Surgical Research Progress of Sentinel Lymph Node Biopsy in Melanoma

Abstract

Malignant melanoma is a highly aggressive tumor, and lymph node metastasis significantly impacts the prognosis and treatment of this condition. Sentinel node biopsy, as a less invasive alternative to traditional dissection, offers convenience, safety, and improved efficiency in assessing local lymph node status. It provides valuable staging information and aids in determining appropriate follow-up treatment. The evolution and enhancement of technical and conceptual aspects associated with sentinel node biopsy have transformed the management of malignant melanoma. Notably, several large multicenter trials have challenged the necessity of complete lymph node dissection, leading to a paradigm shift. While some controversy remains, the standard of care for melanoma is progressing toward a consensus.

Keywords:

• Melanoma
• sentinel lymph node
• biopsy
• staging
• surgical research progress

Subject classification codes:

• Plastic surgery
• cancer
• surgical technique

Background

Malignant melanoma is a highly malignant tumor that originates from melanocytes and commonly affects the skin, mucosa, and other regions [1]. Melanoma exhibits marked malignancy, with a propensity for early lymphatic and hematogenous metastasis, rendering it virtually incurable following distant spread [2]. As the skin cancer with the highest mortality rate, melanoma’s diagnosis, treatment, and prognosis significantly rely on accurate tumor staging. Distinguishing between early-stage (stage I and II) and late-stage (stage III and above) tumors primarily depends on identifying the presence of lymphatic metastasis in patients [2]. Research has shown that preoperative negative imaging does not exclude the possibility of lymph node metastases [3,4]. For many years, lymph node dissection has been the standard for staging and treating melanoma. It was previously believed that early-stage tumors required prophylactic lymph node dissection, even in the absence of clinical signs of local lymph node metastasis [5,6]. Nonetheless, the majority of patients do not experience lymph node metastasis, rendering lymph node dissection unnecessary and exposing patients to avoidable complications [7,8]. In 1992, Morton and Cochran introduced the concept of sentinel lymph node biopsy (SLNB) [9]. The sentinel lymph node (SLN) represents the first group of lymph nodes to which melanoma metastasizes through the lymphatic system. SLNB involves the removal and pathological examination of SLNs in melanoma patients, enabling the determination of lymph node status without subjecting patients to unnecessary risks associated with lymph node dissection. While SLNB is widely acknowledged as the most effective method for evaluating regional lymph node involvement, its standardization remains incomplete, influenced by variations in perception across different time periods, institutions, and medical professionals [10–12]. In recent years, there has been rapid progress in the systemic therapy of melanoma. New targeted therapy drugs, including vemurafenib, dabrafenib, and trametinib, as well as immune drugs such as pembrolizumab and nivolumab, have gradually been implemented in clinical practice [13,14]. As an important basis for treatment and staging, studies on SLNB continue to emerge, this paper aims to review diverse perspectives and advancements in the field.

Indications

Indications for sentinel lymph node biopsy (SLNB) still vary among different institutions and guidelines, but most of them consider tumor Breslow thickness as the primary evaluation criterion [15].

According to the European Society for Medical Oncology (ESMO) 2019 guidelines, SLNB should be performed for melanoma except for lesions with a Breslow thickness less than 0.8 mm and no ulcerations.

The American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) conducted a systematic review and meta-analysis of over 25,000 patients from multiple centers spanning 21 years. In their published guidelines from 2021, they recommended SLNB for melanoma with a Breslow thickness of 1.0–4.0 mm. For melanoma with a Breslow thickness greater than 4.0 mm, SLNB may be considered if it aids in staging or local disease control. SLNB can also be considered for melanoma with a Breslow thickness less than 1.0 mm but with high-risk factors for ulceration or a mitosis rate of ≥1 mitoses/mm², especially in cases where the Breslow thickness ranges from 0.75 to 0.99 mm.

In the 2022 Edition 3 guidelines of the National Comprehensive Cancer Network (NCCN), recommendations are based on the likelihood of positive SLN pathology. For melanoma with a Breslow thickness greater than 1.0 mm, the probability of a positive SLN is usually greater than 10%, and SLNB is recommended. Melanoma with a Breslow thickness of 0.8–1.0 mm or less than 0.8 mm, combined with ulcerations or other adverse features (such as a mitotic rate of >2 mitoses/mm², lymphovascular invasion and younger age), has a positive SLN probability of 5–10%. Therefore, SLNB can be considered in such cases. For lesions with a Breslow thickness less than 0.8 mm and without ulcerations or other adverse features, SLNB is not recommended unless the stage is uncertain, as the probability of a positive SLN is less than 5% (Table 1).

Table 1. Indications in different guidelines.

	Breslow thickness (mm)
	<0.8	0.8–1.0	1.0–4.0	>4.0
ASCO, SSO	Considered		Yes	Considered
NCCN	No	Considered	Yes
ESMO	No	Yes

However, approximately 85% of SLNB yield negative results and do not contribute to therapeutic interventions [16]. Moreover, SLNB procedures carry the risk of complications and higher costs. Therefore, it is crucial to obtain precise risk estimates to minimize healthcare costs and optimize treatment decisions while maintaining safety. Based on the clinicopathological (CP) characteristics and gene expression profiles (GEP) of patients, new methods have been developed to predict the probability of SLNB positivity as well as the risk of recurrence or death. CP-GEP demonstrates the ability to identify patients diagnosed with primary cutaneous melanoma who are at a high risk of disease recurrence, particularly among those with stage I/IIA disease. Therefore, as an adjunct to SLNB or as an alternative when SLNB is not feasible, CP-GEP possesses the potential to emerge as a promising risk stratification tool. However, according to the NCCN guidelines, currently available GEP tests should not replace the pathological staging procedure used to determine eligibility for SLNB or to guide clinical decision making in such patients [17–21]. Furthermore, numerous studies have been dedicated to predicting the risk of melanoma patients and diminishing the reliance on SLNB. This signifies a progressive decrease in the necessity for SLNB. In the foreseeable future, novel technologies are anticipated to autonomously forecast disease risk and offer valuable treatment recommendations and prognoses, thereby circumventing a multitude of complications associated with surgery [10].

Significance of SLNB

The traditional perspective regarding the SLN is that it functions as an intermediate station in the process of “orderly” metastasis from the primary tumor site to a distant location. It has been believed that removal of the SLN can disrupt this spread. However, recent studies indicate that the SLN, as the most crucial prognostic factor, should be utilized as an indicator of tumor properties, particularly the potential for metastasis [10]. This represents a significant paradigm shift, which can be attributed to three landmark studies.

MSLT-I involved 1347 patients with melanoma and Breslow thickness ranging from 1.2 to 3.5 mm between 1994 and 2002 [22]. The patients were divided into two groups: the SLNB group and the observation group. Immediate lymphadenectomy was performed for patients with micro-metastasis identified in the SLNB group, while the observation group underwent delayed lymphadenectomy upon lymph node recurrence. The results revealed that the 3-year and 5-year melanoma-specific survival (MSS) rates were similar between the SLNB group and the observation group. However, the 5-year disease-free survival (DFS) rate was higher in the SLNB group compared to the observation group. Furthermore, SLNB-negative patients demonstrated significantly higher 5-year DFS and MSS rates compared to SLNB-positive patients. These findings demonstrate the prognostic value of SLNB in melanoma. In addition to MSLT-I, 314 patients with high thickness (>3.5 mm) melanoma were enrolled. And the enrolled patients were followed up for a longer period of time. Similarly, results published in 2014 demonstrated that there was still no statistical difference in the 10-year melanoma-specific survival (MSS) rates between the SLNB group and the observation group. However, the 10-year disease-free survival (DFS) rate was higher in the SLNB group compared to the observation group. Furthermore, in the intermediate-thickness melanoma group, 10-year MSS rates were significantly higher in SLNB-negative patients than in SLNB-positive patients. Similarly, in the high thickness group, 10-year MSS rates were also higher in SLNB-negative patients. Morton also discovered that the histopathological status of the SLN (tumor load) was an independent prognostic factors as well as Breslow thickness, ulceration, and primary tumor site. As a supplement to MSLT-I, studies have shown that the above conclusions are also applicable to thin thickness (<1.0 mm) melanoma [23,24].

Controversial CLND

After the publication of the MSLT-I study results, immediate complete lymph node dissection (CLND) was recommended for all patients with confirmed regional lymph node metastasis through SLNB. However, with the rapid development of systemic therapies, controversy has emerged regarding the therapeutic efficacy of SLNB and whether SLNB-positive patients should undergo immediate CLND, considering the risk of complications.

The MSLT-II study included 1939 patients from 34 centers worldwide who underwent SLNB and were randomly assigned to either the immediate CLND group or the serial ultrasound surveillance group [25]. Following a 3-year follow-up period, the results, published in 2017, demonstrated that although the CLND group exhibited a higher rate of local control of lymph node recurrence compared to the observation group, it did not improve the 3-year MSS and DFS while increasing the occurrence of lymphedema. While immediate CLND in SLNB-positive patients can confirm clinical staging and enhance local control of regional lymph nodes, it does not offer a survival benefit to patients [26].

The DeCOG-SLT study, published in 2019, analyzed 1269 SLNB-positive patients from 41 centers in Germany between 2006 and 2014. The study revealed similar survival rates between the CLND group and the observation group, indicating that CLND is not recommended for patients with lymph node metastasis diameter <1 mm [27].

Era after MSLT-II and DeCOG-SLT

Since the results of MSLT-II and DeCOG-SLT were released, some of the studies reached the same conclusion as the two studies, and some of the conclusions can be used as a supplement to the conclusions of MSLT-II and DeCOG-SLT [28].

In a study conducted by Parvez et al., involving 1176 patients from four Canadian centers, no correlation was found between CLND and improved survival. However, they observed that younger patients and those with larger nodal deposits were more inclined to choose CLND [29]. Conversely, Castle et al. suggested that several characteristics were associated with an increased likelihood of undergoing CLND, including male gender, thicker lesions, rural/urban residence, younger age, fewer comorbidities, and treatment at higher-volume centers [30].

A separate study by Blankenstein et al., which involved 2581 patients from the Netherlands, demonstrated that the performance of SLNB staging did not alter the disease outcome for patients with advanced melanoma (stage IIIC or IV) [31].

Farlow et al. conducted a study on patients with head and neck melanoma who had experienced treatment failure [32]. They found that SLN was less predictive of head and neck melanoma compared to other anatomical sites. This observation might be attributed to the fact that tumor transmission in the head and neck region occurs through hematogenous routes rather than lymphatic pathway [33,34].

Of course, there is some controversy about these conclusions [35]. The proportion of patients with heavy tumor load in the MSLT-II study is lower, and many patients have positive results detected by RT-PCR, different from the lymph node evaluation method taken in previous retrospective studies, which may influence the statistical results to some extent, and it is difficult to determine the safety of regional lymph nodes in patients without regular follow-up. As well as patients who were not treated in a lymph node ultrasound facility in a timely manner and were lost to follow-up, this study may be limited. Another part of the controversy is that head and neck melanoma is excluded from DeCOG-SLT and underrepresented in MSLT-II studies.

In terms of tumor load, there are significant differences between European and American populations and Asian populations. Asian melanoma cases are characterized by slightly lower incidence, deep infiltration, high incidence of ulcerations, and high positive rate of SLN. According to the European and American viewpoints, further verification and research are needed to determine whether the treatment method of SLN-positive patients giving up immediate completion of CLND and serial ultrasound surveillance is suitable for all types of patients, especially Asian patients [36].

In fact, overall, multiple studies from around the world have shown a decrease in the number of melanoma patients treated with CLND after a positive SLN following the publication of MSLT-II and DeCOG-SLT results [37–40].

Valuable pathological information

Histopathology serves as the primary diagnostic method for melanoma, and immunohistochemical staining plays a crucial role in its identification. SLNs are fixed in formaldehyde and embedded in paraffin for analysis, while frozen section analysis should be avoided. SLNs are examined using standard hematoxylin and eosin (H&E) staining and immunohistochemical staining (e.g. HMB45 and S100). When reporting on sentinel and regional nodes, it is important to include the total number of nodes detected, the number of metastatic nodes, the largest tumor dimension, the location within the lymph node, and the presence of extramural involvement in the lymph nodes. Molecular assays related to targeted therapy should cover essential genes such as BRAF, CKIT, and NRAS. It is crucial to integrate the pathological diagnosis with clinical evidence, which includes a comprehensive understanding of the patient’s medical history and imaging examinations. Numerous studies conducted at various institutions and large multi-center international clinical trials have consistently demonstrated the prognostic significance and clinical value of the SLN pathological status, establishing it as a vital independent predictor of prognosis [40].

Pathological information pertaining to regional lymph nodes also constitutes a critical basis for tumor staging. In the eighth edition of the American Joint Committee on Cancer (AJCC) staging system, the N staging is further refined to encompass both the number and extent of lymph nodes affected within the tumor area, as well as the extent of metastasis beyond the nodal region. The presence of microsatellites, satellites, or in-transit metastases is classified as N1c, N2c, or N3c, respectively, based on the cumulative count of regional lymph nodes affected. Microsatellite metastases are defined as any microscopic lesions adjacent to or deep but noncontiguous with the primary tumor. Satellite metastases, on the other hand, refer to cutaneous or subcutaneous metastases occurring within 2 cm of the primary lesion but not directly connected to it. In-transit metastases are generally characterized as those located more than 2 cm away from the primary lesion, within the region spanning between the primary lesion and the regional lymph node basin [41].

Technical progress for locating lymph nodes

Biological dyes, such as methylene blue and isosulfide blue, are subcutaneously injected at multiple points 10–20 min before surgery. Following the injection and local massage, blue-stained lymph nodes become visible in the lymphatic drainage area. This method has been employed in clinical practice for over 30 years. It is simple, cost-effective, visible to the naked eye, and non-radioactive. However, due to its low molecular weight and limited residence time in lymph nodes, its imaging effect is not significant, and its accuracy and detection rate are often suboptimal. Furthermore, the injection of biological dyes may cause local pain, allergies, and residual staining [42,43].

Radionuclide scanning: The characteristics of the lymphatic drainage pathway can only provide an anatomical reference for SLNB. The accuracy and detection rate of the biological dye method are limited, necessitating the use of radionuclide scanning for SLN detection. Commonly used radionuclide tracers include ⁹⁹Tc^m-labeled sulfur colloid, rituximab, dextran, Tilmanocept, and other suspensions [44]. These tracers take advantage of the phagocytosis and clearance function of macrophages, exhibiting prolonged residence time in the SLN. However, tumor invasion can disrupt the function of these macrophages, hindering their uptake of radioactive tracers. Typically, the tracer is intradermally injected at 4–5 sites surrounding the biopsy site before SLNB. Imaging examinations are conducted 15–30 min after injection to acquire dynamic or static imaging data. It is important to note that the time interval between radionuclide scanning and SLNB should not exceed 12 h [45]. Imaging examination should cover all known lymphatic drainage areas as well as potential drainage areas. For example, lower extremity lesions require examination of popliteal, groin, and iliac fossa lymph nodes for radionuclide uptake, while upper extremity lesions should include examination of the elbow and axilla. In cases where lymphatic drainage is complex, such as lesions in the head, neck, and trunk, SPECT/CT imaging is recommended as an adjunct to planar imaging. Following SLN localization, mark the SLN position on the body surface. During SLNB surgery, samples are excised and removed with the assistance of a gamma nuclide detector, ensuring that the detection value of each spot in the operative field after surgery does not exceed 10% of the highest value before resection [46].

Radionuclide scanning and Biodye Combination: The use of radionuclides in combination with biodyes remains a topic of debate. Several studies have demonstrated that while the success rate of biological dyes is lower than that of radionuclide scanning alone, the combination of these two techniques yields a higher success rate compared to their individual applications. Moreover, the utilization of biological dyes facilitates intraoperative localization of SLNS (sentinel lymph nodes). Conversely, other studies have shown that the combined approach does not enhance the positive detection rate when compared to radionuclide scanning alone. Additionally, some researchers have speculated that this outcome may be influenced by the surgeon’s level of experience in performing the procedure [42,43].

Fluorescence imaging, particularly the utilization of indocyanine green (ICG) and near-infrared fluorescence (NIRF), was first introduced by Fujiwara et al. in 2009 for SLNB to reduce the false negative rate and enhance regional lymph node management [47]. ICG, a small tricarbocyanine dye, binds to albumin in lymph after intradermal injection, thereby reducing photon absorption and scattering and improving tissue penetration under near-infrared spectroscopy. NIRF imaging, characterized by its lower background interference and deeper tissue penetration, offers a sensitive, rapid, noninvasive, high-resolution, real-time in situ imaging method, widely employed in studying disease mechanisms and evaluating efficacy [48]. The NIRF imaging system detects infrared-excited ICGs 10–15 mm beneath the skin, enabling the tracking of lymphatic pathways bound to the ICG. This method carries no radiation risks and has an anaphylaxis probability of only 0.05% (compared to 1.1% with methylene blue injection). Its visual characteristics facilitate accurate positioning, effectively reducing tissue damage, and the risk of surgical complications. While radionuclide scanning is limited in cases of head and neck melanoma due to dense scan signals caused by proximity of the primary lesion to the draining lymph nodes, the ICG combined with NIRF method is more suitable for complex drainage patterns in head, neck, and trunk lesions, thanks to its lower background interference and visualization of lymphatic pathways [49]. Apart from ICG, other novel tracers, such as the radioactive fluorescent tracer ICG-⁹⁹Tc^m-Nanocolloid, are yet to see extensive clinical use [50]. In summary, fluorescence imaging offers radiation-free, rapidly evolving, dynamic observation capabilities, serving as a valuable supplement to traditional methods. Nonetheless, further studies are required to explore various aspects including injection location, dose, and development time.

Recently, new techniques based on carbon nanoparticles have been tried to locate lymph nodes in other cancers, but more practice is needed in melanoma [51].

Conclusions

The malignant nature of melanoma is significant, and timely diagnosis and intervention can result in a favorable prognosis for the majority of early-stage patients (stage I and stage II). In recent decades, significant progress has been made in melanoma research, revolutionizing the treatment landscape for melanoma patients. Complete lymph node dissection, and even sentinel lymph node biopsy, are no longer obligatory choices. Novel localization and tracer techniques implemented in clinical practice have enhanced the efficiency and accuracy of sentinel lymph node biopsy. Furthermore, the emergence of gene testing, targeted drugs, immunotherapy, and other cutting-edge technologies has paved the way for a multidisciplinary combined treatment model. This model integrates surgical intervention with adjuvant therapy, making it a prominent approach in melanoma treatment, instilling new hope in melanoma patients [52,53].

Disclosure statement

No potential conflict of interest was reported by the authors.