Unexpected locations of sentinel lymph nodes in ...

YGYNO-976818; No. of pages: 6; 4C: Gynecologic Oncology xxx (2017) xxx–xxx

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Unexpected locations of sentinel lymph nodes in endometrial cancer Jeffrey How a, Irina Boldeanu a, Susie Lau a, Shannon Salvador a, Emily How a, Raphael Gotlieb a,b, Jeremie Abitbol a,c, Ajay Halder a, Zainab Amajoud a, Stephan Probst d, Sonya Brin a, Walter Gotlieb a,⁎ a

Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Quebec H2T 1E2, Canada Division of Experimental Surgery, Faculty of Medicine, McGill University, Montreal, Quebec H2T 1E2, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec H2T 1E2, Canada d Department of Nuclear Medicine, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Quebec H2T 1E2, Canada b c

H I G H L I G H T S • SLN are detected in the presacral, hypogastric vein, and parametrial areas. • These areas are not harvested in a routine lymphadenectomy. • SLN is the most likely, and frequently only, lymph node to contain metastasis.

a r t i c l e

i n f o

Article history: Received 4 June 2017 Received in revised form 5 July 2017 Accepted 10 July 2017 Available online xxxx

a b s t r a c t Introduction. To evaluate the anatomical location of sentinel lymph nodes (SLN) following intra-operative cervical injection in endometrial cancer. Methods. All consecutive patients with endometrial cancer undergoing sentinel lymph node mapping were included in this prospective study following intra-operative cervical injection of tracers. Areas of SLN detection distribution were mapped. Results. Among 436 patients undergoing SLN mapping, there were 1095 SLNs removed, and 7.9% of these SLNs found in 13.1% of patients, were detected in areas not routinely harvested during a standard lymph node dissection. These included the internal iliac vein, parametrial, and pre-sacral areas. The SLN was the only positive node in 46.1% (15/36) of cases with successful mapping and completion lymphadenectomy, including 3 cases where the sentinel node in the atypical location was the only node with metastatic disease. Conclusion. SLN mapping using intra-operative cervical injection is capable to map out areas not typically included in a standard lymphadenectomy. The sentinel node is the most relevant lymph node to analyze and may enable to discover metastatic disease in unusual areas. © 2017 Elsevier Inc. All rights reserved.

1. Introduction Extent of lymph node dissection in clinical early stage endometrial cancer continues to be a controversial topic with current recommendations range from no lymph node dissection to complete pelvic and para-aortic lymphadenectomy (LND) [1]. In addition, 2 randomized control trials did not demonstrate any survival benefit when comparing those who received systematic pelvic LNDs compared to those who did not [2,3]. Supporters of routine LND use the LN status to guide post-operative adjuvant therapy while supporters of no LND ⁎ Corresponding author at: Division of Gynecologic Oncology, McGill University SMBD Jewish General Hospital, 3755 Chemin de la Cote-Ste-Catherine, Montreal, QC H3T 1E2, Canada. E-mail address: [email protected] (W. Gotlieb).

instead choose to determine adjuvant therapy based on age and uterine risk factors [4,5]. Unfortunately, both strategies risk overor under-treatment of disease [1]. Sentinel lymph node (SLN) mapping is already established in melanoma [6] breast cancer [7], and vulvar cancer and is showing promise in gynecologic malignancies such as cervical [8] and endometrial cancer [9–12]. As this technique continues to be investigated and refined in endometrial cancer, a number of various injection sites (subserosal myometrial, hysteroscopic peri-tumoral, and cervical) and utilized tracers (blue, technetium, and indocyanine green) have been reported in the literature [13–16]. Although there is no consensus on the optimal technique, the cervical injection route is the most practical and feasible. Despite criticism of the notion that it may not map lymphatic areas draining the uterine fundus, the cervical injection method is still the most reproducible method. In

http://dx.doi.org/10.1016/j.ygyno.2017.07.125 0090-8258/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: J. How, et al., Unexpected locations of sentinel lymph nodes in endometrial cancer, Gynecol Oncol (2017), http:// dx.doi.org/10.1016/j.ygyno.2017.07.125

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J. How et al. / Gynecologic Oncology xxx (2017) xxx–xxx

this study, we seek to determine the areas of SLN detection following an intra-operative cervical injection for patients with endometrial cancer. 2. Methods 2.1. Patient population All consecutive patients diagnosed with clinical stage I endometrial cancer undergoing surgical staging from December 2010 to September 2016 were included into the study. Patients who either had advanced stage disease or prior hysterectomy were excluded from the study. 2.2. Procedure The study was approved by the hospital Institutional Research Board and all patients signed informed consent. All surgeries were performed by North American fellowship trained gynecologic oncologists. Prior to the initiation of this study, the team had performed close to 400 robotic surgeries and had performed sentinel lymph node sampling for vulvar and cervical cancers since 2003. All patients underwent minimally-invasive surgical staging using roboticassisted (using the da Vinci ® surgical platform) or conventional laparoscopic total hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node mapping. For the SLN mapping procedure, all patients underwent an intraoperative cervical injection using combinations of the following tracers [11,17]: 1) Blue dye either methylene blue (methylene blue injection USP, Omega laboratories, Montreal, Canada) or patent blue (patent blue sodium injection Guebert product imported by Methapharm Inc., Brantford, ON, Canada). 2) 99mTc-SC (Tc, microsulfur colloid, Pharmalogic PET services, Montreal, Canada) 3) Indocyanine green (IC-Green, Akorn Pharmaceuticals, Lake Forest, USA) Per patient, the total volume of the injection medium was 4 ml (four 1 ml syringes). The protocol for SLN mapping was similar to the algorithm developed by Abu Rustum et al. [9]. The injection was performed after prepping the patient, just before incision of the skin. The cervix was injected at the 3 o'clock and 9 o'clock positions. At each of these positions, a 1 ml syringe was injected superficially (2–3 mm) into the cervical submucosa and deep (3– cm). The hypothesis underlying the deep injection of the cervix was to reach the lower uterine segment in order to allow for diffusion of the dye into the surrounding uterine area. The pararectal and paravesical spaces were systematically opened for all patients. We always looked at the para-aortic and presacral spaces to determine whether there was any tracer tracking to those areas. If we saw lymphatic channels tracking to the para-aortic or pre-sacral spaces, we subsequently opened these spaces to perform the LN dissection for the SLN. Detection of the SLN was accomplished through any of the three following methods: a) direct visualization of either blue colored lymphatics/nodes b) visualization of green colored lymphatics/nodes via immunofluorescent imaging mode on the da Vinci ® surgical platform c) detection of radioactive nodes by a handheld gamma probe (Daniel Probe, RMD Instruments Corp., Watertown, MA, USA). Detected SLNs were removed and sent for intra-operative frozen section evaluation. In addition to SLN dissection, all patients who had their surgery preceding September 3, 2014 (284 cases) underwent routine complete pelvic lymph node dissection as the predictive value of SLN mapping technique for endometrial cancer was being established at this institution. Defined according to the Gynecologic Oncology Group Surgical Procedures Manual, a complete pelvic lymphadenectomy constituted bilateral

removal of nodal tissue from the distal one-half of each common iliac artery, anterior and medical aspect of the external iliac artery and vein, and obturator fat pad anterior to the obturator nerve [18]. Following September 3, 2014, all patients followed the SLN mapping algorithm outlined by the Memorial Sloan Kettering Cancer Center group and published in the NCCN guidelines [19–21] which entailed 1) peritoneal and serosal evaluation and washings 2) retroperitoneal evaluation including excision of all mapped SLNs and suspicious LNs (N1 cm) regardless of results of mapping 3) Side-specific lymph node dissection was performed if there is no mapping on the hemi-pelvis [22]. Para-aortic lymphadenectomy was performed if the patient had grossly enlarged pelvic LNs suspicious for malignancy or a positive SLN on intra-operative frozen section. Furthermore, pre-operative type II (papillary serous, clear cell, or carcinosarcoma) or grade 3 endometrioid adenocarcinomas had a para-aortic lymphadenectomy. Following completion of lymph node sampling, a total hysterectomy and bilateral salpingo-oophorectomy was performed.

2.3. Histopathology At our institution, all pre-operative endometrial biopsies underwent central review by two pathologists (A.F. and M.P.). Intra-operative frozen section analysis of SLNs was performed in every case. LNs were bisected and stained with hematoxylin and eosin (H&E) staining. Due to budgetary restrictions, only cases performed from September 2011 to August 2014 had the SLN undergo pathologic ultrastaging, with serial sectioning of the entire sentinel lymph node at 200 to 300 μm, with 3 consecutive H&E levels with one slide for immunostaining per level. Immunostaining for cytokeratin (clone AE1/AE3, Milipore Inc., dilution 1:150) was performed on SLNs after H&E routine histologic examination on final pathologic specimen.

2.4. Data collection and statistical analysis All data were prospectively gathered. Using a uniform electronic data recording sheet, all SLN locations and the tracer(s) used to detect the SLN were prospectively documented and maintained in our database as our previous two published studies [11,17]. One study nurse (S.B) documented prospectively during the operative procedure and received training prior to study initiation to ensure compliance to the protocol. Outcomes of interest included overall detection rate, bilateral detection rate, and the distribution of detected SLNs. Detection rate was calculated as the number of patients with at least one detected SLN divided by the total number of patients who underwent SLN mapping. Bilateral detection rates were calculated as the number of patients with detection of the SLN on both sides of the pelvis divided by the total number of patients. Tracer combinations were compared using ×2 test with statistical significance defined as a p-value b 0.05. The distribution of the detectable SLNs was presented as proportions of SLNs found in the following areas: 1) common iliac 2) iliac bifurcation 3) external iliac 4) internal iliac vein (hypogastric vein area, well posterior to the uterine artery, deep in the pararectal fossa) 5) Obturator 6) parametrial 7) pre-sacral 8) para-aortic.

3. Results Demographic and clinicopathologic data is presented in Table 1. Nearly half of the patients (48.2%) had an intra-operative cervical injection of blue and 99mTc-SC while the second most common was a combination of blue, 99mTc-SC, and ICG (41.7%).



3.3. Metastatic disease

Table 1 Patient and tumor characteristics (N = 436). Age (years) BMI (kg/m2) Histology Endometrioid Non-endometrioid Serous Clear cell Carcinosarcoma Other Grade I II III Stage I II IIIA/B IIIC Lymphovascular invasion Present Myometrial invasion N50%

64.2 (+/−10.9) 31.8 (+/−8.7) 355 (81.4%) 49 (11.2%) 13 (2.9%) 16 (3.7%) 3 (0.69%) 198 (45.4%) 119 (27.3%) 119 (27.3%) 348 (79.8%) 27 (6.2%) 13 (2.9%) 47 (10.7%) 89 (20.4%) 129 (29.6%)

BMI = body mass index. 99mTc-SC = technetium-99. ICG = indocyanine green. Age and BMI are reported in mean (+/− standard deviation) with the rest of the parameters reported as n (%).

3.1. Detection rate Among the 436 patients in the study, there were no allergic reactions or toxicities and there were 398 patients with at least one SLN detected making an overall detection rate of 91.3%. Bilateral detection rate was 71.1% (310/436).

3.2. SLN distribution Most of the patients (98.0%) had SLNs detectable in the pelvic region (Table 2). Distribution of the 1095 SLNs among the 436 patients is shown in Fig. 1. Among the 1095 SLNs, the obturator region (46.1%) was the most common location of the SLN followed by the external iliac artery region (25.3%). 5.8% of detectable SLNs were located in the para-aortic region with approximately half of the para-aortic SLNs (33 of 64) located above the inferior mesenteric artery. In addition, 87 SLNs were detected in the internal iliac vein, parametrial, and pre-sacral areas in 57 patients, and accounted for 3.5%, 1.2%, and 3.2% of all SLN nodes, respectively (Fig. 2).

Table 2 Detection of SLNs. Overall SLN detection in patients Yes No

398 38

SLN detection in 398 patients Unilateral Bilateral Pelvic only Para-aortic only Both

88 310 359 8 31

Total number of nodes in 436 patients SLN detected Non-SLN removed

1095 2975

Number of nodes per patient SLN detected Non-SLN removed

2.5 6.8

SLN = sentinel lymph node.

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Among the 436 patients, there were 47 patients with metastatic nodes. Among these patients, most the patients were endometrioid histologic subtype (51.06%) followed by papillary serous (25.5%), carcinosarcoma (12.8%), and clear cell (10.6%). The majority of patients had deep myometrial invasion (89.4%) and presence of LVSI (76.6%). The SLN was detectable in 39 of the 47 cases. Among the 39 cases, there were 3 cases with successful unilateral SLN detection but had failure to detect a SLN in the contralateral pelvic region where metastatic nodes were found following the NCCN algorithm. Additionally, there were three false negative SLNs. In one case, the false negative SLN and the metastatic node were juxtaposed in the para-aortic area and in the remaining 2 cases the SLNs were falsely negative and the reason could not be determined. 43 patients had positive nodes and a systematic pelvic LND, and 36 of them had successful SLN detection. The SLN was the only positive node in 15 of these 36 cases (41.6%) including 3 cases in which the positive sentinel node was located in the medial portion of the hypogastric vein area or the presacral area. There were an additional 30 patients with positive SLNs, making a total of 41 positive SLNs. The majority of these metastatic nodes were located in the obturator (17/41) or external iliac (11/41) regions. We found positive SLNs above the infra-mesenteric artery in 3 patients, 2 positive nodes in the medial portion of the hypogastric vein area, and 1 positive node in the presacral area, for a total of 12.7% of stage IIIc patients. 4. Discussion Detection rates of SLN in this study are compatible with other published studies that have demonstrated favorable detection rates following cervical injection [9,11,16,23,24]. Evaluation of the distribution of SLN mapping demonstrated the obturator and the external iliac area as the most frequent area for SLN detection, representing 46.1% and 25.3% of all resected SLNs, respectively. Despite the concern to potentially miss drainage of fundal tumors, the intra-operative cervical injection technique still mapped to the paraaortic area, with 5.8% of all detectable SLNs found in this region. Specifically, in 19 patients of the 38 patients with para-aortic SLN detection, more than half of the SLNs (33 of 64) were detectable above the inferior mesenteric artery. Interestingly, SLN mapping utilizing the cervical route detected SLNs in the internal iliac vein, parametrial, and presacral areas in 13.1% (57/ 436) of patients, while the sum of the resected nodes in these areas comprised close to 8% of all detectable SLNs. These SLNs found in nodal areas that are not harvested during routine lymphadenectomies are relevant as the SLN is the first lymph node in a chain of nodes that drains the lymphatics of the primary tumor and therefore it is the most likely location of metastatic disease [25]. The SLN was the only positive node in 46.1% (15/36) cases with successful mapping and complete pelvic lymphadenectomy. Among the 30 patients with a complete pelvic lymphadenectomy and positive SLNs, there were 41 metastatic SLNs detected, with 14.6% (6/41) located in areas not routinely sampled in a standard lymphadenectomy. The 6 metastatic SLNs belonged to 6 patients and half had the metastatic SLN node as the only positive node (2 cases in medial portion of the hypogastric vein and 1 case in the presacral region). These findings of metastatic lymph nodes in atypical regions were similar to observations by Geppert et al. where they found that nearly 1/3 of node positive patients had LN metastases in the lymphatic pathway draining to the internal iliac/presacral lymph nodes [26]. Thus, given that the SLN is the most likely LN to harbor metastases and can map in areas non-traditionally sampled, it is the most relevant node to provide to the pathologist. This is further supported by a recent multicenter prospective cohort study that demonstrated similar diagnostic accuracy rates for LN metastases comparing SLN mapping and


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Fig. 1. Distribution of 1095 SLNs in 436 patients R. = right, L. = left, PA = para-aortic, CI = common iliac, IB = iliac bifurcation, EI = external iliac, HV = hypogastric vein, OB = obturator, PM = parametrial, PS = presacral.

complete pelvic lymphadenectomy [27]. Although not all recurrences can be prevented with staging lymphadenectomy, side wall recurrences in nodal basins should be minimized if there is any value of identification of appropriate lymph nodes with their subsequent treatment. In this context, we found in a previous study that there was a 68% reduction of recurrences along the pelvic sidewall at 48 months by integration of a SLN, algorithm (HR 0.32, 95% CI 0.14–0.73, p = 0.007) [28]. Another study has also observed a propensity for less locoregional recurrence in patients who underwent SLN mapping [29]. Thus, given evidence supporting that SLN mapping enables the surgeon to localize the most likely node containing metastatic disease and potentially in locations outside the bounds of a traditional pelvic lymphadenectomy, SLN mapping may offer an effective strategy to stage patients with endometrial cancer that has not been shown to be inferior to systematic pelvic lymphadenectomy [27]. Future studies should compare survival outcomes between those undergoing SLN mapping and those undergoing complete lympadenectomy. This study had several limitations. The first limitation was the limited efficacy of the rigid, straight gamma probe used that hindered the capacity to detect SLNs. The lack of orientation did not allow distinction from the background radiation due to the nearby highly radioactive cervix. In some cases, blue or immunofluorescent green channels could be detected but the SLN could not be detected by blue, ICG, or radioactivity in vivo. However, once the tissue suspicious to contain the SLN was removed, radioactivity could be detected ex-vivo using the radiation probe in the operating room. LN identified in the uncommon regions were always identified by ICG, sometimes in addition to blue. Presence of Tc99 was always confirmed either in vivo or ex vivo after removal of the suspected ICG visible lymph node. Following an acceptably low false negative rate [11,17] in our study cohort of the first 284 cases that underwent completion LND, we applied the NCCN algorithm for SLN in the remaining 152 patients (with 30 cases having a side-specific or full pelvic LND). Barlin et al. also demonstrated that application of a SLN algorithm

can reduce the false-negative rate to 2%, allowing appropriate surgical staging of disease [22]. Furthermore, the SLN is the most likely location for nodal metastasis, being the only positive node in 46.1% of all successfully mapped stage IIIC cases, consistent with other studies [9,11,17]. Although full para-aortic LND was not routinely performed, this area was always examined, and 38 patients were found to have the sentinel lymph node in the para-aortic area. We cannot exclude cases that we would not be able to detect via cervical and lower isthmic injection. However, the risk of isolated para-aortic metastases in early clinical stage endometrial cancer is rare (approximately 1%) even in high grade lesions [30], and pooling the results of 18 studies from 1983 to 2011 revealed a 1.5% cumulative rate of isolated para-aortic metastases [31]. Not all patients underwent ultrastaging, due to budgetary restrictions, and out of the 8% of SLN detected in the non-routinely sampled areas, there may have been more cases with detectable microscopic disease or isolated tumor cells. Retroactive ultrastaging of SLNs in 3 patients with negative nodes but without ultrastaging who suffered a recurrence, revealed metastases in 2 of them, leading to a change in policy in 2017, with universal ultrastaging of all sentinel lymph nodes at our institution [28]. The findings support the use of SLN mapping using an intra-operative cervical injection, which revealed SLN in areas not routinely harvested by a standard lymphadenectomy. Conflict of interest statement All the authors declare no conflict of interest.

Acknowledgements This work was in part supported by the Israel Cancer Research Foundation, the Gloria's Girls Fund, the Jewish General Hospital Foundation, the Susan and Jonathan Wener Fund, and the Garber Fund. We would like to thank Ben Segev's contribution with the creation of the drawing in Fig. 1.



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Fig. 2. Direct (left panel) and immunofluorescent (right panel) visualization following intra-cervical injection of ICG. SLN detection that is high in para-aortic region just inferior to duodenum with lymphatic pathway tracking upwards after passing the midline. SLN detection in right presacral area. SLN detection in right parametrial area. SLN detection adjacent to right hypogastric vein.

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