- Email: [email protected]
Predictors of Positive Retroperitoneal Lymph Nodes in Patients With High Risk Testicular Cancer
Predictors of Positive Retroperitoneal Lymph Nodes in Patients With High Risk Testicular Cancer S. B. Williams, R. Kacker, D. Winston, E. Bahnson, G. S. Steele and J. P. Richie* From the Division of Urology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Purpose: Percent of embryonal carcinoma and lymphovascular invasion in the primary tumor are risk factors for occult retroperitoneal metastatic disease. High risk patients with clinical stage I and IIA nonseminomatous germ cell tumor who underwent primary retroperitoneal lymph node dissection were identified to discern any other risk factors for metastatic disease. Materials and Methods: Patients who had undergone retroperitoneal lymph node dissection at our institution from 1993 to 2009 were identified and clinical charts were reviewed. A total of 90 patients with orchiectomy specimens containing more than 30% embryonal carcinoma who underwent primary retroperitoneal lymph node dissection were identified and perioperative data were obtained. Results: Of 353 patients 90 (25%) had greater than 30% embryonal carcinoma and underwent primary retroperitoneal lymph node dissection. Of these patients 45 (50%) had lymphovascular invasion. Median followup was 1.1 years. Positive lymph nodes identified at retroperitoneal lymph node dissection were noted in 30 (46%) and 15 (60%) patients with clinical stage I vs clinical stage II disease. On multivariate analysis embryonal carcinoma (OR 1.02, 95% CI 1.00 –1.04) and lymphovascular invasion (OR 3.52, 95% CI 1.43– 8.67) were associated with positive lymph nodes at retroperitoneal lymph node dissection. The positive predictive value for 100% embryonal carcinoma was 65.5%, although the negative predictive value for 30% embryonal carcinoma was 85.7%. Conclusions: Embryonal carcinoma and lymphovascular invasion were significantly and independently associated with the risk of occult retroperitoneal metastatic disease. These results should be considered when counseling patients about appropriate treatment options.
Abbreviations and Acronyms CSI ⫽ clinical stage I CSII ⫽ clinical stage II LVI ⫽ lymphovascular invasion P-RPLND ⫽ primary retroperitoneal lymph node dissection PSI ⫽ pathological stage I PSII ⫽ pathological stage II RPLND ⫽ retroperitoneal lymph node dissection Submitted for publication April 25, 2011. Study received institutional review board approval. * Correspondence: 75 Francis St., Boston, Massachusetts 20015 (telephone: 617-732-6325; FAX: 617-566-3475; e-mail: [email protected]).
See Editorial on page 2151.
Key Words: lymph node excision; testicular neoplasms; carcinoma, embryonal OF all clinical stage I nonseminomatous germ cell tumors, approximately 30% will harbor metastatic disease to the retroperitoneum.1 Current treatment options include active surveillance, chemotherapy and/or RPLND. RPLND remains an integral component in the treatment and cure of testicular cancer not only by staging cases more precisely than imaging, but also
by limiting the followup and side effects associated with chemotherapy.2,3 Furthermore, RPLND avoids the need for frequent imaging and the attendant increased risk of secondary malignancies developing many years later.4 With the introduction of modified template nerve sparing approaches, the morbidity associated with this procedure is minimal.5,6
0022-5347/11/1866-2245/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 2245-2248, December 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.07.101
AND
RESEARCH, INC.
www.jurology.com
2245
2246
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
To identify patients at risk for metastatic disease prior studies have confirmed that percent embryonal carcinoma and LVI in the primary tumor are independent risk factors for occult metastasis.7–9 Heidenreich et al positively predicted 88% of patients with CSI disease with greater than 80% embryonal carcinoma and positive vascular invasion had PSII disease.7 Conversely 91.5% of patients with CSI disease with less than 45% embryonal carcinoma and absent vascular invasion were free of metastatic disease. The Testicular Cancer Intergroup study revealed that combining percent embryonal carcinoma with vascular invasion accurately predicted PSII disease in 86% of patients.10 The indication for primary chemotherapy in these high risk patients remains a debate with some groups recommending 2 cycles of platinum based chemotherapy and open RPLND reserved as an alternative treatment.11 Depending on the precise definition of risk factors, up to 50% of these high risk patients who receive chemotherapy harbor metastatic disease.12 Therefore, 50% of patients given chemotherapy for high risk disease are treated unnecessarily, thus exposing these often young patients to the lifelong risks of secondary malignancies3 and cardiopulmonary toxicities.13,14 Prior studies have demonstrated the successful treatment of high risk patients with P-RPLND.12,15 In the current study high risk cases of clinical stage I and IIA nonseminomatous germ cell tumor treated with PRPLND were reviewed to elucidate any other risk factors for metastatic disease.
MATERIALS AND METHODS All patients undergoing RPLND at Brigham and Women’s Hospital and Dana Farber Cancer Center from 1993 to 2009 were candidates for inclusion in this study. All patients with orchiectomy specimens of greater than 30% embryonal carcinoma were identified and perioperative data were obtained. These data were extracted from the Brigham and Women’s Hospital RPLND computerized database and analyzed accordingly.12 This project was approved by the institutional review board at Brigham and Women’s Hospital. At our institution all patients are evaluated in a multidisciplinary clinic, and are counseled regarding the options of active surveillance, surgery and/or chemotherapy as previously described.12 All cases were preoperatively staged with tumor markers (␣-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase), abdominopelvic computerized tomography and computerized tomography of the chest or chest x-ray. All orchiectomy and RPLND specimens were reviewed and reports were confirmed by pathologists at Brigham and Women’s Hospital. All pathology reports had confirmed histology and percent embryonal carcinoma in orchiectomy specimens. In addition, all orchiectomy pathological reports denoted the presence or absence of LVI defined as the presence of
identifiable tumor cells within the lumen of an artery, vein or lymphatic vessel. Data were entered into a computerized database and analyzed. Differences between P-RPLND and RPLND pathological findings based on continuous variables were compared using the Student’s t test. A chi-square test was used to test for differences in proportions among these groups of patients. All variables significantly associated with positive nodes on univariate analysis at p ⫽ 0.05 or better were used in the logistic regression model. Embryonal carcinoma greater than 30% was evaluated as a categorical variable. Since orchiectomy pathological stage is based largely on the presence or absence of LVI, we did not include orchiectomy stage in the multivariate analysis.
RESULTS A total of 353 patients who underwent RPLND at Brigham and Women’s Hospital and Dana Farber Cancer Center between 1993 and 2009 were identified. Of these patients 90 (25%) had greater than 30% embryonal carcinoma and underwent P-RPLND. Of these patients 45 (50%) had combined LVI. Median followup was 1.1 years. There were no perioperative deaths. Patient demographics and primary tumor characteristics according to pathological stage at RPLND are summarized in the table. Positive lymph nodes identified at RPLND were noted in 30 (46%) and 15 (60%) patients with CSI vs CSII disease. There was no difference in patient age or clinical stage between the groups. Average percent embryonal carcinoma in PSI vs PSII was 68.2% vs 81.4%, respectively (p ⫽ 0.011). All other histological subtypes were similar in either group. Patients with PSII disease had a significantly higher percentage of LVI (66.7% vs 33.3%, p ⫽ 0.003) which corresponded with orchiectomy pathological stage (p ⫽ 0.006). On multivariate analysis embryonal carcinoma (OR 1.02, 95% CI 1.001–1.040, p ⫽ 0.038) and LVI (OR 3.52, 95% CI 1.43– 8.67, p ⫽ 0.006) were associated with positive lymph nodes at RPLND. The positive predictive value for 100% embryonal carci-
Patient demographic data and preoperative clinical characteristics Pathological Stage I Pathological Stage II p Value No. pts Mean pt age No. CSI (%) No. CSII (%) No. Ca (%): Choriocarcinoma Seminoma Teratoma Yolk sac No. orchiectomy stage (%): pT1 pT2 or greater
45 29 35 (77.8) 10 (22.2)
45 30 30 (66.7) 15 (33.3)
0.587 0.347
5 (11.1) 17 (37.8) 24 (53.3) 21 (46.7)
3 (46.67) 10 (22.2) 18 (40.0) 12 (26.7)
0.714 0.167 0.291 0.079
29 (64.4) 16 (35.6)
15 (33.3) 30 (66.7)
0.006
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
noma was 65.5%, although the negative predictive value for 30% embryonal carcinoma was 85.7%.
DISCUSSION The surgical and medical management of high risk testicular cancer has been well described with cancer specific survival approaching 99%.16 The 2 factors that have been shown to lead to high rates of retroperitoneal metastasis after orchiectomy are the predominance of embryonal carcinoma and the presence of LVI. Primary chemotherapy for high risk CSI testicular cancer has been favored compared to watchful waiting and surgery.17 Stephenson et al argued that for CSII nonseminomatous germ cell tumors, RPLND cannot be safely omitted after induction chemotherapy in patients with stable disease because the incidence of viable retroperitoneal disease in the form of teratoma or viable malignancy is approximately 20%.18 Furthermore, RPLND obviated the need for routine imaging required for active surveillance or after chemotherapy, which puts patients at risk for malignancy as a result of radiation exposure.4 Lastly, although chemotherapy provides comparable oncologic effectiveness, platinum based chemotherapy regimens place patients at increased risk for the metabolic syndrome and cardiovascular disease.3 The risk of a major late complication with secondary malignancy or cardiovascular disease as a result of chemotherapy for testicular cancer is 1.9-fold greater than with surgery alone.3 This risk is comparable to the effect of smoking.3 Another study in testicular cancer survivors revealed that large doses of cisplatin based chemotherapy or combined chemotherapy and pulmonary surgery equaled twofold to fourfold the effect of smoking.14 Our study has several important findings. We found embryonal carcinoma to be a significant predictor of occult retroperitoneal metastasis. Prior studies showed embryonal carcinoma with or without LVI to be a predictor of PSII disease.7 Specifically Heidenreich et al successfully predicted PSII disease in patients with CSI based on greater than 80% embryonal carcinoma with or without LVI in 85.4%, rather than their less than 45% group in which disease was accurately staged as PSI in 88%.7 The average percent embryonal carcinoma of the PSI and PSII cases in their study was 37.8% and 81.9%, respectively. Although we used greater than 30% as our threshold for embryonal carcinoma at orchiectomy, our average embryonal component was 68.2% and 81.4% in PSI vs PSII disease, respectively. Furthermore, our positive predictive value for 100% embryonal carcinoma was 65.5%, although the
2247
negative predictive value for 30% embryonal carcinoma was 85.7%. In addition, LVI had an almost fourfold increase risk of retroperitoneal disease. This finding coincides with prior studies7,15 which revealed LVI and more importantly vascular invasion as risk factors.11 As previously stated, prior studies found embryonal carcinoma with or without LVI as a predictor of PSII disease.7 Some authors initially suggested that embryonal carcinoma was a risk factor for lymphatic metastases and now find only vascular invasion to be a risk factor.11 A possible explanation for our findings may be the low number of patients in the study cohort. With a larger number of patients it is possible that embryonal carcinoma and LVI would provide more definitive information as to the relative risk of positive lymphadenopathy. Finally, clinical stage was not a predictor of positive lymphadenopathy, thus highlighting the need for improved markers for the detection of occult retroperitoneal metastasis. Even with recent technological advances in imaging, much remains to be improved in regard to the detection of metastatic disease in patients with testis cancer. This is of significant concern for patients who are at high risk and considering active surveillance. Yu et al recently reported approximately 30% adherence to active surveillance protocols in patients diagnosed with CSI testis cancer.19 Thus, although certain centers report excellent outcomes for patients on active surveillance,20 improved diagnostic accuracy is warranted to ensure disease is accurately staged in these patients. RPLND remains a viable diagnostic and therapeutic strategy which provides excellent long-term results1,21 in addition to negating the secondary toxicities of chemotherapy.3,13,14 Our findings must be interpreted in the context of the study design. This is a retrospective study from a tertiary care center with uncontrolled selection biases. Although we performed a multivariate analysis, our findings are hypothesis generating and further study is warranted to validate these results. Another limitation is the lack of a large number of patients which, as previously mentioned, may have underpowered certain findings.
CONCLUSIONS In our contemporary P-RPLND series embryonal carcinoma and LVI were significantly and independently associated with the risk of occult retroperitoneal metastatic disease. These results should be considered when counseling patients about appropriate treatment options.
2248
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
REFERENCES 1. Stephenson AJ, Bosl GJ, Motzer RJ et al: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 2005; 23: 2781. 2. Glendenning JL, Barbachano Y, Norman AR et al: Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer 2010; 116: 2322. 3. van den Belt-Dusebout AW, de Wit R, Gietema JA et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007; 25: 4370. 4. Brenner DJ and Hall EJ: Computed tomography–an increasing source of radiation exposure. N Engl J Med 2007; 357: 2277. 5. Beck SD, Peterson MD, Bihrle R et al: Short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary group of patients. J Urol 2007; 178: 504. 6. Williams SB, McDermott DW, Winston D et al: Morbidity of open retroperitoneal lymph node dissection for testicular cancer: contemporary perioperative data. BJU Int 2010; 105: 918. 7. Heidenreich A, Sesterhenn IA, Mostofi FK et al: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 1998; 83: 1002. 8. Sweeney CJ, Hermans BP, Heilman DK et al: Results and outcome of retroperitoneal lymph
node dissection for clinical stage I embryonal carcinoma–predominant testis cancer. J Clin Oncol 2000; 18: 358.
low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol 2005; 174: 557.
9. Albers P, Siener R, Kliesch S et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. J Clin Oncol 2003; 21: 1505.
16. Schmoll HJ, Souchon R, Krege S et al: European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377.
10. Sesterhenn IA, Weiss RB, Mostofi FK et al: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 1992; 10: 69.
17. Bohlen D, Borner M, Sonntag RW et al: Longterm results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol 1999; 161: 1148.
11. Al-Tourah AJ, Murray N, Coppin C et al: Minimizing treatment without compromising cure with primary surveillance for clinical stage I embryonal predominant nonseminomatous testicular cancer: a population based analysis from British Columbia. J Urol 2005; 174: 2209.
18. Stephenson AJ, Bosl GJ, Motzer RJ et al: Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 2007; 25: 5597.
12. Williams SB, McDermott DW, Dock W et al: Retroperitoneal lymph node dissection in patients with high risk testicular cancer. J Urol 2009; 181: 2097.
19. Yu HY, Madison RA, Setodji CM et al: Quality of surveillance for stage I testis cancer in the community. J Clin Oncol 2009; 27: 4327.
13. Huddart RA, Norman A, Shahidi M et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003; 21: 1513.
20. Sturgeon JF, Moore MJ, Kakiashvili DM et al: Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the Princess Margaret Hospital’s experience. Eur Urol 2011; 59: 556.
14. Haugnes HS, Aass N, Fossa SD et al: Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol 2009; 27: 2779. 15. Stephenson AJ, Bosl GJ, Bajorin DF et al: Retroperitoneal lymph node dissection in patients with
21. 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 1993; 149: 237.
Purpose: Percent of embryonal carcinoma and lymphovascular invasion in the primary tumor are risk factors for occult retroperitoneal metastatic disease. High risk patients with clinical stage I and IIA nonseminomatous germ cell tumor who underwent primary retroperitoneal lymph node dissection were identified to discern any other risk factors for metastatic disease. Materials and Methods: Patients who had undergone retroperitoneal lymph node dissection at our institution from 1993 to 2009 were identified and clinical charts were reviewed. A total of 90 patients with orchiectomy specimens containing more than 30% embryonal carcinoma who underwent primary retroperitoneal lymph node dissection were identified and perioperative data were obtained. Results: Of 353 patients 90 (25%) had greater than 30% embryonal carcinoma and underwent primary retroperitoneal lymph node dissection. Of these patients 45 (50%) had lymphovascular invasion. Median followup was 1.1 years. Positive lymph nodes identified at retroperitoneal lymph node dissection were noted in 30 (46%) and 15 (60%) patients with clinical stage I vs clinical stage II disease. On multivariate analysis embryonal carcinoma (OR 1.02, 95% CI 1.00 –1.04) and lymphovascular invasion (OR 3.52, 95% CI 1.43– 8.67) were associated with positive lymph nodes at retroperitoneal lymph node dissection. The positive predictive value for 100% embryonal carcinoma was 65.5%, although the negative predictive value for 30% embryonal carcinoma was 85.7%. Conclusions: Embryonal carcinoma and lymphovascular invasion were significantly and independently associated with the risk of occult retroperitoneal metastatic disease. These results should be considered when counseling patients about appropriate treatment options.
Abbreviations and Acronyms CSI ⫽ clinical stage I CSII ⫽ clinical stage II LVI ⫽ lymphovascular invasion P-RPLND ⫽ primary retroperitoneal lymph node dissection PSI ⫽ pathological stage I PSII ⫽ pathological stage II RPLND ⫽ retroperitoneal lymph node dissection Submitted for publication April 25, 2011. Study received institutional review board approval. * Correspondence: 75 Francis St., Boston, Massachusetts 20015 (telephone: 617-732-6325; FAX: 617-566-3475; e-mail: [email protected]).
See Editorial on page 2151.
Key Words: lymph node excision; testicular neoplasms; carcinoma, embryonal OF all clinical stage I nonseminomatous germ cell tumors, approximately 30% will harbor metastatic disease to the retroperitoneum.1 Current treatment options include active surveillance, chemotherapy and/or RPLND. RPLND remains an integral component in the treatment and cure of testicular cancer not only by staging cases more precisely than imaging, but also
by limiting the followup and side effects associated with chemotherapy.2,3 Furthermore, RPLND avoids the need for frequent imaging and the attendant increased risk of secondary malignancies developing many years later.4 With the introduction of modified template nerve sparing approaches, the morbidity associated with this procedure is minimal.5,6
0022-5347/11/1866-2245/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 2245-2248, December 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.07.101
AND
RESEARCH, INC.
www.jurology.com
2245
2246
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
To identify patients at risk for metastatic disease prior studies have confirmed that percent embryonal carcinoma and LVI in the primary tumor are independent risk factors for occult metastasis.7–9 Heidenreich et al positively predicted 88% of patients with CSI disease with greater than 80% embryonal carcinoma and positive vascular invasion had PSII disease.7 Conversely 91.5% of patients with CSI disease with less than 45% embryonal carcinoma and absent vascular invasion were free of metastatic disease. The Testicular Cancer Intergroup study revealed that combining percent embryonal carcinoma with vascular invasion accurately predicted PSII disease in 86% of patients.10 The indication for primary chemotherapy in these high risk patients remains a debate with some groups recommending 2 cycles of platinum based chemotherapy and open RPLND reserved as an alternative treatment.11 Depending on the precise definition of risk factors, up to 50% of these high risk patients who receive chemotherapy harbor metastatic disease.12 Therefore, 50% of patients given chemotherapy for high risk disease are treated unnecessarily, thus exposing these often young patients to the lifelong risks of secondary malignancies3 and cardiopulmonary toxicities.13,14 Prior studies have demonstrated the successful treatment of high risk patients with P-RPLND.12,15 In the current study high risk cases of clinical stage I and IIA nonseminomatous germ cell tumor treated with PRPLND were reviewed to elucidate any other risk factors for metastatic disease.
MATERIALS AND METHODS All patients undergoing RPLND at Brigham and Women’s Hospital and Dana Farber Cancer Center from 1993 to 2009 were candidates for inclusion in this study. All patients with orchiectomy specimens of greater than 30% embryonal carcinoma were identified and perioperative data were obtained. These data were extracted from the Brigham and Women’s Hospital RPLND computerized database and analyzed accordingly.12 This project was approved by the institutional review board at Brigham and Women’s Hospital. At our institution all patients are evaluated in a multidisciplinary clinic, and are counseled regarding the options of active surveillance, surgery and/or chemotherapy as previously described.12 All cases were preoperatively staged with tumor markers (␣-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase), abdominopelvic computerized tomography and computerized tomography of the chest or chest x-ray. All orchiectomy and RPLND specimens were reviewed and reports were confirmed by pathologists at Brigham and Women’s Hospital. All pathology reports had confirmed histology and percent embryonal carcinoma in orchiectomy specimens. In addition, all orchiectomy pathological reports denoted the presence or absence of LVI defined as the presence of
identifiable tumor cells within the lumen of an artery, vein or lymphatic vessel. Data were entered into a computerized database and analyzed. Differences between P-RPLND and RPLND pathological findings based on continuous variables were compared using the Student’s t test. A chi-square test was used to test for differences in proportions among these groups of patients. All variables significantly associated with positive nodes on univariate analysis at p ⫽ 0.05 or better were used in the logistic regression model. Embryonal carcinoma greater than 30% was evaluated as a categorical variable. Since orchiectomy pathological stage is based largely on the presence or absence of LVI, we did not include orchiectomy stage in the multivariate analysis.
RESULTS A total of 353 patients who underwent RPLND at Brigham and Women’s Hospital and Dana Farber Cancer Center between 1993 and 2009 were identified. Of these patients 90 (25%) had greater than 30% embryonal carcinoma and underwent P-RPLND. Of these patients 45 (50%) had combined LVI. Median followup was 1.1 years. There were no perioperative deaths. Patient demographics and primary tumor characteristics according to pathological stage at RPLND are summarized in the table. Positive lymph nodes identified at RPLND were noted in 30 (46%) and 15 (60%) patients with CSI vs CSII disease. There was no difference in patient age or clinical stage between the groups. Average percent embryonal carcinoma in PSI vs PSII was 68.2% vs 81.4%, respectively (p ⫽ 0.011). All other histological subtypes were similar in either group. Patients with PSII disease had a significantly higher percentage of LVI (66.7% vs 33.3%, p ⫽ 0.003) which corresponded with orchiectomy pathological stage (p ⫽ 0.006). On multivariate analysis embryonal carcinoma (OR 1.02, 95% CI 1.001–1.040, p ⫽ 0.038) and LVI (OR 3.52, 95% CI 1.43– 8.67, p ⫽ 0.006) were associated with positive lymph nodes at RPLND. The positive predictive value for 100% embryonal carci-
Patient demographic data and preoperative clinical characteristics Pathological Stage I Pathological Stage II p Value No. pts Mean pt age No. CSI (%) No. CSII (%) No. Ca (%): Choriocarcinoma Seminoma Teratoma Yolk sac No. orchiectomy stage (%): pT1 pT2 or greater
45 29 35 (77.8) 10 (22.2)
45 30 30 (66.7) 15 (33.3)
0.587 0.347
5 (11.1) 17 (37.8) 24 (53.3) 21 (46.7)
3 (46.67) 10 (22.2) 18 (40.0) 12 (26.7)
0.714 0.167 0.291 0.079
29 (64.4) 16 (35.6)
15 (33.3) 30 (66.7)
0.006
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
noma was 65.5%, although the negative predictive value for 30% embryonal carcinoma was 85.7%.
DISCUSSION The surgical and medical management of high risk testicular cancer has been well described with cancer specific survival approaching 99%.16 The 2 factors that have been shown to lead to high rates of retroperitoneal metastasis after orchiectomy are the predominance of embryonal carcinoma and the presence of LVI. Primary chemotherapy for high risk CSI testicular cancer has been favored compared to watchful waiting and surgery.17 Stephenson et al argued that for CSII nonseminomatous germ cell tumors, RPLND cannot be safely omitted after induction chemotherapy in patients with stable disease because the incidence of viable retroperitoneal disease in the form of teratoma or viable malignancy is approximately 20%.18 Furthermore, RPLND obviated the need for routine imaging required for active surveillance or after chemotherapy, which puts patients at risk for malignancy as a result of radiation exposure.4 Lastly, although chemotherapy provides comparable oncologic effectiveness, platinum based chemotherapy regimens place patients at increased risk for the metabolic syndrome and cardiovascular disease.3 The risk of a major late complication with secondary malignancy or cardiovascular disease as a result of chemotherapy for testicular cancer is 1.9-fold greater than with surgery alone.3 This risk is comparable to the effect of smoking.3 Another study in testicular cancer survivors revealed that large doses of cisplatin based chemotherapy or combined chemotherapy and pulmonary surgery equaled twofold to fourfold the effect of smoking.14 Our study has several important findings. We found embryonal carcinoma to be a significant predictor of occult retroperitoneal metastasis. Prior studies showed embryonal carcinoma with or without LVI to be a predictor of PSII disease.7 Specifically Heidenreich et al successfully predicted PSII disease in patients with CSI based on greater than 80% embryonal carcinoma with or without LVI in 85.4%, rather than their less than 45% group in which disease was accurately staged as PSI in 88%.7 The average percent embryonal carcinoma of the PSI and PSII cases in their study was 37.8% and 81.9%, respectively. Although we used greater than 30% as our threshold for embryonal carcinoma at orchiectomy, our average embryonal component was 68.2% and 81.4% in PSI vs PSII disease, respectively. Furthermore, our positive predictive value for 100% embryonal carcinoma was 65.5%, although the
2247
negative predictive value for 30% embryonal carcinoma was 85.7%. In addition, LVI had an almost fourfold increase risk of retroperitoneal disease. This finding coincides with prior studies7,15 which revealed LVI and more importantly vascular invasion as risk factors.11 As previously stated, prior studies found embryonal carcinoma with or without LVI as a predictor of PSII disease.7 Some authors initially suggested that embryonal carcinoma was a risk factor for lymphatic metastases and now find only vascular invasion to be a risk factor.11 A possible explanation for our findings may be the low number of patients in the study cohort. With a larger number of patients it is possible that embryonal carcinoma and LVI would provide more definitive information as to the relative risk of positive lymphadenopathy. Finally, clinical stage was not a predictor of positive lymphadenopathy, thus highlighting the need for improved markers for the detection of occult retroperitoneal metastasis. Even with recent technological advances in imaging, much remains to be improved in regard to the detection of metastatic disease in patients with testis cancer. This is of significant concern for patients who are at high risk and considering active surveillance. Yu et al recently reported approximately 30% adherence to active surveillance protocols in patients diagnosed with CSI testis cancer.19 Thus, although certain centers report excellent outcomes for patients on active surveillance,20 improved diagnostic accuracy is warranted to ensure disease is accurately staged in these patients. RPLND remains a viable diagnostic and therapeutic strategy which provides excellent long-term results1,21 in addition to negating the secondary toxicities of chemotherapy.3,13,14 Our findings must be interpreted in the context of the study design. This is a retrospective study from a tertiary care center with uncontrolled selection biases. Although we performed a multivariate analysis, our findings are hypothesis generating and further study is warranted to validate these results. Another limitation is the lack of a large number of patients which, as previously mentioned, may have underpowered certain findings.
CONCLUSIONS In our contemporary P-RPLND series embryonal carcinoma and LVI were significantly and independently associated with the risk of occult retroperitoneal metastatic disease. These results should be considered when counseling patients about appropriate treatment options.
2248
POSITIVE PREDICTORS AT RETROPERITONEAL LYMPH NODE DISSECTION
REFERENCES 1. Stephenson AJ, Bosl GJ, Motzer RJ et al: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 2005; 23: 2781. 2. Glendenning JL, Barbachano Y, Norman AR et al: Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer 2010; 116: 2322. 3. van den Belt-Dusebout AW, de Wit R, Gietema JA et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007; 25: 4370. 4. Brenner DJ and Hall EJ: Computed tomography–an increasing source of radiation exposure. N Engl J Med 2007; 357: 2277. 5. Beck SD, Peterson MD, Bihrle R et al: Short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary group of patients. J Urol 2007; 178: 504. 6. Williams SB, McDermott DW, Winston D et al: Morbidity of open retroperitoneal lymph node dissection for testicular cancer: contemporary perioperative data. BJU Int 2010; 105: 918. 7. Heidenreich A, Sesterhenn IA, Mostofi FK et al: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 1998; 83: 1002. 8. Sweeney CJ, Hermans BP, Heilman DK et al: Results and outcome of retroperitoneal lymph
node dissection for clinical stage I embryonal carcinoma–predominant testis cancer. J Clin Oncol 2000; 18: 358.
low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol 2005; 174: 557.
9. Albers P, Siener R, Kliesch S et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. J Clin Oncol 2003; 21: 1505.
16. Schmoll HJ, Souchon R, Krege S et al: European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377.
10. Sesterhenn IA, Weiss RB, Mostofi FK et al: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 1992; 10: 69.
17. Bohlen D, Borner M, Sonntag RW et al: Longterm results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol 1999; 161: 1148.
11. Al-Tourah AJ, Murray N, Coppin C et al: Minimizing treatment without compromising cure with primary surveillance for clinical stage I embryonal predominant nonseminomatous testicular cancer: a population based analysis from British Columbia. J Urol 2005; 174: 2209.
18. Stephenson AJ, Bosl GJ, Motzer RJ et al: Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 2007; 25: 5597.
12. Williams SB, McDermott DW, Dock W et al: Retroperitoneal lymph node dissection in patients with high risk testicular cancer. J Urol 2009; 181: 2097.
19. Yu HY, Madison RA, Setodji CM et al: Quality of surveillance for stage I testis cancer in the community. J Clin Oncol 2009; 27: 4327.
13. Huddart RA, Norman A, Shahidi M et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003; 21: 1513.
20. Sturgeon JF, Moore MJ, Kakiashvili DM et al: Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the Princess Margaret Hospital’s experience. Eur Urol 2011; 59: 556.
14. Haugnes HS, Aass N, Fossa SD et al: Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol 2009; 27: 2779. 15. Stephenson AJ, Bosl GJ, Bajorin DF et al: Retroperitoneal lymph node dissection in patients with
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