PCOG Papers

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A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging Pamela J. Paley, MD; Dan S. Veljovich, MD; Joshua Z. Press, MD; Christina Isacson, MD; Ellen Pizer, MD; Chirag Shah, MD, MPH

BACKGROUND: The accuracy of sentinel lymph node mapping has

been shown in endometrial cancer, but studies to date have primarily focused on cohorts at low risk for nodal involvement. In our practice, we acknowledge the lack of benefit of lymphadenectomy in the low-risk subgroup and omit lymph node removal in these patients. Thus, our aim was to evaluate the feasibility and accuracy of sentinel node mapping in women at sufficient risk for nodal metastasis warranting lymphadenectomy and in whom the potential benefit of avoiding nodal procurement could be realized. OBJECTIVE: To evaluate the detection rate and accuracy of fluorescence-guided sentinel lymph node mapping in endometrial cancer patients undergoing robotic-assisted staging. STUDY DESIGN: One hundred twenty-three endometrial cancer patients undergoing sentinel lymph node sentinel node mapping using indocyanine green were prospectively evaluated. Two mL (1.0 mg/mL) of dye were injected into the cervical stroma divided between the 2
3 and 9
10 o’clock positions at the time of uterine manipulator placement. Before hysterectomy, the retroperitoneal spaces were developed and fluorescence imaging was used for sentinel node detection. Identified sentinel nodes were removed and submitted for touch prep intraoperatively, followed by permanent assessment with routine hematoxylin and eosin levels. Patients then underwent hysterectomy, bilateral salpingo-oophorectomy, and completion bilateral pelvic and periaortic lymphadenectomy based on intrauterine risk factors determined intraoperatively (tumor size >2 cm, >50% myometrial invasion, and grade 3 histology). RESULTS: Of 123 patients enrolled, at least 1 sentinel node was detected in 119 (96.7%). Ninety-nine patients (80%) had bilateral pelvic or periaortic sentinel nodes detected. A total of 85 patients met criteria

E

ndometrial cancer (EC) is the most common reproductive tract malignancy in North America.1 In the majority of cases, women will be diagnosed at an early stage with uterine-limited disease, amenable to surgical extirpation alone. In 1988, The International

Cite this article as: Paley PJ, Veljovich DS, Press JZ, et al. A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging. Am J Obstet Gynecol 2016;215:117.e1-7. 0002-9378/$36.00 ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.12.046

warranting completion lymphadenectomy. In 14 patients (16%) periaortic lymphadenectomy was not feasible, and the mean number of pelvic nodes procured was 13 (6
22). Of the 71 patients undergoing pelvic and periaortic lymphadenectomy, the mean nodal count was 23.2 (8
51). Of patients undergoing lymphadenectomy, 10.6% had lymph node metastasis on final hematoxylin and eosin evaluation. Notably, the sentinel node was the only positive node in 44% of cases. There were no cases in which final pathology of the sentinel node was negative and metastatic disease was detected upon completion lymphadenectomy in the non-sentinel nodes (no false negatives), yielding a sensitivity of 100%. Of the 14 sentinel nodes ultimately found to harbor metastases, 3 were negative on touch prep, yielding a sensitivity of 78.6% for intraoperative detection of sentinel node involvement. In all 3 of the false-negative touch preps, final pathology detected a single micrometastasis (0.24 mm, 1.4 mm, 1.5 mm). As expected, there were no false-positive results, yielding a specificity of 100%. No complications related to sentinel node mapping or allergic reactions to the dye were encountered. CONCLUSION: Intraoperative sentinel node mapping using fluorescence imaging with indocyanine green in endometrial cancer patients is feasible and yields high detection rates. In our pilot study, sentinel node mapping identified all women with Stage IIIC disease. Low false-negative rates are encouraging, and if confirmed in multi-institutional trials, this approach would be anticipated to reduce the morbidity, operative times, and costs associated with complete pelvic and periaortic lymphadenectomy. Key words: endometrial carcinoma, robotic surgery, sentinel node

mapping

Federation of Gynecology and Obstetrics (FIGO) recognized the shortcomings of clinical staging and formally advocated surgical staging to delineate disease distribution and guide adjuvant therapy. More than 2 decades later, a consensus regarding the criteria for assessment of lymphatic involvement remains elusive, and patient care generally reflects institutional or physician biases. Several aspects of EC have contributed to this debate, including an overall low risk of nodal metastasis, a high proportion of grade 1 or 2 tumors with a favorable prognosis and low risk of extrauterine disease, and an apparent

lack of a survival advantage with lymphadenectomy (LAN) documented in 2 large randomized trials that failed to show a beneficial effect of pelvic LAN on overall or recurrence-free survival.2,3 A recent single-institution trial has redirected focus from a debate between universal staging vs abandoning surgical assessment of regional nodes in EC to the identification of a low-risk group of patients who do not benefit from either LAN or adjuvant radiation therapy.4 Mariani et al.5 reported that in more than 300 patients with FIGO grade 1 or 2 endometrioid adenocarcinoma with less than 50% myometrial penetration, no

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PCOG Papers patients with tumor size less than 2 cm had documented lymph node metastases, developed lymph node recurrences, or died of their disease. Subsequently, their findings were validated by other groups as well as in a prospective series at the Mayo Clinic.5-8 The results of the prospective Gynecologic Oncology Group (GOG) Lap II trial confirmed that there is a low-risk subgroup in which LAN is associated only with potential morbidity and no survival benefit. In it, 7% of women with endometrioid histology participating in Lap II had nodal metastasis. Of these, 48% had less than 50% myometrial invasion, 60% had grade 1 or 2 tumors, and 23% had a tumor diameter less than 2 cm. Notably, it was only when all 3 of these criteria were simultaneously present that the risk of lymph node metastases decreased to an acceptably low level at 0.8%,9 further validating the Mayo Clinic criteria. Sentinel lymph node (SLN) mapping has become the standard of care to assess lymphatic dissemination in breast cancer, melanoma, and vulvar cancer.10-13 The clinical value of SLN mapping is based on a high sensitivity and reliable negative predictive value to detect nodal involvement. Ideally, SLN mapping would be highly feasible and provide the accuracy of systematic LAN in identifying patients with lymph node metastasis while decreasing surgical morbidity and operative times. The accuracy of SLN mapping has been shown in patients with early-stage EC at low risk for nodal involvement.14-17 Studies in low-risk cohorts report rates of high detection (>80%) with false-negative rates ranging from 2 to 16%. In our practice, we acknowledge the lack of benefit of LAN in the lowrisk subgroup and omit systematic LAN in these patients. Thus, the aim of our study was to prospectively evaluate the feasibility of routine SLN mapping and the accuracy of SLN histology in women at sufficient risk for nodal metastasis that warranted systematic LAN in whom the potential substantial benefit of avoiding full LAN could be realized.

ajog.org Materials and Methods Patients and procedure From March 2012 through May 2015, all patients with biopsy-proven EC of any histologic subtype presenting to 1 of 4 gynecologic oncologists (P.J.P., D.S.V., C.A.S., J.Z.P.) with planned roboticassisted surgical management at 1 of 2 Swedish Medical Center campuses were offered enrollment. The study was approved by the Swedish Medical Center institutional review board, and all participants provided written informed consent. All data were collected prospectively and entered into a secure database. Patients were followed daily while in the hospital, and outcomes at 1
2 weeks and 10
12 weeks postoperatively were collected. Two milliliters (1.0 mg/mL) of indocyanine green (ICG; Alcorn Pharmaceuticals, Lake Forest, IL) was injected into the cervical stroma divided between the 2
3 and 9
10 o’clock positions at the time of uterine manipulator placement. Before hysterectomy, the retroperitoneal spaces were developed and robotic camera fluorescence imaging used for SLN mapping. The fluorescence properties of ICG were visualized by the use of an imaging system integrates the SPY scope nearinfrared (NIR) imaging technology (Novadaq Technologies, Bonita Springs, FL) with the daVinci Surgical System (Intuitive Surgical, Sunnyvale, CA). Identified SLNs were removed and submitted intraoperatively for touch prep evaluation, followed by routine hematoxylin and eosin (H&E) levels. Patients subsequently underwent robotic hysterectomy, bilateral salpingooophorectomy, followed by completion bilateral pelvic and periaortic LAN (PPALAN) based on intrauterine risk factors as determined by intraoperative frozen section. PPALAN was performed in patients with at least 1 of the following findings: serous, clear-cell, or carcinosarcoma histology on preoperative biopsy, tumor size >2 cm, >50% myometrial wall invasion, grade 3 histology, grossly suspicious nonsentinel pelvic or periaortic lymph nodes, or SLN positive for metastatic disease on touch prep. In

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cases of mapping failures, completion PPALAN was performed on the basis of the same criteria followed in successful mapping cases. The number and location of SLN was documented prospectively.

Histopathology All identified SLNs were submitted intraoperatively for imprint cytology. Each SLN was cut perpendicular to the long axis with 1 or more touch preps per SLN being reviewed. Each SLN was submitted entirely with multiple sections at an interval of 100
200 microns between each level evaluated by routine H&E staining. The nonsentinel nodes were processed similarly, being entirely submitted for routine H&E levels.

Statistical analysis The detection rate was calculated as the number of patients with at least 1 identified SLN divided by the total number of enrolled patients. The accuracy of SLN mapping was determined by calculating the sensitivity, specificity, and positive and negative predictive values along with 95% confidence intervals (95% CIs) only in those cases in which at least 1 SLN was identified and completion LAN was performed. A value of 100% represents perfect performance of the marker and 50% indicates a level of performance that is expected by chance alone. All statistical analysis was performed with STATA (14.0 for Mac OS X, College Station, TX).

Results One hundred twenty-three patients with EC underwent attempted SLN mapping with key demographic and clinical features outlined in Table 1. The mean age of all participants was 62.5 years (range, 42
86 years) with a mean body mass index of 32 kg/m2 (range, 19
63 kg/m2). Characteristic of the EC population, 51% of participants were obese and 20% morbidly obese. All patients who provided consent experienced successful completion of robotic procedures with no conversions to laparotomy and no malfunctions of the SPY scope NIR imaging technology. The average operating

PCOG Papers

ajog.org room time, defined as skin incision to skin closure, was 161 minutes (range, 60
360 minutes), with a mean estimated blood loss of 48.7 mL (range, 15
200 mL) and an average length of hospital stay of 24.6 hours (range, 15
92 hours). An obstetrics and gynecology resident or gynecologic oncology fellow performed a key component of the case at the surgeon console in 66% of the cases. In 123 patients in whom SLN mapping was attempted, 342 total SLNs were identified and procured intraoperatively (Table 2). The average time from intracervical ICG injection to SLN identification was 19.8 minutes, with a range of 5
55 minutes. At least 1 SLN was identified in 119 patients for a detection rate of 96.7%. In 99 patients (80%) bilateral pelvic and/or periaortic SLNs were mapped successfully. On average 1.6 right SLN (range 1
6) and 1.5 left SLN range 1
5) were detected per patient. SLNs were most commonly identified in the external iliac basins (49% of cases), followed by the obturator fossa (21%), common iliac (12%), periaortic region (8%), presacral (1.5%), and parametrial web (<1%). In 10 cases (3%), the location was not specified and could not be ascertained from review of the operative report or pathology report in the patient’s electronic medical record. Eighty-five patients met criteria warranting PPALAN. In 14 patients (16%), PALAN was not feasible and the mean number of pelvic nodes procured was 13 (range, 6
22). Of the 71 women undergoing PPALAN, the mean nodal count was 23.2 (range, 8
51). Table 3 illustrates the clinicopathologic characteristics of the 85 patients undergoing completion LAN. As anticipated, most women had endometrioid histology (82%), and on final pathology 38% had FIGO grade 1, 28% grade 2, and 34% grade 3 tumors. Table 4 summarizes the performance of SLN mapping in 85 patients undergoing completion LAN. Of these patients, 10.6% had lymph node metastasis on final H&E evaluation. Notably, the SLN was the only positive node in 44% of cases. Of the 14 sentinel nodes ultimately

TABLE 1

Demographic and clinical characteristics of all participants (n [ 123) Characteristic Age, y

62.5 (42
86) 2

Body mass index, kg/m , n (%)

32 (19e63)

>30


63 (51)

>40


25 (20)

Operating room time, min

161 (60
360)

Estimated blood loss, mL

48.7 (15
200)

Length of hospital stay

24.6 (15
92)

Resident and/or fellow on surgeon console, n (%)

81 (66)

All values are mean (range) unless stated otherwise. Paley et al. Fluorescence imaging detection of sentinel lymph nodes in endometrial cancer. Am J Obstet Gynecol 2016.

found to harbor metastases in 9 patients, 3 were negative on intraoperative touch prep, yielding a sensitivity of 78.6% (95% CI, 49.2
95.5%) for detection of SLN involvement with this technique. In all 3 of the false-negative touch preps, H&E detected a single micrometastasis (0.24, 1.4, and 1.5 mm). There were no cases in which H&E of the sentinel node was negative and metastatic disease was detected on PPALAN in the nonsentinel nodes (no false negatives), yielding a sensitivity of 100% (95% CI, 66.4
100%). There were no falsepositive results, yielding a specificity of 100%. Of the women with stage IIIC disease, 33.3% had only 1 criteria for proceeding with PPALAN, 67% of which was tumor size >22 cm in women with grade 1 endometrioid tumors with <50% myometrial invasion. No complications directly attributable to SLN mapping or the ICG dye were encountered. Minor complications occurred in 8 of 123 patients (6.5%), including transient numbness and weakness in the distribution of the left ulnar nerve (n ¼ 1), uncomplicated urinary tract infection (n ¼ 3), lymphocele (n ¼ 2), and puckering of a skin closure site (n ¼ 1). Major complications occurred in 4 of 123 patients (3.3%), including vaginal cuff dehiscence (n ¼ 1), pulmonary embolism (n ¼ 1), postoperative anemia resulting in atrial fibrillation requiring transfusion (n ¼ 1), and pelvic abscess requiring antibiotics and drainage (n ¼ 1).

Comment Substantial evidence argues that intraoperative identification of low-risk EC patient groups is accurate and safely TABLE 2

SLN mapping characteristics Variable 19.8 (5
55)

Time from ICG injection to SLN identification, min, mean (range) Number of right SLN per patient, mean (range)

1.6 (1
6)

Number of left SLN per patient, mean (range)

1.5 (1
5)

SLN detection rate, n (%) Overall

119 (96.7%)

Bilateral

99 (80%)

Failed

4 (3.3)

SLN location, n (%) External iliac

167 (49%)

Obturator

72 (21%)

Common iliac

42 (12%)

Periaortic

29 (8%)

Internal iliac

16 (5%)

Not recorded

10 (3%)

Presacral

5 (1.5%)

Parametrial

1 (<1%)

Patients, n ¼ 123; total SLN, n ¼ 342. ICG, indocyanine green; SLN, sentinel lymph node. Paley et al. Fluorescence imaging detection of sentinel lymph nodes in endometrial cancer. Am J Obstet Gynecol 2016.

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PCOG Papers

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TABLE 3

TABLE 4

Clinicopathologic characteristics of patients undergoing completion lymphadenectomy (n [ 85)a

Performance of SLN mapping in patients undergoing completion lymphadenectomy (n [ 85)

Variable

n (%)

Stage (final pathology)

Variable

n (%)

Patients with any nodal metastasis after completion lymphadenectomy on final H&E

9 (10.6%)

Sensitivity of SLN mapping

Ia

49 (57%)

Touch prep

11/14 (78.6%) 95% CI (49.2
95.5%)

Ib

22 (26%)

Final H&E

9/9 (100%) 95% CI (66.4
100%)

II

1 (1%) 4 (5%)

Patients with isolated metastasis in SLN after completion lymphadenectomy on final H&E

4/9 (44%)

IIIa IIIc1

4 (5%)

IIIc2

5 (6%)

Grade (final pathology endometrioid only) 1

32 (46%)

2

24 (34%)

3

14 (20%)

Histology (final pathology) Endometrioid

70 (82%)

Serous

10 (12%)

Clear cell

3 (3.5%)

Carcinosarcoma

2 (2.5%)

Intraoperative tumor size, cm 22

8 (9%)

>22

77 (91%)

a

Overall, 29 of 85 (34%) patients in whom completion lymphadenectomy was performed had high-grade histologies of any histologic subtype. Paley et al. Fluorescence imaging detection of sentinel lymph nodes in endometrial cancer. Am J Obstet Gynecol 2016.

allows the omission of LAN, thereby averting unnecessary morbidity while potentially decreasing operative times and costs. Specifically, women with grade 1 or 2 endometrioid histology, tumors confined to the inner half of the myometrium, and tumor diameter 1 cm or less have been demonstrated consistently to have negligible risk of lymphatic involvement (<1%).4,6,7,18 Results from 2 randomized trials, the Italian collaborative trial and the ASTEC trial, reported that women undergoing LAN experienced substantially greater rates of surgical morbidity (risk ratio, 3.72; 95% CI, 1.04
13.27) and lymphatic complications (risk ratio,

CI, confidence interval; H&E, hematoxylin and eosin; SLN, sentinel lymph node. Paley et al. Fluorescence imaging detection of sentinel lymph nodes in endometrial cancer. Am J Obstet Gynecol 2016.

8.39; 95% CI, 4.06
17.33) compared with women undergoing hysterectomy and bilateral salpingo-oophorectomy alone.2,3 Both trials have undergone criticism, with significant flaws in methodology being raised.19-21 Both included unselected women with EC with the majority being at low risk for lymphatic spread. In addition, adjuvant therapy was at the discretion of the treating physician and did not differ depending on lymph node status. Finally, in 1 of the trials more than half of the patients had 9 or fewer lymph nodes procured. Each of these factors severely underpowered the trials to detect an impact of LAN on survival. SLN mapping has become the standard of care to assess lymphatic involvement in several solid tumors, most notably breast cancer, and the collective experience with SLN mapping in EC is increasing. A prospective, multiinstitutional trial, the SENTI-ENDO study, reported that SLN biopsy performed well in apparent early-stage EC with sensitivity of 84%.14 Many single-institution reports of retrospective experience with SLN mapping in EC have been encouraging, but the majority have focused on women at low risk for lymphatic dissemination. One of the largest single-institution cohorts suggested that strict adherence to a SLN mapping algorithm may be a reliable alternative to PPALAN with a false-negative rate of 2% when the algorithm was retrospectively applied.15 Although this trial by the group at Memorial Sloan Kettering is hypothesis-

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generating, the true false-negative rate with their algorithm is unknown because full LAN was not performed in all patients. Furthermore, the Memorial study, as well as many others, has incorporated ultrastaging with immunohistochemistry designating SLNs positive if they contained isolated tumor cells (ITCs) in a node otherwise negative on H&E analysis. The clinical significance of this finding in EC is unclear. The experience in breast cancer may be considered a cautionary tale. The ACOSOGZ10 and NSABP B-32 trials both demonstrated independently that ITCs were not clinically significant in patients with breast cancer and did not impact overall survival and thus discouraged the use of IHC for detecting them.22,23 Particularly, in light of 2 large independent randomized trials failing to document a beneficial impact of LAN on disease-free survival or overall survival in a cohort composed mainly of women with EC at low risk for extrauterine spread,2,3 our group sought to prospectively evaluate the feasibility and true accuracy of SLN mapping in women at sufficient risk for nodal metastasis in whom systematic LAN would be indicated in our practice; however the clinical significance of ITCs in a lymph node otherwise negative on H&E evaluation, specifically in EC, is a potentially interesting area for future scientific inquiry. The larger studies evaluating SLN mapping in EC have used a combination of blue dye and radioactive technetium99 microsulfur colloid. Table 5 lists

PCOG Papers

ajog.org reported series of SLN mapping with ICG fluorescence imaging. SLN with ICG consistently produced greater unilateral and bilateral detection rates. Holloway et al.24 compared ICG with blue dye with all 35 patients receiving dual injections. They found a superior bilateral SLN detection rate with ICG compared with blue dye (97% vs 77%, P ¼ .03). Similarly, How et al.25 compared ICG, technetium, and blue dye in 100 patients with all participants undergoing injection with all 3 tracers. ICG was associated with a greater bilateral rate of detection than blue dye (65% vs 45%, P ¼ .002), and there was no difference between ICG and technetium (65% vs 71%, P ¼.36). In our series, at least 1 SLN was identified in 96.7% of patients, which is consistent with previous reports of ICG detection in EC (85
100%, Table 5). Our bilateral detection rate (80%) also is comparable with other groups (60
97%, Table 5). Our findings, along with previous reports, indicate that intracervical ICG injection with fluorescence imaging has reproducibly high detection rates in EC.17,24-27 Another aim of our study was to evaluate the accuracy of ICG-mediated SLN mapping in EC, and our findings suggest a low false-negative rate. In our pilot study, which selectively assessed the sensitivity of ICG SLN mapping in women at significant risk for lymphatic dissemination, SLN mapping identified all women with stage IIIC disease. Low false-negative rates from other centers are also encouraging (5
10%), as seen in Table 5. Furthermore, our data support the assumption that in women with negative SLNs, the likelihood of lymphatic dissemination to nonsentinel nodes is low. In our series, the sentinel node was the only positive node in 44% of cases. Other groups have reported similar high proportions of lymphatic spread confined only to SLN’s.25,28,29 Although intraoperative touch prep of SLNs yielded a sensitivity of 78.6% in our series, in all 3 of the false-negative touch preps, H&E detected a single micrometastasis (1.5 mm) and no metastatic disease was detected in any of the nonsentinel nodes on final pathologic evaluation. Additionally, there were

TABLE 5

SLN mapping with fluorescence imaging Author

Any SLN detected, n (%)

n

Rossi et al., 201227 Holloway et al., 2012

20 24

12 (60%)

5

34 (97%)

10

197

188 (95%)

156 (79%)

NR

Plante et al., 201526

50

48 (96%)

44 (88%)

100

87 (87%)

65 (65%)

10

123

119 (96.7%)

99 (80%)

0

How et al., 2015 Paley 2015

35 (100%)

False-negative rate %

Jewell et al., 201417 25

35

14 (85%)

Bilateral SLN detected, n (%)

6.7

NR, not reported; SLN, sentinel lymph node. Paley et al. Fluorescence imaging detection of sentinel lymph nodes in endometrial cancer. Am J Obstet Gynecol 2016.

no micrometastasis detected on final H&E in any of the women who did not meet criteria warranting completion PPALAN. For both surgeon and patient the key information to be gleaned from intraoperative imprint cytology is the status of the nonsentinel nodes. A negative touch prep accurately detected no additional metastatic foci in nonsentinel nodes on final pathologic evaluation in 100% of cases in our small pilot series. If confirmed in larger series, micrometastasis would be expected to pose a risk of a false-negative finding on touch prep SLN evaluation; however, one could presume that the majority of patients would not harbor metastatic disease in nonsentinel nodes, providing key intraoperative guidance. On the other hand, if the surgeon’s philosophy is that if removal of microscopically lymph nodes is not beneficial to planning adjuvant therapy, it could be argued that touch prep can be eliminated because it does not alter management and increases the cost of care. A comparison of the distribution of SLN between centers also supports the reproducibility of ICG mapping and even suggests that SLN mapping allows for SLN detection in basins not routinely sampled in EC staging. In our series SLNs were identified most commonly in the external iliac and obturator basins (70%), closely approximating other ICG SLN mapping EC series (76
89%).24-26 Cervical injection of ICG led to SLN mapping in a periaortic or presacral node in 9.5% of our cases ,which is in

agreement with the experience of other groups (4.5
14%).24-26 The average operative time in our SLN mapping cohort was 161 minutes, with a range of 60
360 minutes. This finding is in line with a cohort of women in our practice undergoing robotic EC staging without SLN mapping (mean¼184 minutes, range, 78
364 minutes).30 This finding suggests that even with continuing to introduce residents and fellows into the majority of robotic cases in our practice, there was no unacceptable lengthening of operative times with the mapping procedure. Our major complication rate was low at 3.3% (4/123 participants) and is consistent in our previous prospectively reported series of women undergoing robotic EC staging without SLN mapping at 6.4% (24/377 women).30 No complications directly attributable to SLN mapping or the ICG dye were encountered. If SLN mapping in EC becomes an accepted standard of care, ICG fluorescence imaging will likely be the optimal approach. ICG is user friendly, costeffective, and safe. SLN mapping lends itself to a minimally invasive surgical platform and ICG is compatible with robotic or laparoscopic procedures. ICG dye has a superior safety profile compared with blue dye and technetium-99 microsulfur colloid, and ICG avoids the cumbersome nature of using a radioactive material (handling precautions, injection prior to anesthesia, lymphoscintigraphy, requirement of a gamma probe and counter).

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PCOG Papers Our study has several limitations worthy of mention, including a singleinstitution design and small number of cases. Another limitation is that before initiating our institutional review board
approved trial, SLN mapping was not performed in patients with EC in our practice; thus, the initial learning curve associated with implementing a new procedure may have increased our SLN mapping failures. There were no instances of SPY scope NIR imaging system failure; thus, the majority of mapping failures were likely attributable to poor dye injection technique. Possibly compensating for the SLN mapping learning curve was the experience of the gynecologic oncology team, who had collectively performed more than 4000 robotic procedures before study initiation. We also acknowledge that of the patients meeting study criteria for completion PPALAN, in 16% procurement of periaortic nodes was not feasible and the trial did not mandate conversion to laparotomy to complete PPALAN. Although this occurred in a small proportion of cases, it may have underestimated the false negative rate. Our study is strengthened by its prospective design and the availability of an ongoing prospective database with which to compare outcomes in cases prior to the SLN mapping trial. Another strength is proceeding with completion PPALAN in cases included in the SLN diagnostic accuracy analysis allows for a more precise assessment of the sensitivity of this technique. In summary, intraoperative SLN mapping using fluorescence imaging with ICG at the time of EC staging is feasible and yields reproducibly high rates of detection. We believe that a prospective, multi-institutional trial aimed at validating the benefit of SLN mapping should focus on women at significant risk of lymph node dissemination. In our pilot study, which excluded women at negligible risk of lymph node metastasis, SLN mapping identified all women with stage IIIC disease. Our low false-negative rates are encouraging and if confirmed in larger series, SLN mapping could lead to a paradigm shift in the surgical

ajog.org management of women with EC that would be anticipated to reduce the morbidity, operative times, and costs associated with complete PPALAN. n References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63: 11-30. 2. ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized study. Lancet 2009;373:125-36. 3. Benedetii Panici P, Basile S, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008; 100:1707-16. 4. Mariani A, Webb MJ, Keeney GL, Haddock M, Calori G, Podratz K. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000; 182:1506-19. 5. Dowdy SC, Borah BJ, Bakkum-Gamex JN, Weaver AL, McGree ME, Hass LR. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol 2012;127: 5-10. 6. Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008;109:11-8. 7. Kang S, Kang WD, Chung HH, Jeong DH, Seo SS, Lee JM. Preoperative identification of a low-risk group for lymph node metastasis in endometrioid adenocarcinoma of the endometrium. J Clin Oncol 2012;30:1329-34. 8. Convery PA, Cantrell LA, Di Santo N, et al. Retrospective review of an intraoperative algorithm to predict lymph node metastasis in low-grade endometrial adenocarcinoma. Gynecol Oncol 2011;123:65-70. 9. Milam M, Java J, Walker J, Metzinger D, Coleman R. Incidence of nodal metastasis in endometrioid endometrial cancer risk groups: a Gynecologic Oncology Group multicenter review. Gynecol Oncol 2011;120:S4. 10. Veronesi U, Pagnelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546-53. 11. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999;230:453-63. 12. Van der Zee AG, Oonk MH, De Hujllu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008;26:884-9. 13. Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al.

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PCOG Papers

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Author and article information From the Pacific Gynecology Specialists, Division of Gynecologic Oncology, Seattle, WA (Drs Paley, Veljovich, Press, and Shah); and CellNetix Pathology & Laboratories, Seattle, WA (Drs Isacson and Pizer). Received Oct. 14, 2015; revised Dec. 9, 2015; accepted Dec. 23, 2015. This study was conducted at the Swedish Medical Center, Seattle, Washington, USA.

Disclosures: D.S.V. and C.A.S. received consulting honoraria in the amount of $2500 from Intuitive Surgical, Inc. D.S.V. has owned 200 shares of common stock in Intuitive Surgical, Inc, that had a maximum value of $117,134 and P.J.P has owned 50 shares of common stock in Intuitive Surgical, Inc, that had a maximum value of $29,284 in the past 3 years. Funded by a Swedish Foundation Philanthropy at Work Program. Intuitive Surgical, Inc. manufactures the da Vinci Surgical System used in this paper and provided no financial support for this study. Presented at the Pacific Coast Obstetrical and Gynecological Society Eighty-Second Annual Meeting, Kahuku, Oahu, Hawaii, Sept. 2
6, 2015. Corresponding author: Pamela Paley, MD. ppaley@ pacificgyn.com

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