Blog

• The Multicenter Selective Lymphadenectomy Trial-II (MSLT-II):
  • Sought to answer whether CLND was necessary following a positive SLN:
    • By randomizing patients with at least one positive SLN to nodal observation (with nodal basin ultrasound, termed active surveillance) or immediate CLND after a positive SLN
  • Overall, the trial accrued > 1,900 patients and at a median follow-up of 43 months, in the per-protocol analysis:
    • The 3-year melanoma-specific survival (primary endpoint):
      • Was similar in both the CLND group and the observation group
    • Disease control in the regional nodes at 3 years:
      • Was also increased in the dissection group compared to the observation group:
        • 92% vs. 77%; P < .001
    • Nonsentinel node metastases:
      • Identified in 11.5% of the patients in the dissection group were a strong and independent predictor of recurrence (hazard ratio, 1.78; P = .005)
  • Taken together, these initial data support that immediate CLND increased regional disease control and provided prognostic information:
    • But did not increase MSS in these patients with SLN metastases
• In the German multicenter, randomized, phase III DeCOG-SLT clinical trial:
  • 483 patients with a positive SLNB:
    • Were randomly assigned to immediate surgery (i.e., CLND following a positive SLNB) or to regional node observation
  • Of note, 66% of patients had an SLN metastasis of 1 mm or less
  • At a median follow-up of 72 months, among 483 included:
    • The authors found that there was no significant difference in their primary endpoint of 5-year distant metastasis-free survival:
      • 67.6% versus 64.9% for the observation versus immediate complete dissection groups, respectively:
        • HR 1.08, 95% CI 0.83 to 1.39
  • Furthermore, there were no significant differences in RFS and OS
  • Of note, the study did not reach its target accrual of 556 patients:
    • Thus reducing the power of the study
• Taken together, these trials have contributed to a significant paradigm shift in clinical practice for the patient with a positive SLN:
  • As two clinical trials demonstrated that CLND provided no recurrence free survival (RFS) or OS benefit in melanoma patients with a positive sentinel node:
    • The vast majority of melanoma surgical oncologists have integrated nodal observation (with active surveillance) rather than CLND as a preferred strategy into their practice
  • While CLND is still considered an option for these patients according to national consensus melanoma guidelines:
    • In the setting of patient preference related to availability to be surveilled, when adjuvant therapy cannot be considered, particularly in the setting of high-risk disease with increased associated risk of non-SLN involvement:
      • These situations are in clinical practice rather infrequent
  • With this change in practice, new questions have arisen, including the optimal screening algorithm for patients undergoing observation with a positive sentinel node
• In the post MSLT-II era:
  • CLND is generally recommended in the context of multidisciplinary team-based care for regional recurrence discovered during active surveillance / nodal observation post SLN biopsy

• Historical Context:
  • CLND was traditionally recommended for all patients with a positive sentinel lymph node (SLN) to:
    • Remove additional metastatic disease
    • Improve regional control
    • Potentially improve survival
• Paradigm Shift:
  • Key Randomized Trials:
    • MSLT-II (Multicenter Selective Lymphadenectomy Trial II)
      Compared CLND vs observation with ultrasound in SLN-positive patients
      • Findings:
        • No difference in melanoma-specific survival (MSS)
        • Improved regional disease control with CLND (92% vs 77%)
        • Increased surgical morbidity (e.g., lymphedema) in CLND group
      • Reference:
        • Faries MB, et al. N Engl J Med. 2017;376(23):2211–2222.
    • DeCOG-SLT Trial:
      • German study with similar design and findings
      • Conclusion:
        • CLND did not improve survival in SLN-positive patients
      • Reference:
        • Leiter U, et al. Lancet Oncol. 2016;17(6):757–767.
• Current Guidelines:
  • Routine CLND is no longer recommended for all SLN-positive patients
  • Patients should undergo:
    • Active surveillance with high-resolution ultrasound
    • Consideration of adjuvant systemic therapy:
      • Particularly if high-risk
    • References:
      • NCCN Guidelines: Melanoma, Version 2.2024
      • ASCO/SSO Clinical Practice Guidelines, Wong SL, et al. J Clin Oncol. 2018;36(4):399–413.
• Indications for Selective CLND:
  • CLND may still be considered in select high-risk cases:
    • Clinically palpable disease or radiographic nodal enlargement
    • Extensive SLN involvement:
      • > 3 mm tumor burden
      • Extracapsular extension
    • Nodal recurrence during observation

• Prognostic Implications:
  • Presence of additional non-sentinel node (NSLN) metastases worsens prognosis
  • SLN tumor burden and other risk factors help stratify who may harbor additional disease
• Conclusion:
  • Routine CLND is no longer standard for SLN-positive melanoma patients following the MSLT-II and DeCOG-SLT trials
  • Management now emphasizes non-invasive surveillance and adjuvant systemic therapy
  • Selective CLND may still play a role in carefully chosen high-risk patients

• Pathologists have traditionally examined lymph nodes obtained from a lymphadenectomy by:
  • Examining an H&E-stained section from each paraffin block:
    • This conventional approach, however, can miss disease in SLNs:
      • Primarily because of sampling error:
        • In an MD Anderson study, 8 of 10 patients who underwent SLNB and subsequently developed regional nodal failure in nodal basins that were negative for disease according to conventional histologic examination of SLNs had microscopic disease detected when the SLNs were reassessed using specialized pathologic techniques
      • Data from this and other studies suggest that failure to use specialized techniques, rather than failure to correctly identify SLNs, accounts for many cases of false-negative findings on SLNB
      • These studies helped to define the current standards of SLN assessment using more enhanced pathologic evaluation than had been previously performed
• With the SLNB technique, fewer lymph nodes are submitted for analysis than are submitted with formal lymphadenectomy, and the pathologist can therefore focus on only those nodes that are at the highest risk
• Currently, the combination of H&E assessment of several levels (i.e., serial sectioning) and immunohistochemical analysis is generally considered a standard practice in assessing SLNs
• Several antibodies directed against melanoma-associated antigens:
  • S-100, HMB-45, tyrosinase, MAGE3, and MART-1:
    • Are routinely used for immunohistochemical evaluation
  • Because certain antibodies have low specificity (S-100) and others have low sensitivity (HMB-45, MAGE3, and tyrosinase):
    • A panel of antibodies is commonly used
• At MD Anderson Cancer Center:
  • There panel includes an antimelanocytic cocktail:
    • HMB45, anti-MART1 and anti-tyrosinase
• The use of frozen section for immediate evaluation of SLNs has been controversial in melanoma:
  • Frozen sections usually provide suboptimal morphology and may lack the subcapsular region of the lymph node:
    • An area likely involved in SLN metastases
  • Also, processing of the frozen tissue requires additional sectioning:
    • Micrometastases may be lost in the discarded unexamined sections
  • I feel strongly that the use of frozen section risks a lower accuracy of detection of SLN metastases
  • Historically this approach was employed for the rare clinical scenario if a grossly suspicious SLN was identified and if a formal preoperative discussion of possible concomitant CLND was considered:
    • Given the infrequent use of CLND following results of the Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) trial:
      • This approach has been further rendered obsolete
• Purpose:
  • To detect micrometastatic disease in regional lymph nodes
  • Guides prognosis, staging (AJCC), and eligibility for adjuvant therapy
• Gross Examination:
  • SLNs are bisected or serially sectioned at 1 to 2 mm intervals perpendicular to the long axis:
    • All tissue is submitted for histologic evaluation
  • Reference:
    • College of American Pathologists (CAP) Protocol for Melanoma (2023 Update)
• Histologic Evaluation:
  • Hematoxylin and eosin (H&E) staining is the standard initial method
  • Immunohistochemistry (IHC) is used when H&E is equivocal
• IHC Markers:
  • S100: Very sensitive, but not specific
  • Melan-A (MART-1) and HMB-45:
    • More specific for melanocytic lineage
  • Reference:
    • Cochran AJ, Wen DR, Morton DL. Cancer. 1999;85(5):1228–1238.
• Reporting Parameters:
  • Pathologic reports should include:
    • Number of SLNs examined
    • Number of SLNs positive for metastasis
    • Size of the largest tumor deposit (tumor burden)
    • Presence of extracapsular extension
      
    • Location of metastasis:
      • Subcapsular, parenchymal, or multifocal
    • Mitotic activity, if assessable
  • Reference:
    • Gershenwald JE, Scolyer RA, Hess KR, et al. CA Cancer J Clin. 2017;67(6):472–492.
      CAP Cancer Protocol: Melanoma of Skin (2023)
• Tumor Burden Stratification:
  • Micrometastases (< 0.1 mm):
    • Often associated with excellent prognosis
  • Deposits ≥ 1 mm:
    • Significantly higher risk of recurrence and worse melanoma-specific survival
  • Reference:
    • van der Ploeg AP, van Akkooi AC, et al. Ann Surg Oncol. 2011;18(2):519–528.
• Ultrastaging (Optional / Selective):
  • Serial sectioning and multiple IHC stains:
    • May increase detection of minimal disease but has limited proven prognostic value beyond standard pathology
  • Not uniformly recommended due to low clinical significance of isolated tumor cells (ITCs)
• Nodal Staging (AJCC 8th Edition):
  • SLN involvement determines Stage III subcategorization:
    • IIIA:
      • Micrometastases, no ulceration
    • IIIB to IIIC:
      • Larger burden, ulcerated primary, or multiple nodes
• Clinical Implications:
  • SLN positivity leads to consideration of adjuvant immunotherapy or targeted therapy
  • Completion lymph node dissection (CLND) is no longer routine per MSLT-II

• Historically, even thin melanomas were excised with very wide margins (3 cm to 5 cm):
  • Studies have demonstrated, however, that narrower margins are often associated with the same recurrence rates as wider margins

• For thin melanomas:
  • The first randomized study involving surgical margins for melanomas less than 2 mm thick was reported by the WHO Melanoma Group:
    • In an update of the study including 612 patients randomly assigned to a 1-cm or 3-cm margin of excision:
      • There were no local recurrences among patients with primary melanomas thinner than 1 mm
  • • • There were four local recurrences among the 100 patients with melanomas 1 to 2 mm thick:
        • All four occurred in patients with 1-cm margins
      • There was no significant difference in survival between the 1- and 3-cm surgical margin groups
    • These results demonstrate that a 1-cm excision margin is safe for thin (less than 1 mm thick) melanomas
  • A multi-institutional prospective randomized trial from France:
    • Compared 2-cm and 5-cm excisional margins in 362 patients with melanomas less than 2 mm thick:
      • There were no differences in local recurrence rate or survival between the two groups
  • A randomized trial from Sweden compared 989 melanoma patients with lesions less than 2 mm thick excised with 2-cm and 5-cm margins:
    • The results were similar:
      • No differences in local recurrence rate or survival between the two groups

• For thicker melanomas:
  • A randomized clinical trial from the United Kingdom, the United Kingdom Melanoma Study Group (UKMSG) Trial:
    • Compared 1-cm and 3-cm excisional margins in 900 patients with melanomas at least 2 mm thick:
      • With a median follow-up time of 60 months:
  • • • • A 1-cm margin was associated with a significantly increased risk of locoregional recurrence:
          • 37% vs. 32% for 3-cm margins
        • However, overall survival (OS) was similar in the two groups

• For intermediate thickness melanomas:
  • A randomized prospective study conducted by the Intergroup Melanoma Committee compared 2-cm and 4-cm radial margins of excision for 1-mm to 4-mm thickness melanomas:
    • There was no difference in local recurrence rate between the two groups:
      • 46% of patients in the 4-cm group required skin grafts
  • • • Only 11% of patients in the 2-cm group:
        • P < 0.001
    • A trend for improved 10-year disease-specific survival was seen in 4-cm margins (77%) versus 2-cm margins (70%)
  • A clinical trial directly comparing 1-cm and 2-cm margins for 1-mm to 2-mm melanomas has not been performed:
    • Based upon data from the WHO Trial and the Intergroup Melanoma Trial:
      • 2-cm margins are recommended when the anatomic location is favorable and primary closure can be achieved
    • Since there is no demonstrable survival advantage for a 2-cm margin over a 1-cm margin in 1-mm to 2-mm melanomas:
      • A 1-cm margin can be justified in cases in which a 2-cm margin is not easily achievable
• Thick melanomas:
  • The optimal margin width for thick melanomas (greater than 4 mm) is still unknown
  • A retrospective review of 278 patients with thick primary melanomas from The University of Texas MD Anderson Cancer Center and Moffitt Cancer Center:
    • Demonstrated that the width of the excision margin (≤ 2 cm vs. > 2 cm):
      • Did not significantly affect local recurrence, disease-free survival, or OS rates after a median follow-up of 27 months
  • In addition, based upon data from the UKMSG Trial:
    • Investigators concluded that a 3-cm margin is better than 1-cm margin for melanomas 2 mm to 4 mm thick
  • The Intergroup Melanoma Trial:
    • 4-cm margin is not superior to a 2-cm margin for same tumor thickness):
      • A margin greater than 2 cm is not necessary for these thick melanomas

• Based in large part on the data from randomized, prospective trials, several recommendations can be made for margins of excision (Table):

• Patient with melanoma in situ:
  • A 0.5-cm to 1-cm margin is adequate
• Patients with invasive melanoma less than 1 mm thick:
  • Can be treated with a 1-cm margin of excision
• Patients with melanoma 1 mm to 2 mm thick:
  • A simple recommendation is difficult because this patient population has been studied in several trials evaluating a range of excision margins:
    • In general, a 2-cm margin is preferred if anatomically and functionally feasible
  • • In regions of anatomical constraint (e.g., the face), a 1-cm margin is sufficient:
      • This recommendation is based on the fact that OS was similar for patients with 1- and 3-cm margins in the WHO Trial
• Patients with melanoma 2 mm to 4 mm thick:
  • Can be treated with a 2-cm margin
• Patients with a melanoma thicker than 4 mm:
  • A 2-cm margin is probably safe and is generally employed:
    • Although no prospective randomized trials have specifically addressed this thickness group

Rodrigo Arrangoiz MS, MD, FACS

• He is an expert in the management of skin cancer including MELANOMA

  • If you have any questions about the management of melanoma please fill free to contact Dr. Arrangoiz.

  • Article on Melanoma published by Dr. Arrangoiz:

    • http://article.sciencepublishinggroup.com/html/10.11648.j.jctr.20160401.11.html

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#HeadandNeckSurgeon

#CirujanodeTumoresdeCabezayCuello

#CancerSurgeon

#CirujanodeCancer

#MountSiniaMedicalCenter

#MSMC

• The prognostic significance of the pathologic status of the sentinel lymph node (SLN):
  • Has been convincingly demonstrated
• Data from MD Anderson demonstrated that SLN status was:
  • The most significant clinicopathologic prognostic factor with respect to survival in patients with melanoma
  • In an analysis of 1,487 patients who underwent SLNB (median tumor thickness, 1.5 mm):
    • The 5-year survival rate for patients with:
      • Positive SLNs was 73.3%:
        • Compared to 96.8% for patients with negative SLNs
  • Several other multivariate regression analyses:
    • Have shown that regional lymph node status is the most powerful predictor of recurrence (both regional and distant) and survival:
      • Even among patients with thick melanomas
  • Taken together with patients who have clinical regional disease, according to analysis done by the International Melanoma Database and Discovery Platform (IMDDP) that provided revisions to the 8th edition AJCC melanoma staging system:
    • 5-year melanoma-specific survival rates for patients with:
      • Stage III disease range from 93% for patients with IIIA disease to 32% for patients with IIID disease
  • The prognostic importance of distinguishing between:
    • Clinically occult and clinically detected lymph nodes:
      • Has been emphasized by incorporation of this criterion into the 8th edition AJCC melanoma staging system
  • The concept of tumor burden has become important in the era of SLNB:
    • As accurate microscopic staging of SLNs allows patients to be better stratified into similar risk subgroups
  • Several studies have shown that the diameter of the largest SLN tumor nodule and the total SLN tumor volume:
    • Are significant predictors of recurrence and survival
  • The prognostic significance of sentinel node tumor burden continues to be an active area of investigation worldwide
• The landmark prospective Multicenter Selective Lymphadenectomy Trial-I (MSLT-I):
  • Was designed in 1994 to assess whether a selective approach to regional lymphadenectomy limiting completion lymph node dissection:
    • To patients with microscopic disease in SLNs:
      • Confers a survival benefit compared to wide excision of the primary melanoma and observation of the regional nodal basin
  • Patients with primary cutaneous melanomas at least 1 mm thick or with Clark level IV or V tumors with any Breslow thickness were eligible for the trial
  • Two thousand and one patients were randomly assigned to:
    • Wide excision alone and observation of the regional nodal basin(s) (40%) or wide excision and lymphatic mapping and SLNB (60%), with subsequent CLND if any SLNs were positive
  • In 2014, the final trial report was published with 10 years of follow-up data:
    • Ten-year disease-free survival rates were significantly higher in the SLNB group than in the observation group among patients with intermediate-thickness melanomas:
      • 71.3 ± 1.8% in the SLNB group compared to 64.7 ± 2.3% in the observation group (hazard ratio for recurrence or metastasis, 0.76; 95% CI 0.62 to 0.94; P =.01)
    • When the SLNB group was further explored:
      • It was noted that patients who had evidence of microscopic SLN involvement did worse than patients with a negative SLNB
    • For patients with intermediate-thickness primary melanoma (defined in MSLT-I as 1.2 to 3.5 mm):
      • The melanoma-specific survival at 10 years was significantly worse in patients with a positive SLNB compared to those who had a negative SLNB:
        • 62% vs. 85%, HR 3.09, 95% CI 2.12 to 4.49
      • For patients with thick melanoma (defined in MSLT-I as > 3.50 mm):
        • The melanoma-specific survival rate at 10 years was again significantly worse in patients with lymph node involvement compared to those who had a negative lymph node biopsy (48.0% vs. 64.6%, HR 1.75, 95% CI 1.07 to 2.87)
      • Interestingly, when applied to the study cohort, a statistical approach called latent-subgroup analysis (a technique that accounts for the observation that nodal status was initially only known in the SLNB group):
        • Showed a clear benefit of SLNB
      • Among patients who had SLNB and a positive SLN compared to those who developed clinical regional melanoma metastasis after wide excision alone:
        • There was doubling of melanoma-specific and distant disease–free survival and a tripling of disease-free survival
• Sentinel Lymph Node Biopsy (SLNB):
  • Purpose:
    • Identifies microscopic nodal metastases in patients with clinically node-negative melanoma
    • Provides accurate staging (AJCC 8th edition) and guides adjuvant therapy decisions
  • Prognostic Significance:
    • SLN-positive status is the strongest independent prognostic factor for recurrence and survival:
      • In intermediate-thickness melanomas
    • 5-year melanoma-specific survival (MSS):
      • SLN-negative: ~ 90% to 95%
        
      • SLN-positive: ~ 60% to 70%
    • References:
      • Morton DL, Thompson JF, Cochran AJ, et al. N Engl J Med. 2006;355(13):1307–1317. doi:10.1056/NEJMoa060903
        Balch CM, Gershenwald JE, Soong SJ, et al. J Clin Oncol. 2009;27(36):6199–6206.
  • Tumor Burden in SLN Matters:
    • Greater nodal tumor burden equals worse prognosis:
      • < 0.1 mm deposits:
        • Very low risk
      • > 1 mm or multiple SLNs involved
        • Significantly reduced survival
    • Reference:
      • van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Ann Surg Oncol. 2011;18(2):519–528.
  • Impact on Treatment Decisions:
    • SLN status determines eligibility for:
      • Adjuvant immunotherapy:
        • Nivolumab, pembrolizumab
      • Targeted therapy in BRAF-mutant patients:
        • Dabrafenib + trametinib
      • Surveillance protocols
    • Reference:
      • Weber J, Mandala M, Del Vecchio M, et al. N Engl J Med. 2017;377(19):1824–1835.
      • Eggermont AMM, Blank CU, Mandala M, et al. N Engl J Med. 2018;378(19):1789–1801.
  • Supporting Trials:
    • MSLT-I:
      • SLN status is prognostic for recurrence-free and melanoma-specific survival
    • MSLT-II and DeCOG-SLT:
      • No survival benefit with completion lymph node dissection (CLND)
    • References:
      • Morton DL, Thompson JF, Cochran AJ, et al. N Engl J Med. 2006;355(13):1307–1317.
      • Faries MB, Thompson JF, Cochran AJ, et al. N Engl J Med. 2017;376(23):2211–2222.
      • Leiter U, Stadler R, Mauch C, et al. Lancet Oncol. 2016;17(6):757–767.
  • AJCC Staging Integration:
    • SLN status incorporated in Stage III classification:
      • Stage IIIA:
        • Micrometastases + no ulceration = best prognosis
      • Higher sub-stages = greater tumor burden or ulceration
    • Reference:
      • Gershenwald JE, Scolyer RA, Hess KR, et al. CA Cancer J Clin. 2017;67(6):472–492.
  • Guidelines:
    • SLNB recommended for:
      • Breslow depth ≥ 1 mm
      • 0.8mm to 1.0 mm with high-risk features:
        • Ulceration, high mitotic index
    • Reference:
      • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma, Version 2.2024.
• Conclusion:
  • Sentinel lymph node status is a powerful prognostic marker in cutaneous melanoma and has direct implications for staging, risk stratification, treatment planning, and surveillance

• Knowledge of the factors predictive of a positive sentinel lymph node (SLN):
  • Is useful for counseling patients regarding treatment options
• The incidence of positive SLN in patients with cutaneous melanoma varies by:
  • Tumor thickness
  • Histologic subtype
  • Anatomic site
• In most studies, the overall incidence of a positive SLN among patients undergoing SLNB ranges from 15% to 20%
  • Multivariable analyses have revealed several factors associated with an increased risk of positive SLNs:
    • Increasing tumor thickness, ulceration, lymphovascular invasion, high mitotic rate, young age, and melanoma subtype
  • The overall incidence of SLN metastases by AJCC clinical substage among patients who had SLNB from one institutional study:
    • For stages IA, IB, IIA, IIB, and IIC was 2%, 9%, 24%, 34%, and 53%, respectively
  • Based on a published risk prediction model, investigators at Melanoma Institute Australia recently developed an SLN metastasis risk prediction tool that was validated with data from The University of Texas MD Anderson Cancer Center (MD Anderson) to serve as a general guide to estimate individual risk of harboring a tumor involved SLN:
    • https://www.melanomarisk.org.au/index
• For all cutaneous melanomas:
  • The overall SLN positivity rate is approximately:
    • 5% to 8% for thin melanomas (≤ 1 mm)
    • 18% to 40% for acral lentiginous melanoma (ALM) of the fingers, toes, and sole at stage IB to II:
      • In particular, ALM common on the digits and soles:
        • Has a higher risk of SLN positivity compared to other subtypes, with rates of 18.4% for stage IB and 39.5% for stage II
• Predictors of positive SLN include:
  • Breslow thickness:
    • Risk increases with thickness:
      • ≥ 0.8 mm is a key threshold
  • Ulceration:
    • Independently increases risk
  • High mitotic rate:
    • Specially > 1/mm²
  • Younger age:
    • Patient < 60 years have a higher risk
  • Lymphovascular invasion, microsatellitosis, and vertical growth phase:
    • All increase risk
  • Acral lentiginous histology:
    • ALM subtype is an independent predictor
  • Location on the sole, fingers, or toes:
    • ALM and subungual melanomas have higher SLN positivity than other sites
• The American Society of Clinical Oncology and Society of Surgical Oncology recommend:
  • SLN biopsy for melanomas ≥ 0.8 mm or with high-risk features, and specifically highlight the higher risk in ALM and distal extremity sites.
  • Additionally, unique lymphatic drainage patterns in the fingers, toes, and sole may require careful mapping, as drainage to popliteal or epitrochlear nodes is not uncommon
• In summary:
  • ALM of the fingers, toes, and sole has a higher incidence of SLN positivity than other cutaneous melanomas, with Breslow thickness, ulceration, mitotic rate, and younger age being the most important predictors
• References:
  • Sentinel Lymph Node Biopsy Positivity in Patients With Acral Lentiginous and Other Subtypes of Cutaneous Melanoma. Cheraghlou S, Ugwu N, Girardi M. JAMA Dermatology. 2022;158(1):51-58. doi:10.1001/jamadermatol.2021.4812.
  • Predictive Values of Pathological and Clinical Risk Factors for Positivity of Sentinel Lymph Node Biopsy in Thin Melanoma: A Systematic Review and Meta-Analysis. Huang H, Fu Z, Ji J, Huang J, Long X. Frontiers in Oncology. 2022;12:817510. doi:10.3389/fonc.2022.817510.
  • Predictors of Sentinel Lymph Node Metastasis in Patients With Thin Melanoma: An International Multi-Institutional Collaboration. Walker RJB, Look Hong NJ, Moncrieff M, et al. Annals of Surgical Oncology. 2022;29(11):7010-7017. doi:10.1245/s10434-022-11936-z.
    Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. Wong SL, Faries MB, Kennedy EB, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2018;36(4):399-413. doi:10.1200/JCO.2017.75.7724.
    Predictors of Sentinel Lymph Node Positivity in Thin Melanoma Using the National Cancer Database. Conic RRZ, Ko J, Damiani G, et al. Journal of the American Academy of Dermatology. 2019;80(2):441-447. doi:10.1016/j.jaad.2018.08.051.
    The Impact of Factors Beyond Breslow Depth on Predicting Sentinel Lymph Node Positivity in Melanoma. Paek SC, Griffith KA, Johnson TM, et al. Cancer. 2007;109(1):100-8. doi:10.1002/cncr.22382.
  • Surgical Management of Primary Cutaneous Melanomas of the Hands and Feet. Tseng JF, Tanabe KK, Gadd MA, et al. Annals of Surgery. 1997;225(5):544-50; discussion 550-3. doi:10.1097/00000658-199705000-00011.
  • Incidence and Patterns of Lymphatic Drainage to the Epitrochlear and Popliteal Sentinel Lymph Nodes in Malignant Melanoma of the Distal Extremities: A Single-Institution Retrospective Study. Jinnai S, Namikawa K, Takahashi A, Ogata D, Yamazaki N. International Journal of Dermatology. 2022;61(7):855-860. doi:10.1111/ijd.16078.

• Regional lymph nodes:
  • Are the most common site of melanoma metastasis
• Lymph node involvement is categorized as:
  • Clinically occult:
    • Detected by sentinel lymph node mapping (SLNM) and sentinel lymph biopsy (SLNB)
  • Clinically detected:
    • Palpable and / or radiographically detected nodes
• Fine-needle aspiration or core biopsy:
  • Can usually yield a diagnosis in patients who develop clinically enlarged regional nodes
• Incisional or excisional biopsy:
  • Is rarely indicated for diagnostic purposes
• Intraoperative Lymphatic Mapping and Sentinel Lymph Node Biopsy:
  • Beginning in the 1990s after its introduction by Morton and colleagues:
    • Several investigators proposed intraoperative lymphatic mapping and SLNB as a minimally invasive procedure for identifying approximately 15% to 20% of patients offered the procedure who harbor occult microscopic disease
  • This approach is sometimes termed selective lymphadenectomy
  • From a historical standpoint as initially proposed by Morton:
    • The SLNB approach facilitates identification of patients for whom completion lymph node dissection would be recommended
    • Several studies have demonstrated that the SLNs are the first nodes to contain metastases, if metastases are present, and thus the pathologic status of the SLNs reflects that of the entire regional nodal basin
    • If the SLN lacks metastasis, the rest of the regional lymph nodes are unlikely to contain disease, and a completion lymphadenectomy (CLND) would therefore be unnecessary
    • Multiple studies have demonstrated that the immediate false-negative rate for SLNB is less than 5%
    • Other studies have confirmed the validity of the SLN concept and the accuracy of SLNB as a staging procedure
    • It is imperative, however, that the surgeon employing SLNB has adequate pathology and nuclear medicine support
• Sentinel Lymph Node Biopsy Technique:
  • It is strongly preferred that lymphatic mapping and SLNB be performed at the time of wide excision of the primary melanoma
  • If a wide excision has already been performed, SLNB can still generally be performed with equivalent accuracy:
    • However, prior extensive reconstruction of the primary melanoma wide excision site (e.g., by extensive rotational flap reconstruction) that alters lymphatic pathways in the region:
      • May significantly reduce the accuracy of this technique if performed after wide excision in such patients
  • Since the introduction of lymphatic mapping and SLNB, the technique has undergone several refinements that have resulted in improved detection of SLNs:
    • Use of a vital blue dye to identify SLNs has been part of the technique since its introduction:
      • I typically use isosulfan blue 1% or Lymphazurin at our institution
    • If a patient is noted to have a significant history of allergic reactions:
      • You may substitute methylene blue and anecdotally note overall similar results and a favorable side effect profile
    • Some surgeons prefer to give prophylaxis to prevent allergic reactions:
      • Using a cocktail of I.V. diphenhydramine, I.V. hydrocortisone, and I.V. famotidine administered prior to injection of isosulfan blue
  • The blue dye is injected intradermally:
    • Around the residual intact tumor or biopsy site:
      • It is taken up by the lymphatic system and carried via afferent lymphatics to the SLN(s)
      • The draining nodal basin is explored, and the afferent lymphatic channels and first draining lymph nodes (the SLNs) are identified by the uptake of the blue dye
  • With the use of blue dye alone, an approach utilized mostly in the early 1990s:
    • An SLN was identified in approximately 85% of cases:
      • Although this initial approach was promising, 15% of patients were unable to benefit from the procedure because no SLN was identified
  • Subsequently, additional techniques were incorporated that have significantly improved SLN localization:
    • Preoperative lymphoscintigraphy
    • Intradermal injection of technetium-99 (99Tc)-labeled sulfur colloid accompanied by intraoperative use of a handheld gamma probe
  • Preoperative lymphoscintigraphy using 99Tc-labeled sulfur colloid:
    • Facilitates the identification of patients with multiple draining nodal basins and patients with lymphatic drainage to SLNs located outside standard nodal basins, including:
      • Epitrochlear, popliteal, and ectopic /interval / in-transit sites
• In 2013, Tc 99m tilmanocept (Lymphoseek):
  • Was approved by the FDA as a receptor-targeted lymphatic mapping agent:
    • Whose mechanism of action is to bind to mannose receptors on lymphatic tissue
  • It accumulates in lymphatic tissue within minutes and facilitates localization of SLNs:
    • It can be used in place of 99Tc-labeled sulfur colloid for both lymphoscintigraphic imaging as well as for intraoperative management
• In patients with melanomas that drain to multiple regional nodal basins:
  • The histologic status of one draining basin does not predict the status of other basins:
    • Therefore, it is particularly important to identify and assess all at-risk regional nodal basins to properly stage the patient
• An advance from traditional nuclear imaging is the use of single-photon emission computed tomography (SPECT) imaging merged with CT:
  • SPECT / CT facilitates localization of SLNs by overlaying radiotracer uptake activity onto the noncontrast CT image and is particularly helpful in the head and neck region:
    • In one study, the surgical approach was revised because of SPECT / CT imaging in up to 30% of cases

• Perhaps the most important development in the SLNB technique:
  • Has been the introduction of intraoperative lymphatic mapping:
    • Using a handheld gamma probe
  • In this approach, 0.5-mCi 99Tc-labeled sulfur colloid, or Lymphoseek is injected intradermally prior to surgery, either in nuclear medicine prior to arrival in the operating room (sometimes in concert with preoperative lymphoscintigraphy) or after induction of general anesthesia
  • During surgery, a handheld gamma probe is used to transcutaneously identify SLNs to facilitate their removal
  • The use of both blue dye and radiotracer increases the surgeon’s ability to identify the SLN (> 96% to 99% sensitivity) compared to the use of blue dye alone (≈ 84% sensitivity)
  • Although most clinicians use a combined modality approach, some favor the single-agent strategy of radiotracer alone, and some have reported similarly excellent sensitivity compared to a combination strategy

• Epidemiology and Clinical Presentation of Plantar Melanoma:
  • Melanomas of the sole are predominantly acral lentiginous melanoma (ALM):
    • Which is the most common melanoma subtype in patients of African and Asian descent:
      • It is associated with a poorer prognosis due to frequent late-stage diagnosis
  • Acral lentiginous melanomas occur:
    • On the palms (palmar), soles (plantar), or beneath the nail beds (subungual):
      • Although not all palmar, plantar, and subungual melanomas are acral lentiginous melanomas
    • These melanomas account for only 2% to 8% of melanomas in white patients:
      • But for a substantially higher proportion of melanomas (35% to 60%) diagnosed in darker-skinned patients:
        • Their clinical extent at the primary site may be difficult to define, and scouting biopsies are sometimes employed to facilitate clinical assessment of the extent of disease
    • ALM on the sole often presents as an irregularly pigmented, asymmetric lesion with a parallel-ridge dermoscopic pattern:
      • Diagnosis requires a full-thickness excisional biopsy for histopathologic confirmation
• Unique Anatomic and Surgical Challenges of the Sole:
  • The sole is characterized by thick, glabrous skin, minimal subcutaneous tissue, and a weight-bearing function:
    • All of which complicate surgical management
  • Achieving recommended excision margins:
    • Is often difficult due to the risk of exposing or injuring underlying structures and the challenge of primary closure
  • The need for wide excision can result in large defects that are difficult to reconstruct:
    • With a high risk of surgical complications such as delayed healing, infection, and impaired ambulation
  • These factors necessitate complex reconstructive approaches, including:
    • Local flaps or skin grafts, to restore both form and function and to preserve quality of life
• Surgical Management and Margin Recommendations:
  • The standard of care is surgical excision with histologically negative margins
  • The American Academy of Dermatology and the National Comprehensive Cancer Network recommend margin width based on Breslow thickness:
    • 1 cm for melanomas ≤ 1 mm thick, and up to 2 cm for thicker lesions:
      • With excision to but not including the fascia
    • However, in the sole, these margins may need to be modified to preserve function and accommodate anatomic constraints:
      • Though sub-1-cm margins for invasive melanoma are generally not recommended unless absolutely necessary
    • Sentinel lymph node biopsy is indicated for invasive lesions (generally ≥ 0.8 mm or with other high-risk features) and should be performed prior to or at the time of wide excision
    • Closure of surgical defects often requires skin grafts or local flaps, such as medial plantar or sural neurocutaneous flaps, to achieve durable coverage and maintain ambulation
• Special Considerations for Margin Assessment and Recurrence:
  • Melanomas of the sole, like other specialty sites, have higher rates of positive margins, local recurrence, and upstaging compared to trunk and proximal extremity melanomas
  • This is attributed to both the anatomic complexity and the frequent subclinical extension of ALM
  • Staged excision with comprehensive margin assessment (e.g., slow Mohs or complete circumferential peripheral and deep margin assessment [CCPDMA]) may be considered for melanoma in situ or thin ALM in anatomically constrained areas to maximize tissue conservation and ensure complete tumor removal, though prospective data are lacking
  • Mohs micrographic surgery is not recommended for invasive melanoma but may be selectively considered for melanoma in situ or minimally invasive lesions in specialty sites
• Gaps in Evidence and Areas for Further Study:
  • There is a paucity of prospective, site-specific trials for plantar melanoma
  • Most recommendations are extrapolated from studies of melanomas at other sites, and further research is needed to define optimal surgical margins, reconstructive techniques, and long-term outcomes for melanomas of the sole
• In summary:
  • The surgical management of melanomas on the sole requires careful consideration of the unique anatomic and functional challenges, with a focus on achieving negative margins, minimizing morbidity, and optimizing reconstruction to preserve ambulation and quality of life
  • Margin width should be tailored to tumor thickness and anatomic constraints, with a preference for standard margins when feasible, and the use of advanced margin assessment techniques in select cases
• References:
  • Acral Melanoma Foot Lesions. Part 2: Clinical Presentation, Diagnosis, and Management. Desai A, Ugorji R, Khachemoune A. Clinical and Experimental Dermatology. 2018;43(2):117-123. doi:10.1111/ced.13323.
  • Acral Lentiginous Melanoma of Foot and Ankle: A Clinicopathological Study of 7 Cases. Hao X, Yim J, Chang S, et al. Anticancer Research. 2019;39(11):6175-6181. doi:10.21873/anticanres.13825.
  • Management of Acral Lentiginous Melanoma: Current Updates and Future Directions. Dugan MM, Perez MC, Karapetyan L, Zager JS. Frontiers in Oncology. 2024;14:1323933. doi:10.3389/fonc.2024.1323933.
  • Surgical Management of Primary Cutaneous Melanomas of the Hands and Feet. Tseng JF, Tanabe KK, Gadd MA, et al. Annals of Surgery. 1997;225(5):544-50; discussion 550-3. doi:10.1097/00000658-199705000-00011.
  • Surgical Management of Plantar Melanoma: A Retrospective Study in One Center. Wang M, Xu Y, Wang J, et al. The Journal of Foot and Ankle Surgery : Official Publication of the American College of Foot and Ankle Surgeons. 2018 Jul – Aug;57(4):689-693. doi:10.1053/j.jfas.2017.12.004.
  • The Rule of 10s Versus the Rule of 2s: High Complication Rates After Conventional Excision With Postoperative Margin Assessment of Specialty Site Versus Trunk and Proximal Extremity Melanomas. Rzepecki AK, Hwang CD, Etzkorn JR, et al. Journal of the American Academy of Dermatology. 2021;85(2):442-452. doi:10.1016/j.jaad.2018.11.008.
  • NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021. Swetter SM, Thompson JA, Albertini MR, et al. Journal of the National Comprehensive Cancer Network : JNCCN. 2021;19(4):364-376. doi:10.6004/jnccn.2021.0018.
  • Guidelines of Care for the Management of Primary Cutaneous Melanoma. Swetter SM, Tsao H, Bichakjian CK, et al. Journal of the American Academy of Dermatology. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055.

• Practice Guideline:
  • The special anatomic considerations for the surgical management of melanomas of the fingers and toes include:
    • The limited soft tissue between the skin and underlying structures, particularly in the nail apparatus, and the need to balance oncologic control with preservation of function
  • The American Academy of Dermatology recommends:
    • That wide excision of cutaneous melanoma on the digits should be performed with histologically negative margins:
      • But acknowledges that margins may need to be narrower than standard recommendations to preserve function and accommodate the unique anatomy of the fingers and toes
    • For subungual melanoma:
      • Partial amputation at the distal interphalangeal joint has traditionally been performed to avoid complications from degloving the distal digit:
        • But there is no evidence that this improves prognosis or survival compared to more conservative, digit-sparing approaches, especially for thin (≤ 0.8 mm) or in situ lesions
      • Digit-sparing surgery with narrower margins may be considered in select cases to maximize function:
        • But this approach warrants further investigation
      • The depth of excision:
        • Is generally recommended to the level of, but not including, the fascia
      • These recommendations are based on expert consensus and the anatomic constraints of the digits, as high-level evidence is lacking for these specific sites
• In addition to the anatomic and functional constraints previously discussed:
  • Several further considerations are critical for the surgical management of melanomas of the fingers and toes
• The limited subcutaneous tissue and proximity to bone, tendon, and neurovascular structures:
  • Often necessitate tailored excision techniques and may preclude standard wide excision margins, especially in the nail apparatus and subungual region
• For subungual melanoma:
  • Studies have shown that amputation at the level of the distal interphalangeal joint for fingers and at the proximal phalanx or metatarsophalangeal joint for toes achieves local control:
    • But more conservative, digit-sparing resections with histologically negative margins are increasingly favored to preserve function:
      • As the level of resection does not significantly impact survival when margins are clear
• Acral lentiginous melanomas:
  • Which predominate in these locations, are frequently diagnosed at a greater thickness and are associated with higher rates of nodal and systemic metastasis:
    • Underscoring the importance of accurate staging and consideration of sentinel lymph node biopsy for invasive lesions
• The unique anatomy also complicates reconstruction:
  • Often requiring:
    • Skin grafts or local flaps to maintain function and cosmesis
  • In anatomically complex sites where standard margins are not feasible:
    • Staged excision or slow Mohs micrographic surgery may be considered to maximize tissue conservation while ensuring complete tumor removal:
      • With retrospective data supporting comparable local control to conventional excision
• Finally, the risk of surgical complications including:
  • Positive margins, local recurrence, and need for complex reconstruction:
    • Is higher in these specialty sites compared to trunk or proximal extremity melanomas:
      • Necessitating multidisciplinary planning and patient counseling regarding both oncologic and functional outcomes
• References:
  • Guidelines of Care for the Management of Primary Cutaneous Melanoma. Swetter SM, Tsao H, Bichakjian CK, et al. Journal of the American Academy of Dermatology. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055.
  • Surgical Management of Subungual Melanoma: Mayo Clinic Experience of 124 Cases. Nguyen JT, Bakri K, Nguyen EC, Johnson CH, Moran SL. Annals of Plastic Surgery. 2013;71(4):346-54. doi:10.1097/SAP.0b013e3182a0df64.
  • Malignant Melanoma: Beyond the Basics. Pavri SN, Clune J, Ariyan S, Narayan D. Plastic and Reconstructive Surgery. 2016;138(2):330e-340e. doi:10.1097/PRS.0000000000002367.
  • Nail Apparatus Melanoma: Current Management and Future Perspectives. Ito T, Hashimoto H, Kaku-Ito Y, Tanaka Y, Nakahara T. Journal of Clinical Medicine. 2023;12(6):2203. doi:10.3390/jcm12062203.
  • Current Controversies in Melanoma Treatment. Temple-Oberle C, Nicholas C, Rojas-Garcia P. Plastic and Reconstructive Surgery. 2023;151(3):495e-505e. doi:10.1097/PRS.0000000000009936.
  • Surgical Management of Primary Cutaneous Melanomas of the Hands and Feet. Tseng JF, Tanabe KK, Gadd MA, et al. Annals of Surgery. 1997;225(5):544-50; discussion 550-3. doi:10.1097/00000658-199705000-00011.
  • Melanoma of the Hands and Feet (With Reconstruction). Ruffolo AM, Sampath AJ, Kozlow JH, Neumeister MW. Clinics in Plastic Surgery. 2021;48(4):687-698. doi:10.1016/j.cps.2021.05.009.
  • Slow Mohs Micrographic Surgery for Acral Melanoma Treatment in Korean Patients. Seo J, Oh Y, Kim SK, Roh MR, Chung KY. Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [Et Al.]. 2021;47(2):e42-e46. doi:10.1097/DSS.0000000000002827.
  • The Rule of 10s Versus the Rule of 2s: High Complication Rates After Conventional Excision With Postoperative Margin Assessment of Specialty Site Versus Trunk and Proximal Extremity Melanomas. Rzepecki AK, Hwang CD, Etzkorn JR, et al. Journal of the American Academy of Dermatology. 2021;85(2):442-452. doi:10.1016/j.jaad.2018.11.008.

• What are the three types of wound healing?
  • Primary closure / intention
  • Secondary intention
  • Tertiary intention:
    • Delayed Primary Closure (DPC)
• What is primary intention?
  • When the edges of a clean wound are closed in some manner immediately:
    • For example:
      • Suture
      • Steri-Strips®
      • Staples
• What is secondary intention?
  • When a wound is allowed to remain open:
    • And heal by granulation, epithelization, and contraction:
      • Used for dirty wounds:
        • Otherwise an abscess can form
• What is tertiary intention?
  • When a wound is allowed to remain open for a time and then closed:
    • Allowing for débridement and other wound care to reduce bacterial counts prior to closure:
      • Delayed primary closure (DPC)

• Wound Closure:
  • If there is concern regarding the ability to achieve suitable wound closure:
    • A plastic or reconstructive surgeon may be consulted:
      • Ideally in the preoperative setting
• Options for closure include:
  • Primary closure
  • Skin grafting
  • Local and distant flaps
• Primary closure:
  • Is the method of choice for most lesions:
    • But it should be avoided when it will distort the appearance of a mobile facial feature or interfere with function
  • Many defects can be closed using an advancement flap, undermining the skin and subcutaneous tissues to permit primary closure
  • Primary closure may be facilitated with the longitudinal axis of an elliptical incision to be approximately three times the length of the short axis:
    • Lesser extension of the longitudinal axis can also sometimes be employed
  • The skin and subcutaneous tissue are removed down to, but generally not including the underlying muscular fascia
  • Closure of the wound edges is usually performed in two layers:
    • A dermal layer of 3-0 undyed absorbable sutures and either interrupted skin closure using 2-0, 3-0, or 4-0 nonabsorbable sutures and / or a running subcuticular skin closure using 4-0 monofilament absorbable sutures
  • Three layers are sometimes used:
    • Particularly for primary melanomas of the back:
      • With approximation of Scarpa’s fascia
  • After excision:
    • The specimen should be oriented for permanent assessment of histologic margins
• Application of a skin graft is one of the simplest reconstructive methods used for wound closure:
  • Split-thickness skin grafts are most commonly used:
    • For lower extremity primary lesions:
      • Split-thickness grafts can be harvested from the contralateral extremity
  • In general, skin grafts should be harvested from an area remote from the primary melanoma and outside the zone of potential in-transit metastasis
  • A full-thickness skin graft:
    • Can provide a result that is both more durable and of higher aesthetic quality than a split-thickness graft
    • Full-thickness grafts have most commonly been used on the face:
      • Where aesthetic considerations are most significant, but can also be used elsewhere
    • Donor sites for full-thickness skin graft to the face:
      • Should be chosen from locations that are likely to match the color of the face:
        • Such as the postauricular or preauricular skin or the supraclavicular portion of the neck
    • Local flaps:
      • Offer numerous advantages for repair of defects that cannot be closed primarily:
        • Especially on the distal extremities and on the head and neck
      • Color match is excellent, durability of the skin is essentially normal, and normal sensation is usually preserved
    • Transposition flaps and rotation flaps of many varieties have been used:
      • Although for patients with high risk of in-transit metastasis, extensive flap reconstruction may significantly alter regional lymphatics
    • Distant flaps may be considered when sufficient tissue for a local flap is not available and when a skin graft would not provide adequate wound coverage
    • Use of a wound VAC to facilitate granulation tissue:
      • That serves as a healthy tissue bed for subsequent skin graft can often obviate the need for complex reconstructive options (e.g., melanoma arising on the heel of the foot)