Endometrial (uterine) cancer is the most common malignancy of the female genital tract in the United States, with an estimated 66,570 new cases and 12,940 deaths in 2021. In 2019, there were an estimated 807,860 women living with uterine cancer in the United States. Approximately 3.1% of women will be diagnosed with uterine cancer at some point during their lifetime. Hysterectomy remains the mainstay in the treatment of endometrial cancer, which was traditionally accomplished via open laparotomy until the 1990s. Since then, multiple studies demonstrated the feasibility of a minimally invasive laparoscopic approach. , The Gynecologic Oncology Group (GOG) phase III LAP2 trial showed noninferiority of laparoscopy versus laparotomy in terms of recurrence and survival. Robotic-assisted laparoscopy has not been prospectively compared in randomized trials to conventional laparoscopy in endometrial cancer surgical staging, but several retrospective cohort comparison studies suggest equivalency in staging results. ,
Lymph node (LN) metastasis is one of the most important prognostic factors affecting recurrence and survival in endometrial cancer (EC). The presence or absence of LN involvement is a major determinant in staging and affects decisions regarding adjuvant therapies. The incidence of LN metastasis ranges from 0 to approximately 28% in apparent clinical stage I endometrial cancers, with the actual risk dependent upon uterine tumor histology, lesion size, depth of invasion (DOI), and lymphovascular space involvement (LVSI). Traditionally, LN metastases are detected surgically with systematic pelvic and aortic lymphadenectomy. However, comprehensive lymphadenectomy is associated with adverse outcomes including additional blood loss, lymphedema, lymphocysts, and neuralgia. Moreover, a clinically significant percentage of node-negative patients suffer from lymphatic recurrence, suggesting possible deficiencies in the diagnosis and treatment of lymphatic dissemination.
The sentinel lymph node (SLN) biopsy procedure improves sensitivity for the detection of metastases by locating the most likely involved lymph node (i.e., the SLN) and evaluates the SLN with ultra-sectioning and immunohistochemical (IHC) stains. These enhanced pathology techniques increase the detection of isolated tumor cells (ITCs) and micro-metastases, further increasing sensitivity for the detection of lymph node metastases. Morbidity related to surgical staging is reduced by limiting the number of lymph nodes removed. The SLN is the most proximal lymph node in a sentinel pathway emanating from the primary tumor. In the case of uterine cancer, lymphatic pathways leave the uterus bilaterally through the lower uterine segment parametria and either proceed laterally crossing over the superior vesicle artery to the lateral pelvic sidewall nodes, or posteriorly branching to pararectal, internal iliac, presacral, common iliac, or infra-mesenteric aortic lymph nodes. Fundal routes of drainage via the ovarian blood supply are also present; however, mapping the aorta using cervical injection of dyes has not been consistent or well studied. The targeted biopsy of sentinel nodes results in less disruption of pelvic lymphatic drainage and less morbidity than comprehensive lymphadenectomy. SLN mapping is also diagnostically superior to traditional lymphadenectomy because it can detect unexpected drainage pathways that are not universally captured by traditional pelvic lymphadenectomy, such as presacral, parametrial, and internal iliac lymph node basins in approximately 5% of cases.
The sentinel node concept is a relatively contemporary milestone in the understanding of solid malignancy metastasis. Virchow, in the nineteenth century, theorized that lymph nodes filter particulate matter from lymph. The experimental work of Halsted and others supported the hypothesis of sequential dissemination through the lymphatic system. After incidental reports of nonguided sentinel node procedures, it was the introduction of the technique of intra-operative lymphatic mapping in 1989 that initiated the widespread use and general acceptance of this approach.
The sentinel lymph node was first hypothesized by Gould in 1960, who observed that the most likely involved LN was located in close proximity to the primary tumor during en bloc dissection of parotid cancer. The first SLN mapping procedure was described two decades later by Cabanas in penile cancer by cannulating the dorsal lymphatics of the penis and performing lymphangiography. Morton et al. published a landmark study in 1992 using blue dye to introduce a new concept concerning the dynamic physiology of lymphatic drainage, described as quite variable from patient to patient. They fundamentally changed the historical thoughts about lymphatic dissemination, emphasizing that in many patients there was an orderly spread of metastasis from the primary site to sentinel lymph nodes, and then elsewhere via the bloodstream. Pathology ultra-staging of sentinel nodes that uses multiple sections of paraffin-embedded tissue and sensitive cytokeratin stains was first reported in breast cancer by Giuliano and colleagues in 1994. Lymphatic mapping entered the domain of gynecologic cancer first in vulvar cancer by Levenback et al., followed by endometrial cancer by Burke et al. using blue dye, and finally arrived in cervical cancer 3 years later by Echt et al.
The clinical utility of sentinel node biopsies has been demonstrated in several different malignancies. The NSABP 32 trial in breast cancer illustrated that the 8-year disease-free survival, regional control rate, and overall survival were statistically equivalent between the SLN group and the axillary dissection group. Another randomized multicenter trial in breast cancer also concluded that upper extremity morbidity including swelling, sensory loss, mobility loss and quality-of-life (QOL) scores after sentinel node biopsy are better with SLN biopsy. SLN biopsy is now considered the standard of care in vulvar cancer since the publication of the GROINSS-V-I study and GOG-173.
Surgical technique and the surgical algorithm
Sentinel node mapping is feasible with laparoscopic, robotic-assisted laparoscopic, and open abdominal approaches. A meta-analysis of 26 studies on the utilization of SLN biopsy in EC reported no association of sensitivity or detection rate to the surgical approach. The cervix is a midline organ that has bilateral lymphatic drainage in the pelvis. The uterine corpus, however, drains both to bilateral pelvic node beds through the parametria and to the para-aortic basins through the infundibulopelvic (IP) lymphatics and/or via posterior presacral lymphatics. The cervix is the most commonly injected site for endometrial cancer mapping compared to other methods such as fundal and hysteroscopic tumor injections. Corpus injection using transvaginal sonography (TVS) or hysteroscopy is cumbersome, is less reproducible, and has more variability in mapping success than mapping with cervical injections. The National Comprehensive Cancer Network (NCCN) guidelines recommend cervical injection of dyes or a radioactive tracer 1 to 3 mm below the mucosa at either two cardinal points or four cardinal points in the cervix (i.e., 3 and 9 o’clock positions, or 2, 4, 8, 10, or 3, 6, 9, 12 o’clock positions). In our experience, four-point injection has a higher rate of successful mapping than two-point technique especially with less experienced surgeons, although there is no documented difference in outcomes apparent from retrospective comparisons. Aliquots of 0.5 mL of a 1 mg/mL solution of indocyanine green (ICG) dye should be used at each site in the four-quadrant technique, or 1 mL injected at 3 and 9 o’clock. Care should be taken to ensure that the injection is within the lateral cervical stroma with enough depth at 3 to 5 mm to avoid dye leaking back out into the vagina, and also to avoid deep injection into the posterior cul-de-sac, which stains peritoneum obscuring the SLN pathways. Deeper injections in the cervix up to 10 mm are proposed for uterine cancers in an attempt to map the infundibulopelvic lymphatics; however, efficacy and interpretation of these findings is lacking.
Indocyanine green and blue dyes will travel quickly into the parametrial lymphatics within minutes. Visualization through dissection of the retroperitoneum should ideally be initiated within 15 minutes of injection to avoid “washout” of too much dye in the retroperitoneum. Timing of the dye injection is an important consideration in patients with prior abdominal surgeries who may require adhesiolysis before initiating the SLN procedure. Injection of dye should be delayed until access to the pelvis is confirmed in patients with complex surgical abdomens. SLN mapping is initiated by searching for pathways emanating from cervical stroma through the parametria, usually in proximity to the uterine artery. From there, the pathways will diverge most often to the medial external iliac and proximal obturator nodes, and less commonly to common iliac nodes. However, approximately 10% to 15% of pathways will diverge to areas not usually dissected in traditional pelvic lymphadenectomy including internal iliac, pararectal, and presacral lymph nodes through the posterior lymphatic pathways. Posterior pathways have been reported more clinically relevant with node metastasis in patients with type II high-risk histologies more than endometrioid histology. Presacral pathways occasionally cross the common iliac artery and terminate in infra-mesenteric aortic lymph nodes. When opening the retroperitoneum and developing paravesical and pararectal spaces, avoidance of cutting lymphatic pathways by instead performing blunt dissection and tissue spreading will allow more time for dye transit in the event nodes are not initially identified. If one hemi-pelvis lacks propagation of dye, it is beneficial to allow more time by dissecting the opposite hemi-pelvis, isolating and dividing the IP ligaments, or developing the bladder flap. If mapping still fails, a second injection of dye is often helpful, usually if the initial dye injection was too superficial and may have leaked out of the needle track rather than diffuse into the stroma. This concept was supported by Maramai et al. who showed that cervical reinjection resulted in improvement of the bilateral detection rate from 73% to 94%, and thereby reduced the number of side-specific required lymphadenectomies. Consideration should be given to the patient’s history, as sentinel mapping can be negatively affected by prior history of pelvic radiation, chronic inflammatory conditions such as diverticulosis, or lymphoma/leukemia. Also, in regard to their endometrial cancer diagnosis, LVSI, nonendometrioid histology, and intraoperative finding of enlarged lymph nodes were identified as independent risk factors for unsuccessful mapping. The complete surgical algorithm per NCCN is summarized in Fig. 41.1 . ,
Observational studies have suggested that unilateral pelvic SLN status does not accurately predict the presence or absence of metastasis on the contralateral side. Stephens et al. reported a 75% congruency in bilateral mapping, meaning that 25% of sentinel nodes would be inaccurately dissected if the surgeon relied solely on symmetry for SLN location. Barlin et al. retrospectively applied a surgical algorithm that incorporated side specific lymphadenectomy, as well as removal of any suspicious nodes and peritoneal lesions in a study of 498 endometrial cancer patients undergoing SLN mapping. The proposed endometrial surgical algorithm was estimated to reduce the false negative rate (FNR) from 14.9% to 1.9%. The NCCN guidelines recommend utilization of this surgical algorithm for SLN mapping. , Cormier and colleagues subsequently analyzed the efficacy of the NCCN surgical algorithm in endometrial cancer on 1385 patients from a historical database. They observed that 37 of 190 node positive patients had false negative SLNs. Retrospectively applying the Barlin et al. surgical algorithm reduced the FNR from 19% to 5%. Sinno et al. proposed a hypothetical algorithm called the restricted frozen section algorithm that would apparently reduce lymphadenectomy rates. Retrospective application of their algorithm to 114 patients with apparent uterine confined, grade 1/2 endometrial cancer and complex atypical hyperplasia reduced pelvic lymphadenectomy rates to 9.2% in the restricted frozen section algorithm compared to 36.8% in the NCCN surgical algorithm. We utilize this proposed algorithm, where pelvic and para-aortic lymphadenectomy is performed only if SLN mapping fails and if high-risk uterine features are identified on frozen section. If the primary tumor meets Mayo criteria (less than 2 cm, hyperplasia or grade 1 histology, and no myometrial invasion), full lymphadenectomy of a hemi-pelvis that failed mapping is not necessary and can be omitted.
Multiple studies have reported the risk of isolated aortic metastases in endometrial cancers at approximately 1% to 3% in pelvic node-negative patients. The decision to dissect aortic nodes should be determined based on the frozen section information of the primary tumor (grade, depth of invasion, LVSI) or the presence of grossly positive pelvic nodes. When patients are determined to be at risk for aortic metastasis, the target should be the infra-renal para-aortic lymph nodes in addition to infra-mesenteric nodes. Not all patients are candidates for infra-renal dissection based on body habitus or comorbid medical conditions, and the infra-renal lymph nodes can be radiographically monitored for recurrence as an alternative.
The evolution of SLN detection methods
A variety of colored dyes have been used for SLN mapping. The use of methylene blue and isosulfan blue (ISB) dyes are the least expensive technique for mapping because they are visualized in white light and do not require the cost of additional imaging systems. Other limitations include ISB’s risk of anaphylactic reactions (1 per 1000 injections) and cost, as it contains human albumin. While less costly, injection of methylene blue dye can result in paradoxical methemoglobinemia leading to a falsely low serum O 2 saturation. Methylene blue is not FDA approved for lymphatic mapping and has occasionally been associated with skin necrosis in extremity mapping of melanoma. The overall detection rate of SLNs by blue dye alone in endometrial cancer is 93%, with bilateral detection ranging from 44% to 81%.
Technetium-99 (Tc99) is a radiocolloid that uses a gamma camera or single-photon emission computerized tomography (SPECT) scan for detection. The “short” physical half-life of the isotope and its biological half-life of 1 day allows scanning procedures that collect data rapidly but keeps patient radiation exposures low. Tc-99 can be injected the day prior to surgery or on the same day of surgery. A preoperative lymphoscintigram/SPECT scan is taken 30 minutes after the injection and provides the surgeon with the location of the sentinel node. Gamma laparoscopic or hand-held gamma probes are required to help dissect the nodes intra-operatively. Tc-99 has been widely used in breast cancer and malignant melanoma, and more recently in vulvar cancer and endometrial cancer. In a prospective multicenter SENTI-ENDO Trial, cervical dual injection of [99mTc]-labeled colloid and patent blue was used in 125 patients with early-stage endometrial cancer. Ballester et al. reported an overall detection rate of 89% with a sensitivity of 84% and a negative predictive value (NPV) of 97%. How et al. reported an overall detection rate of 92% (bilateral detection rate of 72%), sensitivity of 89%, and NPV of 99% using a pericervical combined injection of patent blue and [99mTc]-labeled colloid in 100 patients. However, the Tc-99 procedure’s issues of cost and requirements for conscious injection of the tumor sites in the nuclear medicine department are inconvenient and somewhat limiting.
ICG is a tricarbocyanine dye that fluoresces when illuminated with 806 nm near-infrared light (NIR). The dye comes in a 25 g powder vial and is diluted with 25 mL of sterile water for injection. The fluorescent light is then captured using an NIR imaging system. It was initially used in vascular procedures for imaging a vessel’s blood flow to document patency; however, its applications have expanded to many other procedures including biliary tract imaging. ICG was first utilized in breast cancer in 2005 by Kitai et al. and then in melanoma by Fujiwara et al. in 2009. In 2012, the combination of blue dye and ICG was described in endometrial cancer with high detection rates by Rossi et al. (88%) and Holloway et al. (100%). Retrospective case series suggest that ICG alone has comparable sensitivity to a combination of colorimetric and radiotracer dyes and is superior to blue dyes alone. A prospective randomized trial showed that ICG plus ISB had overall and bilateral detection rates of 96% and 84% compared to ISB only, which had rates of 76% and 40%, respectively. Fluorescent dyes are considered superior in the detection of SLNs in obese women. Figs. 41.2–41.4 display lymphatic dissemination of ICG in normal light and NIR imaging after retroperitoneal dissection. The main limitation of ICG is rare allergic reactions (1/12,000), possibly more common in patients with iodine allergies. Manufacturers are developing advanced molecules of fluorescent dyes and videoscopes to improve the precision in finding the sentinel nodes. Activatable fluorescent probes (smart probes) are being tested to delineate cancer cells in vivo. Future prospects include the detection of tumor margin in the cervix and vulva, detection of metastatic nodes in vivo, and precise imaging of metastatic disease.
Pathological assessment of sentinel lymph node
Ultra-staging is a more meticulous histologic examination of the SLNs involving multilevel H&E assessment and the use of IHC stains. The number of step sections, the depth of micro-sectioning the tissue block, the interval between sections, and the number of slides used for IHC stains are all variables that can influence the sensitivity of determining ITCs and micro-metastases. Ultra-staging was first reported in 1995 by Giuliano and colleagues when they described the upstaging potential of enhanced histopathological analysis of SLNs in breast cancer using multilevel sectioning and cytokeratin stains.
There is no one universally accepted micro-sectioning/IHC protocol for sentinel lymph nodes in endometrial cancer. The Memorial Sloan Kettering Cancer Center (MSKCC) ultra-staging protocol executes sectioning the H&E negative blocks into two sections 50 μm apart and examining two slides for H&E and two slides for antipan cytokeratin antibody (AE1/AE3) with an additional H&E slide. , The number of sections per block varies in the peer-reviewed published literature, from 3 to 6 step sections, 40 to 200 μm apart. The number of IHC stained slides also varies from 1 to 4. , , Theoretically, serial sectioning at every 2 mm would detect all macro-metastases, and micro-sectioning every 200 μm would detect all micro-metastases. No healthcare system can afford the cost of searching for all ITCs by micro-sectioning down to a few microns. IHC staining can result in clinically false positive results from the detection of benign glandular inclusions, and therefore interpretive experience of the pathologist is critically important.
Significance of micro-metastasis and isolated tumor cells
The seventh edition American Joint Committee on Cancer (AJCC) and the seventh edition Union for International Cancer Control (UICC) guidelines define ITCs as single cells or microscopic clusters up to 200 cells measuring ≤0.2 mm. Micro-metastases (MMs) are foci measuring greater than 0.2 mm but ≤2 mm, and macro-metastases are greater than 2 mm in size. ITCs do not typically show evidence of metastatic activity (e.g., proliferation of stromal reaction) or penetration of vascular or lymphatic sinus walls. ITCs in lymph nodes or distant sites are classified as N0 or M0, respectively, followed by the designation (i+) in the tumor, nodes, and metastases (TNM) staging nomenclature.
Several studies have evaluated the significance of low-volume (i.e., micro-metastases and ITCs) metastases in SLNs and the relationship to non-SLN involvement in endometrial cancer. Touhami et al. found that overall 34% of endometrial cancer patients with positive SLNs had other nonsentinel node metastases. In contrast, those with low-volume SLN metastases had only a 5% risk of other positive non-SLNs. SLNs may not necessarily reflect the largest volume of metastatic disease. The prospective multi-institutional FIRES trial found that approximately 5% of patients with micro-metastatic SLNs had macro-metastatic disease in non-SLNs. The presence of low-volume SLN metastases may also confer a risk of para-aortic disease. Kennard et al. examined cases with ITCs in SLNs and observed aortic metastases in 18.8% of low-risk (endometrioid <50% invasion), 11.8% intermediate-risk (endometrioid greater than 50% invasion), and 33.3% high-risk (nonendometrioid) cases. Similar to the Touhami et al. study, nonsentinel pelvic node metastases were present in 28 (31.5%) of all SLN-positive cases, but only three (8.3%) of SLNs with ITCs. After controlling for confounding risk variables, ITC-positive SLNs had a significant association with pelvic and aortic metastases ( P = .03 and P = .008, respectively).
Several other studies have attempted to assess the oncologic risk of low-volume metastases in endometrial cancer. Todo et al. retrospectively evaluated paraffin-embedded blocks of 61 H&E node-negative stage I-II patients with at least one risk factor for recurrence using IHC staining methods. The presence of ITCs and micro-metastases was identified as an independent risk factor for extra-pelvic recurrence (hazard ratio, 17.9; 95% confidence interval [CI], 1.4 to 232.2). The 8-year recurrence-free survival (RFS) and overall survival (OS) were 55.6% and 71% in the ITC/MM group, respectively, compared to 84% and 92% in the node-negative group ( P > .05). Additionally, there was a trend toward higher disease recurrence in the patients with ITCs or micro-metastases who did not receive adjuvant chemotherapy (100% vs. 28.6%, respectively; P = .17). St. Clair et al. evaluated 844 endometrial cancer patients undergoing SLN mapping and found that 10.8% had LN metastasis including 2.7% ITCs, 2.5% micro-metastasis, and 5.6% macro-metastasis. The 3-year RFS for ITCs (86%) and for micro-metastasis (86%) appeared similar to that of node-negative cases (90%). In contrast, the 3-year RFS for those with macro-metastases was 71%. These findings suggested that low-volume metastases may have a similar outcome to that of node-negative disease. However, the vast majority of patients with low-volume metastasis received adjuvant therapies, making interpretation of the survival findings difficult to interpret. In another study by Plante et al. Five hundred and nineteen patients were prospectively evaluated, of which 85 had positive SLNs and 36% of those contained ITCs. No patients with ITCs and endometrioid histology recurred. At 24 months, 93.8% of patients overall with ITCs were progression free, including 100% of those treated with brachytherapy or observation alone. However, the follow-up period was somewhat limited, overall survival was not assessed, and patients were not assigned adjuvant therapies through protocols, limiting the ability to interpret the independent risk of recurrence associated with ITCs. The authors concluded that clinicians should tailor adjuvant treatment to uterine factors and histology and not base decisions solely on the presence of ITCs. Backes et al. also reported similar conclusions regarding the uncertainty of treating ITCs, evaluating a multi-institutional retrospective database of 175 patients harboring ITCs.
ITCs have been associated with high-risk uterine factors in endometrial cancer. , , , , With the colinearity especially between ITCs, LVSI, and myometrial invasion, it is difficult to ascertain the independent clinical significance of ITCs in patients with high-risk factors. At this time, there are no consensus treatment guidelines with respect to isolated tumor cells; however, most investigators agree that micro-metastases are considered “positive nodes.” Decisions about adjuvant therapy in patients with ITCs should be made in concert with known histopathologic risk factors of the primary uterine tumor.
Sentinel lymph node mapping in endometrial cancer: Reliability
Sentinel lymph node mapping has a category 2A recommendation for staging apparent uterus-confined endometrial cancer in the 2021 NCCN guidelines. The SLN algorithm was first shown to be appropriate for patients with low-risk endometrial histology, and it increased detection of low-volume metastasis-altered therapy. Replacing complete lymphadenectomy with SLN mapping for patients with high-risk histologies (i.e., serous, clear cell, carcinosarcoma) has been questioned, given the higher incidence of metastases. Early studies reported promising results for SLN mapping as an alternative to complete lymphadenectomy in high-risk histologies. More recently, the SENTOR trial was conducted as a prospective multi-institutional cohort study comparing SLN mapping to lymphadenectomy specifically for high-grade endometrial cancers (grade 3 endometrioid, serous, clear cell, carcinosarcoma, undifferentiated, or mixed tumors). All patients underwent SLN biopsy, followed by completion pelvic and aortic lymphadenectomy, and sentinel nodes were submitted for pathology ultra-staging. In their 156-patient cohort, the SLN detection rate was 99% (95% CI, 95 to 100), 88% per hemi-pelvis (95% CI, 83 to 91), and 77% bilaterally (95% CI, 70 to 83). Node metastasis was identified in 17% of patients, with a 96% sensitivity for detection with the SLN algorithm and a negative predictive value of 99%. SLN mapping in high-grade histologies has increased each year from 7.5% in 2012 to 25.2% in 2015 ( P < .001), with academic facilities performing more SLN mapping than community hospitals.
A meta-analysis that included 55 SLN mapping studies totaling over 4000 women found the overall SLN detection rate was 81% and the bilateral rate was 50%. Detection of SLNs was not affected by BMI, tumor histology, or grade. The sensitivity of SLN mapping for the detection of metastases was 96%. Compared to women staged by complete lymphadenectomy, women who underwent SLN mapping were more likely to receive adjuvant therapies. In another meta-analysis, Bogani et al. evaluated 3,536 patients from six studies that underwent SLN mapping (35.3%) or traditional lymphadenectomy (64.7%). Pooled data showed that the pelvic node detection rate was 14.7% vs. 9.9% for SLN mapping and lymphadenectomy, respectively (95% CI: 1.30 to 3.18, P = .002). The rate of para-aortic node metastasis was similar. The overall disease recurrence and lymph node recurrence rates were similar between the groups, implying that SLN mapping was noninferior to standard lymphadenectomy with respect to recurrence of the disease.
There is variation in the FNR by histology risk groups, with high-risk histologies having lower SLN detection rates and higher FNR than endometrioid histology. , However, the overall and bilateral detection rates in a high-risk case series of 36 patients with grade 3 endometrioid, clear cell, serous or carcinosarcoma in one study was 83% and 56%, not dissimilar to other series in the literature with low-risk or mixed populations. In another study of 156 low/intermediate European Society of Medical Oncology (ESMO) and 24 high-risk patients, Naoura et al. demonstrated that the overall and bilateral SLN detection rates were comparable in both the low/intermediate- and high-risk groups. However, the FNR for patients with high-risk endometrial cancers was greater than for low/intermediate patients (6% vs. 20%, P = .0008). Notably, the FNR in the high-risk group decreased from 20% to 9% when the surgical algorithm was applied. Similarly, a 414-patient study by Kennard et al. reported a FNR of 5.1% for high-risk nonendometrioid histologies compared with 0% for low-risk superficially invasive endometrioid cases ( P < .001), and 2.5% for intermediate-risk deeply-invasive endometrioid cases ( P = .41). High-risk histology patients had more macro-metastasis SLNs and non-SLN metastases than low-risk patients who had more low-volume metastases. These findings suggest that special attention should be given to nonsentinel pelvic lymph nodes in patients with high-risk histologies, with the removal of any visibly suspicious lymph nodes as per the NCCN algorithm.
Several proposed factors that may influence the success of SLN mapping include the type and number of dyes used, injection site, operator experience, type of abdominal access, time interval following dye injection, the patient’s BMI, site of tumor, presence of LVSI, and prior treatment with radiation. Tanner et al. evaluated 20 factors for an association with the successful bilateral SLN mapping including the patient factors, inflammatory/lymphatic factors, tumor factors, and surgeon factors. The study concluded that the blue dye, high BMI greater than 30 kg/m 2 , and clinically enlarged lymph nodes were adverse factors for the success of SLN mapping. In a similar study, Eriksson et al. reported that the success of SLN mapping decreased with obesity, irrespective of the dye used. However, SLN mapping has been significantly improved with the use of ICG and NIR fluorescence imaging compared with blue dye irrespective of BMI. ,
Attention to the NCCN SLN algorithm is critical to ensure accurate surgical staging. It is recommended that surgeons perform completion lymphadenectomies with at least the initial 20 SLN biopsy procedures to demonstrate satisfactory SLN detection. The false negative rate should be continuously assessed, recognizing that in low-risk populations with few metastases, many more cases than the initial 20 will be required for assurance of a low false negative rate less than 5%. In a recent analysis, proficiency in SLN mapping technique increased the most between the first 10 and subsequent attempts, with a plateau in the success rate following 30 cases. The mapped lymphatic pathways that emanate from the parametria should be identified first, followed by the excision of the most proximal lymph node in the SLN pathway. Several secondary and tertiary echelon lymph nodes beyond the sentinel will take up dye, and they should not be considered “sentinel.” As suggested by Barlin et al., removal of suspicious lymph nodes and side-specific lymphadenectomy for an unmapped hemi-pelvis is of utmost importance to reduce the false negative rate with SLN mapping in endometrial cancer. Decisions about the performance of para-aortic lymphadenectomy should be based on the status of pelvic lymph nodes, the tumor histology, and the depth of invasion on frozen section analysis.
Sentinel lymph node mapping in preinvasive disease: Reliability
Endometrial intraepithelial neoplasia (EIN; formerly referred to as complex atypical hyperplasia) is associated with up to a 40% risk of harboring endometrial cancer at the time of hysterectomy. An endometrial thickness of more than 2 cm on ultrasound is associated with a 4-times higher probability of invasive carcinoma and twice the risk for high-risk features for lymph node metastases.
Intraoperative frozen section analysis of the uterine tumor has been used to triage patients for staging lymphadenectomy. Sentinel node biopsy is an attractive idea as an alternative to counter the potential inaccuracies of frozen sections and to avoid the morbidity of lymphadenectomy. However, routine SLN mapping may not be cost-effective in the setting of preinvasive disease. The clinical utility of SLN mapping in EIN is therefore uncertain and will require more study. We recommend mapping, but not removing sentinel lymph nodes unless the frozen section analysis identifies invasive malignancy. An accepted preoperative risk stratification of EIN with predictive models that quantify the risk of invasive disease and nodal involvement would be desirable.
Sentinel lymph node mapping in endometrial cancer: Clinical outcomes
After more than a decade of experience with SLN mapping in endometrial cancers and numerous peer-reviewed publications describing sensitivity for the detection of lymph node metastasis, investigators have reported recurrence and survival outcomes. Raimond et al. studied the effect of SLN biopsy protocol with the completion of pelvic lymphadenectomy on adjuvant therapies and compared oncological outcomes to patients who underwent comprehensive lymphadenectomy only. The SLN procedure significantly increased the amount of adjuvant therapy administered compared with the women who had lymphadenectomy or no staging ( P < .001). However, the addition of the SLN procedure did not improve the RFS (HR = 0.89; 95% CI, 0.42 to 1.90; P = .77). Zahl Eriksson et al. performed a multi-institutional study to demonstrate the impact of the SLN protocol on the survival rates in women with superficial myoinvasion. The authors compared clinical outcomes by the SLN approach ( n = 642) with the selective lymphadenectomy approach ( n = 493) and intra-operative histology by frozen section analysis. Disease-free survival and 3-year overall survival were not significantly different between the two cohorts. The same institutions performed a similar analysis in a population of deeply myoinvasive, high-risk histology. Again, the outcomes of overall and progression-free survival were similar with SLN versus lymphadenectomy staging.
In a retrospective Canadian study, How et al. examined 472 patients who underwent either SLN mapping or systematic lymphadenectomy (LND), collected sequentially in nonoverlapping historical time points. There was no significant difference in RFS at 48 months (HR = 0.74; 95% CI, 0.43 to 1.28; P = .29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR = 0.32; 95% CI, 0.14 to 0.74; P = .007). Pelvic sidewall disease accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences). The authors concluded that SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn possibly decreased pelvic sidewall recurrences in their study.
Schiavone et al. compared the oncologic outcomes of 136 patients with carcinosarcoma undergoing SLN mapping ( n = 48) versus routine lymphadenectomy ( n = 88). The authors considered all macro-metastases, micro-metastases, and ITCs (H&E or IHC) equally as metastases. The rate of lymph node metastases in the SLN and lymphadenectomy groups were similar. Consequently, there were no significant differences in the adjuvant therapies received or PFS between the two groups. Because of the frequent use of adjuvant therapies in patients with high-risk histologies, the value of the SLN algorithm may be in the avoidance of morbidity with surgical staging rather than significant improvements in survival.
In 2020, Bogani and colleagues evaluated the long-term outcomes of endometrial cancer patients stratified by either complete lymphadenectomy, SLN mapping followed by lymphadenectomy, or SLN mapping alone. SLN followed by lymphadenectomy detected more stage IIIC disease compared to lymphadenectomy alone ( P = .02); however, no difference in lymph node metastasis was observed for SLN mapping versus SLN followed by lymphadenectomy ( P = .39). At a median follow-up of 69 months, there was also no difference in disease-free or overall survival.
The value of removing lymph nodes has been questioned because of negative results from two separate phase III trials that evaluated lymphadenectomy in endometrial cancer. , Advocates of traditional lymphadenectomy for surgical staging of endometrial cancer criticized the results of these two trials within weeks of publication. , There were several methodologic shortcomings including the relatively small number of retrieved lymph nodes, the high proportion of low-risk patients in the trials, the omission of para-aortic lymphadenectomy even in high-risk histologies, and the significant imbalance in adjuvant radiation and chemotherapy given between the two arms. However, several retrospective studies including large national database analyses have suggested a therapeutic benefit associated with lymphadenectomy in intermediate- and high-risk endometrial cancer. It, therefore, seems logical and consistent with decades of surgical and oncologic experience that removal of macro-metastatic lymph nodes from the pelvic and para-aortic basins improves the efficacy of adjuvant therapies in high-risk endometrial cancer. At a minimum, the SLN technique provides more sensitive detection of lymphatic metastasis that will alter adjuvant therapy while minimizing morbidity compared to traditional lymphadenectomy. Because SLN mapping rarely detects para-aortic lymph nodes, decisions about their dissection should continue to be based on the primary uterine pathology and visual inspection of the lymph nodes. It should be cautioned that all of the above studies are retrospective observational analyses with no uniform adjuvant therapy treatment protocols and relatively limited follow-up times in some studies. Hence, more prospective studies of SLN mapping are warranted that analyze outcomes by risk groups and adjuvant therapies administered in order to make better recommendations about the safety and adequacy of the SLN mapping algorithm for patients with high-risk endometrial cancer.
Cost-effectiveness and quality of life
The cost-effectiveness of the SLN mapping algorithm in endometrial cancer is a complex analysis that must factor in both hospital and physician charges, costs of pathology processing, any ongoing care related to morbidity, and quality of life. The MD Anderson Cancer Center and Mayo Clinic performed a cost-utility analysis comparing three lymphadenectomy strategies for low-risk endometrial carcinoma: (1) routine lymphadenectomy in all patients, (2) selective lymphadenectomy based on intraoperative frozen section criteria, and (3) SLN mapping. Costs and outcomes were obtained from published literature and Medicare reimbursement rates. Cost categories consisted of hospital, physician, operating room, pathology, and lymphedema treatment. Effectiveness was defined as 3-year disease-specific survival adjusted for the impact of lymphedema on quality of life. Compared with routine and selective lymphadenectomy, sentinel lymph node mapping had the lowest cost and highest quality-adjusted survival, making it the most cost-effective strategy in the management of low-risk endometrial carcinoma. For the estimated 40,000 women undergoing surgery for low-risk endometrial carcinoma each year in the United States, the annual cost of routine lymphadenectomy, selective lymphadenectomy, and SLN mapping were projected at US $722 million, $681 million, and $656 million, respectively.
Lymphedema of the lower extremities in endometrial cancer is a major morbidity affecting quality of life and is often underreported. Lymphedema prevalence varies significantly between 0% and 50%, due to a lack of generally accepted standardized terminology and assessment criteria for lymphedema. Lymphadenectomy, number of lymph nodes removed, obesity, and radiation therapy all have been implicated as risk factors for lymphedema. Yost and colleagues noted a 23% risk of patient-reported lymphedema after surgery for endometrial cancer. It is expected that limiting lymphadenectomy to SLN only will reduce this incidence. A prospective trial in Sweden examined the rate of lymphedema in a low-risk SLN-biopsy-only cohort versus a high-risk traditional lymphadenectomy. SLN biopsy resulted in a lower incidence of lymphedema compared to pelvic and infrarenal para-aortic lymphadenectomy (1.3% vs. 18.1%; P = .0003). Complete prevention of lymphedema is not attainable because some patients will require lymphadenectomy for unsuccessful SLN mapping, visibly macro-metastatic nodes, and perhaps protocols in high-risk histologies. The majority of SLNs are detected in the medial external, internal, and obturator lymph nodes. , Therefore, it has been suggested that completion of lymphadenectomies performed as indicated by the NCCN surgical algorithm should be limited to the medial half of the external iliac artery and obturator lymph nodes as a method to reduce lymphedema.
Conclusions and personal views
The SLN surgical algorithm is a reliable strategy to determine lymph node status in apparent early-stage endometrial cancers. This technique provides higher sensitivity for the detection of metastases with less morbidity compared to comprehensive pelvic and aortic lymphadenectomy. Surgical technique and individual surgeon experience, abiding by the NCCN-approved surgical algorithm, are essential to achieving optimal results. Surgeons should work to attain an FNR of less than 5%, including high-risk histologies. Completion lymphadenectomies should be continued during an individual surgeon’s learning curve until the FNR can be established, avoiding the removal of nonsuspicious nodes lateral to the external iliac artery in order to minimize lymphedema. Although initial studies report noninferior recurrence and survival rates with the SLN algorithm, larger prospective trials that standardize adjuvant therapies are desirable to better evaluate the impact of SLN staging on disease recurrence, survival, quality of life, and cost.
There is overwhelming consensus from multiple cohort studies that SLN mapping as described in the NCCN surgical algorithm can replace comprehensive lymphadenectomy in patients with apparently uterine-confined endometrial cancer irrespective of histology, and greatly reduces the morbidity associated with lymphadenectomy. Multiple factors influence the sensitivity for detection of metastasis with SLN mapping, including the type of dye, injection site, patient morphology, tumor histology, surgeon experience, the surgical algorithm, and the pathological protocol used for SLN assessment. Examination of SLNs with enhanced pathology techniques such as serial sectioning and the use of immunohistochemical stains increases the detection of low-volume micro-metastases and ITC metastases compared to routine processing with color dyes. The clinical independent significance of ITC metastases and specifically their prognostic role in determining therapy remains uncertain. ITC metastases are often associated with other high-risk factors such as deep invasion, LVSI, and para-aortic nodal metastasis. Prospective studies will be necessary to determine the effect of SLN biopsy on disease recurrence, survival, cost, and quality of life.
Conflict of interest
Dr. Robert W. Holloway has received honoraria from Intuitive Surgical, Inc. (Sunnyvale, CA) prior to 2018 for conducting surgical training courses and speaking. Other co-authors declare that there are no conflicts of interest associated with this book chapter.