Abstract
Objective
This study aimed to assess the impact of comprehensive staging on survival outcomes in this population.
Methods
Patients who underwent surgery for epithelial ovarian cancer in one of the 14 Francogyn cancer centers between 2000 and 2020 were included in the study. The primary analysis evaluated the impact of lymphadenectomy on overall survival and recurrence-free survival. Lymph node count was analyzed as a continuous variable, and its association with survival, considered as a continuous outcome was assessed using linear regression (secondary analysis). Survival was compared using the log-rank test, and multivariate analysis was performed using a Cox model.
Results
A total of 467 patients with presumed early-stage epithelial ovarian cancer were included, of which 198 underwent complete lymphadenectomy and 266 did not. No significant association was found between lymph node staging and survival in the primary analysis, possibly due to limited statistical power and a selection bias, as patients without lymphadenectomy had more favorable disease profiles (p=0.600 and p=0.700, respectively). Complete lymphadenectomy was associated with a significantly higher risk of complications (34.5% vs. 14%, p<0.001). In secondary analysis, the number of para-aortic lymph nodes harvested was identified as an independent predictor of both overall survival and recurrence-free survival (p=0.007 and p=0.002, respectively). Histological characteristics and adjuvant chemotherapy also showed a significant correlation with improved survival outcomes.
Conclusion
Extensive para-aortic lymphadenectomy in early-stage epithelial ovarian cancer is associated with better overall and recurrence-free survival but comes with an increased risk of complications.
Keywords: Early-Stage Ovarian Cancer, Lymph Node Staging, Clinical Management, Survival
Synopsis
A comprehensive para-aortic lymphadenectomy appears to be appropriate for the accurate evaluation of presumed early-stage epithelial ovarian cancer, as it is linked to better overall and recurrence-free survival. However, the lack of impact of pelvic lymphadenectomy in this context raises questions about the sentinel lymph node procedure.
INTRODUCTION
Epithelial ovarian cancer has the poorest prognosis among gynecologic cancers, with 295,414 new cases and 184,799 new deaths worldwide in 2018 [1,2]. Patients diagnosed with limited ovarian disease represent only 25% of all cases [3].
In early-stage epithelial ovarian cancer, assessing the involvement of lymph nodes is recommended to diagnose occult lymph node invasion, upgrading tumors to higher International Federation of Gynecology and Obstetrics (FIGO) stage IIIA and indicating adjuvant therapies, such as chemotherapy, PARP inhibitors or bevacizumab [1,2]. Indeed, Viveros-Carreño et al. [3] found 12.6% of occult lymph node invasion and Rodrigues Teixeira et al. [2] 8.4% in early stages.
The survival impact of lymph node staging for these patients is still debated. Timmers et al. [4] showed that patients who underwent complete staging had better recurrence-free survival and overall survival than those with no lymph node staging. Bizzarri et al. [5] showed that pelvic and para-aortic lymphadenectomy increased recurrence-free survival without affecting overall survival. Furthermore, the recent LION trial demonstrated that even in patients with advanced disease but no evidence of lymph node invasion on preoperative imaging and intra operative palpation, complete lymphadenectomy had no impact on survival during primary cytoreductive surgery [6].
Therefore, the primary objective of this study was to evaluate the impact of a comprehensive staging on survival in patients with early-stage epithelial ovarian cancer. The secondary objective was to assess the risk of complications and their patterns.
MATERIALS AND METHODS
1. Patients’ inclusion
The research protocol was approved by the Institutional Review Board of the French College of Obstetrics and Gynecology (CEROG 2023-GYN-0606) [7].
A retrospective, multicentric study was conducted within 14 French tertiary referral centers for ovarian cancer of the FRANCOGYN research group: Lariboisiere Hospital, Intercommunal hospital of Creteil, Jean Verdier Hospital, Lille Hospital, Poissy Hospital, Tenon Hospital, European George Pompidou Hospital, La Pitie Salpêtrière Hospital, Lyon Sud Hospital, Marseille Hospital, Strasbourg Hospital, Tours Hospital, Rennes Hospital, and Georges-Francois Leclerc Hospital.
Patients who underwent a surgery for a histologically confirmed early-stage epithelial ovarian cancer between 2002 and 2020 with a FIGO stage up to IIA were included. Patients with a FIGO stage IIB and beyond, incomplete histological data, no follow-up, and those who never underwent surgery were excluded.
2. Data collection
The following data were abstracted from patient charts: sociodemographic characteristics, body mass index, parity, menopausal status, and familial oncological history. The dates of initial surgery, recurrence, and death were also reported.
3. Preoperative and surgical management
The preoperative workup included a clinical examination, CA 125 assay, and imaging, which consisted of a computed tomography (CT) scan and either an ultrasound or magnetic resonance imaging (MRI). All tumors were classified according to the FIGO classification [8]. The essential factors for evaluating the FIGO stage were determined through imaging.
The surgical procedure began with laparoscopic evaluation to exclude peritoneal carcinomatosis. When no peritoneal disease was observed, the treatment plan included hysterectomy with bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy for confirmed epithelial ovarian cancer, omentectomy, and peritoneal staging through multiple biopsies. The anatomical landmarks for pelvic lymphadenectomy were defined as superiorly by the iliac bifurcation, internally by the umbilical artery, deep and laterally by the obturator nerve, and inferiorly by the obturator fossa. Para-aortic lymph nodes were extracted up to the left renal vein (Fig. S1). The choice of surgical approach was determined based on intraoperative challenges, surgeons’ preferences and technical abilities and patients’ history and comorbidities.
Surgical complications were classified according to Clavien-Dindo classification, ranging from grade I (minor complication with no need for medication) to grade V (complication leading to death) [9].
4. Post-operative management
Adjuvant therapy was determined in a multidisciplinary meeting based on FIGO stage, grade, and final histology [4]. If lymph node staging was not conducted during initial surgery, a second surgery for staging purposes was discussed in a multidisciplinary meeting. If lymph nodes histology did not modify the adjuvant therapy, it could have been decided to avoid it [1].
The follow-up visits were scheduled every 4 months during the first 2 years and every 6 months thereafter. Those visits included physical examination and monitoring of CA125 serum levels. A CT scan was only performed if an abnormality was detected [1].
5. Statistical analysis
Data were managed using an Excel database (Microsoft Corporation, Redmond, WA, USA) and analyzed using R v3.3 (Posit Software; PBC formerly RStudio, PBC, Boston, MA, USA). The p-values <0.050 were considered significantly different.
We compared patients who underwent lymph node staging during surgery to those who did not. Statistical analysis was based on the χ2 and Fisher’s exact tests for ordinal variables. For continuous variables, Student’s t test or Mann-Whitney test were used. Then, we evaluated the impact of lymph node surgery on overall survival and recurrence-free survival (primary analysis). Finally, in the subgroup of patients who underwent lymphadenectomy, we assessed the impact of the number of lymph nodes harvested during surgery on overall survival and recurrence-free survival. Pelvic and para-aortic lymphadenectomy were evaluated independently, and the number of nodes was analyzed as a continuous variable (secondary analysis). The assumption of linearity was verified for each association using both visual inspection and formal statistical testing, and the linear model was found to be appropriate in all cases. Recurrence-free survival was defined as the time interval between surgery and relapse, and overall survival was calculated from the date of surgery to death. Patients who were still alive or without recurrence were censored on the date of the last follow-up visit. The Kaplan-Meier method was used to estimate the survival distribution, and the log-rank test was used to compare survival data. Multivariate analysis was also performed with a cox model.
We retrospectively calculated the sample size to evaluate the power of the study. A 2,312 patients were required to detect a difference with a hazard ratio of 1.06 in a population with a prevalence of 0.13, with an alpha risk of 0.05 and a power of 80%.
RESULTS
1. Population
Between January 2000 and December 2022, 2,287 patients were treated for an epithelial ovarian cancer within of the 14 centers of the Francogyn group and 464 patients (20%) were included (Fig. 1). Among those, 198 (42.6%) patients underwent lymph node staging and 266 (57.3%) patients did not.
Fig. 1. Flow chart.
EOC, early-stage ovarian cancer; FIGO, International Federation of Gynecology and Obstetrics.
2. Primary analysis
Patient’s characteristics
Preoperative characteristics of patients included are displayed in Table 1. Patients that underwent lymph node staging had more often FIGO stage over IA that those who did not (53% [140/266] and 35% [71/198] respectively, p<0.001). In the no lymphadenectomy group, 101 patients (37.8%) underwent a preoperative MRI, and 166 patients (62.2%) an ultrasound. In the lymphadenectomy group, 59 patients (29.8%) underwent a preoperative MRI, and 139 patients (70%) an ultrasound (p=0.440).
Table 1. Main preoperative characteristics.
| Characteristics studied | No lymphadenectomy (n=266) | Complete lymphadenectomy (n=198) | p-value | ||
|---|---|---|---|---|---|
| Epidemiological characteristics | |||||
| Age (yr) | 54 (56) | 57 (57) | 0.050 | ||
| BMI (kg/m2) | 25 (24) | 25 (24) | 0.320 | ||
| Nulligravida | 106 (40.0) | 84 (42.0) | 0.420 | ||
| Menopause | 184 (69.0) | 154 (77.0) | 0.060 | ||
| Hormonal substitution treatment | 14 (5.0) | 8 (4.0) | 0.090 | ||
| ASA score | 0.540 | ||||
| 1 | 140 (53.0) | 116 (59.0) | |||
| 2 | 100 (37.0) | 67 (34.0) | |||
| 3 | 23 (9.0) | 14 (7.0) | |||
| 4 | 3 (1.0) | 1 (0.5) | |||
| Genes mutations | 41 (15.0) | 19 (10.0) | 0.080 | ||
| Oncological medical history | |||||
| Breast cancer history | 12 (6.0) | 3 (2.0) | 0.220 | ||
| Gynecologic cancer familial history | 56 (22.0) | 42 (22.0) | 0.570 | ||
| Ovarian cancer | 10 (4.0) | 7 (4.0) | 0.900 | ||
| Cervical cancer | 1 (1.0) | 1 (0.5) | 0.900 | ||
| Endometrial cancer | 6 (2.0) | 6 (3.0) | 0.820 | ||
| Breast cancer | 39 (15.0) | 28 (14.0) | 0.960 | ||
| Radiological assessment of the FIGO stage | <0.001 | ||||
| IA | 140 (53.0) | 71 (35.0) | |||
| IB | 9 (4.0) | 7 (4.0) | |||
| IC | 67 (25.0) | 73 (37.0) | |||
| IIA | 50 (18.0) | 47 (24.0) | |||
Age and BMI are presented as mean (median). Values are presented as number (%), except for age and BMI.
ASA, American Society of Anesthesiologists; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
Surgical outcomes are displayed in Table 2. Lymph node staging was associated with increased duration of surgery, with a mean time of 326 minutes versus 156 minutes if no staging was performed (p<0.001). In the lymphadenectomy group, 35% (69/198) of patients experienced a complication, versus 14% (36/266) of patients in the no lymphadenectomy group (p<0.001). The detail of complication is available in supplementary material Table1. The mean amount of blood loss was 140 mL for the lymphadenectomy group with 8% of patient transfused and 44 mL for the no lymphadenectomy group with 3% of patients transfused (p=0.001 and p=0.025, respectively). In the lymphadenectomy group, 47 patients (24%) had a complication grade under 3, and 22 patients had a complication of at least grade 3 (p<0.001). In the no lymphadenectomy group, 30 patients (11%) had a complication grade under 3, and 6 patients (3%) had a complication of at least grade 3 (p<0.001). One death occurred in each group. The most frequent pathological type was the endometrioid type in both groups (133 patients [50%] in the no lymphadenectomy group, 97 patients [48%] in the lymphadenectomy group). The second most frequent histology was high-grade serous for the lymphadenectomy group, whereas it was low-grade serous in the no lymphadenectomy group (p=0.005). Regarding lymph node involvement, there were 5 patients with pelvic lymph node involvement (2.5%) without para-aortic metastasis and 3 patients with para-aortic lymph node involvement without pelvic lymph node metastasis (1.5%). None of these lymph nodes were suspicious on preoperative imaging.
Table 2. Main surgical outcomes.
| Surgical outcomes | No lymphadenectomy (n=266) | Complete lymphadenectomy (n=198) | p-value | ||
|---|---|---|---|---|---|
| Surgical time (mean, min) | 156 | 326 | <0.001 | ||
| Blood loss | |||||
| Blood loss (mean mL) | 44 | 140 | 0.001 | ||
| Blood transfusion | 7 (3.0) | 15 (8.0) | 0.025 | ||
| Complication | <0.001 | ||||
| Clavien score | |||||
| 1 | 24 (9.0) | 33 (17.0) | |||
| 2 | 6 (2.0) | 14 (7.0) | |||
| 3A | 0 (0.0) | 4 (2.0) | |||
| 3B | 4 (2.0) | 14 (7.0) | |||
| 4 | 1 (0.5) | 3 (1.0) | |||
| 5 | 1 (0.5) | 1 (0.5) | |||
| Lymph node histology | |||||
| Posit if pelvic node | NA | 5 (2.5) | |||
| Posit if para-aortic node | NA | 3 (1.5) | |||
| Histological characteristics | 0.005 | ||||
| High-grade serous cancer | 31 (11.0) | 62 (31.0) | |||
| Low-grade serous cancer | 85 (32.0) | 31 (16.0) | |||
| Mucinous | 10 (4.0) | 7 (4.0) | |||
| Endometrial cancer | 133 (50.0) | 97 (48.0) | |||
| Clear cell cancer | 7 (3.0) | 1 (1.0) | |||
Values are presented as number (%).
NA, not available.
Survival analysis
Mean follow-up was of 43 months for the lymphadenectomy group and 37 months for the no lymphadenectomy group. Recurrence occurred in 41 patients (21%) in the lymphadenectomy group compared to 48 patients (18%) in the no lymphadenectomy group (p=0.560). The most common recurrence pattern was peritoneal carcinomatosis in both groups. It occurred in 38 patients (14%) in the no lymphadenectomy group and 38 patients (19%) in the lymphadenectomy group (p=0.560).
Surgical lymph node staging had no impact on the overall survival (hazard ratio [HR]=0.85; 95% confidence interval [CI]=0.45–1.60; p=0.600) and the recurrence-free survival (HR=0.88; 95% CI=0.46–1.66; p=0.700) (Fig. 2).
Fig. 2. Impact of the surgical staging on overall and recurrence free survival.
CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NA, not available.
Patients in the lymphadenectomy group received significantly more often adjuvant chemotherapy than their counterparts (141 patients [71%] vs. 93 patients [35%] (p<0.001)). In the multivariate analysis, adjuvant chemotherapy was significantly associated with improved recurrence-free survival when adjusted for lymph node staging surgery, histology and FIGO stage (estimate=1.15; 95% CI=1.05–1.26; p=0.001).
3. Secondary analysis
The mean number of lymph node harvested were 14 pelvic lymph nodes and 19 para-aortic lymph nodes. Twenty-five percent of the patients had fewer than 8 pelvic lymph nodes sampled and fewer than 10 para-aortic lymph nodes sampled (Fig. S2).
An extensive pelvic lymphadenectomy was correlated with a poorest overall survival in the linear regression (p=0.046) (Fig. 3). An extensive para-aortic lymphadenectomy was associated with a better overall survival (p=0.013) (Fig. 3) and recurrence-free survival (p=0.007) (Fig. 3). No cut-off in the number of lymph node harvested was identified.
Fig. 3. Impact of the number of pelvic and para-aortic lymph node harvest on overall survival and recurrence free survival.
CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; NA, not available.
In the multivariable analysis, the number of para-aortic lymph node harvested was also an independent predictor of better overall survival (p=0.007) and recurrence-free survival (p=0.002). Furthermore, histological characteristic and adjuvant chemotherapy were also independent predictors of better recurrence-free survival (p=0.012 and p=0.004) and overall survival (p=0.008 and p=0.020).
DISCUSSION
In our study, lymph node staging was not significantly associated with survival outcomes. In the primary analysis, we did not demonstrate a statistically significant impact of lymph node dissection on either overall survival (HR=0.85; 95% CI=0.45–1.60; p=0.600) or recurrence-free survival (HR=0.88; 95% CI=0.46–1.66; p=0.700). However, an extensive para-aortic lymphadenectomy is significantly associated with improved recurrence-free survival and overall survival (p=0.007 and p=0.013), even in the multivariate analysis when adjusted for histological type and adjuvant chemotherapy (p=0.007 and p=0.002 for overall survival and recurrence free survival). Both histological type and adjuvant chemotherapy were also associated with improved recurrence-free survival and overall survival. In contrast, an extensive pelvic lymphadenectomy was associated with a poorest overall survival (p=0.460). This association has not been highlighted in the multivariate analysis (p=0.050).
The purpose of lymph node staging in epithelial ovarian cancer is to determine the lymph node status, but the impact of extensive staging on survival is debated [3,4,5]. Trimbos et al. [10] found that overall survival was improved by complete staging, even for patients who received adjuvant chemotherapy (HR=1.89; 95% CI=0.99–3.60; p=0.05). Chan et al. [11] found that complete lymphadenectomy was associated with a 5-year recurrence-free survival increase from 87.0% to 92.6% (p<0.001), independently of histology, type, or stage of the tumor. In our study, surgical lymph node staging, as a binary variable, had no clear impact on overall survival and recurrence-free survival (p-values of 0.6 and 0.7). However, in the no lymphadenectomy group, tumors had a better prognosis, likely with less occult lymph node involvement. In fact, 53% of patients in this group had a tumor classified as FIGO IA, and 50% of patients had an endometrioid type. European Society of Gynaecological Oncology guidelines support no adjuvant chemotherapy for those patients [1].
Few studies have examined the impact of the number of lymph nodes harvested on overall and recurrence-free survival. Kleppe et al. [12] observed a positive correlation between the number of lymph nodes removed and overall survival for patients with epithelial ovarian cancer, with a cutoff of 10 lymph nodes removed. In our cohort, both recurrence-free survival and overall survival improved as more para-aortic lymph nodes were removed (p=0.007 and p=0.013). No clear cut off was found. In the multivariate analysis, an extensive para-aortic lymphadenectomy emerged as an independent factor for improved recurrence-free survival and overall survival when adjusted for histological characteristics, FIGO stage, and adjuvant chemotherapy (p=0.002 and p=0.007).
In the present cohort, an extensive pelvic lymphadenectomy was not associated with an increase of overall and recurrence free survival in the multivariate analysis (p=0.05 and p=0.06 respectively). It is widely accepted that para-aortic lymph nodes are typically the first lymph nodes affected in ovarian cancer before involvement of pelvic lymph nodes [13,14]. Furthermore, the literature frequently reports cases of isolated para-aortic lymph node invasion or isolated pelvic lymph node invasion. Yu et al. [14] demonstrated 4.2% of isolated pelvic lymph node invasion and 4.8% of isolated para-aortic lymph node invasion in FIGO I ovarian cancer. In our study, we observed pelvic lymph node involvement in 5 patients (2.5%) without para-aortic metastasis, and para-aortic lymph node involvement in 3 patients (1.5%) without pelvic lymph node metastasis. None of the patients exhibited both types of invasions.
The performance of imaging techniques in detecting lymph node invasion is also variable. A meta-analysis by Thomassin-Naggara et al. [15] showed that MRI has a diagnostic accuracy of 87%. Positron emission tomography-CT (PET-CT) is not yet recommended for primary evaluation of early-stage epithelial ovarian cancer [1]. In fact, it lacks specificity to differentiate between borderline and malignant tumors [16]. However, PET-CT outperforms CT and MRI in diagnosing malignant lymph nodes, peritoneal metastasis, and recurrent disease [17]. In fact, FDG PET-CT has a sensitivity of 73% and a specificity of 97% for detecting lymph node metastasis, while CT has a sensitivity of 43% and a specificity of 95%, and MRI has a sensitivity of 55% and a specificity of 88% [17]. In our study, all patients showed no signs of lymph node involvement on imaging. Current imaging is not sufficient for avoiding lymph node dissection in epithelial ovarian cancer. The role of PET scan is therefore still to be defined.
In our study, adjuvant chemotherapy was also identified as an independent factor for both recurrence-free survival (estimate=1.95; 95% CI=0.81–4.47; p=0.020) and overall survival (estimate=1.07; 95% CI=0.06–1.22; p=0.004). The decision to administer adjuvant chemotherapy in epithelial ovarian cancer is typically based on the FIGO stage, histological type, and grade of the tumor. If lymph node metastasis is detected, the tumor is classified as stage IIIA, and it is no longer considered an early-stage epithelial ovarian cancer, necessitating adjuvant chemotherapy [1]. Furthermore, PARP inhibitors and bevacizumab, which have a significant impact on survival, are only recommended for FIGO stages higher than III [1,18].
Harter et al. [6] reported more serious complications requiring surgical intervention in the lymphadenectomy group compared to the no lymphadenectomy group (12.4% vs. 6.5%, p=0.01). In our study, 22 patients (8.5%) in the lymphadenectomy group experienced complications necessitating reintervention, while only 6 patients (3%) in the non-lymphadenectomy group had such complications (p<0.001). The impact of the surgical route on staging of early-stage epithelial ovarian cancer has been evaluated by Merlier et al. [19] in the Francogyn group and showed no difference in recurrence-free survival (p=0.08) or overall survival (p=0.19) between the laparoscopic and the laparotomy approaches.
The limitation of our study needs to be specified. First, it is a retrospective study with some missing data and limited features especially regarding imaging exam preoperatively but also regarding the surgical approach elected and the reason why it was so (minimally invasive or open). Second, due to the low prevalence of lymph node invasion, our study might have lacked of power to observe a significant difference between the no lymphadenectomy and the lymphadenectomy groups. Moreover, as patient management was not randomized, a selection bias is likely—patients who did not undergo lymphadenectomy more frequently had tumors with favorable prognostic features (e.g., FIGO stage IA), which may have influenced the surgical decision and contributed to the observed survival outcomes. However, early-stage epithelial ovarian cancer is quite uncommon and pooling patients from 14 centers enabled to achieve a large cohort.
The feasibility of sentinel lymph node detection is currently under evaluation for epithelial ovarian cancer. A meta-analysis by Agusti et al. [20] reported a detection rate of 93.3% (95% CI=77.8%–100%; p<0.0001). A prospective single-arm study by Agustí et al. [21] showed a detection rate of 90% with a predominant para aortic spread. A phase II prospective trial by Uccella et al. [22] showed a sensitivity of 100%, a false negative rate of 0% and a negative predictive value of 100% for a detection rate of the sentinel lymph node of 67.7% with a 9.2% complication rate. In our study, extensive pelvic lymphadenectomy was associated with poorer overall survival (p=0.046), although no association was found with recurrence-free survival. Eventually, improvement in surgical technics and the development of sentinel lymph node procedures might strongly impact surgical management of these patients. However, the impact on survival outcomes is yet to be determined.
Lymph node staging appears to be necessary for accurately evaluating the stage of early-stage ovarian cancer. The proper addition of chemotherapy along with an extensive para-aortic lymphadenectomy, is associated with improved overall survival and recurrence-free survival. The role of sentinel lymph node procedure remains a subject of debate with the goal to reducing morbidity without impact on survival.
Footnotes
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization:O.S., M.C., D.Y.
- Formal analysis:O.S., A.J., M.C., D.Y.
- Investigation:O.S., A.J., M.C., D.Y.
- Methodology:O.S., M.C., D.Y.
- Supervision:K.Y., Z.E., O.L., B.S., H.C., L.J., L.V., R.E., C.H., D.P.F., G.O., U.J., C.G., A.H., C.X., T.C., M.C., D.Y.
- Validation:O.S., K.Y., Z.E., O.L., B.S., H.C., L.J., L.V., R.E., C.H., D.P.F., G.O., U.J., C.G., A.H., C.X., T.C., M.C., D.Y.
- Writing - original draft:O.S., M.C., D.Y.
- Writing - review & editing:O.S., K.Y., Z.E., O.L., B.S., H.C., L.J., L.V., R.E., C.H., D.P.F., G.O., U.J., C.G., A.H., C.X., T.C., M.C., D.Y.
SUPPLEMENTARY MATERIALS
Para-aortic and pelvic lymphadenectomy boundaries.
Distribution of the number of pelvic and para-aortic lymph nodes harvest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Para-aortic and pelvic lymphadenectomy boundaries.
Distribution of the number of pelvic and para-aortic lymph nodes harvest.