was 24 months (IQ, 12–52 months). All patients were classified as good risk according to IGCCCG risk criteria. Fifteen patients received 4 cycles of EP as induction chemotherapy, whereas 2 patients received either 3 or 4 cycles of bleomycin plus EP. All patients had normal STM levels after chemotherapy.
Three patients who had normal CT scans after chemotherapy underwent elective PC-RPLND at their surgeon's discretion, and all remain NED. The histologic findings in the retroperitoneum were teratoma in 2 patients and fibrosis in 1 patient (Table 2). Fourteen patients were followed expectantly after induction chemotherapy, and all of these patients had no evidence of retroperitoneal lymphadenopathy on radiographic imaging. Ten of these patients remained NED; however, 4 relapsed during follow-up. All patients who relapsed while on surveillance presented with retroperitoneal masses then underwent PC-RPLND, including 1 patient who also had elevated STM who received salvage chemotherapy before PC-RPLND. The retroperitoneum contained teratoma in 3 patients and both teratoma and viable GCT in the patient who was treated with salvage chemotherapy (Table 2). In all, 7 patients underwent PC-RPLND. The retroperitoneal pathology contained teratoma with or without viable GCT in 6 patients (86%) and fibrosis in 1 patient (14%).
In the cohort of 14 patients who underwent RPLND in the primary (n = 7) or postchemotherapy setting (n = 7), 8 patients (57%) had teratomatous elements present in the retroperitoneum. Association between the presence of teratoma in the orchiectomy specimen and teratoma in the retroperitoneum was observed; however, this association was not statistically significant (Table 3) (P = .16).
|Orchiectomy teratoma||No. of patients with teratoma (%)|
|Primary RPLND||PC-RPLND||Overall cohort*|
|Absent||0/3 (0)||2/3 (50)||2/6 (33)|
|Present||2/4 (50)||4/4 (100)||6/8 (75)|
The median follow-up for all survivors was 35 months (IQ, 13–91 months) and there was 1 death from disease. Overall, there were 8 relapses, including 4 that occurred in men who initially were treated with primary RPLND, none of whom received adjuvant chemotherapy. The other 4 relapses occurred in men who initially were treated with induction chemotherapy, none of whom underwent elective PC-RPLND. The 1 patient who died of disease was managed initially with a primary RPLND using a modified right template and had histology that revealed viable GCT and teratoma. This patient subsequently relapsed in the retroperitoneum and was managed with salvage chemotherapy followed by exploratory laparotomy, which revealed teratoma with malignant transformation to unresectable embryonal rhabdomyosarcoma.
This study is the first large series to report on the clinical outcome and patterns of relapse for men with cIS NSGCT who were managed initially with induction chemotherapy. After induction chemotherapy and surveillance for cIS NSGCT, 4 of 14 patients relapsed, all of whom had disease in the retroperitoneum. The 3 patients who proceeded directly to elective RPLND after chemotherapy remained NED. These data suggest that PC-RPLND may be an important component in the management of patients with cIS NSGCT after induction chemotherapy.
Davis et al. reported the Memorial Sloan-Kettering experience with treating cIS NSGCT in 11 patients who underwent primary RPLND with persistently elevated STMs.1 Viable GCT was present in 9 of 11 patients (82%) who underwent primary RPLND with embroyonal sarcoma (EC) present in the retroperitoneal lymph nodes of all 9 patients. Of the 4 patients who initially received induction chemotherapy followed by surveillance, 3 remained NED. One patient with negative markers had teratoma resected at PC-RPLND 6 months after induction chemotherapy.1 All 11 patients, however, subsequently relapsed systemically during follow-up. Because of the high relapse rates after primary RPLND observed by Davis et al., clinical practice was changed to administer induction chemotherapy. Taken together, the studies by Davis et al. and Saxman et al. suggest that persistently elevated STMs after radical orchiectomy indicate not only the presence of retroperitoneal disease but also a high risk of occult, systemic disease.1, 3 Thus, the current initial management of patients with cIS NSGCT should be induction chemotherapy. The importance of initial treatment with induction chemotherapy should be emphasized, because these patients have occult, micrometastatic, systemic disease for which surgery alone is insufficient therapy. However, the management of the retroperitoneum in men with a radiographically normal retroperitoneum after chemotherapy remains controversial.
Of the 7 patients who underwent PC-RPLND, 6 patients (86%) had teratoma present in the retroperitoneum, including all 4 patients who underwent PC-RPLND at relapse. These data suggest that unresected teratoma is a contributing cause of relapse. Resection of retroperitoneal teratoma is an important component that must be considered in the comprehensive treatment of NSGCT. It is chemoresistant and has an unpredictable biologic potential that includes growth with obstruction, invasion or unresectability, a risk of malignant transformation, and late relapse.15–18 Several investigators have demonstrated that, for men with cII and cIII NSGCT and a normal postchemotherapy retroperitoneum on CT imaging, approximately 20% to 30% will harbor teratoma in the retroperitoneum.7, 10, 11 In our current series, at least 8 of 24 patients (33%) had teratoma in the retroperitoneum despite having an initially normal retroperitoneum. These data suggest that, with continued long-term follow-up, initially undetectable microscopic retroperitoneal teratoma will become clinically manifest in many patients, highlighting the importance of timely surgical resection for men who have a normal postchemotherapy retroperitoneum. The death in our series is a patient who demonstrated the potential consequences of more limited resection templates and the devastating biologic potential of unresected retroperitoneal teratoma. We recently demonstrated that up to 25% of patients with pathologic stage II disease will have viable GCT or teratoma outside the boundaries of a modified template, highlighting the importance of a complete bilateral RPLND.19
In conclusion, the management of cIS NSGCT has evolved from primary RPLND to induction chemotherapy. After induction chemotherapy, patients on surveillance remain at risk for relapse in the retroperitoneum, including potential late relapses. We observed that 86% of patients who underwent PC-RPLND had teratoma in the retroperitoneum, which could have become a potential site of relapse. We therefore recommend a multidisciplinary approach to treating cIS NSGCT that includes induction chemotherapy followed by PC-RPLND to manage the retroperitoneum in a disease that is perceived as only a variation of stage I disease. cIS disease represents systemic disease and should be treated accordingly.
- 4National Comprehensive Cancer Network. Testicular Cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, version 1, 2007. Available at URL: http://www.nccn.org/professionals/physician_gls/PDF/testicular.pdf Accessed May 28, 2007.
- 14[No authors listed.] International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers.International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997; 15: 594–603.