Evaluation and management of regional nodes in primary cutaneous melanoma

INTRODUCTION — Cutaneous melanoma is the deadliest form of skin cancer due to its ability to metastasize, with the regional lymph nodes as the most likely initial metastatic site. The surgical management of patients with primary cutaneous melanoma includes wide excision of the primary tumor and selection of an approach to the regional nodal basin(s) at risk for metastatic disease. Accurate staging (table 1A-B) is important to assess prognosis and treatment options. While a consensus has emerged on many major areas of management, optimal management for some issues remains uncertain.

The initial approach to the regional nodal basin(s) is informed by whether the patient has clinically negative nodes or clinically apparent or suspicious nodal disease at presentation. (See "Staging work-up and surveillance of cutaneous melanoma" and "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

The evaluation and management of the regional lymph nodes in patients with primary cutaneous melanoma is reviewed. Surgical excision of the primary tumor and adjuvant therapy are discussed separately. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

CLINICALLY NEGATIVE REGIONAL LYMPH NODES

Approach to the patient — Most patients with primary cutaneous melanoma do not have clinically detectable nodal metastases at the time of diagnosis. In the United States, over 85 percent of patients with melanoma present with clinically localized disease [1]. Although outcomes in this group are generally quite good, because of the enormous number of patients in this category, most melanoma-related deaths over time occur among such patients. Identification of patients with localized melanoma who benefit from further evaluation and treatment is therefore critical to decreasing melanoma mortality overall.

The risk of occult nodal involvement can be estimated using characteristics of the primary tumor, and this assessment largely informs the appropriate approach to managing regional lymph nodes. Validated tools including multiple clinical and pathologic variables can help determine the risk of occult nodal metastasis [2]. (See 'Rationale for surgical staging' below and 'Patient selection' below.)

●Low risk for nodal metastases – Patients at low risk for nodal metastasis can be managed with wide excision of the primary melanoma and clinical monitoring of the regional nodes. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

●Increased risk for metastases – In addition to wide excision of primary melanoma, those at increased risk are generally managed with concomitant lymphatic mapping and sentinel lymph node biopsy (SLNB) to stage the regional nodal basins at risk for metastatic disease. (See 'Lymphatic mapping and sentinel lymph node biopsy' below.)

Rationale for surgical staging — Surgical staging of regional lymph nodes is a component of therapy for patients with clinically localized melanoma. In addition to wide excision of the primary melanoma, patients with an increased risk for occult nodal disease generally undergo SLNB to stage the regional nodal basins. Using this approach, most regional nodal metastases can be detected before they become clinically apparent. The rationale for performing the procedure includes the need for accurate staging regional disease control, reducing morbidity, and informing selection of patients for adjuvant therapy. Early identification and resection of nodal metastases is also associated with improved long-term survival, but this rationale is controversial. SLNB was also historically used to identify patients with occult regional metastasis who would be offered and might benefit from regional lymphadenectomy of the tumor-involved regional nodal basin, but this management strategy has almost completely fallen out of favor because of the outcomes of clinical trials [3,4].

Accurate staging — Complete staging, including pathologic status of the sentinel lymph node (SLN), when appropriate, provides an accurate determination of prognosis and appropriate selection for further management.

The landmark Multicenter Selective Lymphadenectomy Trial-I (MSLT-I) was the largest trial to address the role of lymphatic mapping with SLNB in determining prognosis and its impact on survival [5]. The MSLT-1 trial demonstrated improved melanoma-specific outcomes for biopsy-positive patients who underwent SLNB to stage nodal disease compared with observation and lymphadenectomy when nodal disease became clinically apparent [5,6]. Ten-year disease-free survival was significantly higher in the biopsy group compared with the observation group (intermediate thickness [1.2 to 3.5 mm]: 71.3 versus 64.7 percent, hazard ratio [HR] 0.76, 95% CI 0.62-0.94; thick melanoma [>3.5 mm]: 50.7 versus 40.5 percent, HR 0.70, 95% CI 0.50-0.96).

For patients deemed to have sufficient risk for nodal involvement to recommend SLNB (see 'Patient selection' below), pathologic nodal status is a powerful prognostic indicator [7]. This is true for all primary tumor thicknesses and the effect is independent of other variables including ulceration status and mitotic rate. On multivariate analysis of data from MSLT-1, sentinel-node status was the strongest predictor of disease recurrence or death from melanoma [5,6]. Among patients with intermediate thickness melanoma (1.2 to 3.5 mm), 10-year melanoma-specific survival was significantly reduced for those with compared with those without metastases (62 versus 85 percent, HR 3.1, 95% CI 2.12-4.49). Among patients with thick melanomas (>3.5 mm), melanoma-specific survival was 48 versus 65 percent (HR 1.75, 95% CI 1.07-2.87), respectively. Prognostic factors associated with reduced survival included positive SLN status, increasing primary melanoma thickness, presence of ulceration, and melanoma located on the trunk.

The precision of regional nodal staging allowed by SLNB improves outcome prediction compared with complete lymph node dissection (ie, formal lymphadenectomy in the absence of known clinical or occult regional node basin metastasis) and has resulted in improved accuracy in the current American Joint Commission on Cancer Eighth edition melanoma staging system (table 1A) [8,9]. (See "Staging work-up and surveillance of cutaneous melanoma" and "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

Regional disease control — Removal of SLN metastases also provides effective regional disease control for most patients. MSLT-I demonstrated that microscopic involvement of the SLN predicted outcomes for intermediate-thickness primary melanoma (1.2 to 3.5 mm) [5]. Among patients with nodal metastases, five-year survival was improved for those who underwent immediate lymphadenectomy compared with those who had delayed lymphadenectomy. The subsequent Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) provided additional information on management [10]. About 80 percent of patients with a positive SLN who were observed never developed regional nodal recurrence during long-term follow-up, demonstrating that all nodal metastases were removed at the time of the SLNB. (See 'Negative sentinel lymph node biopsy' below and 'Positive sentinel lymph node biopsy' below.)

Reduced morbidity — Complete lymph node dissection (CLND) is associated with significant complications including wound complications (eg, lymphocele, hematoma, infection) and chronic extremity lymphedema, which reduces quality of life [4,5,11-18]. Reducing morbidity by eliminating of the need for CLND in most SLN-positive patients is another strong potential benefit of the procedure. In the MSLT-II trial, the incidence of lymphedema was significantly higher in patients who underwent immediate lymph node dissection (24.1 versus 6.3 percent) [13]. Similarly, in the DeCOG-SLT trial, adverse events occurred in 13 percent of the CLND group, with lymphedema (20 of 32) and delayed wound healing (5 of 32) as the most common complications, underscoring that CLND is not a benign procedure [4,14,15].

Selection for adjuvant therapy — Many patients with nodal metastases identified by SLNB are offered or recommended systemic adjuvant therapy with PD-1 inhibitor or BRAF/MEK targeted therapy. Some patients may not require adjuvant therapy, but complete consideration of its use generally requires knowledge of the pathologic status of the SLN. However, some patients with high-risk node-negative melanomas (Stage IIB/IIC) may be eligible for adjuvant treatment in the absence of sentinel lymph node information. The decision to proceed with treatment may be substantially affected by complete prognostic assessment. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

Lymphatic mapping and sentinel lymph node biopsy — Lymphatic mapping is based upon the concept that lymphatic channels follow general patterns; however, the specific pathway for a given site on the skin cannot be accurately predicted. Mapping that drainage to identify the sentinel lymph node(s) will identify the mostly likely first site of metastasis within a given lymph node basin (figure 1). If the sentinel lymph node(s) are not involved with tumor, the entire lymph node basin is likely to be free of tumor [19-21].

Patient selection — Selection of patients for lymphatic mapping and SLNB is based primarily on the risk of nodal metastases, but also the patient’s fitness for surgery, and overall treatment goals [22-29]. The first of these can be assessed based on the pathological characteristics of the primary melanoma and clinical characteristics of the patient. Patients undergo lymphatic mapping and SLNB based on their estimated risk of nodal metastases from either the AJCC stage (ie, tumor thickness (table 1A-B)) or by using a validated prediction tool (eg, AJCC, MSKCC, MIA). In general, SLNB is recommended for patients with a nodal metastasis risk of >10 percent, while it is a consideration for those with risks between 5 and 10 percent, and not recommended for those with risks <5 percent. Methods for quantifying this risk vary among different sources.

Primary tumor characteristics — Tumor thickness is the most widely used pathological feature for determining which patients may be offered or recommended SLN biopsy. Beyond thickness, however, there is less agreement on what constitutes a high-risk feature.

●Tumor thickness – Guidelines recommend lymphatic mapping and SLNB for patients with melanomas more than 1 mm in thickness (T2) [22]. For patients with melanomas 0.8 to 1 mm in thickness (T1b), SLNB is suggested, based on a full assessment of the patient and their risks and preferences. For melanomas <0.8 mm in thickness, SLNB is generally not recommended unless other high-risk features are present. In a review of 7568 patients, less than 5 percent of those with a melanoma <0.8 mm thick had a positive SLNB, compared with 5 to 12 percent in those with melanoma 0.8 to 1.0 mm thick [9]. (See "Staging work-up and surveillance of cutaneous melanoma" and "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Tumor thickness'.)

●Other pathological features – Other pathological features have been associated with higher risk for regional nodal metastasis including primary tumor ulceration, a high mitotic rate, and the presence of primary tumor lymphovascular invasion. These features are generally uncommon among truly thin melanomas, and the presence of one or more of these characteristics with a thin tumor thickness measurement confers risk.

●Histologic subtype – Melanoma histologic subtype has also been associated with risk of nodal metastasis with desmoplastic melanomas (particularly "pure" desmoplastic melanomas) having a much lower rate of nodal metastasis [30,31]. Lentigo maligna melanomas have also been associated with lower rates of nodal metastasis.

●Gene expression – Finally, gene expression profiling is an emerging technology for melanoma evaluation and some such assays have been reported to predict nodal metastasis risk, although additional validation of these reports is required to determine where they fit in the overall evaluation.

Patient characteristics — The main patient characteristic is age, with older patients having a lower risk of SLN tumor involvement when controlling for primary tumor features, despite a worse melanoma-specific prognosis overall [32]. Some series have also reported that male patients have a higher risk for regional nodal recurrence compared with female patients, though a similar increase in SLN metastasis rates has generally not been found.

Melanoma risk assessment tool — Several methods have been developed that use a combination of patient and tumor characteristics to help clinicians predict the risk of sentinel lymph node metastasis (eg, National Comprehensive Cancer Network, American Society of Clinical Oncology/Society of Surgical Oncology, Memorial Sloan Kettering Cancer Center online nomogram [MSKCC] [33,34]). One system developed at the Melanoma Institute Australia (MIA) in collaboration with The University of Texas MD Anderson Cancer Center modified the MSKCC model [2,35]. The MIA melanoma Risk Assessment Tool uses six parameters: age, tumor thickness, melanoma subtype, mitoses/mm², ulceration, and lymphovascular invasion, and is available online [36]. In a comparison of models, this tool significantly reduced the number of patients undergoing unnecessary SLNB compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity.

Preoperative lymphatic imaging

Lymphoscintigraphy — We generally obtain lymphoscintigraphy prior to SLNB for melanoma for all patients. Preoperative lymphoscintigraphy can be performed on the same day as planned surgery, or it can be performed in advance. If lymphoscintigraphy is performed in advance of surgery, repeat intradermal injection of radiotracer is performed after the induction of general anesthesia along with the intradermal injection vital blue dye. (See 'SLNB timing and technique' below.)

Injection of the radiotracer enables the use of intraoperatively gamma counting probes to identify and ensure removal of SLNs. Different radiotracers are used in different parts of the world; sulfur colloid and tilmanocept, both conjugated to technetium, are the agents approved for use in the United States.

The technique for injection of the radiotracer is important for accurate mapping. The goal of the injection is to fill the lymphatic channels available to the primary tumor cells, which requires intradermal infiltration surrounding the primary tumor site. Injection of these agents into the subcutaneous tissue is not effective due to the markedly lower number of lymphatic channels at that depth, as well as the risk of inadvertent intravenous injection that can result in hepatic and/or splenic radiotracer uptake.

Early dynamic images are obtained as well as later static images to determine the direction of drainage and location of SLNs. In areas of ambiguous drainage such as from melanomas arising on the trunk or head and neck region, imaging all potential basins is important. In addition, ectopic and interval basins should be imaged as well (eg, popliteal, epitrochlear, intermuscular triangular space of the back, etc) [37].

At most centers, planar images are obtained, but there is evidence that single-photon emission computed tomography (SPECT)/CT imaging may be beneficial [38]. This is most likely to be important in areas where drainage is complex drainage including the head/neck and perineum. The more precise localization provided by SPECT/CT imaging may also facilitate intraoperative identification of the SLN.

SLN locations demonstrated on imaging can be marked on the skin with the help of a hand-held gamma probe.

Failure to identify SLNs after injection should be a very uncommon occurrence. Several techniques can be used if no node is seen initially. These include:

●Repeat intradermal injection of the tracer and gentle massage of the injection site to facilitate lymphatic transit. If no nodal localization persists preoperatively, the at-risk basins should also be evaluated using the gamma probe at the time of surgery, as nodes will often be found using that approach after additional post-injection time has passed.

●If no localization has been found by the time of the operation and repeat intradermal injection did not yield regional basin radiotracer uptake, the basin can be re-evaluated intraoperatively, as an SLN is sometimes able to be found at operation. If no node can be found in the operating room, the basin should be observed potentially with the assistance of ultrasound during follow-up, rather than performing lymph node dissection [39].

Role of ultrasound — Regional nodal basin ultrasound has been used at some centers before lymphatic mapping and SLNB imaging to identify regional nodes suspicious for metastatic disease. However, most centers have not reported preoperative ultrasound to be useful and the Multicenter Selective Lymphadenectomy Trial-II reported a sensitivity of 6.6 percent despite performance by experienced operators at melanoma-focused centers [40]. Ultrasound sensitivity was increased for thicker primary tumors (11.9 percent for melanomas with tumor thickness >4 mm).

Patients with nodal metastases detected prior to SLNB using ultrasound generally have not been included in contemporary neoadjuvant therapy trials and additional data are needed to clarify optimal management of these patients.

SLNB timing and technique — A comprehensive approach to the operation including both lymphoscintigraphic and intraoperative findings is likely to yield optimal identification and harvest of SLNs. Optimal use of SLNB techniques including radiotracer and dye injection as well as identifying, dissecting, and handling the sentinel lymph nodes requires adequate training and experience.

Timing relative to wide excision — Whenever possible, lymphatic mapping and sentinel node biopsy are ideally performed in the same operative setting as the wide excision of the primary melanoma. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Wide excision'.)

However, some patients are referred for consideration of SLNB after wide excision of their primary tumor has already been done. Additional and more extensive surgery may be required to accomplish accurate lymph node staging by SLNB in patients with a prior wide excision, including the possible removal additional lymph nodes.

Importantly though, the same SLNB technique can generally be used, and SLNs can be successfully identified and accurately reflect the status of the regional lymph node basin. In several studies, prior wide excision did not appear to adversely impact the ability to detect lymphatic metastases, although the utility of the procedure in patients who had prior extensive reconstruction of the primary excision site has not been widely studied and may indeed be reduced [41-43].

Intradermal dye/radiotracer injection — Patients proceed to surgery either on the day of the preoperative lymphoscintigram or on or a subsequent day. (See 'Lymphoscintigraphy' above.)

We routinely inject dye as part of a combined modality approach (ie, along with radiotracer), although some surgeons rely solely on radiotracer uptake activity to identify and harvest the SLN(s). The visual cue provided by the dye is often helpful in limiting extent of dissection at the time of surgery.

Isosulfan blue is commonly used in the United States. Some centers use methylene blue, although this agent has been associated with skin necrosis at the injection site if not entirely removed as part of the wide excision [44]. Rare allergic reactions to blue dye can occur but appear to be less frequent than the use of blue dye for lymphatic mapping for breast cancer.

Prior to positioning and prepping the patient, intradermal dye/radiotracer is injected depending on the timing of lymphoscintigraphy.

●Same day lymphoscintigraphy performed – If same-day lymphoscintigraphy was performed, prior to positioning and prepping the patient:

•Confirm the location of the SLN on imaging to ensure the site can be reached during the procedure. Confirmation of the absence of activity at basins without drainage should also be done. For patients with multiple basin drainage, particularly for primary melanomas located on the back, intraoperative repositioning of the patient may be required during the procedure.

•Inject the vital blue dye intradermally at the primary tumor site. Generally, 0.5 to 2 mL of dye is sufficient. Frequently, blue-stained dermal lymphatic channels can be seen at the time of injection. With proper injection technique, massaging the primary tumor injection site is usually not required.

●Same day lymphoscintigraphy not performed – If same-day preoperative lymphoscintigraphy was not performed, inject the vital blue dye intradermally at the primary tumor site as above, and also inject the radiotracer using the same intradermal approach.

Biopsy and specimen handling — The site of one or more SLNs is usually approached before wide excision of the primary tumor, as this approach maintains maximal continuity of the lymphatics and in case reinjection of blue dye or radiotracer is needed. Overall, repeat injection is infrequent. However, identification of the SLN may sometimes be facilitated by removal of the primary tumor site (via wide excision) when a site is located closely to the primary injection site, due to the very high counts at that site (so-called radiotracer "shine through"). Using a collimator on the gamma probe may reduce shine through.

All nodal basins that demonstrate radiotracer uptake should be sequentially approached, and "in-transit" or interval regions between the primary tumor and the draining nodal basin(s) should also be scanned to ensure complete removal of all SLNs. Rescanning with use of the gamma probe is also generally performed after wide excision of the primary tumor has been performed to ensure identification and removal of any SLN whose location may have been obscured by the radiotracer activity related to injection sites.

The SLN(s) should be handled carefully as it is dissected and removed. The capsule of the SLN should not be too firmly grasped, as this may tear and disrupt the most likely location of small metastatic deposits. It is useful to note the activity of the SLN at the time of removal. The basin should be examined again visually and with the gamma probe to identify any residual foci of activity. Any nodes that are blue or radioactive should be considered sentinel nodes and removed for pathologic evaluation. How radioactive a node must be to be considered "hot" remains somewhat a matter of judgement.

Pathologic examination — After removal, SLNs are sent for pathological evaluation. We recommend that a thorough evaluation of the primary tumor biopsy site for the presence of possible residual primary tumor intact component as well as pathologic assessment by a pathologist trained in the evaluation of melanomas to ensure an accurate description, and for example, to identify transection of the base of the primary tumor, if present, such that the lesion may be thicker than measured from the biopsy alone. As significant changes in the diagnosis, tumor classification, and/or staging may be identified, we recommend histopathological review of cutaneous melanocytic lesions by an expert dermatopathologist [45].

Frozen section analysis of SLNs is not recommended, as it is substantially less accurate than permanent section with immunohistochemistry, it sacrifices some diagnostic tissue in processing of the sections, and knowledge of the result rarely leads to a change in surgical management (eg, CLND) at the time of SLNB [46].

Pathological evaluation of the nodes should involve multiple sections. Areas of particular interest in the node include the area with blue staining or greatest radioactivity, which may be marked intraoperatively. Staining by hematoxylin and eosin and by multiple immunohistochemical stains should be performed. These stains vary, but typically include some combination of S100, Melan-A/MART-1, Sox-10, and/or HMB45.

●SLN tumor burden – For patients with cutaneous melanoma, there is no minimum threshold of tumor burden for staging as node-positive (in distinction to the criteria used, for example, in breast cancer). However, the amount of tumor contained in the SLN, so-called SLN tumor burden, which should be noted in the pathology report, is highly correlated with clinical outcomes [47]. Although multiple approaches to estimating SLN tumor burden have been proposed, maximum diameter of the largest SLN tumor deposit is most widely used. In addition, the location of the tumor within the node (subcapsular, parenchymal, combined) is also useful in determining prognosis for patients with SLN metastases.

●False negatives – A small number of SLNBs will be falsely reported as negative even with optimal technique. In the MSLT-I, for example, 3.4 percent of patients with a negative SLNB subsequently relapsed in the regional lymph nodes [5]. A similar rate of relapse was observed in a report from MD Anderson Cancer Center [48]. Ten of 243 patients (4.1 percent) with histologically negative sentinel lymph nodes subsequently developed nodal recurrence in the previously mapped basin. Reexamination of the original pathologic material using serial sections and/or immunohistochemical staining identified melanoma in the sentinel nodes in 8 of these 10 patients. Immunohistochemical staining for the melanoma markers S100, HMB45, or Melan-A/Mart-1 further enhances sensitivity, detecting 1 melanoma cell in 100,000 cells compared with 1 in 10,000 cells with routine hematoxylin and eosin stains (H&E).

Subsequent management

Negative sentinel lymph node biopsy — Until recently, patients with a negative SLNB (ie, no tumor identified, in the sentinel lymph node) were only followed clinically to identify recurrence. Patients with a negative SLN (ie, no tumor identified in the SLN) are at lower risk for melanoma recurrence compared with patients with identical clinicopathological features in whom the SLN contained tumor. This should be particularly true for nodal recurrences in the SLN basin, although patient with microsatellites or in-transit melanoma have a risk for additional regional recurrence. Patients at high risk for recurrence (Stage IIB/IIC) may receive adjuvant therapy. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'High-risk node-negative disease (stage IIB and IIC)'.)

MSLT-I demonstrated that microscopic involvement of the sentinel lymph node was a significant predictor of outcomes [5,6]. In the intermediate-thickness melanoma group, melanoma-specific survival was significantly improved for those who underwent SLNB compared with those initially observed (62.1 versus 41.5 percent, hazard ratio [HR] 0.56, 95% CI 0.37-0.84). The 10-year distant disease-free survival rate was also significantly improved in this subset of patients (54.8 versus 35.6 percent, HR 0.62 95% CI 0.42-0.91). In the thick melanoma group, melanoma-specific survival at ten years was similar between the two treatment approaches (58.9 and 64.4 percent for lymphatic mapping with SLNB and observation groups, respectively, HR 1.12, 95% CI 0.76-1.67). The distant disease-free survival rate was also similar (45.3 versus 43.8 percent, HR 0.96, 95% CI 0.56-1.64). There were too few events to analyze those with thin melanomas (<1.20 mm).

Positive sentinel lymph node biopsy — In the past, it was standard practice to perform a CLND of the basin containing the metastatic SLN. However, most patients who underwent CLND did not have any metastases in the remainder of their regional nodes. Since CLND is also associated with greater morbidity than SLNB, the added value of SLN was questioned, leading to two multicenter clinical trials evaluating its utility, MSLT-II and DeCOG-SLT [4,13].

Observation versus CLND — The MSLT II and DeCOG-SLT evaluated the utility of CLND relative to observation of the basin including nodal ultrasound in follow-up. The trials showed that CLND provided improved in-basin disease control and additional prognostic information, but no benefit in terms of distant metastasis-free survival or melanoma-specific survival. As a result, nodal observation is the standard, preferred option when clinical observation is possible. While CLND adds some prognostic information and decreases the risk of nodal recurrence, this is balanced by increased morbidity in the absence of survival benefit. In practice, extremely few patients today are recommended to have a CLND.

●MSLT II – In the MSLT-II trial, 1934 patients with a positive SLNB (primary melanoma ≥1.20 mm or greater, Clark level III, IV, or V, regardless of Breslow thickness or a primary tumor with ulceration) were randomly assigned to completion node dissection (CLND) or observation [13]. In the observation group, CLND was performed if there was evidence of regional lymph node recurrence. Melanoma-specific survival was similar for immediate CLND and observation (86 percent, adjusted HR 1.08, 95% CI 0.88-1.34). Disease-free survival at three years was improved for patients managed with immediate CLND (68 versus 63 percent), reflecting the lower rate of recurrence in regional lymph nodes. Although melanoma-specific survival was worse in patients with thicker primaries, ulceration of the primary tumor, or positive nonsentinel nodes, no subgroup was identified for whom immediate CLND provided a benefit.

About 80 percent of observed patients with SLN metastases in MSLT-II never developed regional nodal recurrence during long-term follow-up, demonstrating that all nodal metastases were removed at the time of the SLNB [10]. On multivariate analysis, freedom from regional nodal recurrence was associated with age younger than 50 years, thinner primary melanoma (<1.5 mm), SLN metastasis diameter less than 1 mm, and SLN area less than 5 percent. Basin disease-free rates for increasing numbers of risk factors (age 50 years or older, ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5 percent or greater) at five years were:

•No risk factors – 96 percent

•One risk factor – 89 percent

•Two risk factors – 86 percent

•Three risk factors – 80 percent

•Four risk factors – 61 percent

•Five or six risk factors – 54 percent

●DeCOG-SLT – In the multicenter DeCOG-SLT trial, 483 patients with cutaneous melanoma affecting the trunk or extremities were randomly assigned to immediate CLND or observation including ultrasound of the primary site and appropriate lymph node basins [4,14]. Most patients had low-volume metastasis in the sentinel lymph node. In the final analysis with a median follow-up of 72 months, more regional lymph node metastases occurred in the observation arm compared with CLND (16.3 versus 10.8 percent), but the difference was not significant [4]. Distant metastasis-free survival (primary endpoint), relapse-free survival and overall survival at five years were similar between the groups [4,14,15])

Adjuvant therapy and follow-up — Patients with SLN metastases have an increased risk for regional and distant recurrence and should be considered for additional therapy and for follow-up with increased intensity. Patients with negative SLN have a more favorable prognosis, although those with high-risk primary melanomas (Stage IIB/IIC) still have a significant risk. Trials have demonstrated improved recurrence free survival for patients with Stage IIB/IIC disease when treated with programmed cell death receptor 1 (PD-1) blockade and they may also be considered for adjuvant therapy [49,50]. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma" and "Staging work-up and surveillance of cutaneous melanoma".)

Regardless of whether patients undergo systemic therapy, follow-up of patients with SLN metastases is generally more intense than that of patients with negative SLNs. Observed nodal basins should be evaluated with nodal ultrasound in addition to physical exams and any other routine imaging. Recommendations for routine imaging vary across institutions. For SLN positive patients, the rate of true positive imaging at the time of initial treatment is low, but such scans may form a baseline for subsequent comparison. Cross-sectional imaging may include CT of the chest, abdomen, and pelvis, and/or positron emission tomography and possibly magnetic resonance imaging of the brain. The clinical utility of such surveillance is not well defined, but the rationale has increased with the advent of more effective systemic therapies. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Surveillance'.)

CLINICALLY APPARENT REGIONAL LYMPH NODES — Patients who present with clinically apparent regional lymph node involvement that is confirmed cytologically (fine-needle aspiration or core biopsy) or histologically, either at the time of diagnosis or over the course of follow-up, are generally managed with wide excision of the primary tumor and dissection of the involved lymph nodal basin, a procedure known as therapeutic lymph node dissection (TLND). (See 'Therapeutic lymph node dissection' below.)

Patients with clinically detectable nodal metastases have a greater risk for concomitant distant metastases and systemic radiographic staging should be considered prior to therapeutic intervention such as lymph node dissection.

Role of neoadjuvant therapy — There has been much interest in neoadjuvant systemic treatment of patients with macroscopic regional nodal metastases. Some preclinical data suggest systemic checkpoint immunotherapy may be more effective if initiated prior to surgical resection. It also clearly provides an in vivo assessment of response and may decrease the extent of surgery required. At present, neoadjuvant therapy has been largely limited to clinical trials, and enrollment on such trials is strongly supported by the authors. Clinical evidence from the SWOG S1801 trial showed improved relapse-free survival for patients who received preoperative (neoadjuvant) and postoperative (adjuvant) PD-1 blockade compared with those who receive only postoperative anti-PD-1 treatment [51]. These results suggest neoadjuvant immunotherapy may be a reasonable standard option for patients who are candidates for it. While the neoadjuvant approach is not yet available in some places outside of a clinical trial, some guidelines have accepted it as a standard option [22]. Where guidelines address the issue, dissection after systemic therapy should include the planned extent (ie, complete dissection) rather than a more limited dissection, the latter of which is the subject of ongoing clinical trials.(see "Adjuvant and neoadjuvant therapy for cutaneous melanoma")

Therapeutic lymph node dissection

Indications — Therapeutic lymphadenectomy is performed for patients with macroscopic regional nodal metastases. Since the extent of nodal involvement and the location of all involved nodes cannot be reliably predicted preoperatively, the lymphadenectomy should include the entire nodal basin as defined by its anatomic boundaries.

●Synchronous primary and nodal disease – Patients presenting with synchronous primary and nodal disease are generally managed with wide excision and TLND. Partial dissection or lymph node sampling is generally not done because of the propensity of melanoma to spread microscopically to other nodes in the basin.

●Nodal disease with unknown primary melanoma – Patients with nodal disease without a known primary melanoma, so-called "metastatic melanoma" can be managed like those with a known primary. Approximately 10 to 20 percent of patients presenting with clinical nodal melanoma metastases do not have an identifiable primary site. This type of presentation has been associated with similar or more favorable outcomes compared with patients presenting with nodal disease and a synchronous primary skin melanoma [52-54]. In the absence of distant metastases, these are considered stage III. It has been hypothesized that this group may represent patients with primaries that had completely regressed or were treated without biopsy using topical treatments and forgotten, or had primary nodal melanoma based on malignant transformation of nodal nevi. Exome sequencing studies in patients with unknown primaries generally show a mutation pattern consistent with cutaneous melanoma with evidence of characteristic driver mutations and evidence of sun damage-related mutations. A thorough examination of these patients (including any appropriate potential mucosal primary sites) should be undertaken. However, in many cases no primary site will be found.

●Recurrence after treatment of primary melanoma – Patients with recurrence after treatment of prior primary melanoma undergo lymph node dissection.

Specific nodal basins — Therapeutic lymph node dissection carries a moderate risk of short- and long-term morbidity [11,12]. The risk for complications varies by nodal basin which is discussed below for each nodal basin. Complications are more common after inguinal lymph node dissection (for lower extremity lesions or truncal melanoma with inguinal drainage) than after axillary nodal dissection. For both the axillary and inguinal nodal dissection, lymphedema is one of the most concerning long-term morbidities.

Cervical/parotid — If there is evidence of involvement of parotid nodes (figure 2A-B), dissection includes superficial parotidectomy [55].

In the cervical basin, the primary long-term risk is related to nerve injury. Resection of some sensory branches of the cervical plexus is common, but the resulting numbness of the neck or upper chest is generally very well tolerated. Preservation of the greater auricular nerve is desired, as ear numbness is more frequently noticed by patients.

Careful preservation of motor nerves is important and should be done whenever possible. Nerves at risk include the facial nerve (all branches when a superficial parotidectomy is included, and the marginal mandibular branch without), the spinal accessory nerve, the phrenic nerve, and the hypoglossal nerve.

While a chylous leak is possible with injury to the thoracic duct, they are generally self-limited with drainage.

Axillary — Axillary node dissection is performed for upper extremity melanomas or truncal melanomas with lymphatic drainage to the axilla. For axillary node dissections, this should generally include the level III nodes. The morbidity of axillary dissection includes short- and long-term complications. Common short-term complications include wound infection and breakdown, seroma formation, and shoulder dysfunction after axillary dissection. Long-term complications include lymphedema and paresthesias.

Inguinal — Inguinal node dissection is performed for lower extremity melanoma or truncal melanoma with lymphatic drainage to the groin.

Dissection of the inguinal basin is associated with the highest complication rates for both acute wound breakdown, dehiscence, or infection, as well as long-term limb edema [16,56]. Risk factors include obesity and macroscopic nodal involvement. Minimally invasive (videoscopic) dissection has been explored as a means of decreasing acute morbidity, but its effect on long-term morbidity has not been well established [11,12].

The need for dissection of iliac/obturator nodes in the case of inguinal metastases has long been debated since it is not clear whether the addition of a more extensive dissection improves survival [57,58]. The addition of deep groin dissection significantly increases the risk of lymphedema. For these reasons, in general, there has been significant evolution away from routine deep groin dissection. In this era of more effective systemic therapy, we generally reserve consideration of deep groin dissection for those with the presence of radiographic disease.

Numerous criteria for inclusion of those deeper locations have varied across institutions. One such criterion has been the presence of macroscopic disease in the superficial basin. Others include the presence of disease in three or more superficial nodes or suggestive imaging. The reliability of these indicators has varied across multiple studies. In general, in this era of more effective systemic therapy, we generally reserve consideration of ilio-obturator dissection for the presence of radiographic disease.

Patients undergoing inguinal node dissection may benefit from compression support stockings for at least six months postoperatively. Prevention of lymphedema is critical since established lymphedema requires lifelong treatment. (See "Clinical staging and conservative management of peripheral lymphedema", section on 'At risk for postoperative lymphedema'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Regional lymph node evaluation – The overall approach to the regional nodal basin(s) in patients with primary cutaneous melanoma is informed by whether the patient presents with clinically negative or clinically apparent or suspicious regional nodal disease. (See 'Introduction' above.)

●Clinically negative regional lymph nodes — Most patients with primary cutaneous melanoma do not have clinically detectable nodal metastases at the time of diagnosis. Selected patients undergo lymphatic mapping and sentinel lymph node biopsy (SLNB) based on their estimated risk of nodal metastases from either the AJCC stage (table 1A-B) or by using a validated prediction tool (eg, AJCC, MSKCC, MIA). (See 'Patient selection' above.)

•For patients with either AJCC stage T2 or an estimated risk of nodal metastases >10 percent, we recommend performing SLNB.

•For patients with either AJCC stage T1b or an estimated risk of nodal metastases of 5 to 10 percent, SLNB is an option and a detailed discussion with the patient is needed to discuss the potential risks and benefits.

•For patients with either AJCC stage T1a or an estimated risk of nodal metastases <5 percent, we suggest not performing SLNB.

●Lymphatic mapping and SLNB – Regional nodal staging is based on the concept that lymphatic channels follow general patterns; however, the specific pathway for a given site on the skin cannot be accurately predicted. Lymphatic mapping identifies the mostly likely first site of metastasis (ie, sentinel lymph node[s]) within a given lymph node basin. If the sentinel lymph node(s) are not involved with tumor, the entire lymph node basin is likely to be free of tumor. (See 'Lymphatic mapping and sentinel lymph node biopsy' above.)

•SLNB is ideally performed at the same time as wide excision of the primary melanoma lesion. For patients who have already undergone wide excision, SLNs can generally be successfully identified and accurately reflect the status of the regional lymph node basin; however, more extensive surgery may be required.

•We generally obtain lymphoscintigraphy prior to SLNB for all patients, preferably on the same day as surgery. Lymphoscintigraphy involves intradermal injection of a radiotracer at the site of the primary melanoma site with subsequent imaging. A gamma counting probe is also routinely used intraoperatively to detect the radiotracer and identify the SLNs. Prior to surgery, we confirm the location of the SLN(s) on imaging to ensure drainage and that the site(s) receiving radiotracer uptake activity can be reached during the procedure.

•We routinely inject a vital blue dye intradermally in the operating room as part of a combined modality approach to SLNB (ie, along with radiotracer). Combined with intraoperative use of a gamma probe, the visual cue provided by the dye facilitates identification of the SLN(s) and may help limit extent of nodal basin dissection at the time of surgery.

●Subsequent management – Subsequent management depends on the pathology of the SLN(s). (See 'Subsequent management' above.)

•Negative SLNB – Patients with a negative SLNB (ie, no tumor identified in the sentinel lymph node) are followed by careful clinical observation to identify recurrence. The risk of recurrence is lower than that of patients with identical clinicopathological features with a positive SLNB.

•Positive SLNB – For patients with a positive SLNB, we suggest careful clinical observation coupled with ultrasound surveillance of the nodal basin rather than immediate completion lymph node dissection (CLND) (Grade 2C). Therapeutic CLND and/or evaluation for neoadjuvant therapy may be indicated if there is subsequent evidence of regional lymph node recurrence in the absence of distant metastases. (See 'Subsequent management' above.)

●Clinically apparent regional lymph nodes — For patients who present with clinically apparent regional lymph node involvement confirmed cytologically or histologically (AJCC stage III), neoadjuvant immunotherapy initiated prior to surgical resection may become a reasonable standard option for patients who are candidates. The extent of surgery required may decrease for patients who have an excellent response. When lymph node dissection is indicated, we perform complete regional lymphadenectomy rather than partial dissection or lymph node sampling. The extent of nodal involvement and the location of all involved nodes cannot be predicted reliably preoperatively. (See 'Therapeutic lymph node dissection' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Michael D Stone, MD, who contributed to an earlier version of this topic review.