View of Preliminary results of sentinel lymph node removal in the surgical treatment of endometrial cancer

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1 Department of Gynaecology, Division of Gynaecology, University Medical Centre Ljubljana, Ljubljana, Slovenia

2 Department of Gynaecology and

Obstetrics, General hospital Slovenj Gradec, Slovenj Gradec, Slovenia Correspondence/

Korespondenca:

Mija Blaganje, e: mija.

blaganje@gmail.com Key words:

endometrial cancer;

sentinel lymph node;

lymphadenectomy; ICG;

ultrastaging Ključne besede:

rak endometrija;

varovalna bezgavka;

limfadenektomija; ICG;

ultrastaging Received: 26. 9. 2018 Accepted: 10. 6. 2019

eng slo element

en article-lang

10.6016/ZdravVestn.2875 doi

26.9.2018 date-received

10.6.2019 date-accepted

Human reproduction Reprodukcija človeka discipline

Original scientific article Izvirni znanstveni članek article-type

Preliminary results of sentinel lymph node removal in the surgical treatment of endometrial cancer

Začetni rezultati odstranjevanja varovalnih bezgavk pri kirurškem zdravljenju raka endometrija

article-title

Preliminary results of sentinel lymph node removal in the surgical treatment of endometrial cancer

Začetni rezultati odstranjevanja varovalnih bezgavk pri kirurškem zdravljenju raka endometrija

alt-title

endometrial cancer, sentinel lymph node,

lymphadenectomy, ICG, ultrastaging rak endometrija, varovalna bezgavka, limfadenektomija, ICG, ultrastaging

kwd-group The authors declare that there are no conflicts

of interest present. Avtorji so izjavili, da ne obstajajo nobeni

konkurenčni interesi. conflict

year volume first month last month first page last page

2019 88 11 12 509 516

name surname aff email

Mija Blaganje 2 mija.blaganje@gmail.com

name surname aff

Sabina Čas 1

Katja Jakopič Maček 2

Borut Kobal 2

Kristina Drusany Starič 2

Leon Meglič 2

Matija Barbič 2

Branko Cvjetićanin 2

Mija Blaganje 2

eng slo aff-id

Department of Gynaecology and Obstetrics, General hospital Slovenj Gradec, Slovenj Gradec, Slovenia

Oddelek za ginekologijo in porodništvo, Splošna bolnišnica Slovenj Gradec, Slovenj Gradec, Slovenija

1

Department of Gynaecology, Division of Gynaecology, University Medical Centre Ljubljana, Ljubljana, Slovenia

Klinični oddelek za ginekologijo, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija

2

Preliminary results of sentinel lymph

node removal in the surgical treatment of endometrial cancer

Začetni rezultati odstranjevanja varovalnih bezgavk pri kirurškem zdravljenju raka endometrija

Sabina Čas,¹ Katja Jakopič Maček,² Borut Kobal,² Kristina Drusany Starič,² Leon Meglič,² Matija Barbič,² Branko Cvjetićanin,² Mija Blaganje²

Abstract

Background: Preoperative assessment of the depth of endometrial cancer invasion is not reli- able. Surgical treatment consists of hysterectomy and pelvic lymphadenectomy. Sentinel lymph node (SLN) biopsy can replace radical pelvic lymphadenectomy in patients with a low and intermediate risk of disease recurrence.

Methods: From January 2016 to June 2017, 35 patients were included in the clinical audit of SLN biopsy at the UMC Ljubljana’s Division of Gynaecology and Obstetrics. We recorded the reliability of the preoperative histological and ultrasound estimates and the degree of surgical detection of the SLN with an intracervical application of indocyanine green (ICG). All the removed tissues were sent for histological examination by hematoxylin and eosine (H & E) staining method.

Results: Unilateral and bilateral success rate of the surgical detection of SLN was 85.7% (75%–

93%) and 80.0% (63%–92%) respectively. The sentinel lymph node was histologically positive in two cases. Ultrasound assessment of myometrial invasion had 100% (15.8%–100%) sensitivity and 78.9% (54.4%–93.9%) specificity, whereas the ultrasound assessment of cervical stromal invasion only had 33% (0.8%–90.6%) sensitivity and 94.4% (72.7%–99.8%) specificity. Postopera- tive histological differentiation was upgraded in 5.7% and downgraded in 8.6% of cases.

Conclusion: SLN biopsy at the time of surgery allows a personalized treatment approach in pa- tients with endometrial cancer and a secure abandonment of pelvic lymphadenectomy in patients at low and intermediate risk of recurrence. Its final inclusion in the treatment guidelines will require additional experience regarding patient selection, surgical treatment quality track- ing, as well as urgent implementation of histological ultrastaging of the removed SLN.

Izvleček

Izhodišče: Ocena razširjenosti raka endometrija pred operaciji s slikovnimi metodami ni zanesl- jiva. Od ocene je odvisno, ali naj kirurško zdravljenje vključuje pelvično limfadenektomijo ali ne.

Biopsija varovalne bezgavke lahko varno nadomesti radikalno pelvično limfadenektomijo pri bolnicah z nizkim in zmernim tveganjem za ponovitev bolezni.

Metode: Od januarja 2016 do junija 2017 je bilo na Ginekološki kliniki v Ljubljani v pregled začet- nih kliničnih rezultatov ob uvedbi biopsije v varovalni bezgavki v rutinsko klinično prakso vkl- jučenih 35 bolnic. Beležili smo zanesljivost histološke in ultrazvočne ocene pred operacijo ter stopnjo uspešne kirurške detekcije v varovalni bezgavki s cervikalno aplikacijo zelenila indoci-

Slovenian Medical

Journal

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1 Introduction

Endometrial cancer is the most common gynaecological cancer and the fifth most common cancer in women in Slove- nia (1). Between 2010 and 2014 there were an average of 326 newly diagnosed patients a year in Slovenia, with a rough incidence rate of 31.4/100,000 (2). Approximately 75% of endometrial cancer cases were detected in the early stages of the disease (FI- GO stages I and II) (3). Standard treatment is surgical, i.e. the removal of the uterus and adnexa; however, the question of the pelvic and / or paraaortic lymph nodes removal and its extent remains not com- pletely resolved and fully understood (1).

Lymphadenectomy prolongs the duration of the surgery and increases blood loss, resulting in lower limb lymphedema and lymphocyst formation (4). According to the literature, the incidence of lymphedema is 5–38% (5,6). In the group of patients with low-risk endometrial cancer, the risk of nodal metastasis is 1.4% according to

anin. Vsa odstranjena tkiva so bila poslana na histološko preiskavo z barvanjem po metodi he- matoksilin in eozin (H&E).

Rezultati: Enostranska uspešnost kirurške detekcije varovalne bezgavke je bila 85,7 % (75–93

%), obojestranska pa 80,0 % (63–92 %). Varovalna bezgavka je bila histološko pozitivna v dveh primerih. Ultrazvočna ocena invazije v miometrij je imela občutljivost 100 % (15,8–100 %) in specifičnost 78,9 % (54,4–93,9 %), ultrazvočna ocena invazije v stromo materničnega vratu pa le 33 % (0,8–90,6 %) občutljivosti in 94,4 % (72,7–99,8 %) specifičnosti. Ocena histološke stopnje diferenciacije je bila po operaciji višja (angl. upgrading) v 5,7 %, nižja (angl. downgrading) pa v 8,6 %.

Zaključek: Odstranjevanje varovalne bezgavke omogoča individualnejši pristop k zdravljenju bolnic z rakom endometrija in varnejšo opustitev pelvične limfadenektomije pri bolnicah z nizkim in zmernim tveganjem za ponovitev bolezni. Za dokončno umestitev v smernice zdravljenja bodo v našem prostoru potrebne dodatne izkušnje glede izbire bolnic, sledenja kakovosti kiru- rške obravnave in nujna uvedba res poadrobnega histološkega pregleda – t. i. ultrastaginga (angl. ultrastaging) odstranjene varovalne bezgavke.

Cite as/Citirajte kot: Čas S, Jakopič Maček K, Kobal B, Drusany Starič K, Meglič L, Blaganje M, et al.

Preliminary results of sentinel lymph node removal in the surgical treatment of endometrial cancer. Zdrav Vestn. 2019;88(11–12):509–16.

DOI: https://doi.org/10.6016/ZdravVestn.2875

the SEER analysis (7). ESGO-ESMO-ES- TRO guidelines from 2015 recommend the abandonment of pelvic lymphadenectomy in two groups of patients with low and intermediate-risk endometrial cancer due to the low risk of nodal metastasis and since the removal of lymph nodes does not affect their survival, however, it increases intraoperative and postoperative complications (8). On the other hand, no- dial metastasis is the most important risk factor for disease recurrence. In patients with high-intermediate and high-risk endometrial cancer it is recommended to remove the paraaortic lymph nodes to the region of renal vasculature, in addition to removing the pelvic lymph nodes (9). The problem is the possibility of misstaging patients before surgery, since the histological differentiation grade after removing the uterus may be higher than before surgery in 19%, and the stage higher in 18%

(10). Imaging methods (MRI, transvaginal

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ultrasound examination of a trained examiner) assess the invasion of the disease in the myometrium and cervical stroma before surgery and classify patients with histologically confirmed endometrial cancer into different risk groups, which alters the extent of surgical staging and the need for a lymphadenectomy (11). The compromise between a radical lymphadenectomy and no lymph node removal is the removal of the sentinel lymph node (SLN) (1). If the sentinel lymph node is negative, it can be assumed that no metastases are present in other lymph nodes (12). SLN biopsy has already been accepted into the doctrine of treatment for malignant melanoma, breast cancer, and genital cancer (13). By assess- ing the disease in the sentinel lymph node, especially in patients with low-risk endometrial cancer, we can meet the require- ments for surgical assessment of disease invasion to lymph nodes while reducing the incidence of lymphadenectomy complications (1). SLN biopsy algorithm has already been incorporated into the Na- tional Comprehensive Cancer Network (NCCN) guidelines (14) for patients with low and intermediate-risk type I endometrial cancer and the ESGO-ESMO-ESTRO recommendations (8), which thus safely

replaces a lymphadenectomy (15).

SLN biopsy technique involves a subserosal, cervical, or hysteroscopic injection of either a radioactive tracer (technetium - Tc99) or dyes (methylene blue or indocyanine green - ICG) into the endometrium (4), and detecting and removing the sentinel lymph node during surgery. According to the literature, cervical dye application increases the rate of successful detection of the sentinel lymph node status (16).

Our aim was to establish the possibility of performing a SLN biopsy, its success rate, and safety of introducing it into routine clinical practice for the treatment of endometrial cancer in our environment and comparison with data from abroad.

2 Methods

At the University Medical Centre (UMC) Ljubljana we have introduced SLN biopsy into routine clinical practice in January 2016. Patients with histologically confirmed endometrial cancer scheduled for laparoscopic removal of the uterus and ovaries were included in a retrospective review of the clinical data. Prior to the procedure, patients underwent a transvaginal ultrasound to assess the invasion of the disease. SLN mapping involved injecting 4 mL of ICG dye intracervically at 3- and 9-o’clock positions at two different depths, 1 mL at each injection site. ICG dye fluo- resces in infrared light, which is detected during laparoscopy after 10 minutes using a suitable filter (Figure 1 and Figure 2).

Patients with predictably more favourable histological forms (endometrioid carcinoma G1 and endometrioid carcinoma G2) and ultrasound evaluation of invasion in- to the myometrium less than 50% before surgery, limited to the body of the uterus, only had bilateral SLN removed, while in others we removed pelvic lymph nodes alongside SLN, and at the discretion of the surgeon, also the paraaortic lymph nodes.

However, if SLN were not found, we performed a unilateral pelvic lymphadenectomy. Moreover, pelvic lymphadenectomy Figure 1: Sentinel lymph node identification: the ICG dye applied to the

cervix is identified in the sentinel lymph node with a special spectral filter under a direct infrared illumination.

Legend: *- ICG stained sentinel lymph node along the iliac vasculature, # - unstained lymphatic and adipose tissue.

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was left to the discretion of the surgeon also when he/she was not convinced in the reliability of SLN removal. We recorded the duration of surgery, possible complications, blood loss, surgical team, the num- ber of identified SLN, and information on the removal of other lymph nodes. All the removed tissues were sent for histological examination by hematoxylin and eosin (H&E) staining, whereas a particularly de- tailed histological examination of the sentinel lymph node, i.e. ultrastaging, has not yet been performed in the analysed patients. We used a binominal distribution test with MedCalc to calculate sensitivity and specificity for all patients enrolled by June 2017.

3 Results

A total of 35 patients were included in the analysis, where 32 patients had a low risk endometrial carcinoma, histologically an endometrioid carcinoma G1 or G2, preoperative ultrasound assessment of myometrial invasion of less than 50%, and no cervical invasion. These patients underwent SLN removal and possible pel- Figure 2: Sentinel lymph node identification: the ICG dye applied to the cervix is identified in the sentinel lymph node with a special spectral filter under a direct infrared illumination.

Legend: * - ICG stained sentinel lymph node (vertical arrow indicates the sln along the iliac vasculature, horizontal arrow indicates SLN tissue in the surgical forceps during removal), # - unstained lymphatic and adipose tissue.

vic lymphadenectomy at the discretion of the surgeon. Three patients had histologically less favourable forms of endometrial carcinoma: in two cases poorly differentiated serous adenocarcinoma and in one case a combined moderately differentiated endometrioid carcinoma and serous carcinoma. In these cases, a SLN removal was performed first, followed by a pelvic lymphadenectomy.

The surgically described unilateral rate of intraoperative SLN detection was 85.7%

(75-93%) and the bilateral rate was 80.0%

(63-92%). For the surgeon proficient in pelvic lymphadenectomy, the success rate of surgical detection in the first ten proce- dures was 95% for one and 90% for both sides.

All 35 patients were enrolled in the SLN removal algorithm. In a group of 32 patients with pre-operatively assessed low-risk cancer, in addition to the SLN removal, a unilateral pelvic lymphadenectomy was performed in four patients, and bilateral in eight patients at the discretion of the surgeon. In three patients with histologically less favourable types of cancer a radical pelvic lymphadenectomy was performed in addition to the SLN removal, and a paraaortic lymphadenectomy in two patients.

In patients with preoperatively assessed low-risk endometrial cancer, all SLN removed were histologically negative. More- over, other lymph nodes were also negative in these patients in cases where pelvic lymphadenectomy was performed at the discretion of the surgeon. In four patients, a SLN was histologically confirmed only unilaterally, and adipose tissue was removed on the other side instead. Adipose tissue was removed from two patients instead of bilateral SLN. In three patients with histologically less favourable forms of endometrial cancer there were histologically positive SLN in two cases. The remaining removed lymph nodes were negative in one patient and positive in the second. However, in the patient with the poorly differentiated serous cancer, the

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pelvic lymph node was positive despite the false negative SLN.

All patients underwent a preoperative transvaginal ultrasound examination, and only 21/35 (60%) patients underwent a so- called expert ultrasound examination by an experienced examiner with a thorough assessment of the disease invasion and precise measurements. After comparison with histological results, the sensitivity of the expert ultrasound examination was 100% (15.8-100%) for myometrial invasion, with 78.9% (54.4-93.9%) specificity, and for cervical stromal invasion a 33%

(0.8-90.6%) sensitivity and 94.9% (72.7- 99.8%) specificity of the procedure.

In two patients, after receiving a final histological result, the stage of the disease was clinically significantly higher than that estimated by an ultrasound before surgery, since cervical invasions were not identified before surgery. When analysed, final histological examination had higher concordance of differentiation grading (G) in 5.7% (2/35) and lower in 8.6% (3/35) for preoperative endometrial biopsy.

The mean duration of the laparoscopic surgery was 93.3 minutes (35–160 minutes) and the mean blood loss was 197.1 mL (50–300 mL). We observed no intra- or postoperative complications.

4 Discussion

At UMC Ljubljana we are committed to following the guidelines of the interna- tional ESGO-ESMO-ESTRO associations as members of ESGO, which, after 2015, recommend the abandonment of complete pelvic lymphadenectomy in patients with low-risk cervical cancer (8) and allow the use of a sentinel lymph node algorithm.

The guidelines follow the recommendations of ESGO-ESMO-ESTRO, funda- mentally altering the current concept of surgical management of this gynaecological cancer. Based on extensive meta-anal- yses with various tracers, our group de- cided to implement a sentinel lymph node mapping algorithm employing ICG dye

and cervical protocol in accordance with the aforementioned guidelines. The SLN biopsy technique involves the injection of a radioactive tracer or dye into different parts of the uterus (subserosal, cervical, or endometrial) (4). An additional injection of the tracer or dye into the fundus (18) or into the endometrium (19) does not increase the detection rate compared to the cervical injection alone, according to the literature. Cervical ICG injection increases bilateral detection rate (20). Key factors for the successful use of the SLN biopsy algorithm are surgeon experience and adherence to the SLN algorithm (21).

Analysing our initial findings of the SLN detection using the chosen ICG dye method and cervical injection protocol, we found, alongside an acceptable surgery time without described complications, a comparable SLN detection rate with literature data, where an 80-90% detection rate is desired (15). The rate of SLN detection should exceed 90% after 30 interventions (15). An experienced surgeon trained in pelvic lymphadenectomy and manoeu- vring the retroperitoneum achieved 95%

unilateral and 90% bilateral detection rates within first ten interventions.

SLN was positive in two cases (both cases had histologically unfavourable carcinoma, in the first case a poorly differentiated endometrioid carcinoma and in the second case a well differentiated endometrioid carcinoma in combination with poorly differentiated unclassified adenocarcinoma). In both cases, bilateral pelvic lymphadenectomy was performed in accordance with the guidelines for high- risk types of uterine body carcinoma. In the first of the two cases, only the right SLN was histologically positive, all other removed lymph nodes were histologically negative. In the second case, in addition to the left SLN, pelvic lymph nodes were bilaterally histologically positive. After reviewing the data, we found that in the patient with the serous endometrial carcinoma, who underwent a SLN biopsy and total lymphadenectomy, the left pelvic

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lymph node next to the negative SLN was histologically positive. Since histological ultrastaging had not yet been performed at that time, it is not clear in this case whether metastases that could not be detected by a standard histological examination were present in the lymph node, or whether the surgical technique for SLN detection was inappropriate, although ultrastaging would not increase sensitivity to detect metastases according to the meta-analysis (20).

Our study observed a high sensitivity of the ultrasound assessment of myometrial invasion (100%), and the specificity of the examination for the assessment of myometrial invasion (78.9%) alongside the specificity of the assessment of cervical stromal invasion, which was 94.4%, were also relatively high. However, the sensitivity of the ultrasound assessment of cervical stromal invasion was low (33%).

According to the literature, ultrasound assessment of the depth of myometrial invasion has a sensitivity in the range between 68-93% and specificity of 82%, and the assessment of cervical stromal invasion has a sensitivity of 54-93% and specificity of 85-99% (22). The degree of concordance of histological examination of endometrial biopsy with the final histological examination is high in our centre (5.7% upgrading, 8.6% downgrading) compared to foreign literature (19% upgrading) (10). A downgraded disease stage was preoperatively evaluated in patients with histologically less favourable endometrial cancer rather than in the low-risk group. Good preoperative imaging diagnostics may influence the more adequate selection of patients for SLN biopsy alone.

Removing SLN provides a more in- dividualized approach to the treatment of patients with endometrial cancer and

a safer abandonment of pelvic lymphadenectomy in patients with low-risk of disease recurrence. Due to the unreliabil- ity of preoperative assessment, SLN biopsy is the method of choice in patients with prospectively low-risk endometrial cancer whose lymphadenectomy would otherwise be abandoned. Using ultrastaging, an even more accurate histological examination of the lymph nodes, can have an added value to the SLN removal algorithm, which can also detect patients with low-volume metastases that cannot be detected by a classical histological examination (21).

In the literature the incidence of low-volume metastases after histological ultrastaging is 4.5% (23). Their possible presence is important in deciding on ad- juvant therapy and patient follow-up, and the exact oncological and prognostic sig- nificance of low-volume metastases is not yet fully understood (23). Currently, the introduction of ultrastaging has facilitated an additional opportunity for improve- ment.

5 Conclusions

SLN removal using the cervical ICG dye application method in patients with endometrial carcinoma offers an excellent compromise between complete abandonment of a lymphadenectomy in low-risk patients and standard pelvic lymphadenectomy in all patients. However, upon its introduction into standard treatment, it is necessary to monitor the quality of the preoperative assessment (histologic and imaging diagnostics), the quality and reliability of the surgical approach, adherence to the comprehensive SLN mapping algorithm, and the implementation of histological ultrastaging.

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References

1. Kobal B, Cvjetićanin B. Kirurško zdravljenje nizko in srednje rizičnega raka materničnega telesa - endometrija. In: Merlo S, Smrkolj Š, Šegedin B, eds. 2. šola o ginekološkem raku. Rak materničnega telesa. 2016 Nov 11; Ljubljana, Slovenija. Ljubljana: Združenje za radioterapijo in onkologijo SZD : Sekcija internistične onkologije SZD : Združenje za ginekološko onkologijo, kolposkopijo in cervikalno patologijo SZD; 2016.

2. Epidemiologija in register raka. Rak v Sloveniji 2013. Ljubljana: Onkološki inštiut; 2016 [cited 2019 Aug 22].

Available from: https://www.onko-i.si/fileadmin/onko/datoteke/dokumenti/RRS/LP_2013.pdf.

3. Bebar S. Celostna obravnava bolnic z raokom materničnega telesa. In: Merlo S, Smrkolj Š, Šegedin B. 2.

šola o ginekološkem raku. Rak materničnega vratu. 2016 Nov 11; Ljubljana, Slovenija. Ljubljana: Združenje za radioterapijo in onkologijo SZD : Sekcija internistične onkologije SZD : Združenje za ginekološko onkologijo, kolposkopijo in cervikalno patologijo SZD; 2016.

4. Abu-Rustum NR. Update on sentinel node mapping in uterine cancer: 10-year experience at Memorial Sloan-Kettering Cancer Center. J Obstet Gynaecol Res. 2014;40(2):327-34. DOI: 10.1111/jog.12227 PMID:

24620369

5. Abu-Rustum NR, Alektiar K, Iasonos A, Lev G, Sonoda Y, Aghajanian C, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103(2):714-8. DOI: 10.1016/j.

ygyno.2006.03.055 PMID: 16740298

6. Tada H, Teramukai S, Fukushima M, Sasaki H. Risk factors for lower limb lymphedema after lymph node dissection in patients with ovarian and uterine carcinoma. BMC Cancer. 2009;9(1):47. DOI: 10.1186/1471- 2407-9-47 PMID: 19193243

7. Vargas R, Rauh-Hain JA, Clemmer J, Clark RM, Goodman A, Growdon WB, et al. Tumor size, depth of invasion, and histologic grade as prognostic factors of lymph node involvement in endometrial cancer: a SEER analysis. Gynecol Oncol. 2014;133(2):216-20. DOI: 10.1016/j.ygyno.2014.02.011 PMID: 24548726 8. Colombo N, Creutzberg C, Amant F, Bosse T, González-Martínf A, Ledermann J, , et al. ESMO–ESGO–ESTRO

consensus conference on endometrial cancer: Diagnosis, treatment and follow-up. Radiother Oncol.

2015;117(3):559-81. DOI: 10.1016/j.radonc.2015.11.013 PMID: 26683800

9. Merlo S, Vivod G. Operativno zdravljenje raka materničnega telesa – visoko tveganje. In: Merlo S, Smrkolj Š, Šegedin B, eds. 2. šola o ginekološkem raku. Rak materničnega telesa. 2016 Nov 11; Ljubljana, Slovenija.

Ljubljana: Druženje za radioterapijo in onkologijo SZD : Sekcija internistične onkologije SZD : Združenje za ginekološko onkologijo, kolposkopijo in cervikalno patologijo SZD; 2016.

10. Ben-Shachar I, Pavelka J, Cohn DE, Copeland LJ, Ramirez N, Manolitsas T, et al. Surgical staging for patients presenting with grade 1 endometrial carcinoma. Obstet Gynecol. 2005;105(3):487-93. DOI:

10.1097/01.AOG.0000149151.74863.c4 PMID: 15738013

11. JJakopič K, Smrkolj Š, Kobal B. Ultrazvočna preiskava pri odkrivanju in zdravljenju raka na maternični sluznici. In: Merlo S, Smrkolj Š, Šegedin B. 2. šola o ginekološkem raku. Rak materničnega vratu. 2016 Nov 11; Ljubljana, Slovenija. Ljubljana: Združenje za radioterapijo in onkologijo SZD : Sekcija internistične onkologije SZD : Združenje za ginekološko onkologijo, kolposkopijo in cervikalno patologijo SZD; 2016.

12. Sentinel Lymph Node Biopsy in Endometrial Cancer (Scientific Impact Paper No.51). London: Royal College of Obstetricians and Gynaecologists; 2016 [cited 2019 Aug 22]. Available from: https://www.rcog.

org.uk/en/guidelines-research-services/guidelines/sip51.

13. Vakselj A. Biopsija varovalnih bezgavk pri raku materničnega telesa. In: Merlo S, Smrkolj Š, Šegedin B. 2.

šola o ginekološkem raku. Rak materničnega vratu. 2016 Nov 11; Ljubljana, Slovenija. Ljubljana: Združenje za radioterapijo in onkologijo SZD : Sekcija internistične onkologije SZD : Združenje za ginekološko onkologijo, kolposkopijo in cervikalno patologijo SZD; 2016.

14. Uterine Neoplasms. Plymouth Meeting: National Comprehensive Cancer Network; 2015 [cited 2019 Aug 22]. Available from: http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

15. Rossi EC, Kowalski LD, Scalici J, Cantrell L, Schuler K, Hanna RK, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-92. DOI: 10.1016/S1470-2045(17)30068-2 PMID: 28159465 16. Kang S, Yoo HJ, Hwang JH, Lim MC, Seo SS, Park SY. Sentinel lymph node biopsy in endometrial cancer:

meta-analysis of 26 studies. Gynecol Oncol. 2011;123(3):522-7. DOI: 10.1016/j.ygyno.2011.08.034 PMID:

21945553

17. Khoury-Collado F, Glaser GE, Zivanovic O, Sonoda Y, Levine DA, Chi DS, et al. Improving sentinel lymph node detection rates in endometrial cancer: how many cases are needed? Gynecol Oncol. 2009;115(3):453- 5. DOI: 10.1016/j.ygyno.2009.08.026 PMID: 19767064

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18. Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, Soslow RA, Dao F, Sonoda Y, et al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma? Gynecol Oncol. 2009;113(2):163-9. DOI: 10.1016/j.ygyno.2009.01.003 PMID: 19232699

19. 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. DOI: 10.1097/IGC.0b013e3182a616f6 PMID: 24177256

20. Bodurtha Smith AJ, Fader AN, Tanner EJ. Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis. Am J Obstet Gynecol. 2017;216(5):459-476.e10. DOI: 10.1016/j.

ajog.2016.11.1033 PMID: 27871836

21. Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Canc Netw. 2014;12(2):288-97. DOI: 10.6004/jnccn.2014.0026 PMID: 24586087 22. Fischerová D. [Endometrial cancer - preoperative identification of low and high risk endometrial cancer (a

review of the most recent ultrasound studies]. Ceska Gynekol. 2014;79(6):456-65. PMID: 25585554

23. 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. DOI: 10.1097/IGC.0b013e3182954da8 PMID: 23694985