Sentinel Lymph Node Mapping for Endometrial Cancer

CHAPTER 10

Sentinel Lymph Node Mapping for Endometrial Cancer NADEEM R. ABU-RUSTUM

The majority of patients with endometrial cancer have earlystage uterine-confined disease at presentation. However, many patients will still undergo a complete pelvic and sometimes paraaortic lymphadenectomy for staging purposes despite having disease confined to the uterus, resulting in prolonged operating time, additional cost, and potential long-term side effects such as lymphocyst formation and lower extremity lymphedema. Sentinel lymph node (SLN) mapping in endometrial cancer is an acceptable surgical staging strategy in many practices in the United States and provides a middle ground between a complete lymphadenectomy and no nodal evaluation. The technique has been refined over the past decade, and advances in near infrared imaging and improvements in laparoscopic and robotic optics have facilitated the use of this approach in minimally invasive surgery, which is the desired surgical approach in the majority of women with new clinical stage I endometrial carcinoma. Key factors to a successful SLN mapping procedure include the surgeon’s experience and adherence to the SLN algorithm published in 2012 and listed in the National Comprehensive Cancer Network (NCCN) guidelines since 2014.1,2 The Memorial Sloan Kettering Cancer Center (MSKCC) SLN algorithm (Fig. 10.1) is similar to a surgical checklist and is used to ensure standardization and reduce the false-negative rate of mapping. The algorithm takes into account the bilateral nature of pelvic nodal anatomy and the possibility of gross peritoneal or retroperitoneal disease and has been recently validated by several investigators, with good reproducibility of low falsenegative rates.2–5 SLN mapping is an image-guided surgical procedure that is increasingly accepted in the staging of apparent uterineconfined endometrial cancer.6 Gould coined the term sentinel node in 1960 with his observations of carcinoma of the parotid gland.7 In 1977 Cabanas,8 a urologist working in Paraguay and as a surgical fellow at MSKCC, used lymphography and colored dye to define the lymphatic drainage of the penis and established the first clinical report of SLN in men with penile carcinoma. The concept of SLN mapping in endometrial cancer was introduced by Burke in 19969 from the MD Anderson Cancer Center, but the initial results were not encouraging and the concept gained popularity only later, in recent years, after the establishment of a cervical injection technique and standardization of the SLN mapping procedure with a surgical algorithm.1,10,11

Importance of Lymph Node Assessment Endometrial cancer is the most common gynecologic malignancy; approximately 10% to 15% of patients will have metastatic nodal disease, and nearly 15% of patients with grade 1 tumors at presentation preoperatively at office biopsy or dilation and curettage will actually have higher grade disease at final pathologic review after hysterectomy12; therefore it is of utmost importance to stage and treat patients properly and limit missing undetected metastatic disease that could upstage the patient’s condition and change adjuvant therapy. For most gynecologic oncology practices, a low-risk endometrial cancer is a retrospective diagnosis, meaning that one does not know that the patient is at low risk until total hysterectomy has been done and the permanent pathologic assessment has been completed. The majority of patients with newly diagnosed endometrial cancer will undergo initial surgical treatment that will include a total hysterectomy, bilateral salpingo-oophorectomy, and pelvic washings. Proper surgical staging, one of the most important prognostic factors, provides information on the actual extent of disease rather than on perceived risks based on uterine factors such as grade, histologic type, and depth of myometrial invasion, which helps tailor adjuvant therapy.13 Endometrial cancer frequently develops after menopause, and comprehensive lymphadenectomy in elderly women may be associated with side effects, such as lower extremity lymphedema and lymphocyst formation, which can negatively affect quality of life. The more pelvic lymph nodes removed, the greater the likelihood a patient will develop these side effects. The importance of lymph node assessment for proper surgical staging in this patient population cannot be stressed enough.14,15 In a study of 1289 patients with uterine corpus malignancies, 16 (3.4%) of 469 patients who had 10 or more lymph nodes removed at operation developed new postoperative symptomatic leg lymphedema, and this is likely an underestimation of the true incidence.16 Complete lymphadenectomy is also likely associated with greater operating time, prolonged anesthesia, and other potential untoward effects such as blood loss, vascular and nerve injury, and increased conversion rate from laparoscopy to laparotomy to complete the operation successfully. However, because accurate surgical staging is one of the most important prognostic factors, staging with the 141

142

Section 4  Endometrial Cancer

Peritoneal and serosal evaluation and washings

Retroperitoneal evaluation Excision of all mapped SLNs with ultrastaging

Any suspicious nodes must be removed regardless of mapping

If there is no mapping on a hemipelvis, a side-specific LND is performed Paraaortic LND— at discretion of attending physician FIG. 10.1 Sentinel lymph node (SLN) mapping algorithm. LND, Lymph node dissection.

SLN algorithm will provide the necessary pathologic information in the majority of women with apparent uterine-confined disease while limiting morbidity. The SLN algorithm, when applied for staging of all patients with newly diagnosed endometrial cancer, will at a minimum permit bilateral pelvic nodal assessment as part of the surgical staging. The SLN algorithm also increases surgical precision and avoids the “circumflex iliac” lymph nodes, which were often removed during routine bilateral pelvic lymphadenectomy. These nodes are usually benign, especially when other nodal areas are also negative.17 Removing these nodes frequently causes lymphatic obstruction in the lower extremity, increasing the risk of leg lymphedema.18 Unfortunately, many patients with early-stage endometrial cancer will undergo surgical procedures with insufficient nodal evaluation, with their nodes being palpated (with biopsy performed if they are enlarged), sampled, or completely ignored.19 Studies have shown rates of nodal assessment as low as 30%, although that percentage has increased as the importance of nodal assessment has been realized. Rates are higher when a gynecologic oncologist, as opposed to a general gynecologist, performs the operation (83% vs. 26% in one study).20 When surgical staging is inadequately performed, patients can be subjected to unnecessary adjuvant pelvic radiation therapy and its associated side effects. An MSKCC study showed that with the increase in lymph node assessment over a 12-year time period, there was an inverse decrease in the use of adjuvant whole-­ pelvis radiation therapy.13 In an attempt to clarify clinical variables that affect overall survival in women with endometrial cancer, the classification and regression tree (CART) method, a form of recursive partitioning, was used in a study of 1035 International Federation of Gynecology and Obstetrics (FIGO) stage I to IV endometrioidtype endometrial cancer patients. The study showed that stage, age, adjuvant therapy, and the removal of 10 or more lymph nodes were predictors of overall survival in patients with stage I to IIIA disease. Only stage was a predictor of overall survival in patients with stage IIIC to IV disease. The CART method is a tree-building technique in which “predictor” variables are analyzed to determine how they affect an “outcome” variable (overall survival). The study confirmed the importance of age and surgical staging in influencing overall survival, but the increasing number of nodes removed was not a factor, particularly when a patient was assigned stage IIIC (node-positive disease), confirming

FIG. 10.2  The most common drainage routes, usually the lymphatic trunks, condense in the paracervical tissue and cross over the oblit­ erated umbilical ligament. The most common locations of sentinel lymph nodes after a cervical injection are medial to the external iliac, ventral to the hypogastric vessels, or in the superior part of the obtura­ tor space.

the observation that a minimum number of nodes is needed to assign stage properly, but removal of more normal-appearing nodes, particularly in stage IIIC disease, did not improve overall survival.14,15 The use of an SLN mapping algorithm in endometrial cancer patients is an acceptable staging strategy, providing a middle ground between the polarized schools of thought: complete lymphadenectomy and no nodal evaluation. Modern studies of SLN mapping have used the cervical injection technique in the majority of cases. In a study of 42 patients with grade 1 endometrioid endometrial cancer, the most common anatomic sites at which SLNs were identified were the internal iliac (52 [36%]), external iliac (43 [30%]), obturator (34 [23%]), and common iliac (11 [8%]) regions. Only five patients (3%) had paraaortic SLN involvement.12 Figs. 10.2 and 10.3 demonstrate the most common and less common drainage patterns following a cervical injection of dye. Barlin and colleagues sought to evaluate clinical and pathologic factors that influenced overall survival and to determine if a paraaortic nodal assessment at the initial staging operation in patients with endometrial cancer affected overall survival. The study of 1920 patients who had at least one lymph node removed for staging, which also used CART analysis, showed no association between the removal of paraaortic nodes and overall survival (P = .450). The CART method did show that stage I versus stages II to IV and grades 1 or 2 versus grade 3 (a binary grading system of low vs. high grade) were predictors of overall survival.15 In other words, what appear to be important with regard to staging are the proper determination of uterine fundus–contained disease versus disease outside the uterine fundus and the pathologist’s determination of the grade of the tumor—low grade versus high grade (grade 1 or 2 endometrioid

Chapter 10  Sentinel Lymph Node Mapping for Endometrial Cancer

143

FIG. 10.4  Three different options for direct cervical injection: a twoinjection point option (1A) and the four-quadrant options (1B and C). (Courtesy Abu-Rustum NR, Rob L. Sentinel lymph node identification for early-stage uterine and adnexal malignancies. In: Abu-Rustum N, Barakat RR, Levine DA, eds. Atlas of Procedures in Gynecologic Oncology, 3rd ed. Boca Raton, FL: CRC Press; 2013.)

and improved overall survival.15 In a large meta-analysis, Kang and colleagues reported a decrease in detection rates when the cervical method was not used and also recommended that the “subserosal injection only” technique be avoided because of decreased sensitivity.22 The importance of the cervical injection technique has also been recently supported by large review studies.5 

Colored Dye Injection FIG. 10.3  The less common locations of sentinel lymph nodes, usual­ ly seen when lymphatic trunks do not cross over the umbilical ligament but follow the mesoureter cephalad to the common iliac and presacral sentinel lymph nodes.

disease is considered low grade, and grade 3 endometrioid or serous, clear cell carcinoma, or carcinosarcoma is considered high grade). 

Sentinel Lymph Node Mapping Techniques Historically, a radioactive tracer and blue dye were used to locate “hot” nodes or colored nodes. There are three different types of SLN mapping techniques based on site of injection: (1) uterine subserosal, (2) cervical (Fig. 10.4), and (3) endometrial, by means of hysteroscopy. The majority of current SLN users prefer a cervical injection. A rationale for use of a cervical injection includes the following: (1) the main lymphatic drainage to the uterus is from the parametria, and therefore a combined superficial (1–3 mm) and deep (1–2 cm) cervical injection is adequate; (2) the cervix is easily accessible; (3) the cervix in women with endometrial cancer is rarely distorted by anatomic variations, such as myomas, which sometimes make uterine serosal mapping impossible; (4) the cervix in women with endometrial cancer is rarely scarred from prior procedures such as conization or bulky tumor infiltration; and (5) uterine fundal serosal mapping does not reflect the parametrial lymphatic drainage of the uterus (the main route of drainage), and the majority of early-stage endometrial cancers do not have disease infiltrating and ulcerating the uterine fundal serosa.5,11 The main argument against cervical injection is that it has a lower paraaortic detection rate, as opposed to the hysteroscopic approach, but as is well documented, when the pelvic lymph nodes are negative for metastasis, disease is unlikely to be found in the paraaortic nodes (<5% isolated aortic nodal metastasis with negative pelvic nodes),21 and to date there has been no definitive, welldocumented association between paraaortic nodal assessment

Colored dye (isosulfan blue 1% [Lymphazurin], methylene blue 1%, or patent blue 2.5% sodium [bleu patenté V sodique]) is injected while the patient is under anesthesia in the operating room. A spinal needle or Potocky-type needle is used to inject 4 mL of dye into the cervical submucosa and stroma. The injections are given at the 3- and 9-o’clock positions, which correspond to the parametria and will keep the bladder flap from being stained, which frequently occurs with injection at the 12-o’clock position. The dye should be injected slowly, at a rate of 5 to 10 seconds per quadrant.23 Complications with blue dye are rare, consisting mostly of allergic reactions. Montgomery and colleagues reported a 1.6% incidence of allergic reactions and 0.5% incidence of hypotensive reactions in 2392 patients with breast cancer who underwent an SLN mapping procedure.24 Indocyanine green (ICG) recently emerged as an excellent dye for SLN mapping (Figs. 10.5–10.7). The 25-mg dry powder bottle is mixed with 20 mL of sterile water in the operating room, and a total of 2 to 4 mL is injected directly into the cervix in similar fashion to that for use of blue dye. The main contraindication is allergy to iodine, which is contained in the product currently available in the United States. The SLN detection rates with ICG and the bilateral SLN detection rates are comparable or superior to those with blue dye only or radiocolloid. ICG is currently the preferred imaging dye at many institutions, particularly those with robotic and laparoscopic platforms equipped with near infrared mapping technology.25–27 New technologic advances continue to emerge to enhance the surgeon’s ability to visualize lymphatics. One method currently available for clinical use is color-segmented fluorescence (CSF), available on the PINPOINT system by Novadaq (Burnaby, British Columbia, Canada) (see Figs. 10.5–10.7). The current platform allows a picture-in-picture view with four modes simultaneously, including high-definition white light, Spy mode (black and white) with highest precision, PINPOINT mode (green overlay), and CSF mode. The CSF mode has the ability to provide a heat map that allows the surgeon to see the more dominant lymphatics and improve surgical precision to avoid removal of nonnodal tissue.

144

Section 4  Endometrial Cancer

Obesity is an increasing problem affecting women with endometrial cancer, and SLN mapping maybe be an ideal solution for obese patients, in whom lymphadenectomy may be more challenging. Emerging data demonstrate that ICG cervical injection provides a superior bilateral detection rate compared with blue dye mapping and is likely equivalent to combined blue dye and technetium injections (Fig. 10.8).28 Recent published reports

FIG. 10.5  Sentinel lymph node mapping after cervical indocyanine green (ICG) injection in endometrial cancer. The right afferent and ef­ ferent lymphatic trunks and an external iliac sentinel lymph node are shown. Picture-in-picture image with Spy mode (black and white), PIN­ POINT mode (green), and color-segmented fluorescence (heat map) demonstrated.

have confirmed that ICG with near infrared fluorescence results in higher overall and bilateral detection of SLNs in patients with endometrial cancer compared with blue dye. In general, successful mapping decreases with increasing body mass index (BMI) irrespective of dye used, but it is significantly improved with the use of ICG compared with blue dye. Based on these reports, most current gynecologic oncologists recommend use of ICG for patients with endometrial cancer, particularly obese patients.28–30 Even with advances in imaging technologies and increased use of ICG, mapping may not be successful in some patients. In these patients, use of the SLN algorithm will be critical to ensure adequate nodal evaluation. The following strategy will help minimize failed mapping: 1. Use a proper cervical injection technique. 2. Always perform SLN mapping as the first part of the operation after washings have been obtained and peritoneal evaluation has been performed. 3. Perform meticulous dissection at the beginning of the operation to limit blood staining of the retroperitoneum and to identify the lymphatic trunks. 4. Divide the round ligament. 5. Identify the obliterated umbilical vessel, and follow it cephalad to its origin from the internal iliac artery. 6. Look for lymphatic trunks crossing from medial to lateral over the obliterated umbilical vessel. 7. Open the paravesical and pararectal spaces gently. 8. Follow the trunks to the nodal basins. It may be necessary to look deeper in the hypogastric obturator basins to find the sentinel nodes. 9. If trunks are not seen crossing over the umbilical vessels, then look for lymphatic trunks in the mesoureter going to the presacral common iliac regions. 10. Adhere to the SLN algorithm to ensure the quality of the operation. 

Sentinel Lymph Node Mapping Algorithm

FIG. 10.6  Indocyanine green (ICG) injected into the cervix, leading into a right external iliac sentinel lymph node in a patient with endome­ trial carcinosarcoma.

A

Increasing surgical staging precision and maintaining a low false-negative rate are main priorities in any SLN program. Incorporating an SLN mapping algorithm significantly reduces the false-negative rate of the mapping procedure. Applying the MSKCC SLN algorithm reduces the false-negative rate to 2%, because the algorithm takes into account grossly enlarged suspicious nodes and includes a side-specific lymphadenectomy for the nonmapping hemipelvis2 (Table 10.1).

B

FIG. 10.7  A resected large left external iliac sentinel lymph node after intracervical indocyanine green (ICG) injection in grade 1 endometrial cancer, shown in high-definition white light laparoscopic image (A) and picture-in-picture color-segmented fluorescence (heat map) (B).

Chapter 10  Sentinel Lymph Node Mapping for Endometrial Cancer

The SLN algorithm includes (1) peritoneal and serosal evaluation and washings; (2) retroperitoneal evaluation, including the removal of all SLNs and any suspicious nodes; and (3) if there is no mapping on a hemipelvis, a side-specific pelvic, common iliac, and interiliac lymph node dissection. A paraaortic lymphadenectomy is left to the attending physician’s discretion (see Fig. 10.1).1,2 This algorithm has been validated by other investigators.3,4,31 An acceptable SLN detection rate varies among practices, but a detection rate of 80% to 90% or greater is preferred.32 KhouryCollado and colleagues reported on 115 patients with endometrial cancer treated from September 2005 through March 2009. The overall SLN detection rate was 85%. During the early phase of the study (September 2005 through December 2007), however, an SLN was identified in 50 (78%) of 64 cases, with two falsenegative results, and during the late phase (January 2008 through March 2009), an SLN was identified in 48 (94%) of 51 cases, with no false-negative results. Detection rates increased from 77% to 94% (P = .033) during the two time periods, with surgeon experience (30 procedures or more) playing an integral role.31,32 With increasing surgeon experience and a corresponding increase in detection rates to 90% or greater, in addition to a decrease in false-negative rates as a result of adherence to the SLN algorithm, SLN mapping is becoming an established standard of care in many practices worldwide.  100%

Bilateral mapping rate

90% 80% 70% 60% 50% 40% 30% 20% ICG

10% 0% BMI <20

BMI BMI BMI BMI BMI 20–25 25–30 30–35 35–40 40–45 BMI

BMI ≥45

FIG. 10.8 Bilateral mapping rate in relation to body mass index (BMI). Blue dye versus indocyanine green (ICG). (From Eriksson AG, ­Montovano M, Beavis A, et al. Impact of obesity on sentinel lymph node mapping in patients with newly diagnosed uterine cancer ­undergoing robotic surgery. Ann Surg Oncol. 2016;23[8]:2522–2528.) TABLE 10.1  Performance

145

Sentinel Lymph Node Ultrastaging Ultrastaging is an important component of the SLN algorithm. Ultrastaging is done when the initial SLN evaluation with hematoxylin and eosin (H&E) is negative for carcinoma. Ultrastaging has two basic components: serial sectioning and immunohistochemical staining.33 Data from Kim and colleagues suggest that ultrastaging should be limited to endometrial carcinomas with any degree of myoinvasion but not to nonmyoinvasive tumors.33 In endometrial carcinomas with any degree of myoinvasion, ultrastaging detects an additional 8% nodal positivity in the SLN over the initial H&E evaluation; however, if there is no myoinvasion, then ultrastaging detects only an additional 0.8% nodal positivity.33 The SLN ultrastaging protocol varies among institutions, but all include the two main components of serial sectioning and immunohistochemical staining. The SLN ultrastaging algorithm used at MSKCC is as follows (Fig. 10.9)33: SLNs are initially examined by use of routine H&E staining, and subsequent ultrastaging is performed if the initial H&E assessment is negative. Ultrastaging is performed by cutting two adjacent 5-μm sections at each of two levels, 50 μm apart, from each paraffin block lacking metastatic carcinoma. At each level, one slide is stained with H&E, and immunohistochemical staining is performed with the anticytokeratin AE1/AE3 (Ventana Medical Systems, Tucson, Arizona), for a total of five slides per block.33 Both SLNs and nonsentinel lymph nodes are routinely sectioned once and stained with H&E. The ultrastaging pathology protocol for SLNs is implemented if the SLN is negative on initial H&E staining. Ultrastaging reevaluates the presumably negative SLN at two additional levels, 50 μm apart, with an extra H&E-stained slide and immunohistochemical staining with the anticytokeratin AE1:AE3. Ultrastaging detects metastatic nodal disease including both micrometastases and isolated tumor cells. Gynecologic pathologists currently use definitions from the breast cancer literature published by the American Joint Committee on Cancer (AJCC; Breast Cancer Staging, seventh edition). Macrometastases in lymph nodes are defined as tumor cells larger than 2.0 mm; micrometastases are defined as a focus of metastatic cancer that is larger than 0.2 mm or consists of more than 200 cells 2.0 mm or smaller (these are considered positive nodes by most practices), and isolated tumor cells are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross section. Isolated tumor cells may be detected with routine histologic examination or by immunohistochemical methods. There is significant controversy in gynecologic

of Sentinel Lymph Node Technique Alone Compared With Algorithm for All Patients

LN Positive

LN Negative

SLN Alone

Calculation

Result

SLN positive

40

0

40

Sensitivity

40/47

85.1

SLN negative

7 47

354

361

Negative predictive value

354/361

98.1

354

401

False-negative rate

7/47

14.9

LN Positive

LN Negative

Algorithm

Calculation

Result

Algorithm positive

53

0

53

Sensitivity

53/54

98.1

Algorithm negative

1

420

421

Negative predictive value

420/421

99.8

54

420

474

False-negative rate

1/54

1.9

LN, Lymph node; SLN, sentinel lymph node. With permission from Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol. 2012;125:531–535.

146

Section 4  Endometrial Cancer

oncology regarding the biological significance of isolated tumor cells in SLNs and whether they should be treated as metastatic nodes in endometrial cancer. The preliminary data suggest that treated patients with isolated tumor cells who received adjuvant therapy, including chemotherapy, do as well as those with nodenegative disease; however, untreated observational cohorts with

Non-SLN

isolated tumor cells and long-term follow-up are lacking.34 In addition, cytokeratin-positive cells are noted if only single, rare cytokeratin-positive stained cells are present with immunohistochemical staining but are not seen with H&E staining. SLNs containing only cytokeratin-positive cells are considered negative lymph nodes (Tables 10.2 and 10.3).

SLN

1 H&E stain

+

–

Positive (non-SLN and SLN)

Negative

If non-SLN

H and E (level 1)

If SLN

AE1:AE3 (level 1 IHC) Negative control

Stop

50 µm apart

Ultrastaging

H&E (level 2) L1

AE1:AE3 (level 2 IHC)

L2

FIG. 10.9  The endometrial cancer sentinel lymph node (SLN) ultrastaging algorithm used at Memorial Sloan Kettering Cancer Center. H&E, hematoxylin and eosin. (From Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23[5]:964–970.)

TABLE 10.2  Incidence

Myometrial Invasion

of H&E Macrometastases in Sentinel Lymph Nodes by Final Histologic Grade and Depth of

DMI

Grade 1

Grade 2

Grade 3

Total

No invasion

H&E 0 n = 165

H&E 1 n = 39

H&E 1 n = 38

2/242 = 0.8%

Invasion <50%

H&E 6 n = 80

H&E 4 n = 62

H&E 6 n = 56

16/198 = 8.1%

Invasion ≥50%

H&E 6 n = 16

H&E 3 n = 15

H&E 8 n = 37

17/68 = 25.0%

Total

12/261= 4.6%

8/116 = 6.9%

15/131 = 11.5%

35/508 = 6.9%

DMI, Depth of myometrial invasion; H&E, hematoxylin and eosin. With permission from Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23(5):964–970.

Chapter 10  Sentinel Lymph Node Mapping for Endometrial Cancer

147

TABLE 10.3  Incidence

of Ultrastage-Detected, Low-Volume Metastases in Sentinel Lymph Nodes by Final Histologic Grade and Depth of Myometrial Invasion DMI

Grade 1

Grade 2

Grade 3

Total

No invasion

MM 1 ITC 1 n = 165

MM 0 ITC 0 n = 39

MM 0 ITC 0 n = 38

2/242 = 0.8%

Invasion <50%

MM 2 ITC 4 n = 80

MM 0 ITC 4 n = 62

MM 0 ITC 6 n = 56

16/198 = 8.0%

Invasion ≥50%

MM 0 ITC 2 n = 16

MM 0 ITC 0 n = 15

MM 1 ITC 2 n = 37

5/68 = 7.4%

Total

10/261= 3.8%

4/116 = 3.4%

9/131 = 6.9%

23/508 = 4.5%

DMI, Depth of myometrial invasion; ITC, isolated tumor cells; MM, micrometastasis. With permission from Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23(5):964–970.

Summary The SLN mapping algorithm is a reasonable staging strategy for apparent uterine confined endometrial cancer. This approach is gradually becoming the standard of care for surgical staging in many gynecologic oncology practices worldwide. The SLN algorithm allows for at least bilateral pelvic nodal assessment on the majority of new cases of endometrial cancer and can be performed with a minimally invasive approach using near infrared imaging where the technology is available. As our understanding of pathologic biomarkers and the most appropriate adjuvant therapy after hysterectomy continues to be refined, the role of nodal assessment for staging will continue to evolve. References

1.  National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2017. 2016. 2. Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol. 2012;125:531–535. 3. Hagen B, Valla M, Aune G, et al. Indocyanine green fluorescence imaging of lymph nodes during robotic-assisted laparoscopic operation for endometrial cancer. A prospective validation study using a sentinel lymph node surgical algorithm. Gynecol Oncol. 2016;143:479–483. 4. Ehrisman J, Secord AA, Berchuck A, et  al. Performance of sentinel lymph node biopsy in high-risk endometrial cancer. Gynecol Oncol Rep. 2016;17:69–71. 5. Tschernichovsky R, Diver EJ, Schorge JO, Goodman A. The role of lymphadenectomy versus sentinel lymph node biopsy in early-stage endometrial cancer: a review of the literature. Am J Clin Oncol. 2016;39: 516–521. 6. Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol. 2011;122:251–254. 7. Gould EA, Winship T, Philbin PH, Kerr HH. Observations on a “sentinel node” in cancer of the parotid. Cancer. 1960;13:77–78. 8. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456–466. 9. Burke TW, Levenback C, Tornos C, et  al. Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer: results of a pilot study. Gynecol Oncol. 1996;62:169–173. 10. Abu-Rustum NR. The increasing credibility of sentinel lymph node mapping in endometrial cancer. Ann Surg Oncol. 2013;20:353–354.

11. Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Canc Netw. 2014;12(2):288–297. 12. Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, et  al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma? Gynecol Oncol. 2009;113:163–169. 13. Barakat R, Lev G, Hummer AJ, et  al. Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches. Gynecol Oncol. 2007;105:150–156. 14. Abu-Rustum NR, Iasonos A, Zhou Q, et al. Is there a therapeutic impact to regional lymphadenectomy in the surgical treatment of endometrial carcinoma? Am J Obstet Gynecol. 2008;198(457):e1–e5. [discussion e5–e6]. 15. Barlin JN, Zhou Q, St. Clair CM, et al. Classification and regression tree (CART) analysis of endometrial carcinoma: seeing the forest for the trees. Gynecol Oncol. 2013;130(3):452–456. 16. Abu-Rustum NR, Alektiar K, Iasonos A, 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;103:714–718. 17. Hoffman MS, Parsons M, Gunasekaran S, Cavanagh D. Distal external iliac lymph nodes in early cervical cancer. Obstet Gynecol. 1999;94:391–394. 18. Abu-Rustum NR, Barakat RR. Observations on the role of circumflex iliac node resection and the etiology of lower extremity lymphedema following pelvic lymphadenectomy for gynecologic malignancy. Gynecol Oncol. 2007;106:4–5. 19. Soliman PT, Frumovitz M, Spannuth W, et al. Lymphadenectomy during endometrial cancer staging: practice patterns among gynecologic oncologists. Gynecol Oncol. 2010;119(2):291–294. 20. Roland PY, Kelly FJ, Kulwicki CY, et al. The benefits of a gynecologic oncologist: a pattern of care study for endometrial cancer treatment. Gynecol Oncol. 2004;93:125–130. 21. Abu-Rustum NR, Gomez JD, Alektiar KM, et  al. The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. Gynecol Oncol. 2009;115:236–238. 22. Kang S, Yoo HJ, Hwang JH, et  al. Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies. Gynecol Oncol. 2011;123:522–527. 23. Abu-Rustum NR, Khoury-Collado F, Gemignani ML. Techniques of sentinel lymph node identification for early-stage cervical and uterine cancer. Gynecol Oncol. 2008;111:S44–S50. 24. Montgomery LL, Thorne AC, Van Zee KJ, et al. Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer. Anesth Analg. 2002;95:385–388.

148

Section 4  Endometrial Cancer

25. Holloway RW, Bravo RA, Rakowski JA, et  al. Detection of sentinel lymph nodes in patients with endometrial cancer undergoing roboticassisted staging: a comparison of colorimetric and fluorescence imaging. Gynecol Oncol. 2012;126(1):25–29. 26. Jewell EL, Huang JJ, Abu-Rustum NR, et al. Detection of sentinel lymph nodes in minimally invasive surgery using indocyanine green and nearinfrared fluorescence imaging for uterine and cervical malignancies. Gynecol Oncol. 2014;133(2):274–277. 27. 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):1704–1711. 28. Eriksson AG, Montovano M, Beavis A, et al. Impact of obesity on sentinel lymph node mapping in patients with newly diagnosed uterine cancer undergoing robotic surgery. Ann Surg Oncol. 2016;23(8):2522–2528. 29. Papadia A, Zapardiel I, Bussi B, et  al. Sentinel lymph node mapping in patients with stage I endometrial carcinoma: a focus on bilateral mapping identification by comparing radiotracer Tc99(m) with blue dye versus indocyanine green fluorescent dye. J Cancer Res Clin Oncol. 2017;143(3):475–480.

30. Sinno AK, Fader AN, Roche KL, Giuntoli 2nd RL, Tanner EJ. A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer. Gynecol Oncol. 2014;134(2):281–286. 31. Eitan R, Sabah G, Krissi H, et al. Robotic blue-dye sentinel lymph node detection for endometrial cancer—factors predicting successful mapping. Eur J Surg Oncol. 2015;41(12):1659–1663. 32. Khoury-Collado F, Glaser GE, Zivanovic O, et al. Improving sentinel lymph node detection rates in endometrial cancer: how many cases are needed? Gynecol Oncol. 2009;115:453–455. 33. Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23(5):964–970. 34. St Clair CM, Eriksson AG, Ducie JA, et  al. Low-volume lymph node metastasis discovered during sentinel lymph node mapping for endometrial carcinoma. Ann Surg Oncol. 2016;23(5):1653–1659.