ABSTRACT
Introduction
This study examined factors that affected sentinel lymph node (SLN) identification of patients with endometrial cancer having a preoperative estimation of low recurrent risk.
Methods
This study included 97 patients with endometrial cancer who attempted to identify SLN using a uterine cervical injection of technetium‐99 m phytate under laparoscopic or robotic‐assisted surgery at our institute. A preoperative single photon emission computed tomography (SPECT) and intraoperative gamma probe were used to detect hot nodes. Multiple clinical factors, including age, body mass index (BMI), and so on, were investigated for their association with SLN mapping failure.
Results
Among 97 cases, SPECT failed to detect SLN unilaterally in 38 cases (39%) and on both sides in 9 cases (9%). Meanwhile, the gamma probe failed to detect SLN unilaterally in 23 cases (24%) and on both sides in 3 cases (3%). While only age was significantly associated with SLN detection failure using the SPECT detection system, both age and BMI were significantly associated with SLN detection failure using the gamma probe detection system. When limiting to the preoperative SLN detection failure cohort of 47 cases, there was a strong association between intraoperative SLN detection failure and BMI, but not age.
Conclusion
The SLN biopsy system was effectively applied to patients with endometrial cancer who underwent minimally invasive surgery (MIS). Attempts to improve SLN identification in older patients and those with obesity are warranted to obtain maximum benefits of MIS for low‐ or medium‐risk cases.
Keywords: endometrial neoplasm, minimally invasive surgical procedures, sentinel lymph node
1. Introduction
Endometrial cancer remains prevalent in advanced countries, including the United States, with an incidence rate of 8.0 per 100 000 women per year based on 2017–2021 data (National Cancer Institute: https://seer.cancer.gov/statfacts/html/corp.html). In Japan, the incidence rate of newly diagnosed endometrial cancer cases is 27.6 per 100 000 women per year based on 2019 data (National Cancer Center, https://ganjoho.jp/reg_stat/statistics/stat/cancer/18_corpus_uteri.html#anchor1). Fortunately, most cases are diagnosed at early stages, which are optimal indications for minimally invasive surgery (MIS), including laparoscopic surgery or robotic‐assisted surgery. While the operation time is longer, MIS is preferred in the appropriate cases due to a lower incidence of surgical site infection, transfusion, a shorter hospital stay, and earlier resumption of normal activities without adverse effects in perioperative complication and oncologic outcomes [1, 2, 3, 4, 5, 6, 7].
The optimal injection site of the tracer to detect sentinel lymph node (SLN) remains controversial, but the National Comprehensive Cancer Network (NCCN) guideline recommends cervical injection because of the easiness and reproducibility of the procedure [8, 9]. Meta‐analyses revealed that the tracer for the best detection rate of SLN may be a combination of indocyanine green and technetium‐99 m (99mTc) radiolabeled colloid, and 99mTc isotope alone detected SLN with enough high probability [10, 11]. Especially, the advantage of using a 99mTc isotope is to detect deep signals penetrated through the fat tissue of patients with obesity [11].
Unsuccessful SLN detection occurs with a certain probability. Several studies reported that body mass index (BMI) [12, 13, 14, 15], age [12, 16], nonendometrioid histology [12, 13, 17], lymphovascular invasion [12, 17], and lymph node metastasis [13] were associated with SLN detection failure. There are several studies reporting detection rates of both single photon emission computed tomography (SPECT) and intraoperative gamma probe detection systems [18, 19]. However, there are no studies reporting detailed detection sites of the two modalities and clinical factors associated with SLN detection failure for each modality.
This study investigated the SLN detection efficiency of patients with endometrial cancer having a preoperative estimation of low recurrent risk who underwent MIS at our hospital. We used both SPECT and gamma probe detection systems and studied SLN detection rates, detection sites, and clinical factors associated with SLN detection failure for each modality.
2. Materials and Methods
2.1. Design and Setting
This retrospective cohort study recruited women with endometrial endometrioid carcinoma Grade 1 or 2 at estimated Stage IA who underwent MIS at Kyushu University Hospital from June 2019 to March 2023. Of the cases, 43 and 54 were treated laparoscopically and robotically, respectively. The Da Vinci Si system (Intuitive Surgical Inc., Sunnyvale, CA, USA) was used from June 2019 to July 2019 (in 2 cases), and the da Vinci Xi system from September 2019 to March 2023 (in 52 cases). Surgical modalities were randomly selected based on the availability of robotic instruments.
All patients with endometrial cancer considered for MIS underwent histological sampling of endometrial lesions, pelvic magnetic resonance imaging (MRI), and computed tomography. Preoperative clinical staging was identified based on the 2008 International Federation of Gynecology and Obstetrics (FIGO) criteria. A histological diagnosis, including grading, was preoperatively obtained. All patients provided informed consent preoperatively.
The laparoscopic surgeries involved eight gynecologic oncologists authorized by the Japan Society of Gynecologic Oncology. Meanwhile, robotic surgeries involved six gynecologic oncology surgeons authorized by the Japan Society of Gynecologic Oncology and certificated by Intuitive Surgical G.K., Japan.
Patients were placed in the lithotomy or supine position with side split, combined with the Trendelenburg position (10°–15° for laparoscopic surgery and 20°–25° for robotic surgery). Laparoscopic surgery involved five laparoscopic trocar installations in a diamond position, including a 5‐mm assistant trocar placed right to the umbilical position. Robotic surgery involved four da Vinci trocar installations in a horizontal line, including in the umbilical position. A 12‐mm assistant trocar was placed on the left side of the abdominal wall. General anesthesia with endotracheal intubation was applied to perform all surgeries. All cases underwent a simple hysterectomy and bilateral salpingo‐oophorectomy with SLN sampling. Lymphadenectomy, including the external iliac and obturator nodes, was performed on the side with unsuccessful SLN identification. When nodal metastasis was diagnosed by the intraoperative pathological examination, we converted the surgery to laparotomy, including a simple hysterectomy, bilateral salpingo‐oophorectomy, and omentectomy with whole pelvic and paraaortic lymph node dissection up to the renal vein height. Uteri that were too large to be vaginally extracted were collected via a mini‐laparotomy incision.
Surgical uterine and lymph node specimens were postoperatively applied for histological examination. Adjuvant therapy was proposed for patients with intermediate or high risk of recurrence assessed using predominantly used criteria [20, 21].
The Kyushu University institutional ethical committee provided ethical approval (approval number: 23109‐00).
2.2. SLN Detection
One day preoperatively, 99mTc labeled sodium phytate colloid containing 148 MBq (40 mCi) per patient was injected into the subepithelium of the uterine cervix at four spots. Lymphoscintigraphy and SPECT images were obtained 2 h after the injection to locate the hot lymph nodes. A handheld gamma probe (neo2000, Neoprobe Corporation, Dublin, OH, USA) was used for intraoperative SLN detection. A lymph node having at least more than 10 times gamma counts above the background was recognized as an SLN. Intraoperatively, fat tissue was promptly removed from the lymph nodes by surgeons, and the isolated lymph nodes were submitted for intraoperative pathological examination.
2.3. Intraoperative Pathological Examination of SLN (Ultrastaging)
Intraoperatively, dissected SLNs were snap‐frozen and evaluated using 2‐mm‐interval slices along the short axis. Frozen sections from every slice stained with hematoxylin and eosin were diagnosed by institutional pathologists. In addition, SLNs were reevaluated after formalin fixation postoperatively.
2.4. Data Collection
Information on age, BMI (calculated as weight divided by the square of height), surgical modality, date of surgery, uterine tumor thickness measured using MRI, CA125, final histological grading, FIGO staging, myometrial invasion, lymphovascular invasion, lymph node metastasis, and pelvic cavity washing cytology were collected from the medical records at Kyushu University Hospital.
2.5. Statistical Analysis
Univariate and multivariate logistic analyses were conducted to extract clinical factors associated with SLN detection failure. Age, BMI, surgical modality, period when surgery was performed, uterine tumor thickness measured using MRI, CA125, final histological grading, FIGO staging, myometrial invasion, lymphovascular invasion, lymph node metastasis, and pelvic cavity washing cytology were analyzed for their association with SLN detection failure. Categorical variables were analyzed using Pearson's chi‐square test or Fisher's exact test for univariate analysis.
Before conducting multivariate analysis, factors belonging to a similar clinical category were excluded to avoid confounding among the clinical factors. A backward elimination method was used in multivariate logistic regression analysis to extract remarkable clinical factors associated with SLN detection failure. The exact odds ratios (ORs) were reported along with the 95% confidence intervals (CIs) and corresponding p values. We first performed univariate and multivariate analyses on all the 97 cases. We also performed analyses on 47 cases, which is a specific cohort of SLN detection failure using a preoperative SPECT.
JMP software (version 16; SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses. A p < 0.05 was considered statistically significant.
3. Results
3.1. Patient Characteristic and SLN Detection Failure
A total of 97 patients with endometrial cancer underwent laparoscopic or robotic‐assisted hysterectomy were attempted to identify SLN preoperatively using SPECT imaging and intraoperatively using a gamma probe during the study period. Table 1 shows the characteristics of the cohort. Among 97 cases, preoperative SPECT failed to detect SLN unilaterally in 38 cases (39%) and on both sides in 9 cases (9%) (Table 1). Meanwhile, the intraoperative gamma probe failed to detect SLN unilaterally in 23 cases (24%) and on both sides in 3 cases (3%) (Table 1). We did not encounter any cases with empty packets. Two cases were observed to be Grade 3 and clear cell carcinoma. Fourteen cases were at more than Stage IB, including 3, 3, 1, 5, and 2 at Stages IB, II, IIIA, IIIC1, and IIIC2, respectively (Table 1).
TABLE 1.
Patient demographic, clinical characteristics, and SLN detection failure.
| SPECT | SPECT | Gamma probe | Gamma Probe | ||
|---|---|---|---|---|---|
| Group | Total | Detection success | Detection failure | Detection success | Detection failure |
| Patients, n | 97 | 47 (52%) | 50 (48%) | 71 (73%) | 26 (27%) |
| Median age, years (range) | 54.0 (22–80) | 50.0 (22–73) | 59.0 (32–80) | 52.0 (22–80) | 60.0 (32–80) |
| Median BMI (range) | 25.0 (13.7–47.6) | 23.8 (13.7–47.6) | 26.3 (15.3–46.4) | 23.8 (13.7–44.6) | 28.9 (18.6–47.6) |
| Surgical modality, n (%) | |||||
| Laparoscopic | 43 (44%) | 19 (40%) | 24 (48%) | 32 (45%) | 11 (42%) |
| Robotic‐assisted | 54 (56%) | 28 (60%) | 26 (52%) | 39 (55%) | 15 (58%) |
| Number of surgeries each year, n | |||||
| 2019 | 12 | 8 | 4 | 8 | 4 |
| 2020 | 25 | 12 | 13 | 19 | 6 |
| 2021 | 30 | 10 | 20 | 21 | 9 |
| 2022 | 24 | 12 | 12 | 18 | 6 |
| 2023 | 6 | 5 | 1 | 5 | 1 |
| Thickness of tumor measured with MRI, mm (range) | 13 (0–43) | 13 (3–39) | 12 (0–43) | 12 (0–43) | 14 (0–39) |
| Serum CA125, U/mL (range) | 16.4 (5.5–103) | 17.4 (7.1–49) | 15.7 (5.5–103) | 17.1 (5.5–103) | 13.9 (8.2–66.8) |
| Histological grade, n (%) | |||||
| 1 and 2 | 95 (98%) | 47 (100%) | 48 (96%) | 69 (97%) | 26 (100%) |
| 3 and clear cell carcinoma | 2 (2%) | 0 | 2 (4%) | 2 (3%) | 0 |
| FIGO stage, n (%) | |||||
| IA | 83 (86%) | 40 (85%) | 43 (86%) | 61 (86%) | 22 (85%) |
| More than IB | 14 (14%) | 7 (15%) | 7 (14%) | 10 (14%) | 4 (15%) |
| IB | 3 (3%) | 1 (2%) | 2 (4%) | 0 | 3 (11%) |
| II | 3 (3%) | 1 (2%) | 2 (4%) | 2 (3%) | 1 (4%) |
| IIIA | 1 (1%) | 1 (2%) | 0 | 1 (1%) | 0 |
| IIIC1 | 5 (5%) | 3 (6%) | 2 (4%) | 5 (7%) | 0 |
| IIIC2 | 2 (2%) | 1 (2%) | 1 (2%) | 2 (3%) | 0 |
| Myometrial invasion, n (%) | |||||
| Absent | 40 (41%) | 23 (49%) | 17 (34%) | 30 (43%) | 10 (38%) |
| Present | 57 (59%) | 24 (51%) | 33 (66%) | 41 (57%) | 16 (62%) |
| Myometrial invasion depth, n (%) | |||||
| < 1/2 | 89 (92%) | 44 (94%) | 45 (90%) | 66 (93%) | 23 (88%) |
| ≥ 1/2 | 8 (8%) | 3 (6%) | 5 (10%) | 5 (7%) | 3 (12%) |
| Lymphovascular invasion, n (%) | |||||
| Absent | 84 (87%) | 42 (89%) | 42 (84%) | 61 (86%) | 23 (88%) |
| Present | 13 (13%) | 5 (11%) | 8 (16%) | 10 (14%) | 3 (12%) |
| Lymph node metastasis, n (%) | |||||
| Absent | 90 (93%) | 43 (91%) | 47 (94%) | 64 (90%) | 26 (100%) |
| Present | 7 (7%) | 4 (9%) | 3 (6%) | 7 (10%) | 0 |
| Washing cytology of pelvic cavity, n (%) | |||||
| Negative | 84 (88%) | 40 (87%) | 44 (90%) | 59 (86%) | 25 (96%) |
| Positive | 11 (12%) | 6 (13%) | 5 (10%) | 10 (14%) | 1 (4%) |
Note: Two cases were missed in collecting washing cytology of pelvis cavity.
Abbreviations: BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; SLN, sentinel lymph node; SPECT, single photon emission computed tomography.
3.2. Univariate Analysis to Identify Factors Associated With SLN Detection Failure
A univariate logistic analysis was conducted to extract clinical factors associated with one‐sided or both‐sided SLN detection failure. No association was found in SLN detection failure with surgical modalities, period when surgery was performed, uterine tumor thickness measured using MRI, serum CA125, histological grade, or FIGO stage, myometrial invasion, lymphovascular invasion, and lymph node metastasis. However, age was significantly associated with SLN detection failure using the SPECT detection system, and age and BMI were significantly associated with SLN detection failure using the gamma probe detection system (Table 2). The SPECT detection system obtained an OR of 13.7 with a 95% CI of 4.61–40.7 for age (< 56 vs. ≥ 56) (p = 0.0001) (Table 2). Meanwhile, the gamma probe detection system obtained an OR of 8.62 with a 95% CI of 3.10–24.0 for age (< 56 vs. ≥ 56) (p = 0.0001) and an OR of 9.89 with a 95% CI of 2.72–36.0 for BMI (< 24.5 vs. ≥ 24.5) (p = 0.0005) (Table 2).
TABLE 2.
Univariate and multivariate logistic regression analysis of predictors of SLN detection failure.
| SPECT | SPECT | Gamma probe | Gamma probe | |||||
|---|---|---|---|---|---|---|---|---|
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||
| OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | |
| Age | ||||||||
| < 56 | Reference | Reference | ||||||
| ≥ 56 | 13.7 (4.61–40.7) | 0.0001 | 12.9 (4.30–38.7) | 0.0001 | 8.62 (3.10–24.0) | 0.0001 | 7.89 (2.61–23.8) | 0.0003 |
| BMI | ||||||||
| < 24.5 | Reference | Reference | ||||||
| ≥ 24.5 | 2.02 (0.90–4.56) | 0.09 | 1.41 (0.54–3.65) | 0.482 | 9.89 (2.72–36.0) | 0.0005 | 8.97 (2.28–35.4) | 0.0017 |
| Surgical modality | ||||||||
| Laparoscopic | Reference | Reference | ||||||
| Robotic‐assisted | 0.74 (0.33–1.64) | 0.197 | 1.12 (0.45–2.77) | 0.808 | ||||
| Period of surgery | ||||||||
| June 2019 to June 2021 | Reference | Reference | ||||||
| July 2021 to March 2023 | 1.13 (0.51–2.51) | 0.763 | 0.97 (0.40–2.39) | 0.951 | ||||
| Thickness of tumor measured with MRI | ||||||||
| < 20 | Reference | Reference | ||||||
| ≥ 20 | 1.40 (0.57–3.47) | 0.465 | 2.15 (0.82–5.65) | 0.121 | ||||
| Serum CA125 | ||||||||
| < 15 | Reference | Reference | ||||||
| ≥ 15 | 0.68 (0.30–1.52) | 0.345 | 0.51 (0.20–1.26) | 0.143 | ||||
| Histological grade | ||||||||
| 1 and 2 | Reference | Reference | ||||||
| 3 and clear cell carcinoma | NA | NA | NA | NA | ||||
| FIGO stage | ||||||||
| IA | Reference | Reference | ||||||
| More than IB | 0.93 (0.30–2.89) | 0.900 | 1.11 (0.32–3.90) | 0.872 | ||||
| Myometrial invasion | ||||||||
| Absent | Reference | Reference | ||||||
| Present | 1.86 (0.82–4.22) | 0.137 | 1.17 (0.47–2.94) | 0.737 | ||||
| Myometrial invasion depth | ||||||||
| < 1/2 | Reference | Reference | ||||||
| ≥ 1/2 | 1.63 (0.37–7.23) | 0.521 | 1.72 (0.38–7.78) | 0.480 | ||||
| Lymphovascular invasion | ||||||||
| Absent | Reference | Reference | ||||||
| Present | 1.60 (0.48–5.29) | 0.441 | 0.80 (0.20–3.15) | 0.745 | ||||
| Lymph node metastasis | ||||||||
| Absent | Reference | Reference | ||||||
| Present | 0.69 (0.14–3.24) | 0.635 | NA | NA | ||||
| Washing cytology of pelvic cavity | ||||||||
| Negative | Reference | Reference | ||||||
| Positive | 0.76 (0.21–2.68) | 0.666 | 0.24 (0.03–1.93) | 0.180 | ||||
Note: p < 0.05 was considered statistically significant.
Abbreviations: BMI, body mass index; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; NA, not applicable; OR, odds ratio; SLN, sentinel lymph node; SPECT, single photon emission computed tomography.
3.3. Multivariate Analysis to Determine Factors Associated With SLN Detection Failure
Multivariate logistic regression analysis was performed to determine clinical factors associated with one‐sided or both‐sided failure in SLN detection. Using a backward elimination method, age was identified to be strongly associated with SLN detection failure using the SPECT detection system, whereas age and BMI were found to be strongly associated with SLN detection failure using the gamma probe detection system (Table 2). The SPECT detection system obtained an OR of 12.9 with a 95% CI of 4.30–38.7 for age (< 56 vs. ≥ 56) (p = 0.0001) (Table 2). Meanwhile, the gamma probe detection system obtained an OR of 7.89 with a 95% CI of 2.61–23.8 for age (< 56 vs. ≥ 56) (p = 0.0003) and an OR of 8.97 with a 95% CI of 2.28–35.4 for BMI (< 24.5 vs. ≥ 24.5) (p = 0.0017) (Table 2).
3.4. Analysis of an SLN Detection Failure Cohort Using Preoperative SPECT
A specific cohort of SLN detection failure using a preoperative SPECT was analyzed for intraoperative SLN detection using a gamma probe. Among 50 cases, the intraoperative gamma probe failed to detect SLN unilaterally or on both sides in 23 cases (46%) (Table 3). Univariate logistic and multivariate logistic regression analyses were performed for the cohort. BMI was found to be strongly associated with SLN detection failure using the intraoperative gamma probe detection system, but not age. Univariate analysis showed an OR of 15.3 with a 95% CI of 2.96–78.8 (p = 0.0011), whereas multivariate analysis showed an OR of 14.7 with a 95% CI of 2.72–79.2 (p = 0.0018) for BMI (< 24.5 vs. ≥ 24.5) (Table 4).
TABLE 3.
Demographic and clinical characteristics and intraoperative SLN detection of a cohort with unsuccessful SLN detection using SPECT.
| Gamma probe | Gamma probe | ||
|---|---|---|---|
| Group | Total | Detection success | Detection failure |
| Patients, n | 50 | 27 (54%) | 23 (46%) |
| Median age, years (range) | 59.0 (32–80) | 55.0 (36–80) | 61.0 (32–80) |
| Median BMI (range) | 26.3 (15.3–46.4) | 23.8 (15.3–33.3) | 28.7 (18.6–46.4) |
| Surgical modality, n (%) | |||
| Laparoscopic | 24 (48%) | 14 (52%) | 10 (43%) |
| Robotic‐assisted | 26 (52%) | 13 (48%) | 13 (57%) |
| Number of surgeries each year, n | |||
| 2019 | 4 | 0 | 4 |
| 2020 | 13 | 8 | 5 |
| 2021 | 20 | 11 | 9 |
| 2022 | 12 | 8 | 4 |
| 2023 | 1 | 0 | 1 |
| Thickness of tumor measured with MRI, mm (range) | 12 (0–43) | 9 (0–43) | 14 (0–31) |
| Serum CA125, U/mL (range) | 15.7 (5.5–103) | 16.1 (5.5–103) | 14.5 (8.2–66.8) |
| Histological grade, n (%) | |||
| 1 and 2 | 48 (96%) | 25 (93%) | 23 (100%) |
| 3 and clear cell carcinoma | 2 (4%) | 2 (7%) | 0 |
| FIGO stage, n (%) | |||
| IA | 43 (86%) | 23 (85%) | 20 (87%) |
| More than IB | 7 (14%) | 4 (15%) | 3 (13%) |
| IB | 1 (2%) | 0 | 2 (9%) |
| II | 2 (4%) | 1 (4%) | 1 (4%) |
| IIIC1 | 2 (4%) | 2 (7%) | 0 |
| IIIC2 | 1 (2%) | 1 (4%) | 0 |
| Myometrial invasion, n (%) | |||
| Absent | 17 (34%) | 9 (33%) | 8 (35%) |
| Present | 33 (66%) | 18 (67%) | 15 (65%) |
| Myometrial invasion depth, n (%) | |||
| < 1/2 | 45 (91%) | 24 (89%) | 21 (91%) |
| ≥ 1/2 | 5 (9%) | 3 (11%) | 2 (9%) |
| Lymphovascular invasion, n (%) | |||
| Absent | 42 (84%) | 21 (78%) | 21 (91%) |
| Present | 8 (16%) | 6 (22%) | 2 (9%) |
| Lymph node metastasis, n (%) | |||
| Absent | 47 (94%) | 24 (89%) | 23 (100%) |
| Present | 3 (6%) | 3 (11%) | 0 |
| Washing cytology of pelvic cavity, n (%) | |||
| Negative | 44 (90%) | 22 (85%) | 22 (96%) |
| Positive | 5 (10%) | 4 (15%) | 1 (4%) |
Note: One case was missed in collecting washing cytology of pelvis cavity.
Abbreviations: BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; SLN, sentinel lymph node; SPECT, single photon emission computed tomography.
TABLE 4.
Univariate and multivariate logistic regression analyses of predictors of intraoperative SLN detection failure of a cohort with unsuccessful SLN detection using SPECT.
| Gamma probe | Gamma probe | |||
|---|---|---|---|---|
| Univariate analysis | Multivariate analysis | |||
| OR (95% CI) | p | OR (95% CI) | p | |
| Age | ||||
| < 56 | Reference | Reference | ||
| ≥ 56 | 3.88 (1.12–13.5) | 0.0330 | 3.62 (0.87–15.1) | 0.0777 |
| BMI | ||||
| < 24.5 | Reference | Reference | ||
| ≥ 24.5 | 15.3 (2.96–78.8) | 0.0011 | 14.7 (2.72–79.2) | 0.0018 |
| Surgical modality | ||||
| Laparoscopic | Reference | |||
| Robotic‐assisted | 1.40 (0.46–4.28) | 0.555 | ||
| Period of surgery | ||||
| June 2019 to June 2021 | Reference | |||
| July 2021 to March 2023 | 0.85 (0.28–2.59) | 0.777 | ||
| Thickness of tumor measured with MRI | ||||
| < 20 | Reference | |||
| ≥ 20 | 1.52 (0.45–5.14) | 0.497 | ||
| Serum CA125 | ||||
| < 15 | Reference | |||
| ≥ 15 | 0.62 (0.20–1.89) | 0.396 | ||
| Histological grade | ||||
| 1 and 2 | Reference | |||
| 3 and clear cell carcinoma | NA | NA | ||
| FIGO stage | ||||
| IA | Reference | |||
| More than IB | 0.86 (0.17–4.33) | 0.857 | ||
| Myometrial invasion | ||||
| Absent | Reference | |||
| Present | 0.94 (0.29–3.03) | 0.914 | ||
| Myometrial invasion depth | ||||
| < 1/2 | Reference | |||
| ≥ 1/2 | 0.76 (0.12–5.01) | 0.777 | ||
| Lymphovascular invasion | ||||
| Absent | Reference | |||
| Present | 0.33 (0.06–1.84) | 0.208 | ||
| Lymph node metastasis | ||||
| Absent | Reference | |||
| Present | NA | NA | ||
| Washing cytology of pelvic cavity | ||||
| Negative | Reference | |||
| Positive | 0.25 (0.03–2.42) | 0.231 | ||
Note: p < 0.05 was considered statistically significant.
Abbreviations: BMI, body mass index; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; NA, not applicable; OR, odds ratio; SLN, sentinel lymph node; SPECT, single photon emission computed tomography.
3.5. SLN Detection Sites
Out of 97 patients, a preoperative SPECT detected SLN in 88 on either or both sides. Including cases with multiple SLN sites in a pelvic hemisphere, 11 SLNs were detected in the internal iliac area, 44 in the external iliac area, 83 in the obturator area, 1 in the cardinal ligament area, 4 in the common iliac, and none in the paraaortic areas (Figure 1A). Furthermore, out of 97 patients, 94 finally underwent surgery with detectable SLN on either or both sides using a gamma probe. Including cases with multiple SLN sites in a pelvic hemisphere, 5 SLNs were detected in the internal iliac area, 72 in the external iliac area, 91 in the obturator area, and 3 in the cardinal ligament area, 3 in the common iliac area, and none in the paraaortic area (Figure 1B). Seven cases were positive for lymph node metastasis. Among the seven cases, four were positive for lymph node metastasis on both sides. Three cases were diagnosed positive for lymph node metastasis intraoperatively and converted into open surgery. The remaining four cases were diagnosed positive for lymph node metastasis postoperatively, and adjuvant therapy was applied. Among these cases, two were micrometastasis which appeared by postoperative reexamination, whereas the remaining two could not be differentiated from endosalpingiosis intraoperatively. Immunohistochemical analyses using several antibodies against PAX8, estrogen receptor, progesterone receptor, p53, and WT1 were used to compare with original lesions for the final diagnosis. Figure 1C illustrates the sites and number of metastasis‐positive SLN. All the metastasis‐positive SLNs were located either in the external iliac or obturator area (Figure 1C).
FIGURE 1.
Locations of detected SLN and metastasis‐positive lymph nodes. (A, B) Schematic presentation of location and number of intraoperatively detected SLN using the preoperative SPECT (A) and intraoperative gamma probe (B). Numbers in brackets indicate percent values of the total SLN in the pelvic hemisphere. (C) The location and number of pathologically diagnosed metastasis‐positive lymph nodes.
4. Discussion
This study investigated the association between SLN detection failure and various clinical factors of early‐staged endometrial cancer cases who underwent MIS at our institute. As a result, we extracted critical clinical factors, including age and BMI, for predicting SLN detection failure. Several studies reported that BMI [12, 13, 14, 15], age [12, 16], nonendometrioid histology [12, 13, 17], lymphovascular invasion [12, 17], and lymph node metastasis [13] are associated with SLN detection failure. Postoperative diagnosis sometimes differed from preoperative diagnosis as Stage IA/pathological Grade 1 or 2, but our cohort was rather uniform in terms of clinical stage and pathological grading. Hence, ratios of non‐endometrial histology, lymphovascular invasion, and lymph node metastasis were very small. Under this limited condition, age and BMI were considered remarkable clinical factors associated with SLN detection failure. We analyzed the data from the SPECT imaging conducted 1 day before surgery and the intraoperative gamma probe detection. Although strong associations between SLN detection failure and age and BMI were observed in the intraoperative gamma probe data, no remarkable association between BMI and SLN detection failure was found in the preoperative SPECT data. However, when limited to the preoperative SLN detection failure cohort, there was a strong association between intraoperative SLN detection failure and BMI, but not age. These results suggest that age determined early and lasting SLN detection, whereas BMI determined only late SLN detection. Based on our results, obesity but not age may slow lymphatic flow in the pelvis. This is the first study reporting detailed detection sites of the two modalities, the SPECT and gamma probe, and clinical factors associated with SLN detection failure for each modality.
The SLN detection rates in this study were comparable to other studies using 99mTc colloid injections into the uterine cervix for estimated early‐stage endometrial cancer cases (Table 5) [16, 19, 22, 23]. Two of them studied clinical factors associated with SLN detection failure. Martinez et al. found age to be associated with SLN detection failure, but not BMI (Table 5) [16]. Sahbai et al. found bone marrow uptake of radioisotope to be associated with SLN detection failure, but not age and BMI (Table 5) [19]. These variations in data may be caused by differences in the characteristics of each cohort.
TABLE 5.
SLN detection rates and clinical factors associated with SLN detection failure.
| SPECT | SPECT | Gamma probe | Gamma probe | Factors associated with SLN detection failure | ||
|---|---|---|---|---|---|---|
| Authors | n | Overall detection | Bilateral detection | Overall detection | Bilateral detection | |
| Sahbai a | 145 | 76% | NA | 74% | NA | Bone marrow uptake |
| Peritoneal/abdominal radioactivity | ||||||
| Martinez b | 92 | 86% | 40% | NA | NA | Age, myometrial invasion |
| Togami c | 122 | NA | NA | 96% | 88% | NA |
| Frati d , e | 118 | 75% | 37% | 86% | 53% | NA |
| This study | 97 | 91% | 48% | 97% | 73% | Age, BMI |
The underlying pathophysiological mechanism remains unclear, but SLN detection failure in aged patients and those with obesity may be associated with lymphatic dysfunction [15, 24]. Age and obesity were strongly associated with lymphatic dysfunction [25, 26, 27]. Empty packet dissection, which is the absence of lymph nodes on the final pathological diagnosis of the tissue sample submitted as SLN, was positively associated with BMI [15]. Empty packet dissection may cause SLN detection failure associated with BMI. In our study, we promptly removed fat tissue from the lymph nodes and confirmed the presence of lymph nodes before submitting them for intraoperative pathological examination. Therefore, we did not encounter any cases with empty packets. Cabrera et al. reported that using 99mTc colloid reduced the incidence of empty packets to 1.9% [28]. Theoretically, as are relatively large particles, radiotracers remain still in SLNs and do not extravasate.
Our analysis revealed that > 90% of detected SLN were located in the external iliac area or obturator area, which was consistent with previous studies using cervical injection of tracer [29, 30, 31]. All metastasis‐positive lymph nodes in our study were located either in the external iliac or obturator area. The above studies included a small number of cases, in which paraaortic lymph nodes were detected as SLN [29, 30, 31]. In contrast, our study did not detect any paraaortic lymph node as SLN. This discrepancy may be due to the difference in injection technique. The NCCN guideline recommended a combined cervical injection of superficial (1–3 mm) and deep (1–2 cm) sites to deliver the tracer to the main lymphatic channel layer in the cervix and uterus [8, 29]. Cervical injection significantly increased the SLN detection rate compared to injection into the corpus [32]. We would like to emphasize that our technique is mainly applicable to low‐risk endometrial cancer cases, which have an extremely low risk of paraaortic lymph node metastasis [33, 34, 35].
Based on our study, we extract patient groups with a high risk of SLN mapping failure. Some technical modifications related to tracer administration could be considered for such cases. Combined use of multiple tracers would increase the detection success rate [36]. Repeated injection of the same or different tracer may be considered if SLN is not detected after the first injection. Corpus injection may be considered if SLN is not detected after cervical injection [16].
Our study has several limitations. First, the study was based on a limited size of cohort from an institute. The cohort was limited to preoperatively estimated low‐risk Stage IA/pathological Grade 1 or 2 cases. Age and BMI may be extracted by multivariate regression analysis because of this uniform cohort regarding disease aggressiveness. Moreover, we only used a subepithelial 99mTc colloid injection into the uterine cervix. We did not analyze the long‐term prognosis of the cohort because of the short follow‐up period. We also did not perform backup lymphadenectomy for all the cases.
In conclusion, the SLN biopsy system was effectively applied to patients with endometrial cancer. Attempts to improve SLN identification in elderly patients and those with obesity are warranted to obtain maximum benefits of MIS for low‐ or medium‐risk cases.
Author Contributions
All authors agree with the content of the manuscripts. Concept and design of study and acquisition of data and analysis and interpretation of data; drafting the article and revising it critically: K.A. and H.Y. Acquisition of data and revising the article critically for important intellectual content: K. Kodama, K.O., M.Y., I.O., H.Y., S.M., and K.H. Statistical analysis and interpretation of data: M.S. Final approval of the version to be published: K.I., Y.O., and K. Kato.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We thank all the staff members in our department who assisted with this research. This work was supported by JSPS KAKENHI grant numbers JP23K08848 (to Hideaki Yahata) and JP24K12580 (to Keisuke Kodama). The authors would like to thank Enago (www.enago.jp) for the English language review.
Funding: This work was supported by the JSPS KAKENHI grant numbers JP23K08848 (to Hideaki Yahata) and JP24K12580 (to Keisuke Kodama).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Scalici J., Laughlin B. B., Finan M. A., Wang B., and Rocconi R. P., “The Trend Towards Minimally Invasive Surgery (MIS) for Endometrial Cancer: An ACS‐NSQIP Evaluation of Surgical Outcomes,” Gynecologic Oncology 136 (2015): 512–515. [DOI] [PubMed] [Google Scholar]
- 2. Janda M., Gebski V., Davies L. C., et al., “Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease‐Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial,” Journal of the American Medical Association 317 (2017): 1224–1233. [DOI] [PubMed] [Google Scholar]
- 3. Galaal K., Donkers H., Bryant A., and Lopes A. D., “Laparoscopy Versus Laparotomy for the Management of Early Stage Endometrial Cancer,” Cochrane Database of Systematic Reviews 10 (2018): Cd006655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Kornblith A. B., Huang H. Q., Walker J. L., Spirtos N. M., Rotmensch J., and Cella D., “Quality of Life of Patients With Endometrial Cancer Undergoing Laparoscopic International Federation of Gynecology and Obstetrics Staging Compared With Laparotomy: A Gynecologic Oncology Group Study,” Journal of Clinical Oncology 27 (2009): 5337–5342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Walker J. L., Piedmonte M. R., Spirtos N. M., et al., “Laparoscopy Compared With Laparotomy for Comprehensive Surgical Staging of Uterine Cancer: Gynecologic Oncology Group Study LAP2,” Journal of Clinical Oncology 27 (2009): 5331–5336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Walker J. L., Piedmonte M. R., Spirtos N. M., et al., “Recurrence and Survival After Random Assignment to Laparoscopy Versus Laparotomy for Comprehensive Surgical Staging of Uterine Cancer: Gynecologic Oncology Group LAP2 Study,” Journal of Clinical Oncology 30 (2012): 695–700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Mourits M. J., Bijen C. B., Arts H. J., et al., “Safety of Laparoscopy Versus Laparotomy in Early‐Stage Endometrial Cancer: A Randomised Trial,” Lancet Oncology 11 (2010): 763–771. [DOI] [PubMed] [Google Scholar]
- 8. Abu‐Rustum N., Yashar C., Arend R., et al., “Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology,” Journal of the National Comprehensive Cancer Network 21 (2023): 181–209. [DOI] [PubMed] [Google Scholar]
- 9. Ditto A., Casarin I., Pinelli C., et al., “Hysteroscopic Versus Cervical Injection for Sentinel Node Detection in Endometrial Cancer: A Multicenter Prospective Randomised Controlled Trial From the Multicenter Italian Trials in Ovarian Cancer (MITO) Study Group,” European Journal of Cancer 140 (2020): 1–10. [DOI] [PubMed] [Google Scholar]
- 10. Nagar H., Wietek N., Goodall R. J., Hughes W., Schmidt‐Hansen M., and Morrison J., “Sentinel Node Biopsy for Diagnosis of Lymph Node Involvement in Endometrial Cancer,” Cochrane Database of Systematic Reviews 6 (2021): Cd013021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Holloway R. W., Abu‐Rustum N. R., Backes F. J., et al., “Sentinel Lymph Node Mapping and Staging in Endometrial Cancer: A Society of Gynecologic Oncology Literature Review With Consensus Recommendations,” Gynecologic Oncology 146 (2017): 405–415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Cianci S., Rosati A., Vargiu V., et al., “Sentinel Lymph Node in Aged Endometrial Cancer Patients “The SAGE Study”: A Multicenter Experience,” Frontiers in Oncology 11 (2021): 737096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Garrett A. A., Wield A., Mumford B., et al., “Clinical Factors Associated With Failed Sentinel Lymph Node Mapping in Endometrial Cancer,” Gynecologic Oncology Reports 44 (2022): 101080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Insalaco G., Incognito G. G., Genovese F., et al., “Impact of Obesity in the Identification of the Sentinel Lymph Node in Endometrial Cancer: A Retrospective, Monocentric Study and Literature Review,” Archives of Gynecology and Obstetrics 309 (2024): 2779–2788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Vargiu V., Rosati A., Capozzi V. A., et al., “Impact of Obesity on Sentinel Lymph Node Mapping in Patients With Apparent Early‐Stage Endometrial Cancer: The ObeLyX Study,” Gynecologic Oncology 165 (2022): 215–222. [DOI] [PubMed] [Google Scholar]
- 16. Martínez Bravo W. R., García Vicente A. M., Noriega Álvarez E., et al., “Failure of Scintigraphy Lymphatic Mapping in Endometrial Cancer. Causes and Solutions,” Revista Española de Medicina Nuclear e Imagen Molecular 41 (2022): 78–85. [DOI] [PubMed] [Google Scholar]
- 17. Sozzi G., Fanfani F., Berretta R., et al., “Laparoscopic Sentinel Node Mapping With Intracervical Indocyanine Green Injection for Endometrial Cancer: The SENTIFAIL Study—A Multicentric Analysis of Predictors of Failed Mapping,” International Journal of Gynecological Cancer 30 (2020): 1713–1718. [DOI] [PubMed] [Google Scholar]
- 18. Sawicki S., Kobierski J., Łapińska‐Szumczyk S., et al., “Comparison of SPECT‐CT Results and Intraoperative Detection of Sentinel Lymph Nodes in Endometrial Cancer,” Nuclear Medicine Communications 34 (2013): 590–596. [DOI] [PubMed] [Google Scholar]
- 19. Sahbai S., Taran F. A., Staebler A., et al., “Sentinel Lymph Node Mapping Using SPECT/CT and Gamma Probe in Endometrial Cancer: An Analysis of Parameters Affecting Detection Rate,” European Journal of Nuclear Medicine and Molecular Imaging 44 (2017): 1511–1519. [DOI] [PubMed] [Google Scholar]
- 20. Lurain J. R., Mariani A., and Dowdy S. C., “Uterine Cancer,” in Berek & Novak's Gynecology, 15th ed., ed. Berek J. S. (Philadelphia: Lippincot Williams & Wilkins, 2012), 1250–1303. [Google Scholar]
- 21. Miller D. S. and Creasman W. T., “Adenocarcinoma of the Uterine Corpus,” in Clinical Gynecology Oncology, 8th ed., eds. DiSaia P. J. and Creasman W. T. (Elsevier Saunders: Philadelphia, 2012), 141–174. [Google Scholar]
- 22. Togami S., Ushiwaka T., Fukuda M., et al., “Comparison of Radio‐Isotope Method With 99m Technetium and Near‐Infrared Fluorescent Imaging With Indocyanine Green for Sentinel Lymph Node Detection in Endometrial Cancer,” Japanese Journal of Clinical Oncology 52 (2022): 24–28. [DOI] [PubMed] [Google Scholar]
- 23. Frati A., Ballester M., Dubernard G., et al., “Contribution of Lymphoscintigraphy for Sentinel Lymph Node Biopsy in Women With Early Stage Endometrial Cancer: Results of the SENTI‐ENDO Study,” Annals of Surgical Oncology 22 (2015): 1980–1986. [DOI] [PubMed] [Google Scholar]
- 24. Balaya V., Bresset A., Guani B., et al., “Risk Factors for Failure of Bilateral Sentinel Lymph Node Mapping in Early‐Stage Cervical Cancer,” Gynecologic Oncology 156 (2020): 93–99. [DOI] [PubMed] [Google Scholar]
- 25. Jakic B., Kerjaschki D., and Wick G., “Lymphatic Capillaries in Aging,” Gerontology 66 (2020): 419–426. [DOI] [PubMed] [Google Scholar]
- 26. Antoniak K., Hansdorfer‐Korzon R., Mrugacz M., and Zorena K., “Adipose Tissue and Biological Factors. Possible Link Between Lymphatic System Dysfunction and Obesity,” Metabolites 11 (2021): 617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kataru R. P., Park H. J., Baik J. E., Li C., Shin J., and Mehrara B. J., “Regulation of Lymphatic Function in Obesity,” Frontiers in Physiology 11 (2020): 459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Cabrera S., Bebia V., Franco‐Camps S., et al., “Technetium‐99m‐Indocyanine Green Versus Technetium‐99m‐Methylene Blue for Sentinel Lymph Node Biopsy in Early‐Stage Endometrial Cancer,” International Journal of Gynecological Cancer 30 (2020): 311–317. [DOI] [PubMed] [Google Scholar]
- 29. Rossi E. C., Kowalski L. D., Scalici J., et al., “A Comparison of Sentinel Lymph Node Biopsy to Lymphadenectomy for Endometrial Cancer Staging (FIRES Trial): A Multicentre, Prospective, Cohort Study,” Lancet Oncology 18 (2017): 384–392. [DOI] [PubMed] [Google Scholar]
- 30. Restaino S., Buda A., Puppo A., et al., “Anatomical Distribution of Sentinel Lymph Nodes in Patients With Endometrial Cancer: A Multicenter Study,” International Journal of Gynecological Cancer 32 (2022): 517–524. [DOI] [PubMed] [Google Scholar]
- 31. Stephens A. J., Kennard J. A., Fitzsimmons C. K., et al., “Robotic Sentinel Lymph Node (SLN) Mapping in Endometrial Cancer: SLN Symmetry and Implications of Mapping Failure,” International Journal of Gynecological Cancer 30 (2020): 305–310. [DOI] [PubMed] [Google Scholar]
- 32. Bodurtha Smith A. J., Fader A. N., and Tanner E. J., “Sentinel Lymph Node Assessment in Endometrial Cancer: A Systematic Review and Meta‐Analysis,” American Journal of Obstetrics and Gynecology 216 (2017): 459–476.e10. [DOI] [PubMed] [Google Scholar]
- 33. Todo Y., Okamoto K., Hayashi M., et al., “A Validation Study of a Scoring System to Estimate the Risk of Lymph Node Metastasis for Patients With Endometrial Cancer for Tailoring the Indication of Lymphadenectomy,” Gynecologic Oncology 104 (2007): 623–628. [DOI] [PubMed] [Google Scholar]
- 34. Mariani A., Dowdy S. C., Cliby W. A., et al., “Prospective Assessment of Lymphatic Dissemination in Endometrial Cancer: A Paradigm Shift in Surgical Staging,” Gynecologic Oncology 109 (2008): 11–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Han S. S., Cho J. Y., Park I. A., et al., “Feasibility of Routine Lymphadenectomy in Clinical Stage‐I Endometrial Cancer,” Medical Science Monitor 14 (2008): Cr183‐189. [PubMed] [Google Scholar]
- 36. Ballester M., Dubernard G., Lécuru F., et al., “Detection Rate and Diagnostic Accuracy of Sentinel‐Node Biopsy in Early Stage Endometrial Cancer: A Prospective Multicentre Study (SENTI‐ENDO),” Lancet Oncology 12 (2011): 469–476. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.