YGYNO-975523; No. of pages: 6; 4C: Gynecologic Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
3Q1
Abdulrahman K. Sinno, Amanda Nickles Fader, Kara Long Roche, Robert L. Giuntoli II, Edward J. Tanner ⁎ The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, USA
6
H I G H L I G H T S
P
• Seventy one consecutive endometrial cancer sentinel lymph node (SLN) mapping cases utilizing isosulfan blue (ISB) or indocyanine green (ICG) are presented. • Bilateral mapping was higher in the ICG group and BMI a significant predictor for successful mapping in the ISB group. • Utilizing our institutional SLN protocol resulted in a 100% negative predictive value and 100% sensitivity for detecting metastatic lymph nodes.
a r t i c l e
i n f o
19 20 21 22 23 24 25
Keywords: Sentinel lymph node Endometrial cancer Fluorescence imaging Obesity Robotic hysterectomy Indocyanine green
a b s t r a c t
Objective. The study objective was to compare the ability to detect sentinel lymph nodes (SLNs) in women with endometrial cancer (EC) or complex atypical hyperplasia (CAH) using fluorometric imaging with indocyanine green (ICG) versus colorimetric imaging with isosulfan blue (ISB). Methods. Women underwent SLN mapping, with either ISB or ICG, during robotic-assisted total laparoscopic hysterectomy (RA-TLH) from September 2012 to March 2014. SLNs were submitted for permanent pathologic analysis. Completion lymphadenectomy and ultrastaging were performed according to institutional protocols. Results. RA-TLH and SLN mapping was performed in 71 women; 64 had EC (64) and 7 had CAH. Age, body mass index (BMI), stage and tumor characteristics were similar in the ICG versus the ISB cohorts. Overall, SLNs were identified bilaterally (62.0%), unilaterally (21.1%), or neither (16.9%), and in 103 of 142 hemi-pelvises (72.5%). The mean number of SLNs retrieved per hemipelvis was 2.23(SD 1.7). SLNs were identified in the hypogastric (76.8%), external iliac (14.2%), common iliac (4.5%) and paraaortic (4.5%) regions. ICG mapped bilaterally in 78.9% of women compared with 42.4% of those injected with ISB (p = 0.02). Five women (7%) had positive lymph nodes, all identified by the SLN protocol (false negative rate: 0%). On multivariate analysis, BMI was negatively correlated with bilateral mapping success (p = 0.02). When stratified by dye type, the association with BMI was only significant for ISB (p = 0.03). Conclusions. Fluorescence imaging with ICG may be superior to colorimetric imaging with ISB in women undergoing SLN mapping for endometrial cancer. SLN mapping success is negatively associated with increasing patient BMI only when ISB is used. © 2014 Published by Elsevier Inc.
C
T
E
Article history: Received 26 April 2014 Accepted 22 May 2014 Available online xxxx
D
1 4 1 3 15 16 17 18
44 48 46 45 47
N C O
R
R
E
7 8 9 10 11 12
R O
4Q3 5
O
F
2
A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer☆
1
Introduction
50 51
Endometrial cancer is the most common gynecologic cancer in the United States (U.S.) with 49,560 cases expected in 2014 [1,2]. The standard treatment for women diagnosed with this malignancy is a total hysterectomy, bilateral salpingo-oophorectomy and lymph node assessment. Despite being a powerful predictor of recurrence and prognosis [3,4], the role and extent of the lymph node assessment remains
52 53 54 55
U
49
☆ These findings were presented at the Society of Gynecologic Oncology's 45th Annual Meeting on Women's Cancer in Tampa, Florida, March 22–25, 2014. ⁎ Corresponding author at: 600 N Wolfe St, Phipps 281 Baltimore, MD 21287, USA. Fax: +1 410 614 8718. E-mail address: [email protected] (E.J. Tanner).
variable across institutions [5]. The spectrum of lymph node assessment spans from omitting a lymphadenectomy altogether, to perform a complete pelvic and para-aortic lymphadenectomy for all histologies and tumor grades. Some centers utilize intraoperative assessment criteria, based upon histologic and tumor characteristics, to triage patients for lymph node assessment [6–10]. Variability in lymph node assessment strategies reflects unresolved issues regarding the 1) therapeutic benefit (or lack thereof) of lymphadenectomy in women with endometrial cancer [11,12], 2) increased scrutiny regarding the potential morbidity of the procedure, and 3) shifting treatment paradigms for women at high risk for metastatic disease [13]. Given that greater than 75% of women with endometrial cancer will have an early-stage, low grade disease, with an inherently low risk of lymph node metastases [14], most will not benefit from
http://dx.doi.org/10.1016/j.ygyno.2014.05.022 0090-8258/© 2014 Published by Elsevier Inc.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
26 Q4 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
56 57 58 59 60 61 62 63 64 65 66 67 68 69
93 94 95 96 97 98 99 100 101 102
F
O
R O
91 92
P
89 90
Sentinel lymph node mapping algorithm (Fig. 2) Upon induction of anesthesia, the cervix is injected with either ISB or ICG at the time of EUA (ISB) or at the time of uterine manipulator placement (ICG). One 50 mg vial of ISB is reconstituted according to package instructions in 5 mL of normal saline (10 mg/mL). One 25 mg vial of ICG is reconstituted in 10 mL of aqueous solvent and further diluted in 10 mL of normal saline (1.25 mg/mL). The solution is injected at the 3 and 9 o'clock positions of the cervical stroma. One mL is injected superficially (submucosa) and 1 mL is injected deep (~8 mm) in the cervical
D
87 88
111
T
85 86
The Kelly Gynecologic Oncology Service at Johns Hopkins Hospital, Baltimore MD adopted a sentinel lymph node mapping program in September 2012. Four gynecologic oncology surgeons with expertise in sentinel lymph node techniques have participated in this program and contributed patients to this prospectively collected database. The study, which was approved by the institutional review board at Johns Hopkins Hospital, occurred during the period of September 2012 to March 2014. All patients with complex atypical hyperplasia or endometrial cancer undergoing a planned robotic-assisted total laparoscopic hysterectomy with SLN mapping during this time were evaluated. Patients with complex atypical hyperplasia were included due to their risk of concurrent endometrial carcinoma, which has been found to up to 42% in some studies [23].
C
83 84
110
E
81 82
Materials and methods
R
79 80
R
77 78
O
76
103 104
C
74 75
range (NIR). It has the potential advantage of being readily visible through visceral fat. Therefore, our study objective was to compare the sentinel lymph node detection rate of indocyanine green (ICG) versus isosulfan blue (ISB) in women with EC and CAH in a new sentinel lymph program. A secondary objective was to assess whether the ICG dye performed better than ISB in women with increasing body mass index.
N
72 73
lymphadenectomy. Sentinel lymph node (SLN) biopsy, a technique that has revolutionized the approach to lymph node assessment in many other cancer types [15,16], has been proposed for endometrial cancer surgery to minimize both the rate of unnecessary lymphadenectomy in low risk women, as well as the risk of under-staging and hence under-treatment [17]. Since first described by Burke et al. 15 years ago, SLN biopsy techniques for women with endometrial cancer have evolved [18]. Single institution data from the group at Memorial Sloan Kettering Cancer Center suggests that cervical injection with blue or green dye at the time of hysterectomy and staging results in reliable mapping of relevant lymph nodes that drain the uterus [19]. Select U.S. centers have recently adopted this technique, but there is a lack of prospective, multicenter data to validate it. Much remains to be learned about the optimal choice of dye, technique, and overall sensitivity of SLN detection of metastases in women with endometrial cancer. Given the potential advantages of SLN mapping, including reduction of lymphedema and intraoperative complications [5] and improved detection of positive lymph nodes with ultrastaging techniques [20], it is critical that this approach be rigorously studied and optimized to ensure patient safety without oncologic compromise. In addition to a variety of locations proposed for injection, the optimal dye to perform SLN mapping is unclear. Two dyes are currently available. Isosulfan blue (Lymphazurin, Covidien LP, Mansfield MA) has been used in sentinel lymph node mapping for many different cancers. It relies on the surgeon's ability to visualize blue lymph nodes and lymphatic channels and differentiate them from the surrounding tissues (Fig. 1a). This colorimetric technique maybe challenging in cases where visceral fat can impair the surgeons ability to adequately visualize blue lymph nodes and poses a technical challenge in endometrial cancer, given its association with obesity. Indocyanine green (IC-Green, Novadaq Technologies Inc. Mississauga, ON Canada) has been proposed as an alternative to ISB [21,22] (Fig. 1b). This fluorescent dye relies on a fluorometrically capable camera and appears green when excited by light in the near infrared
U
70 71
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
E
2
Fig. 1. (Left) Sentinel lymph node with ISB. (Right) Sentinel lymph node with ICG.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
105 106 107 108 109
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
3
166
All data was collected from a prospectively maintained institutional database. From this database, clinical and pathologic data was abstracted and tabulated. The rate of successful SLN mapping was evaluated for patients undergoing ICG versus ISB guided mapping. Patients were evaluated based on both the rate of successful bilateral SLN mapping as well as the “side-specific” SLN mapping success. In other words, for the sidespecific mapping rate, each patient was counted as having two possible successful mapping locations (right and left). Point estimates of continuous data were compared using two-tailed Student T tests. Categorical results were compared using the Fischer's exact test. Simple logistic regression was performed for continuous variables with binary outcomes and multivariate logistic regression was subsequently employed to test if significant relationships were maintained. SPSS Version 22.0 (IBM Corp, Armonk, NY) was used for statistical calculations with significance set at 0.05 and power at 80%.
167 168
R O
O
F
Data and statistics
Results
141 142
Seventy one patients underwent robotic-assisted total laparoscopic hysterectomy with SLN mapping for endometrial cancer or complex atypical hyperplasia during the study period (Table 1). Median age (62.7 years, range: 37–84) and median BMI (32.5 kg/m2, range: 19– 53) were typical for an endometrial cancer cohort. The most common histologies included grade 1 endometrioid (56.3%), serous carcinoma (15.5%) and complex atypical hyperplasia (9.9%). The final FIGO stages were: IA (40, 56.3%), IB (13, 18.3%), II (3, 4.2%), IIIA (4, 5.6%) IIIC1 (3, 4.2%), and IVB (1, 1.4%). Successful bilateral SLN mapping occurred in 44 cases (62.0%), while 15 cases (21.1%) mapped unilaterally, and 12 cases (16.9%) did not have any SLNs identified. When each hemipelvis was considered separately, 103 of 142 possible hemipelvises (72.5%) were successfully mapped. The mean number of sentinel lymph nodes identified per hemipelvis was 2.2 (SD: 1.7).
143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
C
E
172 173 174 175 176 177 178 179 180 181
D
E
183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 t1:1
Table 1 Clinical and demographic criteria n = 71.
Q2t1:2 Median
Age (years) BMI (units)
171
182
P
139 140
R
138
R
136 137
stroma for a total injection volume of 4 mL. Selection of ISB or ICG was dependent on equipment availability. Currently, our service utilizes 4 robots, only one of which is fluorometrically capable. All patients underwent an attempted sentinel lymph node biopsy. Those with a preoperative endometrial biopsy consistent with high grade disease (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) subsequently underwent full pelvic and para-aortic lymphadenectomy. Patients with complex atypical hyperplasia or grade 1 or 2 endometrioid histology underwent SLN dissection followed by hysterectomy. The hysterectomy specimen was sent for frozen section assessment, which further tailored intraoperative management. Complete pelvic and para-aortic lymphadenectomy was performed according to Gynecologic Oncology Group guidelines (with aortic lymphadenectomy performed to a level above the inferior mesenteric artery) [24] if any of the following features were present: tumor size N 2 cm, myometrial invasion N 50%, or grade 3. If none of these pathologic findings were present and no clinically suspicious lymph nodes were identified, a completion lymphadenectomy was not performed after SLN biopsy. In our algorithm, when a patient fails to map in one hemipelvis, the ipsilateral lymphadenectomy results are used instead. This is of paramount importance so that patients who fail to map and have high risk features are not undertreated. This approach has been validated, shown to significantly increase SLN detection rates, and minimize false negatives [25]. The technique of ultrastaging has been previously described [14]. Due to costs associated with ultrastaging and the low risk of micrometastasis/isolated tumor cells identified in women with grade 1–2 tumors with b 50% myometrial invasion, ultrastaging was only performed post operatively in patients with high grade endometrioid, greater than 50% myometrial invasion, or tumors N 2 cm. Our center has chosen to omit ultrastaging for Type 2 tumors at this time, as the technique is costly, and does not change management in patients who will receive adjuvant chemotherapy regardless of lymph node status. We may reassess this decision in the future.
N C O
134 135
U
133
T
Fig. 2. Endometrial Cancer Sentinel Lymph Node Protocol. *Ultrastaging is omitted for patients with less than 50% invasion and for patient with type II tumors. CAH: complex atypical hyperplasia, LN: lymph nodes, and MI: myometrial invasion TD: tumor diameter.
169 170
64 31.1 Number
Range 37–84 19–53 Percent
Histology Complex atypical hyperplasia Grade I endometrioid Grade II endometrioid Grade III endometrioid Serous Carcinosarcoma Other
7 40 5 4 11 3 1
9.9 56.3% 7.0% 5.6% 15.5% 4.2% 1.4
Stage Stage IA Stage IB Stage II Stage IIIA Stage IIIC1 Stage IVb
40 13 3 4 3 1
56.3 18.3 4.2 5.6 4.2 1.4
t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25
Mapping
Number
Percent
Bilateral Unilateral None Per hemipelvis
44/71 15/71 12/71 103/142
62.0% 21.1% 16.9% 72.5%
Mean (SD)
Range
t1:26 t1:27 t1:28 t1:29 t1:30 t1:31
2.23 (1.67)
0–9
t1:32
Number of sentinel lymph nodes
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241
Isosulfan blue
38 64.5 (39–82) 31.1 (19.0–53.0)
33 62.0, (37–84) 31.4, (20.1–50.3)
29, 76.3% 9, 23.7%
23, 69.7% 10, 30.3%
15 11 2 4
25 2 1 4
30/38, 78.9% 4, 13.8% 3/38, 7.9% 65/76, 85.5% 2.4
14/33, 42.4% 8, 34.8% 9/33 27.3% 38/66, 57.5% 2.0
P value 0.74 0.82 0.92
O
F
0.31
0.02
0.0001 0.38
a Low grade includes CAH grade I and II, high grade includes grade 3, carcinosarcoma, serous and clear cell.
Discussion
R O
219 220
Indocyanine green
P
217 218
Number of cases Age (years) median, (range) BMI (Kg/m2) median, (range) Histologya (n,%) Low grade High grade Stage (n,%) Stage 1a Stage 1b Stage 2 Stage 3–4 Mapping (%) Bilateral Unilateral None Per hemipelvis Number of SLN per hemipelvis
In 2014, the National Comprehensive Cancer Network (NCCN) Endometrial Cancer Guidelines were updated to reflect the emerging data regarding the role of sentinel lymph node biopsy in endometrial cancer. Specifically, the guidelines now state that sentinel lymph node biopsy may be considered for the surgical staging of apparent uterineconfined malignancy when there is no metastasis demonstrated by imaging studies, or no obvious extra-uterine disease at exploration (Level IIB). The guidelines also noted that cervical injection is a “useful and validated technique”. These guidelines were based largely on retrospective, single institution U.S. data and retrospective and limited prospective European data. Further studies are necessary to validate and substantiate the NCCN recommendations. Our study adds to the growing body of literature demonstrating the feasibility of the cervical injection technique with various dyes, and the reliability of the sentinel lymph node approach in endometrial cancer. Multiple injection sites have been described in the literature. These include cervical, myometrial or hysteroscopic tumoral injection sites, or any combination of these methods. One criticism of cervical injection for endometrial cancer SLN detection is the theoretical difference between the lymphatic drainage of the cervix and uterine fundus, where the majority of endometrial cancers originate [4]. However, in anatomic studies, deep injection into the cervix has demonstrated excellent penetration to uterine vessels, parametria, lower uterine segment, and cornual regions [26,27]. Furthermore, in a meta-analysis by Kang et al., cervical injection was the only anatomic site that significantly improved sentinel lymph node detection, and any modality that omitted cervical injection resulted in decreased mapping success [28]. Our study further supports this observation that cervical injection of dye is a reliable method of identifying the lymphatic drainage of the uterus. In our study, BMI was associated adversely with mapping success rate in both univariate and multivariate analysis (p = 0.043 and 0.022 respectively). When mapping success rate was analyzed separately for ISB and ICG, this association was only significant for ISB (p = 0.03) and not for ICG (p = 0.14). It was our experience that the sentinel lymph nodes (and associated lymphatic channels) were more readily identified in thin and in obese patients when the ICG dye was used compared with the ISB dye. The reasons for this observation are multifactorial, but may include the differences in molecular weight of the ISB versus ICG dyes and that the fluorescent green dye was more prominently visualized in the setting of visceral and retroperitoneal fat.
D
215 216
t2:1 t2:2
Table 2 Clinical and demographic outcomes by dye.
T
213 214
C
211 212
E
209 210
R
207 208
R
205 206
O
204
C
202 203
N
200 201
Sentinel lymph nodes were most frequently identified in the hypogastric region (76.8%) followed by external iliac (14.2%), common iliac (4.5%), and para-aortic regions (4.5%) (Fig. 3). Of note, SLNs were identified in separate locations within the same hemipelvis in 9 cases (6.4%). These included para-aortic/hypogastric combinations (n = 4), para-aortic/external iliac combinations (n = 1), hypogastric/external iliac combinations (n = 3), and hypogastric/common iliac combinations (n = 1). Out of 71 total cases, ICG and ISB were used in 38 and 33 cases respectively (Table 2). Age, BMI, stage, and grade did not vary significantly between groups. Cases in which ICG was utilized had a higher bilateral, and per hemipelvis SLN mapping rate than when ISB was utilized (78.9% vs. 42.4%, p = 0.02 and 85.5% vs. 57.5%, p = 0.0001 respectively). The mean number of SLN retrieved was not significantly different between ICG and ISB (2.4 vs. 2.0 SLN/mapped hemipelvis, p = 0.36). Positive lymph nodes were identified in 5/71 (7%) of women, all identified by the SLN protocol. These included four patients with lymph node metastasis identified on routine H&E and one only seen on ultrastaging. In one case, a patient with carcinosarcoma on preoperative biopsy had a clinically suspicious pelvic lymph node which would be considered a “protocol positive” according to our algorithm and the algorithm described by Abu-Rustum, et al. [26]. The next patient had grade 1 disease and ISB failed to identify a lymph node on the left. She, therefore, underwent an ipsilateral lymphadenectomy which demonstrated metastatic carcinoma in the hypogastric lymph nodes. On the right, a hypogastric SLN was identified and metastatic disease was identified in both the SLN and non-SLNs. This patient, too, is considered a protocol positive. The next two patients had successful bilateral mapping and subsequent lymphadenectomy and only the SLNs were positive for metastatic disease. The final patient had isolated tumor cells detected in a sentinel lymph node on ultrastaging but not on routine H and E. She also had positive peritoneal washings. As such, the negative predictive value the algorithm was 100% and the false negative rate was 0%. Finally, on univariate analysis, only dye (OR: 5.1, 95% CI: 1.8–14.4) and BMI (OR: 0.9, 95% CI: 0.88–0.99) were significantly associated with successful bilateral mapping (p = 0.002 and p = 0.043, respectively). On multivariate analysis, BMI (OR: 0.91, 95% CI: 0.85–0.98) and dye used (OR: 7.68, 95% CI: 2.13–27.64) remained independent predictors of successful mapping (p = 0.022 and 0.002, respectively). Interestingly, when the outcomes were stratified by dye used, a significant adverse association between BMI and SLN mapping was only seen in the ISB group (OR: 0.867, 95% CI: 0.78–0.98, p = 0.03) but not in the ICG group (OR: 0.964, 95% CI: 0.88–1.05, p = 0.14).
U
198 199
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
E
4
Fig. 3. Distribution of sentinel lymph node locations. N = 142.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
t2:3 t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21
242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
303 304 305 306 307 308 309 310 311 312 Q5 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343
C
No industry or pharmaceutical support was obtained to conduct this research or produce this manuscript.
F
350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433
O
301 302
E
299 300
R
297 298
R
295 296
N C O
293 294
U
291 292
[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63(1):11–30. [2] Bray F, Dos Santos Silva I, Moller H, Weiderpass E. Endometrial cancer incidence trends in Europe: underlying determinants and prospects for prevention. Cancer Epidemiol Biomarkers Prev 2005;14(5):1132–42. [3] Abu-Rustum NR, Iasonos A, Zhou Q, Oke E, Soslow RA, Alektiar KM, et al. Is there a therapeutic impact to regional lymphadenectomy in the surgical treatment of endometrial carcinoma? Am J Obstet Gynecol 2008;198(4):457 [e1-5; discussion e5-6]. [4] Mariani A, Sebo TJ, Katzmann JA, Keeney GL, Roche PC, Lesnick TG, et al. Pretreatment assessment of prognostic indicators in endometrial cancer. Am J Obstet Gynecol 2000;182(6):1535–44. [5] Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas LR, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol 2012;127(1):5–10. [6] Frederick PJ, Straughn Jr JM. The role of comprehensive surgical staging in patients with endometrial cancer. Cancer Control 2009;16(1):23–9. [7] Kehoe SM, Miller DS. The role of lymphadenectomy in endometrial cancer. Clin Obstet Gynecol 2011;54(2):235–44. [8] Chi DS, Barakat RR, Palayekar MJ, Levine DA, Sonoda Y, Alektiar K, et al. The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology. Int J Gynecol Cancer 2008;18(2):269–73. [9] Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009;373(9658):125–36. [10] Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008;100(23): 1707–16. [11] Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet Jan 10 2009;373:125–36 [9658 SRC - GoogleScholar]. [12] Panici P, Basile S, Maneschi F, Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early stage endometrial carcinoma randomized clinical trial. J Natl Cancer Inst 2008;100(23):1707–16. [13] Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182(6):1506–19. [14] Orr Jr JW, Holloway RW, Orr PF, Holimon JL. Surgical staging of uterine cancer: an analysis of perioperative morbidity. Gynecol Oncol 1991;42(3):209–16. [15] Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127(4):392–9. [16] Cody III HS. Sentinel lymph node mapping in breast cancer. Breast Cancer 1999;6(1):13–22. [17] Kitchener HC. Sentinel-node biopsy in endometrial cancer: a win–win scenario? Lancet Oncol 2011;12(5):413–4. [18] Burke TW, Levenback C, Tornos C, Morris M, Wharton JT, Gershenson DM. Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer: results of a pilot study. Gynecol Oncol 1996;62(2):169–73. [19] Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Cancer Netw 2014;12(2):288–97. [20] Kim CH, Soslow RA, Park KJ, Barber EL, Khoury-Collado F, Barlin JN, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer 2013;23(5):964–70. [21] Rossi EC, Ivanova A, Boggess JF. Robotically assisted fluorescence-guided lymph node mapping with ICG for gynecologic malignancies: a feasibility study. Gynecol Oncol 2012;124(1):78–82. [22] Rossi EC, Jackson A, Ivanova A, Boggess JF. Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection. Int J Gynecol Cancer 2013;23(9):1704–11. [23] Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke II JJ, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106(4):812–9. [24] Gynecologic Oncology Group. Surgical procedures manual. Buffalo, NY: Gynecologic Oncology Group; 2007 [http://www.gog.org. www.gog.org, cited 2013]. [25] Barlin JN, Khoury-Collado F, Kim CH, Leitao MM, Chi DS, Sonoda Y, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125(3):531–5. [26] Abu-Rustum NR, Khoury-Collado F, Gemignani ML. Techniques of sentinel lymph node identification for early-stage cervical and uterine cancer. Gynecol Oncol 2008;111(2 Suppl.):S44–50. [27] Khoury-Collado F, Abu-Rustum NR. Lymphatic mapping in endometrial cancer: a literature review of current techniques and results. Int J Gynecol Cancer 2008; 18(6):1163–8. [28] Kang S, Yoo HJ, Hwang JH, Lim M-C, Seo S-S, Park S-Y. Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies. Gynecol Oncol 2011;123(3):522–7. [29] Holloway RW, Bravo RAM, Rakowski JA, James JA, Jeppson CN, Ingersoll SB, et al. Detection of sentinel lymph nodes in patients with endometrial cancer undergoing robotic-assisted staging: a comparison of colorimetric and fluorescence imaging. Gynecol Oncol 2012;126(1):25–9. [30] Jewell EL, Huang JJ, Abu-Rustum NR, Gardner GJ, Brown CL, Sonoda Y, et al. Detection of sentinel lymph nodes in minimally invasive surgery using indocyanine green and
R O
The authors report no conflicts of interest.
290
349
P
Conflict of interest statement
346 347 348
288 289
References
D
345 Q6
286 287
T
344
The mapping success rate with ISB (42.4%) demonstrated in our study was low, but similar to other published studies [25]. In the largest series to date, Barlin et al. used ISB to achieve a bilateral mapping success rate of 51% [25]. Holloway et al. compared the success rate of ISB to ICG when injected in sequentially in the same patient, and found a 77% and 97% bilateral mapping success rate respectively [29]. In a more recent publication by Jewell et al., the combination of ICG and ISB (used in 13% percent of their patients) was compared with ICG alone (87% of their population) and achieved a bilateral mapping rate of 77% vs. 79% respectively with no benefit observed with the combination of both dyes [30]. Multiple studies, including the current report, suggest that using ISB dye alone does not contribute to reliable bilateral lymphatic mapping rates in this patient population. Radioisotopes have been used in other studies to increase SLN success rates [31–34]. The SENTI-ENDO trial showed an overall bilateral mapping rate of 69% using both radio isotope and colorimetric tracers [35]. However, the use of radioisotope is expensive, painful for the patient, and technically and logistically challenging. It is not readily visible to the surgeon and logistical coordination of radioisotope injection with the nuclear medicine department is necessary if lymphoscintigraphy is performed. Therefore, cervical injection of ICG dye alone in a sedated patient may offer a simpler, cheaper, and equally reliable method to map sentinel lymph nodes in women with primary endometrial cancer. Application of a comprehensive sentinel lymph node protocol in which clinically suspicious nodes are always biopsied regardless of SLN location, and in which ipsilateral lymphadenectomy is performed when mapping fails on one side accurately predicted all five patients with positive lymph nodes, resulting in a 0% false negative rate and 100% sensitivity. This validates the findings of Trimble et al., who used a similar SLN protocol, improved their SLN false negative rates from 15% to 2% [23]. Weaknesses of our study include its retrospective and nonrandomized nature, despite stemming from a prospectively maintained database. As described above, the choice of ICG or ISB was based on equipment availability, and this can lead to potential selection bias. However, no differences in baseline characteristics were found between these two groups of patients. Another weakness is that these results are from a single institution with a newly adopted endometrial cancer sentinel lymph node program, and hence these results might not be generalizable to the general population, or to other institutions. It does however suggest that in a newly adopted program such as ours, ICG injection resulted in a significantly higher SLN detection rate. This becomes increasingly important as more institutions develop their endometrial cancer SLN protocols and find themselves in the early phase of the learning curve of this innovative technique. Whether or not this remains the case as expertise develops will be of interest to observe in future learning curve studies. Multiple questions remain unanswered regarding the role and optimal technique of sentinel lymph node biopsy in endometrial cancer, and the role of ultrastaging in this setting. These will likely require multiinstitutional, well powered, randomized control trials to address. We are eagerly awaiting the results of the FIRES trial (NCT01673022) that may address many of the questions that retrospective, singleinstitution studies have not been able to. The expected completion date for this trial is May, 2017. Our study identified BMI as a significant factor affecting SLN success rates, especially when ISB was used. It is our goal, in future studies, to evaluate other factors associated with successful mapping, with the goal being to achieve a personalized patient specific algorithm that tailors surgical technique to individual patients, rather than a one size fits all strategy.
E
284 285
5
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
6
434 435 Q7 436 437 438 439 440 441 442
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
near-infrared fluorescence imaging for uterine and cervical malignancies. Gynecol Oncol 2014. [31] Torne A, Pahisa J, Vidal-Sicart S, Martinez-Roman S, Paredes P, Puerto B, et al. Transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR): a new method for sentinel lymph node detection in endometrial cancer. Gynecol Oncol 2013:88–94 [128 SRC - GoogleScholar]. [32] Solima E, Martinelli F, Ditto A, Maccauro M, Carcangiu M, Mariani L, et al. Diagnostic accuracy of sentinel node in endometrial cancer by using hysteroscopic injection of radiolabeled tracer. Gynecol Oncol 2012;126(3):419–23.
[33] Niikura H, Okamura C, Utsunomiya H, Yoshinaga K, Akahira J, Ito K, et al. Sentinel lymph node detection in patients with endometrial cancer. Gynecol Oncol 2004;92(2):669–74. [34] Perrone AM, Casadio P, Formelli G, Levorato M, Ghi T, Costa S, et al. Cervical and hysteroscopic injection for identification of sentinel lymph node in endometrial cancer. Gynecol Oncol 2008;111(1):62–7. [35] Ballester M, Dubernard G, Lécuru F, Heitz D, Mathevet P, Marret H, et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). Lancet Oncol 2011;12(5):469–76.
U
N
C
O
R
R
E
C
T
E
D
P
R O
O
F
452
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
443 444 445 446 447 448 449 450 451
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
3Q1
Abdulrahman K. Sinno, Amanda Nickles Fader, Kara Long Roche, Robert L. Giuntoli II, Edward J. Tanner ⁎ The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, USA
6
H I G H L I G H T S
P
• Seventy one consecutive endometrial cancer sentinel lymph node (SLN) mapping cases utilizing isosulfan blue (ISB) or indocyanine green (ICG) are presented. • Bilateral mapping was higher in the ICG group and BMI a significant predictor for successful mapping in the ISB group. • Utilizing our institutional SLN protocol resulted in a 100% negative predictive value and 100% sensitivity for detecting metastatic lymph nodes.
a r t i c l e
i n f o
19 20 21 22 23 24 25
Keywords: Sentinel lymph node Endometrial cancer Fluorescence imaging Obesity Robotic hysterectomy Indocyanine green
a b s t r a c t
Objective. The study objective was to compare the ability to detect sentinel lymph nodes (SLNs) in women with endometrial cancer (EC) or complex atypical hyperplasia (CAH) using fluorometric imaging with indocyanine green (ICG) versus colorimetric imaging with isosulfan blue (ISB). Methods. Women underwent SLN mapping, with either ISB or ICG, during robotic-assisted total laparoscopic hysterectomy (RA-TLH) from September 2012 to March 2014. SLNs were submitted for permanent pathologic analysis. Completion lymphadenectomy and ultrastaging were performed according to institutional protocols. Results. RA-TLH and SLN mapping was performed in 71 women; 64 had EC (64) and 7 had CAH. Age, body mass index (BMI), stage and tumor characteristics were similar in the ICG versus the ISB cohorts. Overall, SLNs were identified bilaterally (62.0%), unilaterally (21.1%), or neither (16.9%), and in 103 of 142 hemi-pelvises (72.5%). The mean number of SLNs retrieved per hemipelvis was 2.23(SD 1.7). SLNs were identified in the hypogastric (76.8%), external iliac (14.2%), common iliac (4.5%) and paraaortic (4.5%) regions. ICG mapped bilaterally in 78.9% of women compared with 42.4% of those injected with ISB (p = 0.02). Five women (7%) had positive lymph nodes, all identified by the SLN protocol (false negative rate: 0%). On multivariate analysis, BMI was negatively correlated with bilateral mapping success (p = 0.02). When stratified by dye type, the association with BMI was only significant for ISB (p = 0.03). Conclusions. Fluorescence imaging with ICG may be superior to colorimetric imaging with ISB in women undergoing SLN mapping for endometrial cancer. SLN mapping success is negatively associated with increasing patient BMI only when ISB is used. © 2014 Published by Elsevier Inc.
C
T
E
Article history: Received 26 April 2014 Accepted 22 May 2014 Available online xxxx
D
1 4 1 3 15 16 17 18
44 48 46 45 47
N C O
R
R
E
7 8 9 10 11 12
R O
4Q3 5
O
F
2
A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer☆
1
Introduction
50 51
Endometrial cancer is the most common gynecologic cancer in the United States (U.S.) with 49,560 cases expected in 2014 [1,2]. The standard treatment for women diagnosed with this malignancy is a total hysterectomy, bilateral salpingo-oophorectomy and lymph node assessment. Despite being a powerful predictor of recurrence and prognosis [3,4], the role and extent of the lymph node assessment remains
52 53 54 55
U
49
☆ These findings were presented at the Society of Gynecologic Oncology's 45th Annual Meeting on Women's Cancer in Tampa, Florida, March 22–25, 2014. ⁎ Corresponding author at: 600 N Wolfe St, Phipps 281 Baltimore, MD 21287, USA. Fax: +1 410 614 8718. E-mail address: [email protected] (E.J. Tanner).
variable across institutions [5]. The spectrum of lymph node assessment spans from omitting a lymphadenectomy altogether, to perform a complete pelvic and para-aortic lymphadenectomy for all histologies and tumor grades. Some centers utilize intraoperative assessment criteria, based upon histologic and tumor characteristics, to triage patients for lymph node assessment [6–10]. Variability in lymph node assessment strategies reflects unresolved issues regarding the 1) therapeutic benefit (or lack thereof) of lymphadenectomy in women with endometrial cancer [11,12], 2) increased scrutiny regarding the potential morbidity of the procedure, and 3) shifting treatment paradigms for women at high risk for metastatic disease [13]. Given that greater than 75% of women with endometrial cancer will have an early-stage, low grade disease, with an inherently low risk of lymph node metastases [14], most will not benefit from
http://dx.doi.org/10.1016/j.ygyno.2014.05.022 0090-8258/© 2014 Published by Elsevier Inc.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
26 Q4 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
56 57 58 59 60 61 62 63 64 65 66 67 68 69
93 94 95 96 97 98 99 100 101 102
F
O
R O
91 92
P
89 90
Sentinel lymph node mapping algorithm (Fig. 2) Upon induction of anesthesia, the cervix is injected with either ISB or ICG at the time of EUA (ISB) or at the time of uterine manipulator placement (ICG). One 50 mg vial of ISB is reconstituted according to package instructions in 5 mL of normal saline (10 mg/mL). One 25 mg vial of ICG is reconstituted in 10 mL of aqueous solvent and further diluted in 10 mL of normal saline (1.25 mg/mL). The solution is injected at the 3 and 9 o'clock positions of the cervical stroma. One mL is injected superficially (submucosa) and 1 mL is injected deep (~8 mm) in the cervical
D
87 88
111
T
85 86
The Kelly Gynecologic Oncology Service at Johns Hopkins Hospital, Baltimore MD adopted a sentinel lymph node mapping program in September 2012. Four gynecologic oncology surgeons with expertise in sentinel lymph node techniques have participated in this program and contributed patients to this prospectively collected database. The study, which was approved by the institutional review board at Johns Hopkins Hospital, occurred during the period of September 2012 to March 2014. All patients with complex atypical hyperplasia or endometrial cancer undergoing a planned robotic-assisted total laparoscopic hysterectomy with SLN mapping during this time were evaluated. Patients with complex atypical hyperplasia were included due to their risk of concurrent endometrial carcinoma, which has been found to up to 42% in some studies [23].
C
83 84
110
E
81 82
Materials and methods
R
79 80
R
77 78
O
76
103 104
C
74 75
range (NIR). It has the potential advantage of being readily visible through visceral fat. Therefore, our study objective was to compare the sentinel lymph node detection rate of indocyanine green (ICG) versus isosulfan blue (ISB) in women with EC and CAH in a new sentinel lymph program. A secondary objective was to assess whether the ICG dye performed better than ISB in women with increasing body mass index.
N
72 73
lymphadenectomy. Sentinel lymph node (SLN) biopsy, a technique that has revolutionized the approach to lymph node assessment in many other cancer types [15,16], has been proposed for endometrial cancer surgery to minimize both the rate of unnecessary lymphadenectomy in low risk women, as well as the risk of under-staging and hence under-treatment [17]. Since first described by Burke et al. 15 years ago, SLN biopsy techniques for women with endometrial cancer have evolved [18]. Single institution data from the group at Memorial Sloan Kettering Cancer Center suggests that cervical injection with blue or green dye at the time of hysterectomy and staging results in reliable mapping of relevant lymph nodes that drain the uterus [19]. Select U.S. centers have recently adopted this technique, but there is a lack of prospective, multicenter data to validate it. Much remains to be learned about the optimal choice of dye, technique, and overall sensitivity of SLN detection of metastases in women with endometrial cancer. Given the potential advantages of SLN mapping, including reduction of lymphedema and intraoperative complications [5] and improved detection of positive lymph nodes with ultrastaging techniques [20], it is critical that this approach be rigorously studied and optimized to ensure patient safety without oncologic compromise. In addition to a variety of locations proposed for injection, the optimal dye to perform SLN mapping is unclear. Two dyes are currently available. Isosulfan blue (Lymphazurin, Covidien LP, Mansfield MA) has been used in sentinel lymph node mapping for many different cancers. It relies on the surgeon's ability to visualize blue lymph nodes and lymphatic channels and differentiate them from the surrounding tissues (Fig. 1a). This colorimetric technique maybe challenging in cases where visceral fat can impair the surgeons ability to adequately visualize blue lymph nodes and poses a technical challenge in endometrial cancer, given its association with obesity. Indocyanine green (IC-Green, Novadaq Technologies Inc. Mississauga, ON Canada) has been proposed as an alternative to ISB [21,22] (Fig. 1b). This fluorescent dye relies on a fluorometrically capable camera and appears green when excited by light in the near infrared
U
70 71
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
E
2
Fig. 1. (Left) Sentinel lymph node with ISB. (Right) Sentinel lymph node with ICG.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
105 106 107 108 109
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
3
166
All data was collected from a prospectively maintained institutional database. From this database, clinical and pathologic data was abstracted and tabulated. The rate of successful SLN mapping was evaluated for patients undergoing ICG versus ISB guided mapping. Patients were evaluated based on both the rate of successful bilateral SLN mapping as well as the “side-specific” SLN mapping success. In other words, for the sidespecific mapping rate, each patient was counted as having two possible successful mapping locations (right and left). Point estimates of continuous data were compared using two-tailed Student T tests. Categorical results were compared using the Fischer's exact test. Simple logistic regression was performed for continuous variables with binary outcomes and multivariate logistic regression was subsequently employed to test if significant relationships were maintained. SPSS Version 22.0 (IBM Corp, Armonk, NY) was used for statistical calculations with significance set at 0.05 and power at 80%.
167 168
R O
O
F
Data and statistics
Results
141 142
Seventy one patients underwent robotic-assisted total laparoscopic hysterectomy with SLN mapping for endometrial cancer or complex atypical hyperplasia during the study period (Table 1). Median age (62.7 years, range: 37–84) and median BMI (32.5 kg/m2, range: 19– 53) were typical for an endometrial cancer cohort. The most common histologies included grade 1 endometrioid (56.3%), serous carcinoma (15.5%) and complex atypical hyperplasia (9.9%). The final FIGO stages were: IA (40, 56.3%), IB (13, 18.3%), II (3, 4.2%), IIIA (4, 5.6%) IIIC1 (3, 4.2%), and IVB (1, 1.4%). Successful bilateral SLN mapping occurred in 44 cases (62.0%), while 15 cases (21.1%) mapped unilaterally, and 12 cases (16.9%) did not have any SLNs identified. When each hemipelvis was considered separately, 103 of 142 possible hemipelvises (72.5%) were successfully mapped. The mean number of sentinel lymph nodes identified per hemipelvis was 2.2 (SD: 1.7).
143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
C
E
172 173 174 175 176 177 178 179 180 181
D
E
183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 t1:1
Table 1 Clinical and demographic criteria n = 71.
Q2t1:2 Median
Age (years) BMI (units)
171
182
P
139 140
R
138
R
136 137
stroma for a total injection volume of 4 mL. Selection of ISB or ICG was dependent on equipment availability. Currently, our service utilizes 4 robots, only one of which is fluorometrically capable. All patients underwent an attempted sentinel lymph node biopsy. Those with a preoperative endometrial biopsy consistent with high grade disease (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) subsequently underwent full pelvic and para-aortic lymphadenectomy. Patients with complex atypical hyperplasia or grade 1 or 2 endometrioid histology underwent SLN dissection followed by hysterectomy. The hysterectomy specimen was sent for frozen section assessment, which further tailored intraoperative management. Complete pelvic and para-aortic lymphadenectomy was performed according to Gynecologic Oncology Group guidelines (with aortic lymphadenectomy performed to a level above the inferior mesenteric artery) [24] if any of the following features were present: tumor size N 2 cm, myometrial invasion N 50%, or grade 3. If none of these pathologic findings were present and no clinically suspicious lymph nodes were identified, a completion lymphadenectomy was not performed after SLN biopsy. In our algorithm, when a patient fails to map in one hemipelvis, the ipsilateral lymphadenectomy results are used instead. This is of paramount importance so that patients who fail to map and have high risk features are not undertreated. This approach has been validated, shown to significantly increase SLN detection rates, and minimize false negatives [25]. The technique of ultrastaging has been previously described [14]. Due to costs associated with ultrastaging and the low risk of micrometastasis/isolated tumor cells identified in women with grade 1–2 tumors with b 50% myometrial invasion, ultrastaging was only performed post operatively in patients with high grade endometrioid, greater than 50% myometrial invasion, or tumors N 2 cm. Our center has chosen to omit ultrastaging for Type 2 tumors at this time, as the technique is costly, and does not change management in patients who will receive adjuvant chemotherapy regardless of lymph node status. We may reassess this decision in the future.
N C O
134 135
U
133
T
Fig. 2. Endometrial Cancer Sentinel Lymph Node Protocol. *Ultrastaging is omitted for patients with less than 50% invasion and for patient with type II tumors. CAH: complex atypical hyperplasia, LN: lymph nodes, and MI: myometrial invasion TD: tumor diameter.
169 170
64 31.1 Number
Range 37–84 19–53 Percent
Histology Complex atypical hyperplasia Grade I endometrioid Grade II endometrioid Grade III endometrioid Serous Carcinosarcoma Other
7 40 5 4 11 3 1
9.9 56.3% 7.0% 5.6% 15.5% 4.2% 1.4
Stage Stage IA Stage IB Stage II Stage IIIA Stage IIIC1 Stage IVb
40 13 3 4 3 1
56.3 18.3 4.2 5.6 4.2 1.4
t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25
Mapping
Number
Percent
Bilateral Unilateral None Per hemipelvis
44/71 15/71 12/71 103/142
62.0% 21.1% 16.9% 72.5%
Mean (SD)
Range
t1:26 t1:27 t1:28 t1:29 t1:30 t1:31
2.23 (1.67)
0–9
t1:32
Number of sentinel lymph nodes
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241
Isosulfan blue
38 64.5 (39–82) 31.1 (19.0–53.0)
33 62.0, (37–84) 31.4, (20.1–50.3)
29, 76.3% 9, 23.7%
23, 69.7% 10, 30.3%
15 11 2 4
25 2 1 4
30/38, 78.9% 4, 13.8% 3/38, 7.9% 65/76, 85.5% 2.4
14/33, 42.4% 8, 34.8% 9/33 27.3% 38/66, 57.5% 2.0
P value 0.74 0.82 0.92
O
F
0.31
0.02
0.0001 0.38
a Low grade includes CAH grade I and II, high grade includes grade 3, carcinosarcoma, serous and clear cell.
Discussion
R O
219 220
Indocyanine green
P
217 218
Number of cases Age (years) median, (range) BMI (Kg/m2) median, (range) Histologya (n,%) Low grade High grade Stage (n,%) Stage 1a Stage 1b Stage 2 Stage 3–4 Mapping (%) Bilateral Unilateral None Per hemipelvis Number of SLN per hemipelvis
In 2014, the National Comprehensive Cancer Network (NCCN) Endometrial Cancer Guidelines were updated to reflect the emerging data regarding the role of sentinel lymph node biopsy in endometrial cancer. Specifically, the guidelines now state that sentinel lymph node biopsy may be considered for the surgical staging of apparent uterineconfined malignancy when there is no metastasis demonstrated by imaging studies, or no obvious extra-uterine disease at exploration (Level IIB). The guidelines also noted that cervical injection is a “useful and validated technique”. These guidelines were based largely on retrospective, single institution U.S. data and retrospective and limited prospective European data. Further studies are necessary to validate and substantiate the NCCN recommendations. Our study adds to the growing body of literature demonstrating the feasibility of the cervical injection technique with various dyes, and the reliability of the sentinel lymph node approach in endometrial cancer. Multiple injection sites have been described in the literature. These include cervical, myometrial or hysteroscopic tumoral injection sites, or any combination of these methods. One criticism of cervical injection for endometrial cancer SLN detection is the theoretical difference between the lymphatic drainage of the cervix and uterine fundus, where the majority of endometrial cancers originate [4]. However, in anatomic studies, deep injection into the cervix has demonstrated excellent penetration to uterine vessels, parametria, lower uterine segment, and cornual regions [26,27]. Furthermore, in a meta-analysis by Kang et al., cervical injection was the only anatomic site that significantly improved sentinel lymph node detection, and any modality that omitted cervical injection resulted in decreased mapping success [28]. Our study further supports this observation that cervical injection of dye is a reliable method of identifying the lymphatic drainage of the uterus. In our study, BMI was associated adversely with mapping success rate in both univariate and multivariate analysis (p = 0.043 and 0.022 respectively). When mapping success rate was analyzed separately for ISB and ICG, this association was only significant for ISB (p = 0.03) and not for ICG (p = 0.14). It was our experience that the sentinel lymph nodes (and associated lymphatic channels) were more readily identified in thin and in obese patients when the ICG dye was used compared with the ISB dye. The reasons for this observation are multifactorial, but may include the differences in molecular weight of the ISB versus ICG dyes and that the fluorescent green dye was more prominently visualized in the setting of visceral and retroperitoneal fat.
D
215 216
t2:1 t2:2
Table 2 Clinical and demographic outcomes by dye.
T
213 214
C
211 212
E
209 210
R
207 208
R
205 206
O
204
C
202 203
N
200 201
Sentinel lymph nodes were most frequently identified in the hypogastric region (76.8%) followed by external iliac (14.2%), common iliac (4.5%), and para-aortic regions (4.5%) (Fig. 3). Of note, SLNs were identified in separate locations within the same hemipelvis in 9 cases (6.4%). These included para-aortic/hypogastric combinations (n = 4), para-aortic/external iliac combinations (n = 1), hypogastric/external iliac combinations (n = 3), and hypogastric/common iliac combinations (n = 1). Out of 71 total cases, ICG and ISB were used in 38 and 33 cases respectively (Table 2). Age, BMI, stage, and grade did not vary significantly between groups. Cases in which ICG was utilized had a higher bilateral, and per hemipelvis SLN mapping rate than when ISB was utilized (78.9% vs. 42.4%, p = 0.02 and 85.5% vs. 57.5%, p = 0.0001 respectively). The mean number of SLN retrieved was not significantly different between ICG and ISB (2.4 vs. 2.0 SLN/mapped hemipelvis, p = 0.36). Positive lymph nodes were identified in 5/71 (7%) of women, all identified by the SLN protocol. These included four patients with lymph node metastasis identified on routine H&E and one only seen on ultrastaging. In one case, a patient with carcinosarcoma on preoperative biopsy had a clinically suspicious pelvic lymph node which would be considered a “protocol positive” according to our algorithm and the algorithm described by Abu-Rustum, et al. [26]. The next patient had grade 1 disease and ISB failed to identify a lymph node on the left. She, therefore, underwent an ipsilateral lymphadenectomy which demonstrated metastatic carcinoma in the hypogastric lymph nodes. On the right, a hypogastric SLN was identified and metastatic disease was identified in both the SLN and non-SLNs. This patient, too, is considered a protocol positive. The next two patients had successful bilateral mapping and subsequent lymphadenectomy and only the SLNs were positive for metastatic disease. The final patient had isolated tumor cells detected in a sentinel lymph node on ultrastaging but not on routine H and E. She also had positive peritoneal washings. As such, the negative predictive value the algorithm was 100% and the false negative rate was 0%. Finally, on univariate analysis, only dye (OR: 5.1, 95% CI: 1.8–14.4) and BMI (OR: 0.9, 95% CI: 0.88–0.99) were significantly associated with successful bilateral mapping (p = 0.002 and p = 0.043, respectively). On multivariate analysis, BMI (OR: 0.91, 95% CI: 0.85–0.98) and dye used (OR: 7.68, 95% CI: 2.13–27.64) remained independent predictors of successful mapping (p = 0.022 and 0.002, respectively). Interestingly, when the outcomes were stratified by dye used, a significant adverse association between BMI and SLN mapping was only seen in the ISB group (OR: 0.867, 95% CI: 0.78–0.98, p = 0.03) but not in the ICG group (OR: 0.964, 95% CI: 0.88–1.05, p = 0.14).
U
198 199
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
E
4
Fig. 3. Distribution of sentinel lymph node locations. N = 142.
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
t2:3 t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21
242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
303 304 305 306 307 308 309 310 311 312 Q5 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343
C
No industry or pharmaceutical support was obtained to conduct this research or produce this manuscript.
F
350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433
O
301 302
E
299 300
R
297 298
R
295 296
N C O
293 294
U
291 292
[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63(1):11–30. [2] Bray F, Dos Santos Silva I, Moller H, Weiderpass E. Endometrial cancer incidence trends in Europe: underlying determinants and prospects for prevention. Cancer Epidemiol Biomarkers Prev 2005;14(5):1132–42. [3] Abu-Rustum NR, Iasonos A, Zhou Q, Oke E, Soslow RA, Alektiar KM, et al. Is there a therapeutic impact to regional lymphadenectomy in the surgical treatment of endometrial carcinoma? Am J Obstet Gynecol 2008;198(4):457 [e1-5; discussion e5-6]. [4] Mariani A, Sebo TJ, Katzmann JA, Keeney GL, Roche PC, Lesnick TG, et al. Pretreatment assessment of prognostic indicators in endometrial cancer. Am J Obstet Gynecol 2000;182(6):1535–44. [5] Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas LR, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol 2012;127(1):5–10. [6] Frederick PJ, Straughn Jr JM. The role of comprehensive surgical staging in patients with endometrial cancer. Cancer Control 2009;16(1):23–9. [7] Kehoe SM, Miller DS. The role of lymphadenectomy in endometrial cancer. Clin Obstet Gynecol 2011;54(2):235–44. [8] Chi DS, Barakat RR, Palayekar MJ, Levine DA, Sonoda Y, Alektiar K, et al. The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology. Int J Gynecol Cancer 2008;18(2):269–73. [9] Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009;373(9658):125–36. [10] Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008;100(23): 1707–16. [11] Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet Jan 10 2009;373:125–36 [9658 SRC - GoogleScholar]. [12] Panici P, Basile S, Maneschi F, Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early stage endometrial carcinoma randomized clinical trial. J Natl Cancer Inst 2008;100(23):1707–16. [13] Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182(6):1506–19. [14] Orr Jr JW, Holloway RW, Orr PF, Holimon JL. Surgical staging of uterine cancer: an analysis of perioperative morbidity. Gynecol Oncol 1991;42(3):209–16. [15] Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127(4):392–9. [16] Cody III HS. Sentinel lymph node mapping in breast cancer. Breast Cancer 1999;6(1):13–22. [17] Kitchener HC. Sentinel-node biopsy in endometrial cancer: a win–win scenario? Lancet Oncol 2011;12(5):413–4. [18] Burke TW, Levenback C, Tornos C, Morris M, Wharton JT, Gershenson DM. Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer: results of a pilot study. Gynecol Oncol 1996;62(2):169–73. [19] Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Cancer Netw 2014;12(2):288–97. [20] Kim CH, Soslow RA, Park KJ, Barber EL, Khoury-Collado F, Barlin JN, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer 2013;23(5):964–70. [21] Rossi EC, Ivanova A, Boggess JF. Robotically assisted fluorescence-guided lymph node mapping with ICG for gynecologic malignancies: a feasibility study. Gynecol Oncol 2012;124(1):78–82. [22] Rossi EC, Jackson A, Ivanova A, Boggess JF. Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection. Int J Gynecol Cancer 2013;23(9):1704–11. [23] Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke II JJ, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106(4):812–9. [24] Gynecologic Oncology Group. Surgical procedures manual. Buffalo, NY: Gynecologic Oncology Group; 2007 [http://www.gog.org. www.gog.org, cited 2013]. [25] Barlin JN, Khoury-Collado F, Kim CH, Leitao MM, Chi DS, Sonoda Y, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125(3):531–5. [26] Abu-Rustum NR, Khoury-Collado F, Gemignani ML. Techniques of sentinel lymph node identification for early-stage cervical and uterine cancer. Gynecol Oncol 2008;111(2 Suppl.):S44–50. [27] Khoury-Collado F, Abu-Rustum NR. Lymphatic mapping in endometrial cancer: a literature review of current techniques and results. Int J Gynecol Cancer 2008; 18(6):1163–8. [28] Kang S, Yoo HJ, Hwang JH, Lim M-C, Seo S-S, Park S-Y. Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies. Gynecol Oncol 2011;123(3):522–7. [29] Holloway RW, Bravo RAM, Rakowski JA, James JA, Jeppson CN, Ingersoll SB, et al. Detection of sentinel lymph nodes in patients with endometrial cancer undergoing robotic-assisted staging: a comparison of colorimetric and fluorescence imaging. Gynecol Oncol 2012;126(1):25–9. [30] Jewell EL, Huang JJ, Abu-Rustum NR, Gardner GJ, Brown CL, Sonoda Y, et al. Detection of sentinel lymph nodes in minimally invasive surgery using indocyanine green and
R O
The authors report no conflicts of interest.
290
349
P
Conflict of interest statement
346 347 348
288 289
References
D
345 Q6
286 287
T
344
The mapping success rate with ISB (42.4%) demonstrated in our study was low, but similar to other published studies [25]. In the largest series to date, Barlin et al. used ISB to achieve a bilateral mapping success rate of 51% [25]. Holloway et al. compared the success rate of ISB to ICG when injected in sequentially in the same patient, and found a 77% and 97% bilateral mapping success rate respectively [29]. In a more recent publication by Jewell et al., the combination of ICG and ISB (used in 13% percent of their patients) was compared with ICG alone (87% of their population) and achieved a bilateral mapping rate of 77% vs. 79% respectively with no benefit observed with the combination of both dyes [30]. Multiple studies, including the current report, suggest that using ISB dye alone does not contribute to reliable bilateral lymphatic mapping rates in this patient population. Radioisotopes have been used in other studies to increase SLN success rates [31–34]. The SENTI-ENDO trial showed an overall bilateral mapping rate of 69% using both radio isotope and colorimetric tracers [35]. However, the use of radioisotope is expensive, painful for the patient, and technically and logistically challenging. It is not readily visible to the surgeon and logistical coordination of radioisotope injection with the nuclear medicine department is necessary if lymphoscintigraphy is performed. Therefore, cervical injection of ICG dye alone in a sedated patient may offer a simpler, cheaper, and equally reliable method to map sentinel lymph nodes in women with primary endometrial cancer. Application of a comprehensive sentinel lymph node protocol in which clinically suspicious nodes are always biopsied regardless of SLN location, and in which ipsilateral lymphadenectomy is performed when mapping fails on one side accurately predicted all five patients with positive lymph nodes, resulting in a 0% false negative rate and 100% sensitivity. This validates the findings of Trimble et al., who used a similar SLN protocol, improved their SLN false negative rates from 15% to 2% [23]. Weaknesses of our study include its retrospective and nonrandomized nature, despite stemming from a prospectively maintained database. As described above, the choice of ICG or ISB was based on equipment availability, and this can lead to potential selection bias. However, no differences in baseline characteristics were found between these two groups of patients. Another weakness is that these results are from a single institution with a newly adopted endometrial cancer sentinel lymph node program, and hence these results might not be generalizable to the general population, or to other institutions. It does however suggest that in a newly adopted program such as ours, ICG injection resulted in a significantly higher SLN detection rate. This becomes increasingly important as more institutions develop their endometrial cancer SLN protocols and find themselves in the early phase of the learning curve of this innovative technique. Whether or not this remains the case as expertise develops will be of interest to observe in future learning curve studies. Multiple questions remain unanswered regarding the role and optimal technique of sentinel lymph node biopsy in endometrial cancer, and the role of ultrastaging in this setting. These will likely require multiinstitutional, well powered, randomized control trials to address. We are eagerly awaiting the results of the FIRES trial (NCT01673022) that may address many of the questions that retrospective, singleinstitution studies have not been able to. The expected completion date for this trial is May, 2017. Our study identified BMI as a significant factor affecting SLN success rates, especially when ISB was used. It is our goal, in future studies, to evaluate other factors associated with successful mapping, with the goal being to achieve a personalized patient specific algorithm that tailors surgical technique to individual patients, rather than a one size fits all strategy.
E
284 285
5
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
6
434 435 Q7 436 437 438 439 440 441 442
A.K. Sinno et al. / Gynecologic Oncology xxx (2014) xxx–xxx
near-infrared fluorescence imaging for uterine and cervical malignancies. Gynecol Oncol 2014. [31] Torne A, Pahisa J, Vidal-Sicart S, Martinez-Roman S, Paredes P, Puerto B, et al. Transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR): a new method for sentinel lymph node detection in endometrial cancer. Gynecol Oncol 2013:88–94 [128 SRC - GoogleScholar]. [32] Solima E, Martinelli F, Ditto A, Maccauro M, Carcangiu M, Mariani L, et al. Diagnostic accuracy of sentinel node in endometrial cancer by using hysteroscopic injection of radiolabeled tracer. Gynecol Oncol 2012;126(3):419–23.
[33] Niikura H, Okamura C, Utsunomiya H, Yoshinaga K, Akahira J, Ito K, et al. Sentinel lymph node detection in patients with endometrial cancer. Gynecol Oncol 2004;92(2):669–74. [34] Perrone AM, Casadio P, Formelli G, Levorato M, Ghi T, Costa S, et al. Cervical and hysteroscopic injection for identification of sentinel lymph node in endometrial cancer. Gynecol Oncol 2008;111(1):62–7. [35] Ballester M, Dubernard G, Lécuru F, Heitz D, Mathevet P, Marret H, et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). Lancet Oncol 2011;12(5):469–76.
U
N
C
O
R
R
E
C
T
E
D
P
R O
O
F
452
Please cite this article as: Sinno AK, et al, A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.022
443 444 445 446 447 448 449 450 451
