The role of technetium-99m isotope in sentinel lymph node identification in gynecological cancers

Abstract

Sentinel lymph node (SLN) identification plays a crucial role in the diagnosis and management of gynecological cancers, particularly in the context of lymph node metastases that often remain undetectable through standard imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). Therefore, surgical assessment of lymph nodes remains an essential component of diagnostic procedures.

SLN biopsy enables the detection of small metastatic deposits while reducing the need for extensive lymphadenectomy and minimizing associated complications. Lymphoscintigraphy using technetium-99m (Tc-99m) is one of the most commonly applied techniques for lymphatic mapping and is considered the standard method for SLN identification. In clinical practice, Tc-99m is frequently combined with indocyanine green (ICG) or methylene blue (MB) to allow dual visualization. The dye method, despite its simplicity, has certain limitations, such as shorter retention time in lymph nodes and the risk of diffusion into capillaries, which may reduce detection efficiency.

Lymphoscintigraphy with Tc-99m provides precise visualization of lymphatic drainage pathways and SLNs, contributing to a more accurate determination of cancer staging and reducing the number of unnecessary lymphadenectomies. The appropriate application of this technique lowers the risk of complications, such as lymphedema, while maintaining high diagnostic accuracy.

This review summarizes current evidence on the clinical application of Tc-99m in SLN detection for gynecological cancers, analyzing both its advantages and the challenges related to its practical implementation. Additionally, it discusses the technical aspects of Tc-99m use and its role as a reliable tool for optimizing oncological outcomes.

Introduction

The lymphatic system consists of vessels and lymphoid organs, including the thymus, tonsils, lymphatic nodules, and lymph nodes. Its key roles involve maintaining fluid balance by draining excess interstitial fluid and supporting immune responses by transporting immune cells. The sentinel lymph node (SLN) is the first lymph node in a given lymphatic drainage pathway that receives lymph from a tumor site. In cases where no malignant cells are detected in the SLN, the likelihood of further metastases in additional lymph nodes is significantly reduced, often allowing surgeons to avoid extensive lymph node dissection and associated complications.

The concept of the SLN has been studied for over six decades. The first detailed observation of a sentinel node was described in 1960 by Gould and colleagues in parotid gland cancer [1]. The first clinical application of SLN biopsy was introduced by Cabanas in 1977 for the treatment of penile cancer [2]. Subsequently, in the 1970s, clinicians explored its use in diagnosing malignant skin tumors, particularly melanoma, by employing radiotracers to map lymphatic drainage [2–4]. SLN detection using technetium-99m (Tc-99m) was subsequently adopted in melanoma, where full lymphadenectomy did not show a clear survival advantage. This approach remains a standard recommendation in the National Comprehensive Cancer Network (NCCN) guidelines [6].

Further advancements in the 1990s extended SLN mapping to breast cancer. Krag et al. [7] demonstrated that Tc-99m-based SLN localization was feasible in most patients. Over time, studies confirmed that performing SLN biopsy, rather than complete lymphadenectomy, did not negatively impact survival outcomes in breast cancer patients following partial mastectomy and radiotherapy [8]. Consequently, Tc-99m lymphoscintigraphy became an integral part of SLN identification in breast oncology [9].

Although the transition from complete lymphadenectomy to SLN biopsy has led to significant improvements in reducing surgical morbidity, this shift has occurred relatively recently, and there are still ongoing debates regarding the standardization of SLN procedures, particularly in gynecological cancers. The optimal mapping technique, the accuracy of SLN biopsy in different tumor types, and the best imaging modalities for SLN detection remain subjects of active discussion. Despite accumulating evidence supporting the reliability of SLN mapping in selected cases, further studies are needed to refine protocols and address concerns about false-negative rates and the oncologic safety of omitting full lymphadenectomy.

Characteristics of technetium-99m

Technetium-99m (Tc-99m) has been widely adopted in nuclear medicine due to its favorable physical properties, making it an optimal radionuclide for diagnostic imaging [10]. With a half-life of approximately six hours, it enables high-resolution imaging while minimizing radiation exposure to patients [11]. The ideal characteristics of Tc-99m-labeled agents contribute to their effectiveness, facilitating accurate visualization of physiological and pathological processes with relatively low radiation doses [12].

Initially, unfiltered sulfur colloid with particle sizes ranging from 100 to 1000 nm was employed for SLN mapping, effectively aiding in localization [13]. In contemporary clinical practice, human serum albumin colloid with particle sizes between 50 and 200 nm is predominantly used in Europe, as it demonstrates enhanced retention within the lymph nodes due to its affinity for albumin [14].

The efficiency of Tc-99m in lymphoscintigraphy is significantly influenced by the particle size of the carrier medium, which determines its migration rate and retention within the lymphatic system [15]. The optimal particle size for interstitial lymphoscintigraphy falls within the tens of nanometers, with particles ranging from 100 to 200 nm striking a balance between effective migration and sufficient retention in the SLN [16]. Following injection, Tc-99m-labeled colloids initially move through interstitial spaces before entering the lymphatic system, where they travel toward regional lymph nodes specific to the organ of interest [17]. Within the SLN, macrophages capture these radiocolloids via phagocytosis, facilitating their retention and enabling both preoperative visualization using lymphoscintigraphy and intraoperative localization through gamma detection probes [18].

Lymph nodes regulate lymphatic drainage by possessing fewer efferent than afferent vessels, which slows lymphatic transit and contributes to the accumulation of tracers within the node [19]. The afferent vessels transport lymph into the node, where filtration occurs before it exits via efferent channels. However, in cases where the lymphatic vessels are positioned superficially on the node, the complete drainage of lymphatic fluid may be impeded, potentially leading to diagnostic inaccuracies. As described by Tanis et al. [19], this phenomenon may result in false-negative findings when cancer cells bypass the SLN and metastasize to higher-tier lymph nodes undetected.

The diagnostic reliability of SLN biopsy is determined by its sensitivity, specificity, and false-negative rate (FNR). Generally, the specificity of SLN biopsy approaches 100%, as false-positive results are rare [19]. Several key performance indicators are evaluated in SLN studies, including the detection rate (DR), which quantifies the proportion of patients in whom at least one SLN is identified. Additionally, the bilateral detection rate (BDR) refers to cases where SLNs are successfully mapped on both sides of the body. The FNR represents the proportion of patients with metastatic SLNs that remain undetected. Sensitivity is defined as the proportion of patients with a true positive SLN result among those with metastatic disease, while the negative predictive value (NPV) indicates the likelihood that a negative SLN truly lacks metastases [19]. High sensitivity and a low FNR are essential for SLN biopsy to be considered a reliable staging tool.

SLN identification in gynecologic oncology is more complex than in breast cancer or melanoma due to anatomical and lymphatic differences. Vulvar cancer (VC) was the first gynecologic malignancy for which SLN mapping gained acceptance, with ongoing research refining its application in cervical and endometrial cancer (EC) [19].

Vulvar cancer

Vulvar cancer is a rare malignancy affecting the external female genitalia, including the labia and clitoris, and is most frequently diagnosed in women over the age of 60. It accounts for approximately 0.7% of all malignant tumors in women. The prognosis in early-stage vulvar cancer largely depends on the status of the inguinal lymph nodes. The 5-year survival rate is estimated at 90% for patients with negative lymph nodes, whereas it declines to 62% in cases where metastases are present [20]. At diagnosis, nearly 30% of patients with early-stage vulvar cancer (T1/T2 < 4 cm) exhibit lymph node metastases, necessitating lymphadenectomy [20]. However, given that the risk of complications associated with complete inguinofemoral lymphadenectomy ranges from 24% to 70% [20], SLN identification and biopsy serve as an effective strategy to reduce the extent of surgical intervention, particularly in elderly patients and those with comorbidities.

The multicenter GROINSS-V study [21], which included 403 patients with vulvar cancer (T1/T2 < 4 cm) undergoing SLN identification through dual labeling with blue dye and isotope, demonstrated that in cases where the SLN was negative, inguinofemoral lymphadenectomy could be safely omitted. Among the 259 patients who did not undergo lymphadenectomy, a significant reduction in both short- and long-term postoperative complications was observed compared to those who underwent complete lymphadenectomy. Specifically, the rates of inguinal wound breakdown (11.7% vs. 34%), cellulitis (4.5% vs. 21.3%), and leg lymphedema (1.9% vs. 25.2%) were considerably lower in patients managed with SLN biopsy alone. A follow-up analysis of the GROINSS-V study [22] reported that after five years the rate of isolated groin recurrences was 2.5% in patients with negative SLNs and 8% in those with positive SLNs.

According to the European Society of Gynaecological Oncology (ESGO) guidelines, SLN detection in patients with vulvar cancer (VC) during preoperative lymphoscintigraphy requires the administration of Tc-99m-labeled colloid approximately 2 to 4 hours before surgery [23]. The tracer is injected in four separate doses, each containing 37 MBq in a volume of 0.1 ml in the single-day protocol, whereas in the two-day protocol, the activity is increased to 74 MBq per injection, with a volume of 0.2 ml. SLN identification is deemed successful when at least one sentinel node is detected and excised, while the surrounding tissue exhibits radioactivity levels below 10% of the most radioactive SLN [24].

A critical advantage of lymphoscintigraphy in VC is its ability to reveal non-standard lymphatic drainage patterns, including pathways to paraaortic or presacral lymph nodes. If SLN visualization fails during lymphoscintigraphy or the SLN cannot be identified intraoperatively, systematic lymphadenectomy is recommended [25]. However, emerging evidence suggests that selective lymph node removal from specific anatomical locations, such as the proximal obturator, intercalary, and PULT regions, may serve as an alternative to a complete side-specific pelvic lymphadenectomy in cases of failed SLN mapping [92]. Notably, the obturator fossa remains the dominant site of metastatic involvement in EC [92]. Additionally, if bilateral SLN biopsy is attempted but an SLN is not identified on one side, a complete lymphadenectomy on the affected side is advised [26].

When a vulvar cancer lesion is located near the midline, careful consideration is required before omitting bilateral lymphadenectomy based solely on lymphoscintigraphy findings. Research by Louis-Sylvestre et al. demonstrated that among 13 patients with tumors less than 1 cm from the midline, and showing unilateral lymphatic drainage on imaging, contralateral lymph node metastases were still present in three cases [27]. Similarly, in a study by Warmerdam et al. [28] analyzing 171 women treated for VC, lymphoscintigraphy failed to detect SLNs in 13 patients (7.6%). In cases where the tumor involved the midline, bilateral drainage was observed in 72.1% of patients, while the failure rate for detecting bilateral SLNs in such tumors was 27.9%, aligning with findings from other studies [29–31].

To minimize the risk of missing metastatic involvement in inguinal lymph nodes and reduce the likelihood of groin recurrence, Tc-99m radiotracer and lymphoscintigraphy should be utilized to assess bilateral drainage patterns and identify potential alternative lymphatic pathways [32].

Findings from the GROINSS-V studies [21, 22, 33] and research conducted by Wanderman et al. [38] support the notion that the risk of isolated groin recurrence remains low (2.6%) in patients with a negative SLN biopsy. This is a critical observation, as recurrence in the groin region is linked to a particularly poor prognosis. Data from Zach et al. [34] indicate that the 4-year survival rate in such cases is only 10.3%. As a result, the use of Tc-99m radiotracer and lymphoscintigraphy for SLN identification has been established as the standard of care in VC patients with clinically negative lymph nodes at early stages (T1–T2, ≤ 4 cm) [35]. This approach aligns with the most recent ESGO guidelines from 2023 [23].

Vaginal cancer

Vaginal cancer (VC) is an uncommon gynecologic malignancy, representing approximately 1–2% of all gynecologic cancers. The predominant histological type is squamous cell carcinoma, whereas less frequent subtypes include melanoma, clear cell carcinoma, and adenocarcinoma, which together account for a minority of cases. Notably, at the time of diagnosis, metastatic spread is already present in over 80% of patients with VC. Surgical intervention is considered in cases where radiotherapy has been ineffective, as well as for specific tumor types, such as non-epithelial malignancies (e.g., melanoma) or Stage I clear cell carcinoma in younger women [36].

The lymphatic drainage patterns of the vagina remain incompletely characterized. It is generally accepted that tumors in the upper third of the vagina primarily drain to pelvic and para-aortic lymph nodes via the cervical lymphatic system, while malignancies in the lower third typically spread through the vulvar lymphatic channels to the inguinofemoral nodes. However, some anatomical studies suggest that portions of the anterior vaginal wall may have direct drainage to pelvic nodes [37]. De Hullu et al. [38] reported that half of the tumors in the lower third of the vagina drained to pelvic nodes, while the remaining half showed inguinofemoral lymphatic drainage. Given these complex and variable drainage patterns, lymphoscintigraphy has emerged as a promising tool for identifying SLNs in VC. In patients undergoing primary radiotherapy, SLN mapping can provide valuable guidance for determining the optimal radiation field, ensuring the inclusion of suspicious lymph nodes [38].

Cervical cancer

Cervical cancer (CC) ranks as the fourth most frequently diagnosed malignancy among women worldwide and is also the fourth leading cause of cancer-related mortality in this population [39]. Annually, approximately 570,000 new cases of CC are reported, with an estimated 60% of affected women ultimately succumbing to the disease. While lymph node metastases occur in fewer than 20% of patients diagnosed at an early stage, their presence significantly worsens prognosis [8]. In particular, para-aortic lymph node involvement is associated with poorer survival outcomes compared to metastases confined to pelvic lymph nodes [35, 40]. Given that metastatic lymph nodes in CC are often smaller than 2 mm — comprising between 22% and 60% of detected metastases — their identification through imaging techniques such as pelvic magnetic resonance imaging (MRI) or positron emission tomography–computed tomography (PET-CT) remains challenging [41, 42]. Consequently, surgical verification via lymphadenectomy continues to be a crucial approach for staging and treatment planning [43]. Among patients with negative PET-CT results who subsequently underwent surgical evaluation of para-aortic lymph nodes, false-negative rates ranged from 8% to 22%. Notably, laparoscopic surgical staging has been deemed both safe and effective, leading to disease upstaging in over 30% of cases [44].

The role of SLN identification in CC has been investigated in multiple studies, collectively encompassing 831 patients, with findings summarized by Frumovitz et al. [45]. Across these analyses, the overall SLN DR, regardless of the mapping technique employed — whether using blue dye, Tc-99m radiotracer, or lymphoscintigraphy—was reported at 90%. The FNR was 8%, while the NPV reached 97%. When a dual-tracer approach utilizing both Tc-99m radiotracer and blue dye was implemented, the DR improved to 96%. Importantly, the DRs and NPVs were superior for tumors measuring less than 2 cm compared to larger lesions (94% vs. 84% and 99% vs. 89%, respectively).

NCCN guidelines, SLN identification serves as an alternative to pelvic lymphadenectomy in the management of early-stage CC [6]. In contrast, the ESGO guidelines restrict the use of SLN biopsy without additional pelvic lymphadenectomy to stage IA disease [46].

One of the primary advantages of lymphoscintigraphy is its capacity to identify SLNs in the para-aortic region, an area that is particularly difficult to assess surgically, especially in its supramesenteric segment [8]. Additionally, this technique facilitates the detection of SLNs in non-standard anatomical sites, such as sacral nodes [47]. The SENTICOL study demonstrated that the majority of detected SLNs were located in proximity to the external iliac nodes (60.5%), while others were found near the common iliac nodes (19.6%), within the para-aortic region (10.8%), and in the parametrium (6%). The identification of these atypical drainage routes is crucial for reducing the false-negative rate.

Despite these benefits, lymphoscintigraphy has certain limitations in precisely localizing SLNs [48]. Tc-99m-labeled colloids are typically administered in smaller volumes compared to dyes used in alternative mapping techniques, which can lead to slower tracer migration and suboptimal visualization of lymphatic pathways. Moreover, the conventional 30-minute dynamic imaging phase may be insufficient for detecting all sentinel nodes. Additionally, the resolution of planar images may not always allow for clear differentiation between adjacent lymph node groups, such as external and internal iliac nodes. Given the two-dimensional nature of standard imaging, precise spatial localization of SLNs remains challenging. To address these limitations, integrating single-photon emission computed tomography (SPECT)/CT into preoperative lymphatic system evaluation enhances SLN detection by providing three-dimensional anatomical detail, thereby improving intraoperative guidance using gamma probes [49, 50].

A meta-analysis conducted by Hoogendam et al. [51], which included patients with CC, demonstrated that SPECT/CT significantly improves SLN DRs, achieving 98.6% compared to 85.3% with conventional planar lymphoscintigraphy. The efficiency of SLN identification is also influenced by the site of radiotracer injection. Studies have shown that pericervical administration results in a higher DR than peritumoral injection, both in preoperative lymphoscintigraphy [52] and in SPECT/CT imaging [53], as well as during intraoperative SLN mapping using a gamma probe [54]. However, certain patient-related factors, such as advanced age and obesity, have been associated with an increased risk of SLN detection failure [55].

The detection of micrometastases in SLNs among early-stage CC patients is a key prognostic factor, as their presence is linked to reduced overall survival. Consequently, SLN identification and biopsy play a crucial role in staging and treatment planning for these patients [56]. Notably, a history of cone biopsy or prior chemotherapy does not preclude the feasibility of SLN biopsy [45]. The advent of laparoscopic gamma probe technology has facilitated a minimally invasive approach to SLN detection. This advancement is particularly beneficial in cases where chemoradiotherapy is planned, as it allows treatment to commence immediately after surgery, circumventing the standard 4–6-week delay.

Despite its clinical utility, SLN identification and biopsy have not yet been universally adopted as the gold standard for CC staging. The long-term oncologic safety of this approach remains an area of ongoing investigation. Several prospective studies — SENTIX [57], PHENIX [58], and SENTICOL III [59] — are currently underway to evaluate the oncologic outcomes and validate the effectiveness of SLN biopsy in CC management.

Endometrial cancer

EC represents the most frequently diagnosed malignancy of the female reproductive tract in developed nations [60]. The presence of pelvic or para-aortic lymph node metastases significantly worsens prognosis, with five-year survival rates ranging from 44% to 52% [61]. Notably, approximately 90% of EC cases are diagnosed at an early stage, and despite lymph node involvement occurring in fewer than 20% of patients, systematic lymphadenectomy remains a common practice. However, this procedure carries a substantial risk of complications, particularly in obese individuals and those with multiple comorbidities. As a result, SLN mapping has emerged as a potential alternative, offering the possibility of omitting extensive lymphadenectomy even in high-risk cases, thereby reducing the incidence of post-surgical complications such as lower limb lymphedema.

The lymphatic drainage of EC primarily involves three regions: two within the pelvis and one para-aortic basin. A study conducted by Baiocchi et al. [62], which examined 236 patients with high-risk advanced-stage EC, compared SLN detection using the patent blue dye technique (n = 75) with conventional lymphadenectomy (n = 161). Findings indicated that SLN mapping led to the identification of twice as many metastatic lymph nodes as lymphadenectomy (26.7% vs. 14.3%, p = 0.02). The SLN DR reached 85.3%, while the BDR was recorded at 60%. The sensitivity of SLN mapping was 90%, with a NPV) of 95.7%, corresponding to a FNR of 4.3%.

A Swedish study evaluating robot-assisted surgery in 257 patients with high-risk EC demonstrated that the application of their SLN detection protocol using indocyanine green (ICG) resulted in a sensitivity and NPV of 100%, along with a BDR of 95% [63]. Furthermore, research conducted by Koh et al. at Memorial Sloan-Kettering Cancer Center introduced an optimized SLN detection algorithm aimed at reducing the false-negative rate, ultimately achieving a decrease to 2% [64].

NCCN has endorsed SLN mapping for patients with EC confined to the uterus, provided there is no radiological evidence of extrauterine disease [64]. These guidelines also support SLN identification in high-risk, early-stage EC, including histologic subtypes such as serous carcinoma, clear cell carcinoma, and carcinosarcoma [64]. The preferred approach for SLN mapping in EC involves tracer injection at the cervix, as anatomical studies have shown that the tracer disseminates through the uterine vessels, isthmus, parametrium, and uterine corpus [65]. Deeper injections may also facilitate migration to para-aortic lymph nodes via the infundibulopelvic ligament. The selection of an optimal tracer for SLN mapping remains a subject of ongoing research. Tc-99m radiocolloid has been shown to offer distinct advantages over dye-based methods in challenging anatomical conditions, particularly in cases involving extensive manipulation of the retroperitoneal space. In such scenarios, dyes frequently leak from lymphatic vessels, complicating the visualization of SLNs. In contrast, Tc-99m provides enhanced stability and enables precise localization through gamma probe detection, ensuring reliable SLN identification even under less favorable surgical conditions [90].

As early as 1996, Burke et al. [66] described the use of lymphazurin blue dye for SLN identification in EC, reporting an increased intraoperative SLN DR when the tracer was injected the day prior to surgery in a two-day protocol (DR 80%) compared to a single-day protocol (DR 62%) [67]. In Tc99m-based lymphoscintigraphy, radiolabeled nanocolloid albumin may be administered on the day of surgery (short protocol) or one day prior (long protocol). The short protocol involves injecting a radiotracer dose of 0.2–1.0 mCi up to six hours preoperatively, followed by lymphoscintigraphy approximately 30 minutes post-administration. The long protocol, in contrast, requires a dose of 2.0–4.0 mCi when administered the previous day [68]. Given that Tc99m is eliminated via renal and hepatobiliary pathways, dosage adjustments are necessary in patients with renal or hepatic impairment.

Findings from the multicenter SENTI-ENDO study further support the efficacy of the long protocol in lymphoscintigraphy, demonstrating higher SLN DRs compared to the short protocol (DR 80.3% vs. 68.2%, p = 0.02). Additionally, the long protocol facilitated the identification of SLNs in atypical lymphatic drainage sites, such as para-aortic and sacral nodes, in 30.5% of cases. Notably, para-aortic metastases were more frequently detected in patients undergoing the long protocol [68].

The integration of single-photon emission computed tomography with computed tomography (SPECT/CT) in lymphatic mapping enhances anatomical precision, aiding both surgeons and nuclear medicine specialists in the intraoperative identification of SLNs [69]. The incorporation of CT imaging allows for improved attenuation correction, effectively minimizing background noise and reducing false-positive signals, particularly in cases where radioactivity accumulates in dilated lymphatic vessels [70]. This imaging modality proves especially valuable for distinguishing lymph nodes in close proximity to one another and for pinpointing SLNs located near the tracer injection site, where radiation scatter can obscure visualization [71]. Research indicates that SPECT/CT significantly enhances the accuracy of SLN topography and facilitates the detection of lymphatic drainage to nonstandard anatomical sites [72].

For patients with EC classified as Stage I or II, SPECT/CT has been associated with superior overall and SLN BDRs compared to standard lymphoscintigraphy [73]. García et al. [74] reported an SLN DR of 77.8% using SPECT/CT, which was higher than the 73.7% achieved with planar lymphoscintigraphy in patients diagnosed with EC stages IA–IIIA. Similarly, findings from Belhocine et al. [75] indicated that SPECT/CT identified additional SLNs not visualized by conventional planar imaging, with a recorded false-negative rate of 0%.

Studies utilizing SPECT/CT for SLN detection in EC have reported instances where visualization failure was more frequent when radiotracer accumulation was notably high in organs such as the liver, spleen, and bone marrow, independent of whether the tracer was administered via cervical or tumor injection [76]. The established propensity of nanocolloids to localize within these organs following intravenous administration suggests that a portion of the radiotracer may be diverted through vascular rather than lymphatic pathways [77]. Elevated uptake in the bone marrow, in particular, indicates significant venous drainage, potentially attributable to localized tissue damage at injection sites, which can contribute to unsuccessful SLN detection [68, 76].

Various elements influence the adequacy of lymphatic drainage, including the choice of short or long injection protocols, tumor-specific factors, patient-related characteristics, and the level of surgical expertise. Research by Khoury-Collado et al. [78] demonstrated that achieving an SLN DR exceeding 90% with a false-negative rate of 0% required the completion of approximately 30 procedures. Factors such as advanced patient age (≥ 70 years), obesity (BMI > 40), anatomical irregularities in the pelvic region, adhesions, and lymphatic vessel disruption have been identified as potential impediments to effective SLN identification [78,79]. While larger tumor size is often considered a risk factor for SLN detection failure, some investigations have found no statistically significant impact of tumor size on DRs [80]. Similarly, tumor histology—including endometrioid, clear cell, and carcinosarcoma subtypes — does not appear to markedly influence SLN detectability [74, 77]. However, the extent of myometrial invasion may hold clinical relevance [74]. Additionally, the size of metastasis within the SLN serves as a prognostic factor, with a threshold of 2 mm below which the risk of metastasis to non-SLN sites is considered minimal [81]. Notably, despite the widespread adoption of SLN mapping, there is still a lack of studies investigating its correlation with the molecular classification of EC. Given the increasing recognition of molecular profiling as a key determinant in EC management, further research is needed to evaluate whether specific molecular subtypes influence SLN DRs or metastatic patterns [91]. Multiple studies affirm the role of lymphatic mapping and SLN detection in EC, utilizing Tc99m-labeled colloids alone or in conjunction with blue or green dyes [82, 83].

Ovarian cancer

Ovarian cancer (OC) ranks among the most frequently diagnosed gynecologic malignancies, predominantly affecting women between the ages of 40 and 70. In early-stage disease, standard surgical management includes systematic pelvic and para-aortic lymphadenectomy. However, considering the substantial risk of postoperative complications associated with extensive lymph node dissection, the identification of SLNs is being explored as a potential alternative approach.

A prospective investigation known as the MELISA study [84] assessed the SLN DR and diagnostic accuracy of this technique in early-stage epithelial OC. The study protocol involved injecting 0.2 ml of Tc99m-labeled nanocolloid albumin (37 MBq) and 2 mL (2.5 mg/ml) of indocyanine green into the infundibulopelvic and utero-ovarian ligaments. SLNs were successfully identified in 90% of cases (27 patients), yielding an overall DR of 89%. Notably, para-aortic drainage was the predominant lymphatic pathway, observed in 26 out of 27 patients. These findings indicate that SLN mapping and detection could serve as a viable alternative to comprehensive lymphadenectomy for patients diagnosed with early-stage OC.

Ultrastaging for sentinel nodes, micrometastases and isolated tumour cells

Standard histopathological assessment of SLNs may not always detect micrometastases. Ultrastaging, which involves deeper sectioning and immunohistochemical staining, enhances diagnostic accuracy and improves metastatic DRs.

Recent studies have refined ultrastaging protocols to improve reproducibility and standardization. Chiang et al. (2024) proposed updated guidelines emphasizing consistent sectioning techniques, systematic use of keratin markers, and digital pathology tools to enhance detection reliability [89]. These refinements aim to minimize interlaboratory variability and improve risk stratification for patients with EC.

Previous studies have shown that ultrastaging increases micrometastasis DRs. Kim et al. (2013) identified micrometastases or isolated tumor cells (ITCs) in 4.5% of EC patients through ultrastaging, with a lower DR (0.8%) in cases lacking myometrial invasion [85]. Naoura et al. (2015) reported a higher DR (41%) in poorly differentiated tumors [86].

The prognostic impact of micrometastases is well established, with studies indicating a 20% reduction in both 8-year overall survival (OS) and recurrence-free survival [87, 88]. While micrometastases in SLNs often necessitate adjuvant therapy, ITCs are not currently considered a decisive factor for treatment modification in early-stage EC. However, with evolving ultrastaging methods, including those outlined by Chiang et al. (2024), future changes in treatment recommendations may emerge [89].

Conclusions

Technetium-99m remains one of the most effective and widely used methods for sentinel lymph node (SLN) detection in gynecological cancers, particularly in vulvar cancer, where it is considered the gold standard. Due to its high sensitivity and ability to precisely map the lymphatic system, Tc-99m plays a crucial role in the accurate staging of gynecologic malignancies, allowing for the detection of microscopic metastases and reducing the need for extensive lymphadenectomy.

Despite the growing interest in alternative techniques, such as fluorescence-guided mapping with indocyanine green (ICG) or blue dye methods, Tc-99m remains a superior option in complex anatomical conditions, particularly in cases where extensive retroperitoneal manipulation compromises lymphatic integrity. Additionally, its combination with SPECT/CT has further enhanced detection accuracy, particularly in non-standard drainage pathways.

Given the continuous evolution of SLN mapping, further refinement of Tc-99m-based techniques is warranted to optimize its diagnostic performance and expand its applicability across all gynecologic malignancies. Future research should focus on standardizing SLN detection protocols, improving tracer retention within lymph nodes, and integrating molecular classification into the nodal assessment process. By advancing these methods, Tc-99m will continue to serve as a reliable and indispensable tool in gynecologic oncology, ensuring accurate staging while minimizing surgical morbidity.