- Email: [email protected]
Risk of Recurrence for Clinical Stage I and II Patients With Teratoma Only at Primary Retroperitoneal Lymph Node Dissection
Oncology Risk of Recurrence for Clinical Stage I and II Patients With Teratoma Only at Primary Retroperitoneal Lymph Node Dissection Nick W. Liu, Clint Cary, Andrew C. Strine, Stephen D. W. Beck, Timothy A. Masterson, Richard Bihrle, and Richard S. Foster OBJECTIVE MATERIALS AND METHODS RESULTS
CONCLUSION
To evaluate the oncologic outcomes of patients with retroperitoneal teratoma only at primary retroperitoneal lymph node dissection (RPLND) who did not receive adjuvant chemotherapy. Between 1979 and 2010, 23 patients with clinical stage (CS) I and II disease underwent primary RPLND at our institution with teratoma only in the retroperitoneum. No patient received adjuvant chemotherapy and the minimum follow-up was 2 years. At the initial diagnosis, 13 patients (56.5%) had CS I disease and 10 patients (43.5%) had CS II disease. Pathologic staging demonstrated IIA in 13 patients (56.5%), IIB in 8 patients (34.8%), and IIC in 2 patients (8.7%). The 5-year disease-free survival (DFS) was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing pathologic stage IIA vs IIB/IIC disease (P ¼ .73). Two patients (14%) developed late relapses. One patient had a pelvic recurrence 11 years after primary RPLND. Final pathology from the pelvic resection demonstrated embryonal carcinoma. He remains disease free after his second surgery. The second patient had a contralateral retroperitoneal recurrence with yolk-sac tumor and teratoma 11 years after primary RPLND. He was treated with chemotherapy followed by postchemotherapy RPLND. The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Adjuvant chemotherapy is therefore not recommended in the management of these patients. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
T
eratoma is a common histology in both adult and pediatric germ cell tumors (GCTs). Pure teratoma in the prepubertal gonad is considered a benign condition that can be successfully managed with radical orchiectomy alone.1 In other words, prepubertal teratoma is not associated with lymphatic or hematogenous metastasis. Pure teratoma in the adult gonad is associated with metastasis of GCTs and retroperitoneal lymph node dissection (RPLND) is a treatment option. Approximately 2% of clinical stage (CS) I patients will demonstrate teratoma only in the retroperitoneal specimen following a primary RPLND.2,3 The exact mechanism of metastasis in pure teratoma remains unknown, but one hypothesis is that undifferentiated GCTs in the primary tumor metastasize and differentiate into mature
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Indiana University School of Medicine, Indianapolis, IN Address correspondence to: Clint Cary, M.D., M.P.H., Department of Urology, Indiana University School of Medicine, 535 Barnhill Drive, Suite 420, Indianapolis, IN 46202. E-mail: [email protected] Submitted: March 17, 2015, accepted (with revisions): June 1, 2015
ª 2015 Elsevier Inc. All Rights Reserved
teratoma at the new site.4 The question now is: are there associated nonteratomatous elements not identified at primary RPLND? Perhaps this explains why some institutions have advocated the use of adjuvant chemotherapy when the only identified histology at primary RPLND is teratoma.2,5 So seemingly, the impetus for adjuvant chemotherapy in this setting is to address potentially unrecognized nonteratomatous germ cell elements. Patients with pathologic stage (PS) II metastatic disease are typically offered either surveillance or adjuvant chemotherapy. Either of these options is reasonable. The only difference is that surveillance patients who relapse are typically treated with 3 cycles of bleomycin, etoposide, and cisplatin chemotherapy. Conversely, 50%-70% of patients found to have retroperitoneal metastasis at RPLND are cured with surgery alone and are not subject to long-term side effects of chemotherapy.6-8 Although 2 courses of adjuvant chemotherapy after primary RPLND reduces the risk of relapse to less than 1%, it does not improve the overall survival and unnecessarily exposes a significant number of patients to chemotherapy who were http://dx.doi.org/10.1016/j.urology.2015.06.004 0090-4295/15
1
otherwise cured with surgical therapy alone.9 Those who recur are still salvaged with standard chemotherapy in the majority of cases. The purpose of this study is to determine the risk of systemic relapse in patients with teratoma only at primary RPLND who did not receive adjuvant chemotherapy.
MATERIALS AND METHODS Our testis cancer database was retrospectively reviewed to identify all patients with CS I and II nonseminomatous GCT (NSGCT) who presented after radical orchiectomy and underwent primary RPLND at Indiana University from 1979 to 2010. Inclusion criteria include normalization of postorchiectomy serum tumor markers, PS II disease with teratoma only in the retroperitoneal specimen, no adjuvant chemotherapy, and follow-up greater than 2 years. This study was approved by the institutional review board at Indiana University. A total of 23 patients met these criteria and were the subject of this study. The following variables were evaluated: surgical template, PS, retroperitoneal histology, location and time of recurrence, and histology at relapse. Based on the results of nodal distribution studies, our institution has routinely performed primary RPLND using the modified template for lowvolume stage II NSGCT.10 The most common indication for bilateral template RPLND is presence of disease burden outside the primary landing zone on preoperative imaging. Follow-up information was obtained by medical chart review and/or direct contact with patients. Each follow-up visit included history and physical examination, chest X-ray, and serum tumor markers. In the event of a recurrence, the location and type of relapse was confirmed with radiographic studies obtained during follow-up and pathologic specimens obtained from any subsequent surgery after primary RPLND. The primary outcome was disease-free survival (DFS). The time to relapse was calculated from the time of primary RPLND to the date of first relapse or most recent follow-up. Survival analysis was performed using the Kaplan-Meier method, and comparisons were made using the log-rank test. Statistical analysis was performed using Stata version 12.1 with P <.05 considered statistically significant.
RESULTS Table 1 lists the clinical characteristics and oncologic outcomes of the 23 patients included in this study. Overall, 13 (56.5%), 8 (34.8%), and 2 (8.7%) patients had PS IIA (pN1), IIB (pN2), and IIC (pN3) disease, respectively. The 5-year DFS of entire cohort irrespective of PS was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing PS IIA vs IIB/IIC disease (see Fig. 1). There were 2 recurrences (14%), and both were late relapses diagnosed by elevated tumor markers during follow-up. One patient with PS IIA disease had a pelvic recurrence 11 years after primary RPLND. The final pathology of the pelvic mass demonstrated embryonal carcinoma. He is currently free of disease 2 years after his second surgery without adjuvant chemotherapy. The second patient with PS IIB disease had a right modified RPLND 2
Table 1. Clinical characteristics and oncologic outcomes of patients with teratoma only at primary RPLND Patient Characteristics Number of patients Median age, y (range) Modified RPLND (%) Full bilateral RPLND (%) Nerve-sparing approach (%) Primary orchiectomy histology (%) Teratomatous elements Pure teratoma Lymphovascular invasion Clinical stage (%) I II Pathologic stage (%) IIA (pN1) IIB (pN2) IIC (pN3) Number of relapse (%) 5-Year DFS (%) Median follow-up, y (range)
N (%) 30 19 4 14
23 (16-43) (82.6) (17.3) (60.8)
19 (82.6) 9 (39.1) 1 (4.3) 13 (56.5) 10 (43.5) 13 8 2 2
(56.5) (34.8) (8.7) (14) 100 5.8 (2.1-25.4)
DFS, disease-free survival; RPLND, retroperitoneal lymph node dissection.
Figure 1. Kaplan-Meier curve shows disease-free survival for patients with teratoma only at RPLND. Solid curve indicates pathologic stage IIA. Dashed curve indicates pathologic stage IIB/IIC. RPLND, retroperitoneal lymph node dissection.
initially and developed elevated alpha-fetal protein and a solitary left-sided retroperitoneal recurrence 10 years after his surgery. He was given cisplatinum-based chemotherapy followed by a recent postchemotherapy RPLND on the left side. Final pathology demonstrated mixed NSGCT with yolk-sac tumor and teratoma. Of the 4 patients who underwent bilateral template RPLND, 1 patient had CS IIA disease whereas the remaining 3 had CS IIB disease. The patient with CS IIA disease had RPLND in 1979, which is prior to when modified template had become the standard of practice for low-volume CS II disease at our institution. Bilateral template RPLND was recommended in the remaining 3 patients because all had disease burden in both landing UROLOGY
-
(-), 2015
zones (left and right) on preoperative imaging. None of these patients developed a recurrence during the followup period.
COMMENT The rationale for primary RPLND in patients with CS I/II NSGCT is because of its diagnostic and therapeutic potential for a significant proportion of patients found to have PS II disease. For patients with PS IIA disease, 70% are cured with surgery alone and the 30% who relapse remain curable with 3 courses of chemotherapy.9,11,12 Although adjuvant chemotherapy provides an excellent oncologic outcome, it unnecessarily exposes 70% of patients who were never destined to relapse to 2 cycles of cisplatin-based chemotherapy, therefore negating the therapeutic benefit of primary RPLND. The remaining 30% of patients are still salvaged with only 1 additional cycle of chemotherapy (total of 3 cycles) with no difference in the overall survival.9 These findings suggest a more expectant approach for the management of lowvolume PS II disease. Using more selective criteria for surveillance, several investigators have indeed achieved a relapse rate as low as 10% in patients with PS IIA disease.13,14 Ideally, the decision to administer adjuvant chemotherapy in PS II NSGCT should be restricted to patients identified as high risk for systemic failure. Unfortunately, such a risk stratification scheme has not been identified, and commonly felt risk factors such as extranodal extension, positive lymph nodes, and lymph node density have not been shown to predict disease recurrence.15,16 Currently, the guidelines from both the National Comprehensive Cancer Network and European Association of Urology rely on pathologic staging as the primary determining factor to guide further therapy after primary RPLND.17,18 We do not rely upon these guidelines. In addition to pathologic staging, we believe retroperitoneal histology plays an important role in predicting systemic failure after primary RPLND. Our institution previously reported the significance of histologic subtype on the risk of relapse following a primary RPLND. Although the retroperitoneal histology was not predictive of relapse, none of the 8 patients with pure teratoma recurred.19 In a series of 25 patients with teratomatous elements at primary RPLND, the investigators at Memorial Sloan Kettering reported no disease recurrence at a median follow-up of 27 months.2 However, 16 of the 25 patients (64%) received adjuvant chemotherapy, which may have included 8 patients with teratoma only in the retroperitoneum. The rationale for adjuvant chemotherapy was based on pathologic staging, not histologic subtype. In the current series, patients with teratoma only at RPLND without adjuvant chemotherapy had a 100% DFS at a median follow-up of 5.5 years. PS, including those with IIB/IIC disease, did not predict for recurrence in this population. Therefore, adjuvant chemotherapy would seem to provide little benefit in this cohort. In this UROLOGY
-
(-), 2015
series, we chose to offer primary RPLND to 2 patients with larger volume retroperitoneal disease who had pathologic IIC disease. Both of these patients had 100% pure teratoma in the orchiectomy specimen with normal serum tumor markers and were felt to harbor pure teratoma in the retroperitoneum. Because of the chemoresistance of teratoma, these patients underwent primary RPLND as opposed to standard chemotherapy. Late relapse is an uncommon event that poses a significant risk for testis cancer patients.20,21 The most common sites of late relapse after RPLND are lungs and the retroperitoneum.22 The present study identified 2 late relapses at an interval of 10 years after their primary RPLND, highlighting the importance of surveillance in these patients. However, there is no consensus regarding the frequency of follow-up or the need for surveillance imaging or laboratory evaluation in patients treated with RPLND after 5 years. There were several limitations to this study. It was retrospective in nature and included a relatively small number of patients from a single institution, which may limit its external validity. Furthermore, there were a small number of events, which limits the ability to draw significant conclusions. A larger, multi-institutional series may be informative in evaluating the oncologic outcomes of patients with not only teratoma but also other retroperitoneal histologic subtypes at primary RPLND.
CONCLUSION The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Therefore, adjuvant therapy is unlikely to provide a significant benefit. For those that do recur, surgical management remains feasible and curative. In addition to pathologic staging, retroperitoneal histology at primary RPLND, specifically teratoma, should be taken into consideration to guide adjuvant therapy. References 1. Carver BS, Al-Ahmadie H, Sheinfeld J. Adult and pediatric testicular teratoma. Urol Clin North Am. 2007;34:245-251; abstract x. 2. Sheinfeld J, Motzer RJ, Rabbani F, et al. Incidence and clinical outcome of patients with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection for clinical stages I and IIA nonseminomatous germ cell tumors. J Urol. 2003;170:11591162. 3. Leibovitch I, Foster RS, Ulbright TM, Donohue JP. Adult primary pure teratoma of the testis. The Indiana experience. Cancer. 1995; 75:2244-2250. 4. Simmonds PD, Lee AH, Theaker JM, et al. Primary pure teratoma of the testis. J Urol. 1996;155:939-942. 5. Kondagunta GV, Sheinfeld J, Mazumdar M, et al. Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol. 2004;22:464-467. 6. Brydoy M, Oldenburg J, Klepp O, et al. Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors. J Natl Cancer Inst. 2009; 101:1682-1695.
3
7. Sagstuen H, Aass N, Fossa SD, et al. Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol. 2005; 23:4980-4990. 8. Foster R, Bihrle R. Current status of retroperitoneal lymph node dissection and testicular cancer: when to operate. Cancer Control. 2002;9:277-283. 9. Williams SD, Stablein DM, Einhorn LH, et al. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med. 1987;317:14331438. 10. Donohue JP. Evolution of retroperitoneal lymphadenectomy (RPLND) in the management of non-seminomatous testicular cancer (NSGCT). Urol Oncol. 2003;21:129-132. 11. Pizzocaro G, Monfardini S. No adjuvant chemotherapy in selected patients with pathologic stage II nonseminomatous germ cell tumors of the testis. J Urol. 1984;131:677-680. 12. Hermans BP, Sweeney CJ, Foster RS, et al. Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol. 2000; 163:1721-1724. 13. Pohar KS, Rabbani F, Bosl GJ, et al. Results of retroperitoneal lymph node dissection for clinical stage I and II pure embryonal carcinoma of the testis. J Urol. 2003;170:1155-1158. 14. 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; 23:2781-2788.
4
15. Beck SD, Cheng L, Bihrle R, et al. Does the presence of extranodal extension in pathological stage B1 nonseminomatous germ cell tumor necessitate adjuvant chemotherapy? J Urol. 2007;177: 944-946. 16. Beck SD, Foster RS, Bihrle R, et al. Impact of the number of positive lymph nodes on disease-free survival in patients with pathological stage B1 nonseminomatous germ cell tumor. J Urol. 2005; 174:143-145. 17. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: testicular cancer. J Natl Compr Canc Netw. 2009;7:672-693. 18. Albers P, Albrecht W, Algaba F, et al. [EAU guidelines on testicular cancer: 2011 update. European Association of Urology]. Actas Urol Esp. 2012;36:127-145. 19. Beck SD, Foster RS, Bihrle R, et al. Does the histology of nodal metastasis predict systemic relapse after retroperitoneal lymph node dissection in pathological stage B1 germ cell tumors? J Urol. 2005; 174:1287-1290; discussion: 1290. 20. Rice KR, Beck SD, Pedrosa JA, et al. Surgical management of late relapse on surveillance in patients presenting with clinical stage I testicular cancer. Urology. 2014;84:886-890. 21. Oldenburg J, Martin JM, Fossa SD. Late relapses of germ cell malignancies: incidence, management, and prognosis. J Clin Oncol. 2006;24:5503-5511. 22. Beck SD, Foster RS. Long-term outcome of retroperitoneal lymph node dissection in the management of testis cancer. World J Urol. 2006;24:267-272.
UROLOGY
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(-), 2015
CONCLUSION
To evaluate the oncologic outcomes of patients with retroperitoneal teratoma only at primary retroperitoneal lymph node dissection (RPLND) who did not receive adjuvant chemotherapy. Between 1979 and 2010, 23 patients with clinical stage (CS) I and II disease underwent primary RPLND at our institution with teratoma only in the retroperitoneum. No patient received adjuvant chemotherapy and the minimum follow-up was 2 years. At the initial diagnosis, 13 patients (56.5%) had CS I disease and 10 patients (43.5%) had CS II disease. Pathologic staging demonstrated IIA in 13 patients (56.5%), IIB in 8 patients (34.8%), and IIC in 2 patients (8.7%). The 5-year disease-free survival (DFS) was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing pathologic stage IIA vs IIB/IIC disease (P ¼ .73). Two patients (14%) developed late relapses. One patient had a pelvic recurrence 11 years after primary RPLND. Final pathology from the pelvic resection demonstrated embryonal carcinoma. He remains disease free after his second surgery. The second patient had a contralateral retroperitoneal recurrence with yolk-sac tumor and teratoma 11 years after primary RPLND. He was treated with chemotherapy followed by postchemotherapy RPLND. The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Adjuvant chemotherapy is therefore not recommended in the management of these patients. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
T
eratoma is a common histology in both adult and pediatric germ cell tumors (GCTs). Pure teratoma in the prepubertal gonad is considered a benign condition that can be successfully managed with radical orchiectomy alone.1 In other words, prepubertal teratoma is not associated with lymphatic or hematogenous metastasis. Pure teratoma in the adult gonad is associated with metastasis of GCTs and retroperitoneal lymph node dissection (RPLND) is a treatment option. Approximately 2% of clinical stage (CS) I patients will demonstrate teratoma only in the retroperitoneal specimen following a primary RPLND.2,3 The exact mechanism of metastasis in pure teratoma remains unknown, but one hypothesis is that undifferentiated GCTs in the primary tumor metastasize and differentiate into mature
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Indiana University School of Medicine, Indianapolis, IN Address correspondence to: Clint Cary, M.D., M.P.H., Department of Urology, Indiana University School of Medicine, 535 Barnhill Drive, Suite 420, Indianapolis, IN 46202. E-mail: [email protected] Submitted: March 17, 2015, accepted (with revisions): June 1, 2015
ª 2015 Elsevier Inc. All Rights Reserved
teratoma at the new site.4 The question now is: are there associated nonteratomatous elements not identified at primary RPLND? Perhaps this explains why some institutions have advocated the use of adjuvant chemotherapy when the only identified histology at primary RPLND is teratoma.2,5 So seemingly, the impetus for adjuvant chemotherapy in this setting is to address potentially unrecognized nonteratomatous germ cell elements. Patients with pathologic stage (PS) II metastatic disease are typically offered either surveillance or adjuvant chemotherapy. Either of these options is reasonable. The only difference is that surveillance patients who relapse are typically treated with 3 cycles of bleomycin, etoposide, and cisplatin chemotherapy. Conversely, 50%-70% of patients found to have retroperitoneal metastasis at RPLND are cured with surgery alone and are not subject to long-term side effects of chemotherapy.6-8 Although 2 courses of adjuvant chemotherapy after primary RPLND reduces the risk of relapse to less than 1%, it does not improve the overall survival and unnecessarily exposes a significant number of patients to chemotherapy who were http://dx.doi.org/10.1016/j.urology.2015.06.004 0090-4295/15
1
otherwise cured with surgical therapy alone.9 Those who recur are still salvaged with standard chemotherapy in the majority of cases. The purpose of this study is to determine the risk of systemic relapse in patients with teratoma only at primary RPLND who did not receive adjuvant chemotherapy.
MATERIALS AND METHODS Our testis cancer database was retrospectively reviewed to identify all patients with CS I and II nonseminomatous GCT (NSGCT) who presented after radical orchiectomy and underwent primary RPLND at Indiana University from 1979 to 2010. Inclusion criteria include normalization of postorchiectomy serum tumor markers, PS II disease with teratoma only in the retroperitoneal specimen, no adjuvant chemotherapy, and follow-up greater than 2 years. This study was approved by the institutional review board at Indiana University. A total of 23 patients met these criteria and were the subject of this study. The following variables were evaluated: surgical template, PS, retroperitoneal histology, location and time of recurrence, and histology at relapse. Based on the results of nodal distribution studies, our institution has routinely performed primary RPLND using the modified template for lowvolume stage II NSGCT.10 The most common indication for bilateral template RPLND is presence of disease burden outside the primary landing zone on preoperative imaging. Follow-up information was obtained by medical chart review and/or direct contact with patients. Each follow-up visit included history and physical examination, chest X-ray, and serum tumor markers. In the event of a recurrence, the location and type of relapse was confirmed with radiographic studies obtained during follow-up and pathologic specimens obtained from any subsequent surgery after primary RPLND. The primary outcome was disease-free survival (DFS). The time to relapse was calculated from the time of primary RPLND to the date of first relapse or most recent follow-up. Survival analysis was performed using the Kaplan-Meier method, and comparisons were made using the log-rank test. Statistical analysis was performed using Stata version 12.1 with P <.05 considered statistically significant.
RESULTS Table 1 lists the clinical characteristics and oncologic outcomes of the 23 patients included in this study. Overall, 13 (56.5%), 8 (34.8%), and 2 (8.7%) patients had PS IIA (pN1), IIB (pN2), and IIC (pN3) disease, respectively. The 5-year DFS of entire cohort irrespective of PS was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing PS IIA vs IIB/IIC disease (see Fig. 1). There were 2 recurrences (14%), and both were late relapses diagnosed by elevated tumor markers during follow-up. One patient with PS IIA disease had a pelvic recurrence 11 years after primary RPLND. The final pathology of the pelvic mass demonstrated embryonal carcinoma. He is currently free of disease 2 years after his second surgery without adjuvant chemotherapy. The second patient with PS IIB disease had a right modified RPLND 2
Table 1. Clinical characteristics and oncologic outcomes of patients with teratoma only at primary RPLND Patient Characteristics Number of patients Median age, y (range) Modified RPLND (%) Full bilateral RPLND (%) Nerve-sparing approach (%) Primary orchiectomy histology (%) Teratomatous elements Pure teratoma Lymphovascular invasion Clinical stage (%) I II Pathologic stage (%) IIA (pN1) IIB (pN2) IIC (pN3) Number of relapse (%) 5-Year DFS (%) Median follow-up, y (range)
N (%) 30 19 4 14
23 (16-43) (82.6) (17.3) (60.8)
19 (82.6) 9 (39.1) 1 (4.3) 13 (56.5) 10 (43.5) 13 8 2 2
(56.5) (34.8) (8.7) (14) 100 5.8 (2.1-25.4)
DFS, disease-free survival; RPLND, retroperitoneal lymph node dissection.
Figure 1. Kaplan-Meier curve shows disease-free survival for patients with teratoma only at RPLND. Solid curve indicates pathologic stage IIA. Dashed curve indicates pathologic stage IIB/IIC. RPLND, retroperitoneal lymph node dissection.
initially and developed elevated alpha-fetal protein and a solitary left-sided retroperitoneal recurrence 10 years after his surgery. He was given cisplatinum-based chemotherapy followed by a recent postchemotherapy RPLND on the left side. Final pathology demonstrated mixed NSGCT with yolk-sac tumor and teratoma. Of the 4 patients who underwent bilateral template RPLND, 1 patient had CS IIA disease whereas the remaining 3 had CS IIB disease. The patient with CS IIA disease had RPLND in 1979, which is prior to when modified template had become the standard of practice for low-volume CS II disease at our institution. Bilateral template RPLND was recommended in the remaining 3 patients because all had disease burden in both landing UROLOGY
-
(-), 2015
zones (left and right) on preoperative imaging. None of these patients developed a recurrence during the followup period.
COMMENT The rationale for primary RPLND in patients with CS I/II NSGCT is because of its diagnostic and therapeutic potential for a significant proportion of patients found to have PS II disease. For patients with PS IIA disease, 70% are cured with surgery alone and the 30% who relapse remain curable with 3 courses of chemotherapy.9,11,12 Although adjuvant chemotherapy provides an excellent oncologic outcome, it unnecessarily exposes 70% of patients who were never destined to relapse to 2 cycles of cisplatin-based chemotherapy, therefore negating the therapeutic benefit of primary RPLND. The remaining 30% of patients are still salvaged with only 1 additional cycle of chemotherapy (total of 3 cycles) with no difference in the overall survival.9 These findings suggest a more expectant approach for the management of lowvolume PS II disease. Using more selective criteria for surveillance, several investigators have indeed achieved a relapse rate as low as 10% in patients with PS IIA disease.13,14 Ideally, the decision to administer adjuvant chemotherapy in PS II NSGCT should be restricted to patients identified as high risk for systemic failure. Unfortunately, such a risk stratification scheme has not been identified, and commonly felt risk factors such as extranodal extension, positive lymph nodes, and lymph node density have not been shown to predict disease recurrence.15,16 Currently, the guidelines from both the National Comprehensive Cancer Network and European Association of Urology rely on pathologic staging as the primary determining factor to guide further therapy after primary RPLND.17,18 We do not rely upon these guidelines. In addition to pathologic staging, we believe retroperitoneal histology plays an important role in predicting systemic failure after primary RPLND. Our institution previously reported the significance of histologic subtype on the risk of relapse following a primary RPLND. Although the retroperitoneal histology was not predictive of relapse, none of the 8 patients with pure teratoma recurred.19 In a series of 25 patients with teratomatous elements at primary RPLND, the investigators at Memorial Sloan Kettering reported no disease recurrence at a median follow-up of 27 months.2 However, 16 of the 25 patients (64%) received adjuvant chemotherapy, which may have included 8 patients with teratoma only in the retroperitoneum. The rationale for adjuvant chemotherapy was based on pathologic staging, not histologic subtype. In the current series, patients with teratoma only at RPLND without adjuvant chemotherapy had a 100% DFS at a median follow-up of 5.5 years. PS, including those with IIB/IIC disease, did not predict for recurrence in this population. Therefore, adjuvant chemotherapy would seem to provide little benefit in this cohort. In this UROLOGY
-
(-), 2015
series, we chose to offer primary RPLND to 2 patients with larger volume retroperitoneal disease who had pathologic IIC disease. Both of these patients had 100% pure teratoma in the orchiectomy specimen with normal serum tumor markers and were felt to harbor pure teratoma in the retroperitoneum. Because of the chemoresistance of teratoma, these patients underwent primary RPLND as opposed to standard chemotherapy. Late relapse is an uncommon event that poses a significant risk for testis cancer patients.20,21 The most common sites of late relapse after RPLND are lungs and the retroperitoneum.22 The present study identified 2 late relapses at an interval of 10 years after their primary RPLND, highlighting the importance of surveillance in these patients. However, there is no consensus regarding the frequency of follow-up or the need for surveillance imaging or laboratory evaluation in patients treated with RPLND after 5 years. There were several limitations to this study. It was retrospective in nature and included a relatively small number of patients from a single institution, which may limit its external validity. Furthermore, there were a small number of events, which limits the ability to draw significant conclusions. A larger, multi-institutional series may be informative in evaluating the oncologic outcomes of patients with not only teratoma but also other retroperitoneal histologic subtypes at primary RPLND.
CONCLUSION The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Therefore, adjuvant therapy is unlikely to provide a significant benefit. For those that do recur, surgical management remains feasible and curative. In addition to pathologic staging, retroperitoneal histology at primary RPLND, specifically teratoma, should be taken into consideration to guide adjuvant therapy. References 1. Carver BS, Al-Ahmadie H, Sheinfeld J. Adult and pediatric testicular teratoma. Urol Clin North Am. 2007;34:245-251; abstract x. 2. Sheinfeld J, Motzer RJ, Rabbani F, et al. Incidence and clinical outcome of patients with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection for clinical stages I and IIA nonseminomatous germ cell tumors. J Urol. 2003;170:11591162. 3. Leibovitch I, Foster RS, Ulbright TM, Donohue JP. Adult primary pure teratoma of the testis. The Indiana experience. Cancer. 1995; 75:2244-2250. 4. Simmonds PD, Lee AH, Theaker JM, et al. Primary pure teratoma of the testis. J Urol. 1996;155:939-942. 5. Kondagunta GV, Sheinfeld J, Mazumdar M, et al. Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol. 2004;22:464-467. 6. Brydoy M, Oldenburg J, Klepp O, et al. Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors. J Natl Cancer Inst. 2009; 101:1682-1695.
3
7. Sagstuen H, Aass N, Fossa SD, et al. Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol. 2005; 23:4980-4990. 8. Foster R, Bihrle R. Current status of retroperitoneal lymph node dissection and testicular cancer: when to operate. Cancer Control. 2002;9:277-283. 9. Williams SD, Stablein DM, Einhorn LH, et al. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med. 1987;317:14331438. 10. Donohue JP. Evolution of retroperitoneal lymphadenectomy (RPLND) in the management of non-seminomatous testicular cancer (NSGCT). Urol Oncol. 2003;21:129-132. 11. Pizzocaro G, Monfardini S. No adjuvant chemotherapy in selected patients with pathologic stage II nonseminomatous germ cell tumors of the testis. J Urol. 1984;131:677-680. 12. Hermans BP, Sweeney CJ, Foster RS, et al. Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol. 2000; 163:1721-1724. 13. Pohar KS, Rabbani F, Bosl GJ, et al. Results of retroperitoneal lymph node dissection for clinical stage I and II pure embryonal carcinoma of the testis. J Urol. 2003;170:1155-1158. 14. 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; 23:2781-2788.
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