Ann Surg Oncol https://doi.org/10.1245/s10434-023-14065-3 ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY Accuracy and Survival Outcomes after National Implementation of Sentinel Lymph Node Biopsy in Early Stage Endometrial Cancer Silvia Cabrera, MD, PhD1 , Natalia R. Gómez‑Hidalgo, MD, PhD1, Virginia García‑Pineda, MD2, Vicente Bebia, MD1, Sergi Fernández‑González, MD3, Paula Alonso, MD4, Tomás Rodríguez‑Gómez, MD5, Pere Fusté, MD, PhD6, Myriam Gracia‑Segovia, MD2, Cristina Lorenzo, MD7, Enrique Chacon, MD8, Fernando Roldan Rivas, MD9, Octavio Arencibia, MD10, Marina Martí Edo, MD11, Soledad Fidalgo, MD12, Josep Sanchis, MD13, Pablo Padilla‑Iserte, MD, PhD14, Manuel Pantoja‑Garrido, MD15, Sergio Martínez, MD, PhD16, Ricard Peiró, MD17, Cecilia Escayola, MD18, M. Reyes Oliver‑Pérez, MD, PhD19, Cristina Aghababyan, MD20, Carmen Tauste, MD21, Sara Morales, MD22, Anna Torrent, MD23, Jesus Utrilla‑Layna, MD24, Francesc Fargas, MD25, Ana Calvo, MD26, Laura Aller de Pace, MD27, and Antonio Gil‑Moreno, MD, PhD1on behalf of the Spain-GOG and the MULTISENT Study Group 1 Gynecologic Oncology Unit, Hospital Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 2Gynecologic Oncology Unit, La Paz University Hospital, Madrid, Spain; 3Gynecologic Oncology Unit, Hospital Universitari de Bellvitge, Barcelona, Spain; 4Department of Obstetrics and Gynecology, Hospital Universitario Gregorio Marañón, Madrid, Spain; 5Department of Obstetrics and Gynecology, Hospital Virgen de la Victoria, Málaga, Spain; 6Gynecologic Oncology Unit, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain; 7Department of Obstetrics and Gynecology, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain; 8Department of Obstetrics and Gynecology, Clinica Universidad de Navarra, Pamplona, Spain; 9 Department of Obstetrics and Gynecology, Hospital Clínico Universitario de Zaragoza, Zaragoza, Spain; 10Department of Obstetrics and Gynecology, Hospital Universitario Gran Canarias Dr. Negrín, Las Palmas, Spain; 11Department of Obstetrics and Gynecology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; 12Department of Obstetrics and Gynecology, Hospital Universitario Central de Asturias, Oviedo, Spain; 13Gynecologic Oncology Unit, Instituto Valenciano de Oncologia (IVO), Valencia, Spain; 14Gynecologic Oncology Unit, Hospital Politécnico Universitario La Fe, Valencia, Spain; 15Department of Obstetrics and Gynecology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 16Department of Gynecology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 17Department of Obstetrics and Gynecology, Hospital General de Catalunya, Barcelona, Spain; 18Department of Obstetrics and Gynecology, El Pilar Quiron, Barcelona, Spain; 19Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre, 12 de Octubre Research Institute (i+12), Complutense University of Madrid, Madrid, Spain; 20Department of Obstetrics and Gynecology, Hospital General Universitario de Valencia, Valencia, Spain; 21Department of Obstetrics and Gynecology, Hospital Universitario de Navarra, Pamplona, Spain; 22Department of Obstetrics and Gynecology, Hospital Infanta Leonor, Madrid, Spain; 23Department of Obstetrics and Gynecology, Hospital Universitari Son Espases, Palma de Mallorca, Spain; 24Department of Obstetrics and Gynecology, Fundación Jimenez Diaz, Madrid, Spain; 25Department of Obstetrics and Gynecology, Hospital Universitari Quirón Dexeus, Barcelona, Spain; 26Department of Obstetrics and Gynecology, Hospital Universitari Arnau de Vilanova, Lleida, Spain; 27Department of Obstetrics and Gynecology, Hospital Marqués de Valdecilla, Santander, Spain © The Author(s) 2023 First Received: 11 May 2023 ABSTRACT Accepted: 23 June 2023 Background. Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endome- S. Cabrera, MD, PhD trial cancer at early stage, which is key to tailoring adjuvant e-mail: silvia.cabrera@vallhebron.cat Vol.:(0123456789) S. Cabrera et al. treatments. Our aim was to evaluate the national implemen- of low-volume disease. Several protocols for ultrastaging tation of SLN biopsy in terms of accuracy to detect nodal have been reported,11,12 and recently one-step nucleic acid disease in a clinical setting and oncologic outcomes accord- amplification (OSNA) has emerged as a new strategy to ing to the volume of nodal disease. detect node disease with high accuracy.13,14 Low-volume Patients and Methods. A total of 29 Spanish centers par- disease, a term that includes micrometastases and isolated ticipated in this retrospective, multicenter registry including tumor cells (ITC), represents more than 50% of the nodal patients with endometrial adenocarcinoma at preoperative disease diagnosed in endometrial cancer when using SLN early stage who had undergone SLN biopsy between 2015 biopsy.7,8,15 The clinical significance of these small amounts and 2021. Each center collected data regarding demographic, of malignant cells in SLN has been assessed,15–19 as it sup- clinical, histologic, therapeutic, and survival characteristics. poses a new phenomenon that needs to be elucidated at the Results. A total of 892 patients were enrolled. After the time of clinical implementation of SLN biopsy in EC man- surgery, 12.9% were suprastaged to FIGO 2009 stages agement. Previous reports suggest that isolated tumor cells III–IV and 108 patients (12.1%) had nodal involvement: (ITC, clusters of malignant cells less than 0.2 ­mm20) are 54.6% macrometastasis, 22.2% micrometastases, and 23.1% usually present in patients with well-differentiated endome- isolated tumor cells (ITC). Sensitivity of SLN biopsy was trioid histology and limited myometrial invasion,21 entailing 93.7% and false negative rate was 6.2%. After a median no impact on recurrence-free or overall survival of patients follow up of 1.81 years, overall surivial and disease-free with EC. Nevertheless, micrometastases (node metastases survival were significantly lower in patients who had mac- that range between 0.2 and 2 m ­ m20) show worse prognosis rometastases when compared with patients with negative than node-negative patients in several studies.16,22 nodes, micrometastases or ITC. We present the results of a retrospective, consecutive, Conclusions. In our nationwide cohort we obtained high multicenter, national cohort of early-stage EC patients, who sensitivity of SLN biopsy to detect nodal disease. The onco- received SLN biopsy as a part of their surgical protocol. logic outcomes of patients with negative nodes and low- Our primary objective was to evaluate the accuracy of SLN volume disease were similar after tailoring adjuvant treat- biopsy technique to detect nodal disease in a clinical setting, ments. In total, 22% of patients with macrometastasis and assessing factors affecting the detection of disease in the 50% of patients with micrometastasis were at low risk of SLN. Secodary objective was to analyse the oncologic out- nodal metastasis according to their preoperative risk factors, comes of patients according to the volume of nodal disease. revealing the importance of SLN biopsy in the surgical man- agement of patients with early stage EC. PATIENTS AND METHODS Cohort Selection Endometrial cancer (EC) is the most diagnosed gyneco- logical malignancy in developed countries,1 and surgery A total of 29 Spanish centers participated in the setting- remains the cornerstone of its treatment. Surgical treatment up of a retrospective, consecutive, multicenter, national is especially important in early stage disease, when it also registry including patients older than 18 years of age diag- allows for a proper stratification of risk of recurrence and nosed with endometrial cancer (of any grade or histology) helps to tailor adjuvant therapies.2 or endometrial atypical hyperplasia, operated on between Systematic lymphadenectomy in early stage EC has been January 2015 and April 2021 with preoperative clinical stage widely questioned due to the lack of survival impact of this I–II EC FIGO 2009 and who had undergone SLN biopsy strategy reported in different prospective trials.3,4 Neverthe- as a part of their surgical protocol (MULTISENT registry). less, the need to know lymph node status as the most impor- From this national database, we selected patients with final tant prognostic factor in these patients brought the adoption biopsy of adenocarcinoma with at least one SLN detected of sentinel lymph node (SLN) biopsy as a new technique during surgery. Patients with suspected clinical or radio- to assess lymph node disease in patients with early stage logical lymph node disease, advanced stage at diagnosis, EC.2,5 Several prospective trials have reported an excellent those who received neoadjuvant therapy prior to surgery, accuracy of SLN biopsy in detecting lymph node disease,6–10 or histology of uterine sarcomas were excluded. Every par- describing the technical issues implied in achieving a higher ticipating center obtained their institutional review board overall and bilateral detection and bringing to the fore the (IRB) approval. importance of performing ultrastaging of the specimens to increase the detection of disease and equalize, or even Data Extraction increase, the sensitivity of systematic lymphadenectomy. Ultrastaging consists of the ultra-sectioning of SLN and Each participating center collected retrospective data its immunohistochemistry staining to improve the detection regarding demographic, clinical, histologic, therapeutic, and Accuracy and Survival Outcomes after … survival characteristics. SLN biopsy was performed using Imputation of missing values was not performed. Oncologic different tracers [indocyanine green (ICG) alone or com- outcomes were analyzed using the Kaplan–Meier method bined with 99m-Technetium (99mTC), or 99mTC alone or and the log-rank test. Univariate and multivariate adjusted combined with blue dyes] and different sites of injections logistic regression models were used for the comparison (cervical, uterine, and both) according to each center proto- between groups. For the construction of the multivariate col. Intraoperative frozen section of SLN or uterus were per- model, a selection method based on maximum likelihood formed at surgeon’s discretion. SLN found negative in Hema- estimation and Akaike information criterion (AIC) was used, toxilin/Eosin (H/E) routine study were processed according considering all relevant variables related to the primary end to each center’s ultrastaging protocol, although minimum point. ultrastaging protocol should include ultrasectioning and inmunohystochemistry (IHC) staining of SLN or OSNA RESULTS analysis. Disease was classified according to its volume into macrometastases (tumor ≥ 2.0 mm in diameter), microme- Patient and Tumor Characteristics tastases (tumor cell aggregates between 0.2 and 2.0 mm in diameter), or isolated tumor cells (ITC, individual Out of the 1455 patients included in MULTISENT reg- tumor cells or aggregates < 0.2 mm in diameter and < 200 istry, 194 patients had insufficient data to be considered for cells).20 Some centers performed OSNA analysis of the this study, 10 patients presented final histology of endo- specimen, and the volume of the disease was reported as metrial atypical hyperplasia, therefore not meeting inclu- follows: absence of copies of CK19 mRNA were considered sion criteria, and 150 additional patients were not included negative nodes; values < 250 copies/µL of CK19 mRNA were because no SLN was detected after the performance of considered ITC; values between 250 and 4999 copies/µL the technique. Patients without ultrastaging performed on were considered micrometastases; and values ≥ 5000 copies/µL were considered macrometastases.23 For calcu- lating accuracy rates of SLN biopsy we used as reference standard the pathologic result of pelvis ± aortic staging lym- MULTISENT COHORT phadenectomy performed on the same patient. SLNs were n=1455 considered positive when any size of disease was diagnosed through H/E or ultrastaging, although patients with ITCs only on SLN [pN0(i+)] were classified as node negative for FIGO 2009 staging and patients with micrometastases Patients with atypical [pN1(mic)] or macrometastases (pN1) were considered node Patients with incomplete data hyperplasia in final histology positive. n=194 n=10 All variables were recorded in a Research Electronic Data Capture (REDCap)24 electronic database, designed for this study and hosted at Vall d’Hebron Institute of Research (VHIR). After the inclusion of the patient, the investigators Patients without any SLN Patients without ultrastaging of assigned a preoperative risk of lymph node disease accord- detected (n=139) or empty negatives SLN nodes (n=11) ing to preoperative imaging and diagnostic biopsy. The allo- n= 209 n=150 cation was as follows: low risk (preoperative stage IA and endometrioid low grade), high risk (preoperative stage IB or II and endometrioid high grade, or any non-endometrioid histology), and intermediate risk (preoperative stage IB or COHORT FOR SURVIVAL II and endometrioid low grade, or preoperative stage IA and ANALYSIS endometrioid high grade). n=892 Statistical Analysis COHORT FOR ACCURACY Stata statistical program (version 14.2) was used for data ANALYSIS analysis. Continuous variables were expressed as median Patients with pelvic +/- aortic and interquartile range (IQR) and were compared using the lymphadenectomy Kruskal–Wallis test. Categorical variables were expressed n=466 as frequencies and percentages and compared using the χ2 test or the Fisher’s exact test. All tests were two-tailed. FIG. 1  Flow diagram for cohort selection. SLN: sentinel lymph node S. Cabrera et al. negative SLN were also excluded (209 patients). Finally, 892 When assessing factors associated to the detection of patients were considered for survival analysis. Out of them, disease in the SLN, we identified high CA125, myometrial 466 patients had at least unilateral pelvic lymphadenectomy invasion > 50%, and presence of LVSI as predictors of SLN and were included for accuracy analysis (Fig. 1). disease in multivariant analysis (Tables 3, 4). In fact, we Median age at diagnosis was 62.5 (IQR 55.7–70.4) years, observed a close correlation between the volume of nodal and mean body mass index was 28.9 (IQR 25.4–33.6) kg/m2. disease in SLN and the presence of LVSI in surgical speci- A total of 87% of patients had endometrioid histology at final men, and this association was evident in low-grade and high- pathology report, and 78.6% were low grade (G1–2). Almost grade tumors (Fig. 2). half of the cohort (48.8%) was considered at preoperative low risk of lymph node metastases, and they were exclu- Oncologic Outcomes according to Nodal Disease sively staged with SLN biopsy. In addition, 47.4% of the patients received a bilateral lymphadenectomy in association Regarding adjuvant treatment, the use of brachytherapy to SLN, and 25.5% underwent an aortic lymphadenectomy (BT) was similar across the global cohort and independ- as well. Regarding SLN technique, 73.2% of patients were ent of nodal status. We observed a significant higher use of mapped using ICG alone or in combination with 99mTc, and chemotherapy and external beam radiotherapy in patients 95.8% received a cervical injection. with micrometastases and macrometastases (Table 5). In this In total, 115 patients (12.9%) were suprastaged to FIGO context of adjuvant treatment, and after a median follow 2009 stages III or IV after surgery, 65 patients (7.3%) were up of 1.81 (IQR 0.91–2.97) years, cancer-specific survival staged as FIGO 2009 IIIC1, and 17 patients (1.9%) as FIGO and disease-free survival were significantly lower in patients 2009 IIIC2 after surgery, while 108 patients (12.1%) had who had macrometastases when compared with patients nodal disease; 59 with macrometastasis (54.6%) and 49 who had not nodal disease or with low-volume disease only (45.3%) with low-volume disease only. Among the latter, 24 (Fig. 3). had micrometastases and 25 ITCs. Excluding patients with When analyzing risk factors associated to cancer-specific ITCs, 9.3% of patients included had positive SLNs. Patients survival in our cohort, only older age, high-grade histology, with macrometastases were older and showed a significant and FIGO 2009 stages III–IV remained as significant in mul- higher proportion of high-grade tumors, bigger tumoral size, tivariate analysis (Table 4). and more lymphovascular space invasion (LVSI) (Table 1). DISCUSSION SLN Accuracy for Detecting Nodal Disease We describe the results of a retrospective, multi-institu- The overall sensitivity of SLN technique was 92.5% and tional cohort of patients with early stage EC studied with the overall false negative rate was 7.5%. There were six SLN biopsy as a part of their surgical treatment. Patients patients reported as false negative cases of SLN technique in included in this study received their surgical treatment when the overall results. Two of them presented negative bilateral SLN biopsy was not a wide recommendation in clinical pelvic SLN but had isolated aortic metastases. One patient ­guidelines25 and the best detection technique had not yet presented positive pelvic lymph nodes in a non-mapped been established.2 Therefore, the injection site and tracers hemipelvis and was correctly diagnosed after performing used for SLN mapping were in some cases different from the selective pelvic lymphadenectomy (MSKCC a­ lgorithm5). the most recent recommendations. In these patients, SLN The three remaining cases correspond to true false negative technique was performed by different surgical teams, accord- cases of the technique, as they had negative pelvic SLN but ing to each center’s protocol and facilities, making these presented nodal disease in the same hemipelvis. The algo- results representative of the implementation of SLN biopsy rithm sensitivity was 93.7% and the algorithm false-negative in a real clinical scenario. In addition, this cohort includes rate dropped to 6.2%, including patients with isolated aor- the learning curve of most of the Spanish centers in this tic metastases. Two patients had isolated aortic metastases, technique. However, we reach high rates of sensitivity and corresponding to one patient with endometrioid grade 2 low false negative rates. Interestingly, 22% of patients with tumor with bilateral and negative pelvic SLN and another macrometastasis in SLN and 50% of patients with microme- patient with serous histology, who received bilateral pelvic tastasis had been classified as patients at low risk of nodal SLN biopsy and pelvic lymphadenectomy, both negative. disease according to their preoperative characteristics (his- Thus, the rate of isolated aortic metastases in our cohort tology, myometrial infiltration, cervical invasion). In for- was 1.6%. It was higher in patients with high-grade endo- mer clinical guidelines,25 these patients were not candidates metrioid or non-endometrioid histology than in patients with to receive any nodal assessment and would not have been low-grade endometrioid histology (2.8% vs. 0.7%, p = 0.35) adequately diagnosed, therefore revealing the importance of (Table 2). Accuracy and Survival Outcomes after … TABLE 1  Clinicopathological and surgical characteristics of patients Variable [mean (SD), median pN0 (n = 784) pN0(i+) (n = 25) pN1(mi) (n = 24) pN1 (n = 59) Total (n = 892) p value (IQR), or n (%)] Age (years) 62.1 (55.4–70.1) 63.7 (57.4–65.9) 61.8 (56.5–72.4) 66.7 (61.4–72.6) 62.5(55.7–70.4) 0.015 BMI (kg/m2) 29.2 (25.4–33.4) 28.8 (26.1–32.5) 29.3 (24.3–35.8) 28.7 (24.8–34.2) 28.9 (25.4–33.6) 0.931 Preoperative risk groups for LN involvement Low risk 401 (51.2) 9 (36.0) 12 (50.0) 13 (22.0) 435 (48.8) < 0.001 Medium risk 258 (32.9) 14 (56.0) 8 (33.3) 23 (39.0) 303 (34.0) High risk 101 (12.9) 2 (8.0) 3 (12.5) 23 (39.0) 129 (14.5) Not assigned 24 (3.1) 0 (0.0) 1 (4.2) 0 (0.0) 25 (2.8) Pelvic lymphadenectomy No 397 (50.6) 12 (48.0) 10 (41.7) 8 (13.6) 427 (47.9) < 0.001 Bilateral 349 (44.5) 13 (52.0) 13 (54.2) 48 (81.4) 423 (47.4) Unilateral 38 (4.9) 0 (0.0) 1 (4.2) 3 (5.1) 42 (4.7) Aortic lymphadenectomy 184 (23.5) 6 (24.0) 6 (25.0) 31 (52.5) 227 (25.5) < 0.001 Histology Endometrioid 691 (88.1) 22 (88.0) 21 (87.5) 42 (71.2) 776 (87.0) 0.057 Serous 50 (6.4) 2 (8.0) 3 (12.5) 13 (22.0) 68 (7.6) Clear cell 9 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) 9 (1.0) Mixed 11 (1.4) 1 (4.0) 0 (0.0) 1 (1.7) 13 (1.5) Mucinous 4 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 4 (0.5) Undifferentiated 5 (0.6) 0 (0.0) 0 (0.0) 0 (0.0) 5 (0.6) Carcinosarcoma 14 (1.8) 0 (0.0) 0 (0.0) 3 (5.1) 17 (1.9) Grade G1 324 (41.3) 11 (44.0) 8 (33.3) 15 (25.4) 358 (40.1) 0.013 G2 301 (38.4) 10 (40.0) 12 (50.0) 20 (33.9) 343 (38.5) G3 149 (19.0) 4 (16.0) 4 (16.7) 24 (40.7) 181 (20.3) Unknown 10 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 10 (1.1) LVSI No 653 (83.3) 17 (68.0) 11 (45.8) 13 (22.0) 694 (77.8) < 0.001 Yes 115 (14.7) 8 (32.0) 12 (50.0) 44 (74.6) 179 (20.1) Unknown 16 (2.0) 0 (0.0) 1 (4.2) 2 (3.4) 19 (2.1) Max tumor diameter (mm) 25 (15–35) 22.5 (6–35) 30 (10–37) 31.5 (20–50) 25 (15–35) 0.024 Lymphadenectomy, nodes per patient Pelvic (median, IQR) 11 (7.5–15) 10 (9–12) 12.5 (7–16) 12 (9–16) 11 (8–15) 0.501 Aortic (median, IQR) 10 (5–15) 5.5 (4–9) 8 (5–16) 11 (6–14) 9.5 (5–15) 0.302 FIGO stage (2009) IA 501 (63.9) 13 (52.0) 0 (0.0) 0 (0.0) 514 (57.6) < 0.001 IB 213 (27.2) 8 (32.0) 0 (0.0) 0 (0.0) 221 (24.8) II 41 (5.2) 1 (4.0) 0 (0.0) 0 (0.0) 42 (4.7) IIIA 15 (1.9) 3 (12.0) 0 (0.0) 0 (0.0) 18 (2.0) IIIB 10 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 10 (1.1) IIIC1 0 (0.0) 0 (0.0) 24 (100.0) 41 (69.5) 65 (7.3) IIIC2 0 (0.0) 0 (0.0) 0 (0.0) 17 (28.8) 17 (1.9) IVB 4 (0.5) 0 (0.0) 0 (0.0) 1 (1.7) 5 (0.6) Tracer used for SLN detection ICG 348 (44.4) 11 (44.0) 9 (37.5) 23 (39.0) 391 (43.8) 0.936 ICG + 99mTc 229 (29.2) 6 (24.0) 9 (37.5) 18 (30.5) 262 (29.4) 99mTc ± blue dye 205 (26.2) 7 (28.0) 6 (25.0) 18 (30.5) 236 (26.5) Unknown 2 (0.3) 1 (4.0) 0 (0.0) 0 (0.0) 3 (0.3) Tracer injection method Cervix 733 (93.5) 23 (92.0) 24 (100.0) 53 (89.8) 833 (93.4) 0.109 Cervix + uterus 15 (1.9) 1 (4.0) 0 (0.0) 5 (8.5) 21 (2.4) Uterus 30 (3.8) 0 (0.0) 0 (0.0) 1 (1.7) 31 (3.5) Unknown 6 (0.8) 1 (4.0) 0 (0.0) 0 (0.0) 7 (0.8) S. Cabrera et al. Table 1  (continued) SLN sentinel lymph node, LVSI lymphovascular space invasion, ICG indocyanine green, 99mTc 99m-Technetium, pN0 pathologic node negative patients, pN0(i+) pathologic isolated tumor cell in SLN, pN1(mi) pathologic micrometastasis in SLN, pN1 pathologic macrometastasis TABLE 2  Accuracy of SLN biopsy for detecting nodal disease Overall accuracy of SLN biopsy SLN status per patient, n (%) pN0 (n = 784) pN0(i+) (n = 25) pN1(mi) (n = 24) pN1 (n = 59) Total (n = 892) Positive 0 25 (100) 24 (100) 53 (89.3) 102 (11.4) ITC 0 25 (100) 0 1 (1.7) 26 (2.9) Micrometastasis 0 0 24 (100) 6 (10.2) 30 (3.4) Macrometastasis 0 0 0 46 (77.9) 46 (5.2) SLN accuracy, n (%) (over the patients pN0 (n = 386) pN0(i+) (n = 13) pN1(mi) (n = 14) pN1 (n = 53) Total (n = 466) who received pelvic ± aortic LND) True positive 0 13 (100) 14 (100) 47 (88.7) 74 (15.9) False negative 0 0 0 6 (11.3) 6 (1.3) True negative 386 (100) 0 0 0 (0.0) 386 (82.8) Overall sensitivity: 92.5 % (74/80); overall FNR: 7.5% (6/80) Assessment of false negative cases Case Pelvic map- Number Tracer Injection Pelvic Aortic Pelvic Aortic Total Histology Classification ping of SLN site LND LND positive positive nodes nodes nodes 1 Bilateral 2 ICG Cervix Bilateral Yes 6 1 14 Serous False nega- pelvic tive 2 Bilateral 3 ICG Cervix Bilateral Yes 1 1 38 Serous False nega- pelvic tive 3 Unilateral 1 ICG Cervix Bilateral No 2 (right) – 5 Endometri- False nega- pelvic oid G3 tive (right) 4 Bilateral 2 ICG Cervix No Yes 0 1 5 Endometri- Isolated pelvic oid G2 aortic metastasis 5 Bilateral 3 ICG Cervix Bilateral Yes 0 1 21 Serous Isolated pelvic aortic metastasis 6 Unilateral 1 ICG Cervix Unilateral No 2 (left) – 8 Serous Detected by pelvic algorithm (right) Algorithm Sensitivity: 93.7 % (75/80); Algorithm FNR: 6.2% (5/80) SLN sentinel lymph node, ITC isolated tumor cells, LND lymph node dissection, FNR false negative rate, pN0 pathologic node negative patients, pN0(i+) pathologic isolated tumor cell in SLN, pN1(mi) pathologic micrometastasis in SLN, pN1 pathologic macrometastasis TABLE 3  Univariate and Variable Univariate analysis Multivariate analyisis multivariate analysis of risk factors associated to disease in OR CI 95% p value OR CI 95% p value SLN Age 1.03 (1.01–1.05) 0.004 1.01 (0.98–1.04) 0.473 CA125 1.02 (1.01–1.03) < 0.001 1.01 (1.00–1.02) 0.001 Non-endometrioid histology 1.72 (1.00–2.95) 0.052 Myometrial invasion > 50% 3.48 (2.27–5.34) < 0.001 2.23 (1.16–4.31) 0.017 High grade (G3) 1.46 (0.91–2.35) 0.115 LVSI 8.47 (5.41–13.3) < 0.001 5.39 (2.85–10.18) < 0.001 Accuracy and Survival Outcomes after … TABLE 4  Univariate and Variable Univariate analysis Multivariate analyisis multivariate analysis of risk factors associated to cancer- HR CI 95% p value HR CI 95% p value specific survival Nodal status Reference Reference Negative Micrometastasis + ITC 1.37 (0.18–10.54) 0.762 0.31 (0.03–3.10) 0.318 Macrometastasis 5.33 (1.88–15.15) 0.002 0.44 (0.10–1.92) 0.272 Age 1.09 (1.03–1.14) 0.001 1.07 (1.00–1.12) 0.028 CA125 1.01 (1.00–1.01) 0.088 Non-endometrioid histology 8.00 (3.15–20.3) < 0.001 1.45 (0.46–4.59) 0.525 FIGO 2009 stage I–II Reference Reference III–IV 8.20 (3.24–20.79) < 0.001 6.51 (1.85–22.86) 0.003 High grade (G3) 21.2 (6.14–73.3) < 0.001 10.4 (2.2–49.8) 0.003 LVSI 6.20 (2.40–16.03) < 0.001 2.77 (0.91–8.46) 0.074 Adjuvant treatment 12.14 (1.62–91.27) 0.015 0.98 (0.10–9.50) 0.989 LVSI positive probability adjusted predictions with 95% Cls of isolated aortic metastases of 1.6%, similar to previously reported results.9 The high proportion of low-volume dis- 1 ease in this cohort (45%) is also in agreement with previous reported cohorts (54% in FIRES trial,7 67% in FILM ­trial8). .8 LVSI positive probability Even though the rate of low-volume disease may change .6 depending on the technique used for SLN ultrastaging,27 it is indisputable that any ultrastaging method will lead to the .4 detection of patients bearing low-volume disease in SLN in a high number. Defining the best adjuvant management for .2 these patients is a clinical need when implementing SLN biopsy as an effective tool of lymph node evaluation in EC. 0 0 pN0 pN0(i+) pN1(mi) pN1 Nodal status In the present study, the use of pelvic external beam radio- Endometrioid Low Grade Endometrioid High Grade / Non-endometrioid therapy, chemotherapy, or both was almost universal among patients who had micrometastases or macrometastases. FIG. 2  LVSI probability according to the volume of disease in SLN Patients with ITC in SLN received adjuvant treatment simi- larly to patients who had negative nodes, as recommended by most recent clinical guidelines.2 In this context, patients SLN biopsy implementation in the management of patients with low-volume disease (ITC and micrometastases) had with early stage EC. similar results in terms of overall and disease-free survival We report a rate of positive SLN of 9.3% after exclud- than patients with negative nodes. These findings had been ing ITCs, probably related to the fact that less than 15% previously reported by other authors and are the basis for the of the cohort was considered at high risk of nodal disease recommendation of not to treat as node positive the patients preoperatively, and most of the patients were at low and that only present ITC in SLN biopsy.15,16 intermediate risk. These results are in agreement with previ- In our cohort, patients with micrometastases showed ously published data. The review and meta-analysis recently an excellent prognosis after being treated as node-positive published by the Cochrane C ­ ollaboration26 including 2237 patients, and their outcome was more favorable than patients women, reported rates of positive lymph nodes (excluding with macrometastases. Ignatov et al. reported the outcomes ITCs) ranging from 5.2% to 34.4% with a mean of 20.1% of 95 patients with micrometastases who received adjuvant (95% CI 17.7–22.3%). treatment and 31 patients with micrometastases without The high number of patients with lymphadenectomies adjuvant treatment. Without adjuvant therapy, disease-free performed (47% pelvic and 25% aortic) allows for the survival was significantly reduced as compared with dis- calculation of the accuracy of SLN technique when used in a ease-free survival in the node-negative cohort (p = 0.0001). clinical setting. After applying the algorithm, we obtained a With adjuvant therapy, the median disease-free survival of sensitivity of 93.7% and a false negative rate of 6.2%, which patients was similar to node-negative patients (p = 0.648).22 is in line with the results of other studies.19 We found a rate Despite growing evidence as to the prognostic significance S. Cabrera et al. TABLE 5  Adjuvant treatment and survival outcomes according to nodal disease Variable, n (%), median (IQR) pN0 (n = 784) pN0(i+) (n = 25) pN1(mi) (n = 24) pN1 (n = 59) Total (n = 892) p value Adjuvant treatment Received adjuvant treatment 391 (49.9) 16 (64.0) 24 (100.0) 58 (98.31) 489 (54.8) < 0.001 Radiotherapy 376 (48.0) 15 (60.0) 22 (91.7) 51 (86.4) 464 (52.0) < 0.001 EBRT* 125 (33.2) 5 (33.3) 19 (86.4) 47 (92.2) 196 (42.2) < 0.001 Brachytherapy* 341 (90.7) 14 (93.3) 17 (77.3) 42 (82.4) 414 (89.2) 0.068 Chemotherapy 90 (11.5) 2 (8.0) 13 (54.2) 48 (81.4) 153 (17.2) < 0.001 Concurrent chemoradiotherapy 1 (0.1) 1 (4.0) 2 (8.3) 7 (11.9) 11 (1.2) < 0.001 Survival Median follow-up (years) 1.82 (0.92–0.97) 1.25 (0.70–2.37) 2.29 (2.34–1.05) 1.60 (0.80–3.08) 1.81 (0.91–2.97) 0.092 OS 3y 95.8 (93.2–97.4) 100 (NC–NC) 94.1 (65.0–99.2) 84.8 (66.6–93.5) 95.1 (92.6–96.7) 0.034 DFS 3y 90.8 (87.4–93.3) 100 (NC–NC) 89.1 (62.5–97.2) 68.0 (48.5–81.3) 89.3 (86.0–91.9) 0.001 CSS 3y 98.0 (96.2–99.0) 100 (NC–NC) 94.1 (65.0–99.2) 87.3 (69.0–95.2) 97.2 (95.2–98.4) 0.005 Status at last control Alive without disease 739 (94.3) 25 (100.0) 21 (87.5) 51 (86.4) 836 (93.7) 0.052 Alive with disease 23 (2.9) 0 (0.0) 2 (8.3) 2 (3.4) 27 (3.0) Dead 22 (2.8) 0 (0.0) 1 (4.2) 6 (10.2) 29 (3.3) Death caused by disease 11 (50.0) 0 (0.0) 1 (100.0) 5 (83.3) 17 (58.6) Other causes for death 11 (50.0) 0 (0.0) 0 (0.0) 1 (16.7) 12 (41.4) * Percentages are calculated over the patients who received radiotherapy as adjuvant treatment EBRT external beam radiotherapy, OS overall survival, DFS disease free survival, CSS cancer-specific survival, pN0 pathologic node negative patients, pN0(i+) pathologic isolated tumor cell in SLN, pN1(mi) pathologic micrometastasis in SLN, pN1 pathologic macrometastasis CSS Kaplan-Meier estimates DFS Kaplan-Meier estimates 1.00 1.00 0.75 0.75 0.50 0.50 0.25 0.25 pN0 pN0(i+) pN0 pN0(i+) pN1 (mi) pN1 pN1 (mi) pN1 0.00 0.00 0 1 2 3 4 5 0 1 2 3 4 5 analysis time (years) analysis time (years) FIG. 3  Cancer-specific survival and disease-free survival estimates of node-negative patients (pN0), patients with ITC [pN0(i+)], patients with micrometastases [pN1(mi)], and patients with macrometastases (pN1) of micrometastases, the clinical relevance of ITC on SLN is However, the authors were cautious with these results, as still a matter of debate. Ghoniem et al. reported one of the longer follow-up of these patients was needed.16 largest series of patients with ITC detected on SLN, includ- We identified older age, advanced FIGO stage, and ing 132 patients. Of them, 47 patients with endometrioid his- high-grade histology as factors associated to decreased tology did not receive any adjuvant treatment or only vaginal cancer-specific survival. Non-endometrioid histology, brachiterapy. Patients with endometrioid grade 1 disease and LVSI, and uterine serosal invasion had also been previ- neither LVSI nor uterine serosal involvement showed low ously reported as independent predictors of recurrence recurrence rates despite the omission of adjuvant treatment. in patients with low-volume disease on SLN. 16 We also Accuracy and Survival Outcomes after … observed that LVSI behaves as a potent predictor of SLN OPEN ACCESS This article is licensed under a Creative Commons disease. This finding highlights the importance of LVSI Attribution 4.0 International License, which permits use, sharing, adap- tation, distribution and reproduction in any medium or format, as long as a prognostic marker in EC and reveals that more efforts as you give appropriate credit to the original author(s) and the source, should be made to identify preoperative surrogates of LVSI provide a link to the Creative Commons licence, and indicate if changes that could detect patients at higher risk of nodal disease. were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in Strengths and Limitations the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will This is the first study evaluating the outcomes of need to obtain permission directly from the copyright holder. To view a patients undergoing SLN mapping for early stage endo- copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. metrial cancer across many different centers in Spain. The number of cases included provides good statistical power, but the retrospective nature of the study entails biases that REFERENCES should be considered. The median follow-up period is close but does not exceed 2 years, which is considered the 1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, time of higher risk of relapse and could be a limitation of 2022. CA Cancer J Clin. 2022;72(1):7–33. https://​doi.​org/​10.​ the study. 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