INTRODUCTION — Surgical excision is the appropriate treatment for primary melanoma. Although resection usually controls the primary lesion, melanoma often metastasizes through lymphatic channels to regional lymph nodes. Accurate staging at diagnosis is important to assess the prognosis and determine whether the patient would benefit from adjuvant therapy or is eligible for clinical trials (table 1A-B). (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)
The physical examination of regional lymph nodes is often inaccurate, since approximately 20 percent of clinically node-negative patients have metastatic involvement, and 20 percent of those patients with clinically positive nodes have pathologically negative basins. More definitive information about the status of the regional nodes can be obtained from ultrasound-guided fine-needle aspiration or sentinel lymph node biopsy (SLNB) [1,2].
The staging of subclinical disease using lymphatic mapping followed by SLNB, the management of patients with a positive SLNB, and the management of clinically apparent regional lymph nodes will be reviewed here. The surgical management of the primary lesion 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
Sentinel lymph node biopsy — Lymphatic mapping with sentinel lymph node biopsy (SLNB) is the standard approach for the management of patients with melanoma in whom there is a significant risk of regional node metastasis. This approach provides important prognostic information and permits the identification of patients with a positive sentinel lymph node who may be candidates for adjuvant therapy. Proper application of this technique requires sufficient experience to identify the sentinel lymph nodes and ensure a low false negative rate.
Rationale — Lymphatic mapping is based upon the concept that sites of cutaneous melanoma have specific patterns of lymphatic spread and that one or more nodes are the first to be involved with metastatic disease within a given lymph node basin (figure 1). If the sentinel lymph nodes are not involved, the entire basin is highly likely to be free of tumor [3-5].
Knowledge of the regional lymph node status is important for several purposes [6,7]:
●To determine prognosis
●To select patients who may benefit from adjuvant therapy
●To select candidates for clinical trials
Tc-99 can be used for both preoperative mapping and for sentinel node identification in the operating room using a hand-held gamma probe [3,8]. The technique for SLNB is discussed elsewhere. (See "Imaging studies in melanoma", section on 'Lymph node evaluation'.)
Lymphatic mapping is particularly useful to identify one or more lymph node basins draining from primary sites located in areas of ambiguous and possibly multiple nodal basin drainage. These areas include the trunk, head and neck, and distal extremities. Dynamic lymphatic flow studies have shown that ambiguous and multidirectional flows are common [9,10].
While a learning curve exists for the technical aspects of SLNB, the importance of a coordinated and consistent approach, including surgeon, nuclear medicine clinician, and pathologist cannot be overstated.
The use of this approach for head and neck melanomas is more difficult because of the complexity of the lymphatic drainage patterns and the frequent need to remove sentinel nodes from the parotid gland, thereby risking damage to the facial nerve. That being said, sentinel nodes can be identified in 95 percent of cases with appropriate imaging techniques . (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Head and neck'.)
Sensitivity and specificity — In early studies the sentinel lymph node was identified in 75 to 90 percent of cases. A positive non-sentinel lymph node (found by planned completion lymph node dissection) despite a negative sentinel lymph node was found in 1 to 2 percent. In subsequent studies, SLNB was followed by completion lymph node dissection only if the sentinel node contained tumor. In a literature review and meta-analysis involving a much larger subsequent experience, sentinel nodes were successfully identified in 97 to 98 percent of patients. The frequency of metastases in the sentinel node was similar to the frequency of regional disease observed in earlier studies .
The false negative rate in a meta-analysis that included data on 25,000 patients in 71 studies was 12.5 percent . The false negative rate needs to be distinguished from the negative predictive value (the number of patients with a negative SLNB who do not recur divided by the total number of patients with a negative SLNB), which depends upon the patient population studied.
The test characteristics for SLNB are illustrated by results from the Sunbelt Melanoma Trial . In this trial, 59 patients had a late regional lymphatic recurrence and 486 had a positive SLNB for an overall false negative rate of 11 percent but a negative predictive value of 97 percent for that patient population.
Multicenter Selective Lymphadenectomy Trial-I — The landmark Multicenter Selective Lymphadenectomy Trial-I (MSLT-I) is the largest trial to address the role of lymphatic mapping with SLNB in determining prognosis and its impact on survival [14,15]. The subsequent Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) provides important information on the management of patients found to have a positive sentinel lymph node. (See 'Multicenter Selective Lymphadenectomy Trial-II' below.)
The final results of the MSLT-I confirmed the role of lymphatic mapping with SLNB as a prognostic tool. Furthermore, the trial demonstrated a significant melanoma-specific survival advantage in those patients with intermediate-thickness melanoma with microscopic lymph node involvement who were assigned to lymphatic mapping with SLNB and underwent early regional lymphadenectomy, compared with those managed with wide excision of the primary melanoma followed by observation without lymphatic mapping and SLNB. The conclusions of the MSLT-I are also supported by the larger, retrospective series of 5840 patients in the Melanoma Institute Australia database treated between 1992 and 2008 .
In the MSLT-I, 2001 patients were randomly assigned to lymphatic mapping with SLNB (60 percent) or to observation (40 percent) between 1994 and 2002 .
●Patients randomly assigned to lymphatic mapping with SLNB underwent immediate completion lymphadenectomy if a histologically positive node was identified, while those with a negative SLNB were observed and underwent therapeutic lymphadenectomy if there was clinical evidence of subsequent nodal recurrence.
●Individuals assigned to observation had a therapeutic lymphadenectomy only if there was clinical evidence of nodal recurrence.
The final report of the trial was published in 2014, and was based upon 10-year follow-up .
Prognostic significance of the sentinel node — The presence of microscopic involvement of the sentinel lymph node at presentation was a significant predictor of subsequent relapse in patients with intermediate or thick primary melanomas. There were too few events to analyze in those with thin melanomas.
●For patients with intermediate-thickness melanoma (1.2 to 3.5 mm), the melanoma-specific survival rate at 10 years was significantly worse in patients with lymph node involvement compared with those who had a negative SLNB (62 versus 85 percent, hazard ratio [HR] 3.09, 95% CI 2.12-4.49).
●For patients with thick melanoma (>3.50 mm), the melanoma-specific survival rate at 10 years was significantly worse in patients with lymph node involvement compared with those who had a negative SLNB (48.0 versus 64.6 percent, HR 1.75, 95% CI 1.07-2.87).
Intermediate-thickness melanomas — The primary study group was defined as the 1347 patients with intermediate-thickness melanomas (1.2 to 3.5 mm), which was the group thought to be most likely to benefit from lymphatic mapping with SLNB . In this group, lymphatic mapping with SLNB resulted in a significant improvement in melanoma-specific survival in those patients found to have lymph node involvement.
Incidence of nodal metastases — The cumulative incidence of regional lymph node involvement in patients with intermediate-thickness melanoma was similar in the two groups :
●Among the 770 patients randomly assigned to lymphatic mapping with SLNB, a positive lymph node was found in 122 of 765 (16.0 percent) who had a sentinel lymph node. An additional 4.8 percent subsequently relapsed in the regional lymph nodes, for an estimated overall incidence of nodal involvement of 20.8 percent.
●Among the 500 patients randomly assigned to observation, 87 (17.4 percent) had a clinical relapse in regional lymph nodes, at a median of 19 months after randomization.
Melanoma-specific survival — For the entire group of patients with intermediate-thickness melanoma randomly assigned to lymphatic mapping with SLNB, the difference in melanoma-specific survival was not statistically significant compared with those managed with observation (81.4 versus 78.3 percent; HR for death 0.84, 95% CI 0.64-1.09).
However, the 10-year melanoma-specific survival rate was significantly improved in those found to have nodal metastases who underwent SLNB compared with those initially managed with observation followed by treatment when clinical disease was detected (62.1 versus 41.5 percent; HR for death 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).
Thick melanomas — The study included 314 patients with thick melanomas (>3.50 mm), of whom 311 were available for per protocol analysis. Lymph node metastases were identified in 32.9 percent of patients with thick melanomas at SLNB. An additional 12 patients, who were initially SLNB negative, subsequently were found to have nodal disease. The estimated incidence of disease at 10 years was 42 percent.
Overall, there was no significant difference between the two treatment approaches in melanoma-specific survival for the entire group of patients with thick melanoma (10 year melanoma specific survival rate 58.9 versus 64.4 percent for the lymphatic mapping with SLNB versus initial observation, respectively, HR 1.12, 95% CI 0.76-1.67).
When the analysis was limited to those patients in whom lymph node metastasis was present, the 10-year melanoma-specific survival rate was not significantly different in those who underwent SLNB compared with those initially managed with observation (48.0 versus 45.8 percent; HR for death 0.92, 95% CI 0.53-1.60). There also was no significant difference in the distant disease-free survival rate (45.3 versus 43.8 percent, HR 0.96, 95% CI 0.56-1.64).
Thin melanomas — The study included 340 patients with thin melanomas (<1.20 mm). However, there were too few events in this group to permit analysis of outcomes.
Complications of SLNB — SLNB is associated with significantly fewer complications than regional lymphadenectomy. This was illustrated in 2120 patients enrolled on the Sunbelt Melanoma Trial, of whom 444 underwent completion lymph node dissection . At a median follow-up of 16 months, the overall complication rate was significantly lower for SLNB alone (5 versus 23 percent with SLNB plus completion lymphadenectomy).
Reduced complication rates were seen with wound infection (1 versus 7 percent with completion lymphadenectomy), lymphedema (0.7 versus 11.7 percent), hematoma/seroma (2 versus 6 percent), and sensory nerve injury (0.2 versus 1.8 percent) . Differences in complication rates were particularly striking in patients who underwent groin procedures (total complications 8 versus 51 percent, and lymphedema 2 versus 32 percent).
Minimal metastases — Because fewer nodes are resected with SLNB compared with elective lymph node dissection, more careful pathologic evaluation is possible. Serial sectioning increases the likelihood of detecting melanoma metastases, although 8 to 10 sections may be required .
Even though studies have shown that low-volume involvement of the sentinel lymph node is only rarely associated with tumor involvement of other lymph nodes, follow-up suggests that even minimal metastasis in the sentinel lymph node confers an increased risk of relapse and death relative to patients with no sentinel lymph node involvement.
The prognostic impact of the extent of sentinel lymph node involvement is illustrated by a study of 1009 patients with a positive sentinel lymph node who underwent completion lymph node dissection over a 15-year period at nine European Organisation for Research and Treatment of Cancer (EORTC) melanoma centers . Among the 113 patients with sentinel lymph node tumor size <0.1 mm, 10 (9 percent) were found to have tumor involvement of non-sentinel lymph nodes. The frequency of involvement of non-sentinel lymph nodes increased progressively with tumor size in the sentinel lymph node (16 percent for those with a 0.1 to 1.0 mm tumor and 25 percent for those with a tumor >1.0 mm). On multivariate analysis, less tumor involvement was significantly associated with improved melanoma-specific survival.
Nonetheless, these data were inadequate to distinguish subsets of patients who might avoid completion lymph node dissection based upon the extent of tumor involvement in the sentinel lymph node, and completion lymph node dissection was thought to be indicated for patients with a positive SLNB regardless of the extent of tumor involvement. These issues are addressed in the MSLT-II. (See 'Multicenter Selective Lymphadenectomy Trial-II' below.)
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 .
A similar rate of relapse was observed in a report from MD Anderson Cancer Center . 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).
Patient selection — SLNB is the standard approach for the management of patients with melanoma in whom there is a significant risk of regional node metastasis. The likelihood of detecting metastatic deposits in a SLNB increases with the thickness of the primary lesion, providing a rationale for deciding which patients may benefit from this procedure.
The generally accepted approach focuses on tumor thickness and related risk factors. For patients with clinically negative nodes and a primary melanoma at intermediate or high risk for lymph node metastasis, lymphatic mapping with SLNB is recommended. This includes patients with melanomas >0.8 mm thick, and melanomas <0.8 mm thick but with ulceration, for whom the data are conflicting. Recommendations should be individualized based upon age, comorbidities, and discussion with the patient. In low-risk patients, the managing physician should discuss the pros and cons of SLNB: the prognostic importance, likelihood of finding a positive node, lack of difference in overall survival, increased recurrence-free survival, impact of SLNB findings on decision making regarding adjuvant therapy, additional surgery and cost, and small risk of extremity edema, seroma, or nerve injury.
The incorporation of tumor thickness and ulceration, and the revised role of mitotic rate in the eighth edition American Joint Committee on Cancer (AJCC) staging system, and its impact on prognosis are discussed separately. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Primary tumor (T)'.)
Management of a positive SLNB — Completion dissection of all involved nodal basins was considered the standard treatment approach for patients with a positive SLNB; however, the results of two randomized trials support no additional surgery with careful follow-up of the regional nodal basin that includes serial ultrasonography followed by lymph node dissection in the event of a regional lymph node recurrence. In these two trials melanoma-specific survival and distant metastasis-free survival are similar for immediate completion lymph node dissection compared with observation [22,23].
Multicenter Selective Lymphadenectomy Trial-II — The phase III MSLT-II trial included 1934 evaluable patients who had a positive SLNB as well as a wide local excision of a primary melanoma that had a Breslow thickness ≥1.20 mm or greater and a Clark level III, a Clark level IV or V regardless of Breslow thickness, or a primary tumor with ulceration regardless of thickness or Clark level .
Patients were randomly assigned to completion lymph node dissection or observation, which included ultrasound evaluation of appropriate lymph node basins at each follow-up visit. Completion lymph node dissection was performed if there was evidence of regional lymph node recurrence. Follow-up for all patients was carried out every four months for two years, every six months for years 3 to 5, and then annually. Most patients had low-volume (<1 mm) metastasis deposits in the positive sentinel node.
At a median follow-up of 43 months, key results included the following:
●Melanoma-specific survival, the primary endpoint of the trial, was the same for both immediate lymph node dissection and observation (three-year rate 86 versus 86 percent, adjusted HR 1.08, 95% CI 0.88-1.34).
●Disease-free survival at three years was improved in patients managed with immediate completion lymph node dissection (68 versus 63 percent), reflecting a lower rate of recurrence in regional lymph nodes in patients undergoing immediate completion lymph node dissection compared with observation (8 versus 23 percent).
●The incidence of lymphedema was higher in patients who underwent immediate lymph node dissection (24.1 versus 6.3 percent).
●Although melanoma-specific survival was worse in patients with thicker primaries, ulceration of the primary tumor, or positive non-sentinel nodes, no subgroups could be identified in whom completion lymphadenectomy provided benefit.
DeCOG-SLT trial — In the multicenter DeCOG-SLT trial, 483 patients with cutaneous melanoma affecting the trunk or extremities were randomly assigned to immediate complete lymph node dissection (CLND) or observation including ultrasound of the primary site and appropriate lymph node basins [22,24]. Most patients had low-volume metastasis in the sentinel lymph node.
In the final analysis with a median follow-up of 72 months, regional lymph node metastases were more frequent in the observation arm (16.3 percent) compared with CLND (10.8 percent), but the difference was not significant . In spite of this observed (and expected) difference in regional node recurrence rate, distant metastasis-free survival (DMFS; primary endpoint), relapse-free survival and overall survival at five years were similar between the groups. With longer follow-up (35 to 72 months median follow-up [22,25]), DMFS decreased by approximately 10 percent in both arms but remained similar between the groups (77 to 67.6 percent for observation, 74.9 to 64.9 percent for CLND). Recurrence-free survival at five years for observation versus CLND was 59.9 versus 60.9 percent, respectively, and overall survival was 72.3 versus 71.4 percent. Adverse events occurred in 13 percent of the CLND arm, 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.
The staging evaluation of a patient with a positive regional lymph node is discussed separately. (See "Staging work-up and surveillance of cutaneous melanoma".)
The role of adjuvant immunotherapy following completion lymph node dissection is discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)
Guidelines — Joint guidelines from the American Society of Clinical Oncology (ASCO) and the Society for Surgical Oncology are similar to the above approach, recommending SLNB for patients with intermediate-thickness (1 to 4 mm) melanomas as well as suggesting SLNB for patients with thin melanomas (<1 mm) that have other high-risk features [6,7]. Those guidelines also suggest considering SLNB for patients with a thick melanoma (>4 mm) for prognostic purposes, to aid in achieving regional disease control, and to identify patients for adjuvant therapy or investigational trials.
CLINICALLY APPARENT REGIONAL LYMPH NODES
Therapeutic lymphadenectomy — Surgical (therapeutic) lymphadenectomy is the preferred treatment for clinically detectable and cytologically (fine-needle aspiration) or pathologically proven regional lymph node involvement in patients with melanoma . This approach is associated with long term disease free survival in a subset of patients. Even if patients subsequently develop distant metastases, regional therapy at presentation may prevent morbidity caused by mass effect from involved nodes or skin breakdown.
Approximately 20 to 40 percent of patients with clinically apparent (macroscopic, N1b or N2b) metastatic involvement of regional nodes are alive at 10 years following therapeutic lymphadenectomy . The number of metastatic lymph nodes is a significant prognostic factor; patients with only one positive node have a better prognosis (40 to 50 percent) than those with more than one positive node . (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)
Extent of dissection and morbidity — Complete regional lymphadenectomy, rather than partial dissection or sampling, is necessary for clinically positive melanoma lymph node metastasis because of the high risk of additional nodal metastases within the basin and/or extranodal spread.
The morbidity of completion axillary dissection for upper extremity melanomas or truncal melanomas with lymphatic drainage to the axilla includes short- and long-term complications. Common short-term complications include wound infection and breakdown, seroma formation, and shoulder dysfunction after axillary dissection (table 2) [18,28]. Long-term complications include lymphedema and paresthesias.
Complications are more common after inguinal lymph node dissection (for lower extremity lesions or truncal melanoma with inguinal drainage) than after axillary nodal dissection, with lymphedema being a frequent problem [18,28]. Some surgeons electively add a deep ilioinguinal dissection to the superficial inguinal node dissection when the highest superficial node (Cloquet's node ) contains metastatic melanoma, when multiple superficial inguinal nodes contain melanoma, and when imaging suggests deep ilioinguinal metastatic disease.
The role of a deep ilioinguinal dissection is controversial, since it is not clear whether the addition of a more extensive dissection improves survival [29,30]. The addition of deep ilioinguinal lymphadenectomy significantly increases the risk of subsequent lymphedema . 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".)
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 5th to 6th 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 10th to 12th 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
●Sentinel lymph node mapping – Lymphatic mapping with sentinel lymph node biopsy (SLNB) is the standard clinicopathologic approach to evaluate regional lymph nodes in patients without clinical evidence of lymph node involvement. (See 'Sentinel lymph node biopsy' above.)
●Patient selection for SLNB – For patients with clinically negative regional lymph nodes, SLNB is the standard approach for the management of patients with melanoma in whom there is a significant risk of regional lymph node metastasis. (See 'Patient selection' above.)
•For patients with a melanoma 0.8 mm thick or greater, we recommend performing SLNB. This recommendation includes patients with intermediate and thick primary lesions, as well as those with thin melanomas 0.8 to 1.0 mm thick. These patients should have nodal basin ultrasonography prior to lymphatic mapping and sentinel lymphadenectomy.
•For patients with a melanoma <0.8 mm thick and at increased risk for nodal involvement due to ulceration of the primary tumor, we favor performing an SLNB. However, the absolute risk of a positive sentinel lymph node is small in this group, and a detailed discussion with the patient is needed to discuss the potential risks and benefits.
•SLNB is not indicated for patients with a melanoma <0.8 mm and no other factors placing the patient at increased risk for nodal involvement.
●Positive SLNB – For patients with a positive SLNB, we suggest careful clinical observation coupled with ultrasound surveillance of the positive nodal basin rather than immediate completion lymph node dissection (Grade 2B). Completion lymph node dissection is indicated if there is subsequent evidence of regional lymph node recurrence in the absence of distant metastases. (See 'Management of a positive SLNB' above.)
●Clinically apparent lymph nodes – For patients who present with clinically apparent regional lymph node involvement that is confirmed cytologically (fine-needle aspiration) or histologically, we recommend therapeutic regional lymphadenectomy (Grade 1B). Partial dissection or lymph node sampling is not considered an acceptable alternative because of the propensity of melanoma to spread microscopically to other nodes in the basin. (See 'Clinically apparent regional lymph nodes' above.)
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