Sentinel lymph node biopsy in gynecologic cancers

Abstract

Sentinel lymph node (SLN) biopsy has emerged as a promising, less morbid alternative to complete lymphadenectomy in gynecologic oncology, enabling accurate nodal staging with a reduced surgical burden. Its use has expanded across endometrial, cervical, vulvar, and selected ovarian malignancies. Recent reviews suggest that SLN mapping can lower treatment-related morbidity without compromising oncologic outcomes. However, several challenges persist, including mapping failure, false-negative results, operator learning curves, variability in tracer techniques, and inconsistencies in ultrastaging interpretation. In early-stage cervical cancer, comparative studies demonstrate no significant differences in progression-free or overall survival between SLN biopsy alone and SLN combined with pelvic lymphadenectomy, supporting its use in carefully selected patients. In endometrial cancer, the FIRES trial reported a sensitivity of 97.2% and a negative predictive value of 99.6% with indocyanine green mapping. In response, emerging consensus guidelines aim to standardize SLN assessment to ensure diagnostic accuracy. Nevertheless, global surveys reveal substantial variation in the adoption of SLN strategies across regions and practice settings. While negative sentinel nodes generally obviate the need for further treatment, the detection of micro metastases-particularly in cervical and endometrial cancers-has gained clinical importance, often prompting adjuvant radiotherapy and/or chemotherapy. As precision surgery continues to evolve, this editorial explores whether the current evidence, infrastructure, and multidisciplinary preparedness are sufficient for SLN biopsy to become standard practice, or whether it remains an innovation still awaiting widespread readiness.

Key Words: Sentinel lymph node biopsy; Gynecological cancers; Cervical cancer; Endometrial cancer; Vulval cancer; Ovarian cancer

Core Tip: Sentinel lymph node (SLN) biopsy is redefining nodal staging in gynecologic oncology by reducing surgical morbidity without compromising oncologic outcomes. Evidence supports its use in early-stage cervical and endometrial cancers, with high diagnostic accuracy and survival equivalence to full lymphadenectomy in selected patients. However, technical variability, learning curves, and inconsistent global adoption remain barriers. As micrometastatic disease increasingly influences adjuvant treatment decisions, the challenge is no longer proof of concept, but whether health systems are ready to implement SLN biopsy as routine standard care.

INTRODUCTION

Sentinel lymph node (SLN) biopsy holds promise as a less morbid alternative to full lymphadenectomy in gynecologic oncology, offering precise nodal staging with reduced surgical burden. SLN techniques have increasingly been adopted for endometrial, cervical, vulvar, and even select ovarian tumors. Recent reviews underscore that SLN detection may reduce morbidity while maintaining oncologic fidelity[1]. Nonetheless, challenges remain-mapping failures, false negatives, learning curves, heterogeneity in tracer protocols, and interpretative variability in ultrastaging. In cervical cancer, comparative studies report no significant differences in progression-free or overall survival between SLN biopsy alone (SLNB) and SLN plus pelvic lymphadenectomy (PL) in early-stage disease, supporting its potential in selected patients[2]. In endometrial cancer, the FIRES trial demonstrated a sensitivity of 97.2% and a negative predictive value (NPV) of 99.6% using indocyanine green (ICG) mapping[3]. Emerging consensus guidelines are now attempting to standardize SLN evaluation thresholds to safeguard diagnostic reliability[4]. Yet, global surveys continue to reveal wide variation in the uptake of SLN strategies across regions and practice settings[5]. Negative sentinel nodes (SN) require no further treatment but the presence of micrometastasis has gained significance in cervical and endometrial cancer as indications for adjuvant treatment by radiation and or chemotherapy. As precision surgery advances, this editorial examines whether the evidence base, infrastructure, and multidisciplinary readiness are sufficient for SLN biopsy to enter mainstream practice-or whether it remains an evolving innovation awaiting true prime time.

TECHNIQUES OF SLN BIOPSY

The procedure is performed by injecting fluorescent or coloured dye or radiocolloid, peritoumorally into the cervix. A commonly used method is the “four-quadrant” technique, injecting 1 mL of dye at 12, 3, 6, and 9 o'clock positions (total 4 mL), first superficial or subepithelial 1-3 mm then deeper or stromal 1-2 cm into the cervix. This achieves access to the lymphatics. Dye injection is typically done after the patient is under anesthesia but before placing in surgical position, or at the start of the surgery (e.g., prior to or during laparoscopy/Laparotomy). A 25-gauge spinal needle or similar fine-gauge needle is typically used to facilitate easy deep injection. Combining blue dye with radiotracer technetium-99 (Tc99) or ICG is superior to using blue dye alone, as it increases the detection rate of SNs. The interval between injection and exploration is not less than 15 minutes or more than 30 minutes. In cervical cancer the lymph nodes medial to the external iliac vessels, ventral to the hypogastric vessels and the superficial obturator region are mapped most. In endometrial cancer if the lymphatics cross over the obliterated umbilical, then the region medial to external iliac shows SN. In cases where the lymphatics do not cross the obliterated umbilical artery, the SN can be mapped cephalad through the meso-ureteric channels, in the common iliac, presacral or paraaortic region[6]. Adequate procedure is defined by removal of all positively traced nodes, along with any enlarged or suspicious nodes. In case of negative mapping a side specific complete lymphadenectomy must be performed. In case of failed mapping a re-injection of dye can be done on the ipsilateral side of the cervix.

SLN biopsy must ideally be performed before hysterectomy. There are no major complications associated specifically with the procedure. Vascular or ureteric injury rates as observed in complete lymph node dissection are much lower in SLN biopsy.

A survey among Chinese gynaecological oncologists revealed a low uptake of the procedure among them. The factors of having theoretical knowledge of SLN mapping, the use of ultra staging, and working in cancer research centre were related to a higher acceptance of SLN. The most common barrier in uptake of this technique was “lack of familiarity” with the procedure, followed by “lack of equipment and tracer availability”, “concern about diagnostic accuracy” and “lack of institutional support”[7].

CERVICAL CANCER

SN mapping is recommended for stage 1 disease of cervical cancer, preferably up to 2 cm tumor size; however, prospective multicentric trials SENTICOL 1 & 2 have reported that SN biopsy is safe for larger lesions (4 cm) and up to FIGO (2009) stage 2A. The studies compare the oncological outcomes of patients with early-stage cervical cancer and negative nodes who underwent SLNB vs PL. Although this technique has been performed on tumors of size up to 4 cm, the best detection rates are in tumors < 2 cm. The near-infrared dyes radiocolloid Tc99 and ICG are recommended for detection.

The most robust evidence is provided by SENTICOL 1 & 2 and the SENTIX study published recently. In SENTICOL 2, most patients had stage IB1 (FIGO 2009) lesions (87.4%), and no false-negative cases were observed in the SN + pelvic lymph node dissection (PLND) arm. Lymphatic morbidity was significantly lower in the SN arm (31.4%) than in the SN + PLND arm (51.5%; P = 0.0046)[8].

A post-hoc survival analysis of SENTICOL 1 & 2 early-stage patients (FIGO 2009 I-IIA) with negative bilateral SLN and non-SLN found similar disease free survival (DFS) and disease specific survival between SLNB and PL groups (85.1% vs 80.4%, P = 0.24; 90.8% vs 97.2%, P = 0.22), suggesting that omitting full PL in these patients does not increase recurrence risk. However, effects on overall survival require confirmation from prospective trials[9].

The SENTICOL group also assessed the clinical impact of low volume LN metastasis and reported a strong correlation of stromal invasion with micrometastases and isolated tumor cells (ITCs), with the highest sensitivity and specificity at 8 mm depth of invasion and a NPV of 97% at invasion < 8 mm followed by stage greater than 1B1. The low-volume metastasis did not impact DFS or recurrence risk after treatment[10].

An intention-to-treat analysis performed on 145 patients in a multicentric study following SENTICOL protocol reported the superiority of SLNB over routine PLND, where 38.2% of patients had at least one SLN in an unexpected area and 5.1% had SLNs only in unexpected areas. This trial concluded that SLNB detects unusual drainage pathways and micrometastasis in a substantial proportion of patients, thus improving nodal staging[11].

SENTICOL 3 is an international study validating SLNB in early cervical cancer. Its main goal is to compare 3-year disease-free survival and health-related quality of life after SLNB or SLNB plus PL. The hypothesis is that DFS is non-inferior and health-related quality of life is superior after SLNB compared with SLNB + PL, with the primary endpoint associating the 3-year survival with quality of life. This study is due to complete the follow-up in 2026[12].

The SENTIX trial recently reported outcomes for stage IA1/Lymphovascular space invasion-positive to IB2 (≤ 4 cm, or ≤ 2 cm for fertility-sparing) cervical cancer patients without suspicious lymph nodes on imaging, all of whom underwent mandatory SLN frozen section assessment and pathological ultrastaging. The LNs of patients negative for frozen section were assessed postoperatively by ultrastaging for inclusion in the trial. This trial discovered that no SLNs were identified outside the seven pelvic regions. Most nodes-including positive ones-were located below the common iliac bifurcation, with only 2% above it. Frozen-section analysis failed to detect 54% of positive lymph nodes, including 28% of cases with macro metastases and 90% with micro metastases (Table 1)[13].

Table 1 Sentinel lymph node biopsy trials in gynecologic cancers.

Cancer type	Trial/study	Study design and population	Key SLNB results	Conclusion
Cervical	SENTICOL 1 & 2	Prospective multicentric; early-stage cervical cancer (FIGO I-IIA)	Comparable DFS and DSS between SLNB alone vs PLND; lower lymphatic morbidity with SLNB (31.4% vs 51.5%, P = 0.0046)	SLNB safe in bilateral SLN-negative patients; reduces morbidity
Cervical	SENTIX	Prospective multicenter observational	Frozen section missed 54% positive nodes (28% macrometastasis, 90% micrometastasis); most SLNs below common iliac bifurcation	Ultrastaging essential; frozen section alone unreliable
Cervical	Multicentric SENTICOL protocol study	Prospective multicenter (n = 145)	38.2% had SLN in unexpected areas; improved detection of micrometastasis	Improves nodal staging and detects atypical drainage
Cervical	SENTICOL 3	Ongoing international validation	Primary endpoint: 3-year DFS and QoL after SLNB vs SLNB+PLND	Results awaited (expected 2026)
Endometrial	FIRES trial	Multicenter prospective cohort (n = 385)	Sensitivity 97.2%; NPV 99.6%; minimal procedure-related adverse events	SLNB feasible and reliable; ICG mapping effective
Endometrial	High-risk histology prospective trial	Prospective study (n = 123); clear cell/serous/carcinosarcoma	Sensitivity 95%; FNR 5%; FNPV 1.4%	Valid even in high-risk histology
Vulvar	GROINS-V I	Prospective multicenter; T1 vulvar SCC < 4 cm	FNR 2%; low isolated groin recurrence; long-term follow-up available	Safe alternative to full lymphadenectomy in selected patients
Vulvar	GROINS-V II	Prospective; SLN-positive patients	High recurrence with RT alone for metastasis > 2 mm; protocol modified	Metastasis size guides adjuvant treatment
Vulvar	GROINS-V III	Ongoing phase II	Evaluating chemoradiation instead of lymphadenectomy for macrometastasis	Results awaited (completion expected 2029)
Ovarian	SELLY trial	Prospective multicenter; stage I-II serous ovarian cancer	Up to 25% nodal metastasis missed; ultrastaging detected additional positives	SLNB not yet reliable for routine staging
Ovarian	SENTOV	Phase II prospective feasibility (n = 20)	Mapping feasible; no major short-term morbidity	Feasible but not standard yet

FNPV: False negative predictive value; DFS: Disease free survival; DSS: Disease specific survival; SLN: Sentinel lymph node; SCC: Squamous cell carcinoma; SLNB: Sentinel lymph node biopsy; FNR: Full nodal resection; PLND: Pelvic lymph node dissection; NPV: Negative predictive value; ICG: Indocyanine green; QoL: Quality of life.

ENDOMETRIAL CANCER

Detection of metastasis in uterus-confined disease in endometrial cancer is necessary for staging; however, a complete PL does not improve survival but adds morbidity, especially in the background of unfavorable molecular subtypes[14,15]. The FIRES trial is a multicentric prospective cohort study comprising 385 endometrial cancer patients, with a primary end point of the number of patients successfully detected with lymph node metastasis on SLNB. It demonstrated a sensitivity of 97.2% and an NPV of 99.6% using ICG mapping, with only one procedure-related adverse event, establishing that SLNB is both feasible and reliable in predicting nodal metastasis. It also showed that near-infrared immunofluorescence with ICG is an effective method for stage 1 endometrial cancer of all histopathology[16]. Another randomized prospective trial studied 123 patients exclusively diagnosed with high-risk histopathology (clear cell, serous, and carcinosarcoma) and reported a sensitivity of SLNB of 95% (19/20), a false-negative rate (FNR) of 5% (1/20), and the false NPV was 1.4% (1/71)[17]. Both studies established the role of SLNB in early-stage endometrial cancer using a low-cost immunofluorescence dye, which is widely available and makes the procedure both safer and more cost-effective, establishing it as the standard of care (Table 1).

VULVAL CANCER

The SN procedure for vulval cancer is more significant, owing to the morbidity associated with complete inguinofemoral dissection. It has been studied only in the squamous type of histopathology and is therefore recommended only in this variety of carcinoma. The GROINS V trials provide strong evidence supporting SN detection with Tc99 dye as a safe alternative to complete inguinofemoral lymphadenectomy for T1 vulvar squamous cell cancer under specific conditions. In the GROINS V 1 prospective multicenter study, the FNR was 2% for tumors < 4 cm. The SN metastasis size did not predict further metastasis, allowing omission of full dissection. Long-term follow-up showed that SLN-negative patients had local recurrence rates of 24.6% at 5 years and 36.4% at 10 years, whereas SLN-positive rates were 33.2% and 46.4%. Additionally, 15.4% of SLN-negative patients required further lymphadenectomy for recurrence, with isolated groin recurrences in 2.5% (SLN-negative) and 8% (SLN-positive). A distant recurrence occurred only in SLN-positive patients (6.8%)[18]. GROINS V2 studied the efficacy and treatment-related morbidity of inguinofemoral radiotherapy in patients with positive SLNB. Initially, radiotherapy (50 Gy) was given to all SN-positive patients, but high recurrence rates were noted in those with lymph node metastases > 2 mm. Subsequently, the protocol was changed: Radiotherapy was given only for nodal metastases < 2 mm, while larger lesions received complete inguinofemoral dissection followed by radiation[19]. The findings of GROINS V I & II were incorporated into the ESGO/ESTRO guidelines; however, the SLNB is limited by the requirement of a radionucleotide scanning facility and may not be widely applicable. Therefore, studies using ICG and blue dye require further evaluation on robust trial designs, making SLNB more feasible in varied settings[20]. The GROINS V III is a multicentric, single-arm, phase 2 study commenced in 2021, with the objective of evaluating the local recurrence rate in patients presenting with macrometastasis (> 2 mm) on SLNB. The treatment protocol includes chemoradiation, consisting of a total dose of 48-50 Gy delivered in 1.8 Gy daily fractions to the inguinofemoral and external iliac nodal regions, with an additional boost to the involved inguinal site for a cumulative equivalent dose of 56 Gy over 5-6 weeks, administered in conjunction with weekly cisplatin at 40 mg/m². This study aims to assess whether chemoradiation can safely replace inguinofemoral lymphadenectomy for early-stage vulvar cancer patients with a SN macrometastasis (> 2 mm) or extracapsular extension. The main outcome is groin recurrence within two years after treatment. Data collection and analysis will finish in 2029 (Table 1)[21].

OVARIAN CANCER

The SELLY multicenter trial in stage I-II serous epithelial ovarian cancer showed that SLNB lacked sufficient sensitivity, missing up to 25% of cases with lymphatic spread. Ultrastaging improved detection, identifying 35% of node-positive cases that were otherwise overlooked[22]. The SENTOV II trial group observed the factors of technique standardization and surgeon experience as major challenges to routine SNB. In their prospective study of 20 patients, 99mTc and ICG were injected during surgical staging, and postoperative morbidity associated with the procedure was monitored for 30 days (Table 1). The results indicated that SLN mapping is feasible in early-stage ovarian cancer and has no serious short-term safety concerns[23].

OTHER GYNAECOLOGICAL CANCERS

SLNB has not been studied in vaginal cancer owing to rarity of the cancer more so in the early stage.

CONCLUSION

SLNB is a major step in oncologic surgery toward minimalism and a conservative approach without compromising on the oncological outcomes. Additionally, the current evidence establishes this procedure as the standard of care for endometrial cancers. In vulval cancer, adjuvant treatment for macrometastasis of SLN is being explored, where chemoradiation at a higher dose may replace surgery. On the other hand, frozen section for SNB is not oncologically safe in cervical cancer; dual dye (Tc99 and ICG) is the preferred and a reliable method. Ovarian cancer remains the last bastion in gynecological cancers, where minimal node resection is yet to be standardized. Ultrastaging is an essential part of the procedure, and the presence of ITCs and micrometastasis provides additional information that may be explored in future prospective studies regarding their significance in terms of recurrence and DFS in all gynecological cancers. As a procedure ultrastaging requires infrastructure and training to achieve optimal results and this can be achieved by dedicated practice of the technique.