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Lymph Node Yield in Primary Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumors Madhur Nayan, Michael A. S. Jewett, Joan Sweet, Lynn Anson-Cartwright, Philippe L. Bedard, Malcolm Moore, Peter Chung, Padraig Warde and Robert J. Hamilton*,† EQ1
From the Division of Urology, Department of Surgery (MN, MASJ, LAC, RJH) and Department of Medicine (PLB, MM), University of Toronto and Departments of Pathology (JS) and Radiation Oncology (PC, PW), Princess Margaret Hospital and Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre (PLB, MM), University Health Network, Toronto, Ontario, Canada
Purpose: The number of lymph nodes removed at surgery for various malignancies has diagnostic and prognostic value. However, there are limited data on the significance of the number of nodes removed at retroperitoneal lymph node dissection performed for testicular nonseminoma germ cell tumors. Materials and Methods: From 1979 to 2012 primary open retroperitoneal lymph node dissection was performed by a single experienced surgeon for clinical stage I/II testicular nonseminoma germ cell tumor in 157 patients. Node count was available in 111 cases (71%). Factors associated with total node count and nodes with viable cancer were assessed by linear regression. The association between node count and time to relapse was assessed by multivariate Cox proportional hazards models controlled for adjuvant chemotherapy. Results: The median total lymph node count was 28 (IQR 19e38). Patient age, cancer laterality, body mass index, clinical stage, time from orchiectomy to retroperitoneal lymph node dissection, pathologist and lymph node dissection year were not associated with total lymph node count. A viable germ cell tumor was found in 70 patients (63%). Total node yield was not associated with nodal cancer metastasis. After lymph node dissection 17 patients (16%) received adjuvant chemotherapy. At a median 57-month followup 18 cases (17%) relapsed after primary retroperitoneal lymph node dissection. Increasing total node count was associated with a decreased risk of relapse on univariate and multivariate analysis (HR 0.96, 95% CI 0.92e0.99, p ¼ 0.03 and HR 0.94, 95% CI 0.89e0.99, p ¼ 0.017, respectively). Conclusions: No analyzed clinical or pathological variable was associated with the node yield of primary retroperitoneal lymph node dissection. However, there may be a relationship between the total node yield at retroperitoneal lymph node dissection and the risk of relapse.
Abbreviations and Acronyms BMI ¼ body mass index CS ¼ clinical stage EC ¼ embryonal carcinoma MSKCC ¼ Memorial SloanKettering Cancer Center NSGCT ¼ testicular nonseminoma germ cell tumor RFS ¼ relapse-free survival RPLND ¼ retroperitoneal lymph node dissection Accepted for publication March 12, 2015. Study received research ethics board approval. * Correspondence: Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, 610 University Ave., 3-130, Toronto, Ontario, Canada, M5G 2M9 (telephone: 416-946-2909; FAX: 416-946-6590; e-mail: [email protected]). † Financial interest and/or other relationship with Janssen and Bayer.
Key Words: testis, nonseminomatous germ cell tumor, lymph node excision, risk, recurrence
TESTICULAR cancer is the most common cancer diagnosed in 20 to 39-year-old North American men with an increasing incidence worldwide.1e3 While most cases present with
localized disease, the retroperitoneum is the initial site of metastatic spread in 70% to 80%. The standard treatment recommendation for CS I NSGCT with normal markers at
0022-5347/15/1942-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2015.03.100 Vol. 194, 1-6, August 2015 Printed in U.S.A.
www.jurology.com
FLA 5.2.0 DTD JURO12483_proof 5 May 2015 2:27 pm EO: JU-14-2358
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
LYMPH NODE YIELD IN GERM CELL TUMORS
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
Princess Margaret Cancer Centre is active surveillance. Primary RPLND is recommended in patients who present with CS IIa/b disease and normal or minimally increased but stable markers and in those on active surveillance with progression in the retroperitoneum alone.4 Several studies have demonstrated the prognostic and staging value of the total number of lymph nodes resected for various malignancies, such as colon, breast, prostate and bladder cancer.5e11 Only a few groups have examined these associations in the setting of RPLND for germ cell tumors.12e16 To our knowledge no group to date has evaluated the association between node yield and relapse after primary RPLND. We hypothesized that increasing the total node yield would be associated with a decreased relapse risk.
MATERIALS AND METHODS A total of 157 patients underwent primary RPLND for CS I or II NSGCT as performed by a single surgeon between 1979 and 2012. With research ethics board approval we obtained clinical and pathological data from our prospectively maintained surgical database. The total number of lymph nodes removed was available in pathology reports for 111 patients (71%). In all patients bilateral complete dissection was performed. The upper limits of dissection included the skeletonized renal vessels and crus of the diaphragm. The lower limits included the external iliac vessels on the ipsilateral side and the bifurcation of the great vessels on the contralateral side. A nerve sparing approach was used from 1984 and thereafter. Packets consisting of the paracaval, interaortocaval, para-aortic and ipsilateral iliac lymph nodes were submitted routinely for pathological examination. On occasion interiliac or contralateral iliac lymph nodes were removed and submitted separately. The decision to administer adjuvant chemotherapy after RPLND was made by the treating physician. Generally it was administered in patients with extranodal extension, extensive positive lymph node involvement, intraoperative concerns (eg tumor rupture) or increased tumor markers before RPLND which remained increased after RPLND. Lymph node packets were received for pathological evaluation from the operating room in a fresh state labeled by anatomical zone. Adipose tissue was dissected free by visual inspection, palpation and blunt dissection with scissors. All firm, rubbery areas suspicious for a lymph node were then separated and submitted for microscopic examination. If no lymph nodes were palpated, the tissue packet was submitted for microscopic examination in its entirety, consistent with others.13 After primary RPLND patients were followed bimonthly during the first 2 years, every fourth month in year 3 and every 6 months in years 4 and 5 according to a standardized surveillance schedule. History, focused physical examination and tumor marker determination were completed at each visit. Thoracic computerized Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 RESULTS 217 218 Patient Characteristics Table 1 lists patient characteristics at RPLND. ½T1 219 220 Mean SD age was 30.3 7.7 years and mean time 221 from orchiectomy to RPLND was 157 304 days. 222 RPLND was performed in 16 patients (14%) with 223 stage 1 disease while 95 (86%) had stage 2 disease. 224 Reasons for RPLND in patients with stage I were 225 patient preference, distance from a tertiary care 226 center or uncertain compliance with the surveil227 lance schedule. The mean total node count was 30 228 (median 28, range 5 to 77). Of the patients 41 (37%)
tomography was performed every 4 months in year 1 and then at years 2 and 5. Baseline abdominopelvic computerized tomography was done 4 months after RPLND and thereafter only if there was a specific clinical indication. Followup, time to recurrence and RFS were measured from the date of RPLND. Disease relapse was defined as imaging or physical examination evidence of new metastasis and/or increased serum tumor markers. Observation intervals were censored at the date of last followup. Overall survival was measured from the date of RPLND to the date of death from any cause. Factors associated with the total node count and the number of nodes with viable tumor were assessed using linear regression models including age, BMI, orchiectomy side, RPLND year, time from orchiectomy to RPLND, CS (I vs II), preRPLND tumor markers (S0 vs S1) and pathologist. Pathologist was grouped into 4 categories. There was 1 category for each of the 3 expert genitourinary high volume pathologists (61% of samples), defined as having assessed 15 or more primary RPLND specimens. The remaining category was for nonhigh volume pathologists. Logistic regression was used to analyze factors associated with viable tumor at RPLND, adjusting for the factors listed. The association between total node count and time to relapse was assessed in Cox proportional hazards models controlling for the factors listed as well as for adjuvant chemotherapy. Given the low number of relapse events after primary RPLND, a priori we decided to examine the relationship between total node count and time to relapse using a simplified multivariate model. Positive nodes were modeled categorically (yes/no) rather than as a continuous variable since a previous study demonstrated that the number of positive nodes was not associated with recurrence in primary RPLND cases.17 Furthermore, based on studies from MSKCC we included BMI and surgery year because they were shown to be associated with an increased lymph node count.13e15 We also included node status (positive vs negative) and receipt of adjuvant chemotherapy since other studies showed that these factors are associated with relapse.18,19 The total node count was almost normally distributed and transformations (eg logarithmic) did not alter associations. Therefore, it was modeled as a continuous variable throughout analysis. All statistical analysis was performed using StataÒ, version 12 with p
Lymph Node Yield in Primary Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumors Madhur Nayan, Michael A. S. Jewett, Joan Sweet, Lynn Anson-Cartwright, Philippe L. Bedard, Malcolm Moore, Peter Chung, Padraig Warde and Robert J. Hamilton*,† EQ1
From the Division of Urology, Department of Surgery (MN, MASJ, LAC, RJH) and Department of Medicine (PLB, MM), University of Toronto and Departments of Pathology (JS) and Radiation Oncology (PC, PW), Princess Margaret Hospital and Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre (PLB, MM), University Health Network, Toronto, Ontario, Canada
Purpose: The number of lymph nodes removed at surgery for various malignancies has diagnostic and prognostic value. However, there are limited data on the significance of the number of nodes removed at retroperitoneal lymph node dissection performed for testicular nonseminoma germ cell tumors. Materials and Methods: From 1979 to 2012 primary open retroperitoneal lymph node dissection was performed by a single experienced surgeon for clinical stage I/II testicular nonseminoma germ cell tumor in 157 patients. Node count was available in 111 cases (71%). Factors associated with total node count and nodes with viable cancer were assessed by linear regression. The association between node count and time to relapse was assessed by multivariate Cox proportional hazards models controlled for adjuvant chemotherapy. Results: The median total lymph node count was 28 (IQR 19e38). Patient age, cancer laterality, body mass index, clinical stage, time from orchiectomy to retroperitoneal lymph node dissection, pathologist and lymph node dissection year were not associated with total lymph node count. A viable germ cell tumor was found in 70 patients (63%). Total node yield was not associated with nodal cancer metastasis. After lymph node dissection 17 patients (16%) received adjuvant chemotherapy. At a median 57-month followup 18 cases (17%) relapsed after primary retroperitoneal lymph node dissection. Increasing total node count was associated with a decreased risk of relapse on univariate and multivariate analysis (HR 0.96, 95% CI 0.92e0.99, p ¼ 0.03 and HR 0.94, 95% CI 0.89e0.99, p ¼ 0.017, respectively). Conclusions: No analyzed clinical or pathological variable was associated with the node yield of primary retroperitoneal lymph node dissection. However, there may be a relationship between the total node yield at retroperitoneal lymph node dissection and the risk of relapse.
Abbreviations and Acronyms BMI ¼ body mass index CS ¼ clinical stage EC ¼ embryonal carcinoma MSKCC ¼ Memorial SloanKettering Cancer Center NSGCT ¼ testicular nonseminoma germ cell tumor RFS ¼ relapse-free survival RPLND ¼ retroperitoneal lymph node dissection Accepted for publication March 12, 2015. Study received research ethics board approval. * Correspondence: Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, 610 University Ave., 3-130, Toronto, Ontario, Canada, M5G 2M9 (telephone: 416-946-2909; FAX: 416-946-6590; e-mail: [email protected]). † Financial interest and/or other relationship with Janssen and Bayer.
Key Words: testis, nonseminomatous germ cell tumor, lymph node excision, risk, recurrence
TESTICULAR cancer is the most common cancer diagnosed in 20 to 39-year-old North American men with an increasing incidence worldwide.1e3 While most cases present with
localized disease, the retroperitoneum is the initial site of metastatic spread in 70% to 80%. The standard treatment recommendation for CS I NSGCT with normal markers at
0022-5347/15/1942-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2015.03.100 Vol. 194, 1-6, August 2015 Printed in U.S.A.
www.jurology.com
FLA 5.2.0 DTD JURO12483_proof 5 May 2015 2:27 pm EO: JU-14-2358
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
LYMPH NODE YIELD IN GERM CELL TUMORS
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
Princess Margaret Cancer Centre is active surveillance. Primary RPLND is recommended in patients who present with CS IIa/b disease and normal or minimally increased but stable markers and in those on active surveillance with progression in the retroperitoneum alone.4 Several studies have demonstrated the prognostic and staging value of the total number of lymph nodes resected for various malignancies, such as colon, breast, prostate and bladder cancer.5e11 Only a few groups have examined these associations in the setting of RPLND for germ cell tumors.12e16 To our knowledge no group to date has evaluated the association between node yield and relapse after primary RPLND. We hypothesized that increasing the total node yield would be associated with a decreased relapse risk.
MATERIALS AND METHODS A total of 157 patients underwent primary RPLND for CS I or II NSGCT as performed by a single surgeon between 1979 and 2012. With research ethics board approval we obtained clinical and pathological data from our prospectively maintained surgical database. The total number of lymph nodes removed was available in pathology reports for 111 patients (71%). In all patients bilateral complete dissection was performed. The upper limits of dissection included the skeletonized renal vessels and crus of the diaphragm. The lower limits included the external iliac vessels on the ipsilateral side and the bifurcation of the great vessels on the contralateral side. A nerve sparing approach was used from 1984 and thereafter. Packets consisting of the paracaval, interaortocaval, para-aortic and ipsilateral iliac lymph nodes were submitted routinely for pathological examination. On occasion interiliac or contralateral iliac lymph nodes were removed and submitted separately. The decision to administer adjuvant chemotherapy after RPLND was made by the treating physician. Generally it was administered in patients with extranodal extension, extensive positive lymph node involvement, intraoperative concerns (eg tumor rupture) or increased tumor markers before RPLND which remained increased after RPLND. Lymph node packets were received for pathological evaluation from the operating room in a fresh state labeled by anatomical zone. Adipose tissue was dissected free by visual inspection, palpation and blunt dissection with scissors. All firm, rubbery areas suspicious for a lymph node were then separated and submitted for microscopic examination. If no lymph nodes were palpated, the tissue packet was submitted for microscopic examination in its entirety, consistent with others.13 After primary RPLND patients were followed bimonthly during the first 2 years, every fourth month in year 3 and every 6 months in years 4 and 5 according to a standardized surveillance schedule. History, focused physical examination and tumor marker determination were completed at each visit. Thoracic computerized Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 RESULTS 217 218 Patient Characteristics Table 1 lists patient characteristics at RPLND. ½T1 219 220 Mean SD age was 30.3 7.7 years and mean time 221 from orchiectomy to RPLND was 157 304 days. 222 RPLND was performed in 16 patients (14%) with 223 stage 1 disease while 95 (86%) had stage 2 disease. 224 Reasons for RPLND in patients with stage I were 225 patient preference, distance from a tertiary care 226 center or uncertain compliance with the surveil227 lance schedule. The mean total node count was 30 228 (median 28, range 5 to 77). Of the patients 41 (37%)
tomography was performed every 4 months in year 1 and then at years 2 and 5. Baseline abdominopelvic computerized tomography was done 4 months after RPLND and thereafter only if there was a specific clinical indication. Followup, time to recurrence and RFS were measured from the date of RPLND. Disease relapse was defined as imaging or physical examination evidence of new metastasis and/or increased serum tumor markers. Observation intervals were censored at the date of last followup. Overall survival was measured from the date of RPLND to the date of death from any cause. Factors associated with the total node count and the number of nodes with viable tumor were assessed using linear regression models including age, BMI, orchiectomy side, RPLND year, time from orchiectomy to RPLND, CS (I vs II), preRPLND tumor markers (S0 vs S1) and pathologist. Pathologist was grouped into 4 categories. There was 1 category for each of the 3 expert genitourinary high volume pathologists (61% of samples), defined as having assessed 15 or more primary RPLND specimens. The remaining category was for nonhigh volume pathologists. Logistic regression was used to analyze factors associated with viable tumor at RPLND, adjusting for the factors listed. The association between total node count and time to relapse was assessed in Cox proportional hazards models controlling for the factors listed as well as for adjuvant chemotherapy. Given the low number of relapse events after primary RPLND, a priori we decided to examine the relationship between total node count and time to relapse using a simplified multivariate model. Positive nodes were modeled categorically (yes/no) rather than as a continuous variable since a previous study demonstrated that the number of positive nodes was not associated with recurrence in primary RPLND cases.17 Furthermore, based on studies from MSKCC we included BMI and surgery year because they were shown to be associated with an increased lymph node count.13e15 We also included node status (positive vs negative) and receipt of adjuvant chemotherapy since other studies showed that these factors are associated with relapse.18,19 The total node count was almost normally distributed and transformations (eg logarithmic) did not alter associations. Therefore, it was modeled as a continuous variable throughout analysis. All statistical analysis was performed using StataÒ, version 12 with p
