Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Practice Guideline:
  • The American Society of Clinical Oncology recommends programmed death ligand 1 (PD-L1) combined positive score (CPS) testing by immunohistochemistry:
    • For all patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) to guide first-line immunotherapy selection
• For first-line treatment:
  • Pembrolizumab monotherapy is recommended for patients with PD-L1 CPS ≥ 1
    • While pembrolizumab plus platinum-based chemotherapy is recommended for those with symptomatic or rapidly progressive disease, regardless of PD-L1 status
  • For patients with platinum-refractory recurrent or metastatic HNSCC:
    • Either nivolumab or pembrolizumab is appropriate regardless of PD-L1 status:
      • Based on improved overall survival compared to standard chemotherapy
• The guideline also notes that tumor mutational burden (TMB) is not routinely used:
  • But may be considered in rare cases where PD-L1 CPS is unavailable or for rare head and neck cancers:
    • For rare head and neck cancers with high TMB (≥ 10 mutations / megabase):
      • Pembrolizumab may be considered
• The American Society of Clinical Oncology:
  • Does not currently recommend immunotherapy in the curative-intent (locoregionally advanced) setting outside of clinical trials:
    • As evidence is insufficient to support its routine use in combination with chemoradiation or as neoadjuvant / adjuvant therapy
• The rationale for these recommendations:
  • Is based on randomized trials demonstrating survival benefit of immune checkpoint inhibitors in the recurrent / metastatic setting, and the predictive value of PD-L1 CPS for response to anti–PD-1 therapy
• Building on these recommendations:
  • Recent clinical trial data and expert reviews:
    • Further clarify the evolving role of immunotherapy in head and neck squamous cell carcinoma (HNSCC)
• Immune checkpoint inhibitors (ICIs):
  • Specifically anti–PD-1 agents such as pembrolizumab and nivolumab:
    • Have become the standard of care for recurrent or metastatic HNSCC:
      • With objective response rates in the range of 14% to 22% and durable responses in a minority of patients
  • The KEYNOTE-048 trial:
    • Established the benefit of pembrolizumab, either as monotherapy in PD-L1 positive tumors or in combination with platinum-based chemotherapy:
      • As first-line therapy for recurrent / metastatic disease, and this approach is now widely adopted in clinical practice
• Despite these advances, attempts to incorporate ICIs into the curative-intent setting:
  • Such as concurrent administration with chemoradiation or as neoadjuvant / adjuvant therapy:
    • Have not demonstrated clear survival benefit and are not standard outside clinical trials
  • Early-phase studies of neoadjuvant immunotherapy have shown promising signals of response:
  • But larger trials are ongoing to determine their impact on long-term outcomes
• The use of tumor mutational burden (TMB) as a biomarker remains investigational:
  • With PD-L1 combined positive score (CPS) being the primary biomarker guiding immunotherapy selection in routine practice
• In summary, the integration of immunotherapy into the management of HNSCC is most firmly established in the recurrent / metastatic setting, with biomarker-driven selection based on PD-L1 CPS
• The use of ICIs in the curative-intent setting remains investigational, and ongoing research aims to refine patient selection and optimize combination strategies
• References:
  • Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline. Yilmaz E, Ismaila N, Bauman JE, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(5):1132-1146. doi:10.1200/JCO.22.02328.
  • Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline Q and A. Yilmaz E, Ismaila N, Dabney R, Saba NF, Mell LK. JCO Oncology Practice. 2023;19(4):194-196. doi:10.1200/OP.22.00802.
    Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Narrative Review. Sim ES, Nguyen HCB, Hanna GJ, Uppaluri R. JAMA Otolaryngology– Head & Neck Surgery. 2025;151(5):521-528. doi:10.1001/jamaoto.2024.5254.
  • Immunotherapeutic Strategies in Head and Neck Cancer: Challenges and Opportunities. Liu X, Harbison RA, Varvares MA, Puram SV, Peng G. The Journal of Clinical Investigation. 2025;135(8):e188128. doi:10.1172/JCI188128.
  • Immunotherapy, Chemotherapy, or Both: Options for First-Line Therapy for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Ho AL. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(4):736-741. doi:10.1200/JCO.22.01408.
  • Treating Head and Neck Cancer in the Age of Immunotherapy: A 2023 Update. Bhatia A, Burtness B. Drugs. 2023;83(3):217-248. doi:10.1007/s40265-023-01835-2.
  • Integrating Immunotherapy Into Multimodal Treatment of Head and Neck Cancer. Rao YJ, Goodman JF, Haroun F, Bauman JE. Cancers. 2023;15(3):672. doi:10.3390/cancers15030672.

• General:
  • For groin dissection the patient is placed in a slight frog-leg position with hip externally rotated and the knee partially flexed
• Incision:
  • A lazy-S incision is made from superomedial to the anterior superior iliac spine, vertically down to the inguinal crease:
    • Obliquely across the crease, and then vertically down to the apex of the femoral triangle (Figure)
  • Previous SLNB incisions and underlying cavities:
    • Should be excised en bloc with the specimen
• Skin Flaps:
  • The limits of the skin flaps are:
    • Medially:
      • To the pubic tubercle and the midbody of the adductor magnus muscle
    • Laterally:
      • To the lateral edge of the sartorius muscle
    • Superiorly:
      • To approximately 5 cm above the inguinal ligament
    • Inferiorly:
      • To the apex of the femoral triangle
• Lymph Node Dissection:
  • Dissection is carried down to the:
    • Muscular fascia superiorly
  • All fatty, node-bearing tissue is swept down to the inguinal ligament and off the external oblique fascia
  • Medially, the spermatic cord or round ligament is exposed, and nodal tissue is swept laterally
  • Nodal tissue is swept off the adductor fascia to the femoral vein
  • At the apex of the femoral triangle, the saphenous vein is identified:
    • If the saphenous vein can be preserved:
      • Nodal tissue is removed from the vessel circumferentially; otherwise, it is sacrificed
  • Laterally, nodal tissue is dissected off the sartorius muscle and the femoral nerve
  • With dissection in the plane of the femoral vessels:
    • The nodal tissue is elevated up to the level of the fossa ovalis:
      • Where the saphenous vein is suture-ligated at the saphenofemoral junction if it is sacrificed
    • The specimen is dissected to the inguinal ligament:
      • Although excision of Cloquet node (the lowest iliac node), accompanied by intraoperative frozen-section examination, has historically sometimes been employed to inform concomitant iliac-obturator node dissection in patients without clinically apparent or suspicious deep groin metastasis, this approach is uncommonly employed currently
• Sartorius Muscle Transposition:
  • If the sartorius muscle is to be transposed:
    • It is divided at its origin on the anterior superior iliac spine
  • The lateral femoral cutaneous nerve:
    • Is preserved if possible
  • The proximal neurovascular bundles going to the sartorius muscle:
    • Are divided to facilitate transposition, with care to preserve others to the maximal extent possible to ensure a vascularized pedicle
  • The rotated muscle is placed over the femoral vessels:
    • Its is tacked to the inguinal ligament, fascia of the adductor, and vastus muscle groups
• Wound Closure:
  • The skin edges are examined for viability and trimmed back to healthy skin, if necessary:
    • Intravenous administration of fluorescein followed by examination using a Wood lamp:
      • May be used to identify poorly perfused skin edges
  • Two closed-suction drains are generally placed through separate small incisions superiorly:
    • One is laid medially, and the other is laid laterally within the operative wound
  • The wound is closed with interrupted # 3-0 undyed absorbable sutures in the dermis and followed by skin staples or a running # 4-0 subcuticular suture
  • In some patients, interrupted nylon sutures are used overlying the area of skin crease
• Postoperative Management:
  • The patient begins ambulating the day following surgery
  • A custom-fit elastic stocking may be used during the day for 6 months
  • After this period, the stocking may be discontinued if no leg swelling occurs
  • Suction drainage is continued until output is less than 20 mL to 30 mL per day for 2 consecutive days
  • By approximately 4 weeks, the suction catheters are removed, regardless of the amount of drainage, to mitigate risk of infection

• The most recent updates on head and neck cancer presented at the American Society of Clinical Oncology (ASCO) 2025 conference:
  • Continue to emphasize the evolving role of immunotherapy:
    • Particularly immune checkpoint inhibitors (ICIs):
      • In both recurrent / metastatic and curative-intent settings
  • The American Society of Clinical Oncology has published guidelines recommending biomarker-driven use of ICIs:
    • Such as pembrolizumab or nivolumab:
      • For recurrent or metastatic head and neck squamous cell carcinoma (HNSCC):
        • With programmed death ligand-1 (PD-L1) expression guiding first-line therapy selection
    • These guidelines also address the use of immunotherapy in platinum-refractory disease:
      • They highlight the importance of biomarker testing to optimize patient selection
• Recent clinical trial data discussed at ASCO and summarized in the literature show that while ICIs have improved outcomes for a subset of patients with recurrent / metastatic HNSCC:
  • Durable responses remain limited:
    • To approximately 15% to 20% of patients
• Efforts to expand the benefit of immunotherapy into the definitive (curative) setting:
  • Such as concurrent or sequential use with chemoradiation or as neoadjuvant / adjuvant therapy:
    • Have yielded mixed results:
      • With ongoing trials investigating optimal timing and combinations
• The American Head and Neck Society:
  • Notes that neoadjuvant immunotherapy, particularly anti-PD-1 agents:
    • Is under active investigation, with early-phase trials showing promising signals but no definitive change in standard of care yet
• For HPV-associated oropharyngeal cancer:
  • De-intensification strategies and novel immunotherapeutic approaches, including therapeutic vaccines and adoptive cell therapies, are being explored, but these remain investigational and are not yet standard practice
• In summary, the ASCO 2025 updates reinforce the central role of immunotherapy in recurrent /metastatic HNSCC, the need for biomarker-driven treatment selection, and the ongoing investigation of immunotherapy in earlier disease settings, as recommended by the American Society of Clinical Oncology and highlighted by the American Head and Neck Society
• References:
  • Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline. Yilmaz E, Ismaila N, Bauman JE, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(5):1132-1146. doi:10.1200/JCO.22.02328.
  • Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Narrative Review. Sim ES, Nguyen HCB, Hanna GJ, Uppaluri R. JAMA Otolaryngology– Head & Neck Surgery. 2025;151(5):521-528. doi:10.1001/jamaoto.2024.5254.
  • Neoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma: A Review From the American Head and Neck Society. Contrera KJ, Kansara S, Goyal N, et al. JAMA Otolaryngology– Head & Neck Surgery. 2025;:2833345. doi:10.1001/jamaoto.2025.0410.
  • Update: Immunotherapeutic Strategies in HPV-Associated Head and Neck Squamous Cell Carcinoma. Sun F, Colevas AD. Viruses. 2025;17(5):712. doi:10.3390/v17050712.

• Technical Considerations:
  • General Axillary dissection in melanoma includes:
    • Levels I, II, and III lymph nodes (Figure)
  • The arm, shoulder, and chest:
    • Are prepped and included in the surgical field
  • Incision:
    • I generally use a slightly S-shaped incision:
      • Beginning anteriorly along the superior portion of the lateral edge of the pectoralis major muscle:
        • Traversing the axilla over the fourth rib and extending inferiorly along the anterior border of the latissimus dorsi muscle
    • The incision should be constructed:
      • So that previous scars can be excised en bloc with the specimen
  • Skin Flaps:
    • Skin flaps are raised:
      • Anteriorly to the lateral border of the pectoralis muscle and the midclavicular line
      • Inferiorly to the sixth rib
      • Posteriorly to the anterior border of the latissimus dorsi muscle
      • Superiorly to just below the pectoralis major insertion
    • The medial side of the latissimus dorsi muscle:
      • Is dissected free from the specimen, exposing the thoracodorsal vessels and nerve
    • The lateral edge of the dissection:
      • Then proceeds cephalad to the axillary vein
    • In a lateral to medial fashion:
      • The thoracodorsal neurovascular bundle is skeletonized and preserved:
        • These maneuvers generally allow the next portion of the dissection to proceed from medial to lateral
    • The fatty and lymphatic tissue adjacent to the pectoralis major muscle:
      • Is dissected free around to its undersurface:
        • Where the pectoralis minor muscle is encountered
    • The interpectoral groove is exposed
  • Lymph Node Dissection:
    • The medial pectoral nerve is generally preserved
    • The interpectoral nodes are dissected free and lymphoareolar tissue swept from Rotter’s space
    • At this point, the dissection generally proceeds in a lateral to medial fashion, with lymph node bearing tissue swept medially:
      • The thoracodorsal bundle is again visualized:
        • The long thoracic nerve is identified and preserved
    • The fatty tissue between the two nerves is separated from the subscapularis muscle and included with the specimen
    • The upper axilla is exposed:
      • By bringing the patient’s arm over the chest by adduction and internal rotation
    • If nodes are bulky:
      • The pectoralis minor muscle may be divided to facilitate exposure
    • Dissection of the upper axillary lymph nodes should be sufficiently complete:
      • That the thoracic outlet beneath the clavicle, Halsted’s ligament, and subclavius muscle are seen
    • Fatty and lymphatic tissues are dissected downward over the axillary vein
    • The apex of the dissected specimen may be tagged
    • The specimen is removed from the lateral chest wall
  • Wound Closure:
    • One #15 French closed-suction drain:
      • Is usually placed percutaneously through the inferior flap into the axilla
    • An additional drain may be inserted through the inferior flap depending on body habitus
    • The skin is closed with interrupted 3-0 undyed absorbable sutures and running 4-0 subcuticular absorbable sutures
  • Postoperative Management:
    • Suction drainage is generally continued until output is less than 20mL to 30 mL per day for 2 consecutive days:
      • By approximately 4 weeks, the suction catheters are usually removed, regardless of the amount of drainage, to reduce the likelihood of infection
    • Subsequent fluid collections are removed by needle aspiration, or on occasion by percutaneous drainage

• Definition and Clinical Presentation:
  • Clinically detectable lymph node disease in cutaneous melanoma refers to:
    • The presence of palpable or radiologically evident nodal metastases:
      • Distinguishing it from microscopic (sentinel lymph node-positive) disease:
        • Which is only identified histologically after sentinel lymph node biopsy
    • Clinically detectable (macroscopic) nodal disease typically presents as:
      • Enlarged, firm, or fixed lymph nodes on physical examination or as nodal masses on imaging:
        • It is classified as stage III melanoma in the absence of distant metastases
• For patients who present with clinically apparent or detectable disease in the regional lymph node basin:
  • A staging work up is recommended
• A thorough clinical examination is essential:
  • With particular attention to the regional lymph node basins and a complete skin survey.[2][4] Laboratory studies may be considered if clinically indicated, but are not routinely recommended in the absence of symptoms.[4]
• Physical examination:
  • Should be performed to identify lesions suspicious for additional primary melanoma:
    • As well as to identify satellite disease and / or in-transit metastases
  • A thorough nodal examination should also be performed to exclude clinically suspicious nodal disease in other regional basins
• Staging evaluation typically includes baseline imaging with:
  • CT chest / abdomen / pelvis or PET/CT, and MRI of the brain:
    • This approach allows the surgeon to identify disease beyond the regional basin:
      • That may preclude a recommendation for lymphadenectomy
    • This is recommended by the American Academy of Dermatology and the National Comprehensive Cancer Network
  • If not already excised at the time of referral:
    • Image-guided biopsy (generally fine-needle aspiration biopsy or core) is preferred over excision to confirm regional disease
    • A similar approach may be used to document other patterns of metastasis, such as distant disease, that would alter treatment planning
• Mutation testing for BRAF should also be performed
• In the absence of distant metastasis:
  • Regional nodal disease has generally been approached with a recommendation for formal therapeutic lymphadenectomy followed by consideration of adjuvant therapy
• Therapeutic lymph node dissection (TLND):
  • Is the standard of care for patients with clinically detectable lymph node metastases from cutaneous melanoma:
    • Provided there is no evidence of distant metastatic disease
  • The goal is complete resection of all involved nodal tissue in the affected basin:
    • The extent of surgery may be individualized based on the burden and distribution of nodal disease, patient comorbidities, and evolving evidence regarding the prognostic and therapeutic impact of nodal clearance
  • In select cases, less extensive surgery may be considered if the index node can accurately predict response, but this approach remains investigational
• Role of Systemic Therapy:
  • Following complete surgical resection:
    • Adjuvant systemic therapy is recommended to reduce the risk of recurrence
  • Immune checkpoint inhibitors (such as nivolumab or pembrolizumab):
    • Are standard options, and for patients with BRAF V600-mutant melanoma:
      • Adjuvant targeted therapy with dabrafenib plus trametinib is also an established approach:
        • These therapies have demonstrated improvements in recurrence-free survival
  • Neoadjuvant systemic therapy:
    • Is under active investigation and may be considered in select cases:
      • Particularly in the context of clinical trials or multidisciplinary discussion:
        • But is not yet standard of care
• Multidisciplinary Approach and Patient Counseling:
  • Management should be coordinated in a multidisciplinary setting:
    • Involving surgical oncology, medical oncology, and radiology:
      • To ensure optimal staging, treatment planning, and integration of systemic therapies
    • Shared decision-making is critical, with discussion of the risks and benefits of surgery, the role of adjuvant therapy, and the importance of surveillance for recurrence
• Areas Needing Further Evidence:
  • The optimal sequencing and selection of neoadjuvant versus adjuvant systemic therapy, as well as the potential for de-escalation of surgery in select patients, are areas of ongoing research and require further evidence before routine adoption into clinical practice
• References:
  • Current Management of Melanoma Patients With Nodal Metastases. Han D, van Akkooi ACJ, Straker RJ, et al. Clinical & Experimental Metastasis. 2022;39(1):181-199. doi:10.1007/s10585-021-10099-7.
  • 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.
  • The Extent of Surgery for Stage III Melanoma: How Much Is Appropriate?. Franke V, van Akkooi ACJ. The Lancet. Oncology. 2019;20(3):e167-e174. doi:10.1016/S1470-2045(19)30099-3.
  • 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.

• Candidates for SLN biopsy include:
  • Patients with newly diagnosed clinically node-negative primary cutaneous melanoma:
    • Who are predicted to be at intermediate or high risk of harboring occult regional nodal disease based on primary tumor characteristics
  • Many melanoma clinicians consider a threshold risk of a positive SLN:
    • Of at least 5% to be sufficient in an otherwise healthy individual to offer lymphatic mapping and sentinel node biopsy
• Although uniform risk thresholds have not been completely resolved:
  • A tumor thickness threshold for SLN of at least 0.8 mm or for tumors < 0.8 mm with ulceration or other high-risk features, including:
  • Lymphovascular invasion or high mitotic rate:
    • Particularly when associated with young age:
      • Can be considered for SLNB
• The Melanoma Institute Australia SLN metastasis risk prediction tool may also be referenced as a useful guide to estimate individual risk of harboring a tumor-involved SLN:
  • https://www.melanomarisk.org.au/index

• Technical Considerations:
  • Performed using preoperative lymphoscintigraphy and intraoperative blue dye and / or radiotracer
  • Nodes identified are sent for detailed histologic and immunohistochemical analysis
• Special Scenarios:
  • Head & Neck Melanoma:
    • SLNB feasible but technically challenging:
      • Should be done in experienced centers
  • Acral Lentiginous Melanoma:
    • SLNB recommended if ≥ 1 mm or high-risk features present
    • Elderly Patients:
      • Consider individual comorbidities and life expectancy
      • Age alone is not a contraindication
• Contraindications to SLNB:
  • Clinically or radiographically positive nodes
  • Medical unfitness for anesthesia / surgery
  • Limited life expectancy or competing risks that outweigh benefit
• Prognostic Value:
  • SLN status is the strongest predictor of survival in clinically node-negative melanoma
  • SLNB guides adjuvant systemic therapy decisions
  • References:
    • Morton DL et al., N Engl J Med. 2006;355(13):1307–1317.
    • Faries MB et al., N Engl J Med. 2017;376(23):2211–2222.
    • Gershenwald JE et al., CA Cancer J Clin. 2017;67(6):472–492.
• Follow-Up:
  • SLN-negative:
    • Routine clinical and imaging surveillance
  • SLN-positive:
    • Consider adjuvant immunotherapy or targeted therapy
    • Imaging surveillance recommended
• Conclusion:
  • SLNB is a vital component of melanoma management for accurate staging and treatment guidance
  • It should be offered to patients based on tumor thickness and high-risk features, per NCCN and international consensus guidelines

• Historically, patients who have a melanoma-positive sentinel lymph node (SLN) identified by SLNB:
  • Had completion lymph node dissection (CLND):
    • Pathologic evaluation of CLND specimens:
      • Often reveals no additional disease
• It is important to remember that CLND specimens are routinely assessed with standard histologic techniques rather than the more rigorous approach employed for SLNB specimens:
  • As a result, there may be additional disease in the completion node dissection specimen that goes undetected:
    • This disease, in theory, represents a potential source of subsequent recurrence if it were not removed:
      • CLND performed for microscopic disease provides the potential for improved regional control
      • In addition, identifying patients with minimal disease burden by using the SLN approach may help identify the group of patients who may derive an improved survival benefit from early CLND
      • Furthermore, knowledge of the pathologic status of the SLNs allows proper staging and thus facilitates decision making regarding adjuvant treatment
• In several studies, when the non-SLNs in a CLND specimen were evaluated by H&E staining and immunohistochemistry:
  • Only 8% to 25% of CLND specimens:
    • Contained additional nodes with metastatic disease
  • Since most patients have metastatic disease identified only in SLNs:
    • There has been interest in identifying patients who, despite having a positive SLN, have a low probability of metastatic disease in non-SLNs
• In an analysis of primary tumor and SLN characteristics:
  • The number of SLNs harvested, the Breslow thickness of the primary tumor, and SLN burden (largest focus of metastasis, total area of metastases, number of metastatic foci, and extracapsular extension):
    • Most accurately predicted the presence of tumor in non-SLNs

• Clinical Relevance:
  • Among patients with a positive sentinel lymph node (SLN):
    • The presence of metastasis in non-sentinel lymph nodes (NSLNs):
      • Which occurs in 8% to 25% of the cases:
        • Worsens prognosis
  • Historically, completion lymph node dissection (CLND) was performed to detect such diseas:
    • But is no longer routine due to lack of survival benefit (MSLT-II, DeCOG-SLT):
      • However, identifying patients at high risk for NSLN positivity remains important for risk stratification and surveillance planning
• Incidence of NSLN Metastasis:
  • Approximately 15% to 20% of patients with a positive SLN will have additional NSLN metastases on CLND
  • References:
    • 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.
• Predictors of NSLN Positivity:
  • Several clinicopathologic features are associated with increased likelihood of NSLN involvement please see table
  • Reference:
    • van Akkooi AC, Nowecki ZI, Voit C, et al. Eur J Cancer. 2008;44(15):2196–2204.

• Predictive Models and Nomograms:
  • Several models estimate the risk of NSLN involvement to guide decision-making:
    • Rotterdam Criteria:
      • Based on size of largest metastasis in SLN
    • Dewar Criteria:
      • Considers subcapsular vs parenchymal SLN involvement
    • Sunbelt Melanoma Trial:
      • Proposed a model incorporating tumor burden and other pathologic features
  • References:
    • van Akkooi AC, de Wilt JH, Verhoef C, et al. Ann Surg Oncol. 2006;13(10):1511–1518.
    • Dewar DJ, Newell B, Green MA, et al. J Clin Pathol. 2004;57(6):602–606.
• Current Practice and Surveillance:
  • Routine CLND is no longer recommended for all SLN-positive patients (per MSLT-II and DeCOG-SLT)
  • Close nodal basin ultrasound surveillance is now standard
  • Patients with high-risk features may be considered for intensified follow-up or adjuvant systemic therapy
  • Guidelines:
    • NCCN Guidelines for Melanoma, Version 2.2024
    • ASCO/SSO Clinical Practice Guidelines
• Prognostic Implications:
  • Patients with NSLN involvement have significantly worse melanoma-specific survival (MSS) and recurrence-free survival (RFS) than those with SLN-only disease
  • Presence of NSLN metastases upstages patients within AJCC stage IIIC / IIID
  • Reference:
    • Gershenwald JE, Scolyer RA, Hess KR, et al. CA Cancer J Clin. 2017;67(6):472–492.
• Conclusion:
  • While routine CLND is no longer standard, identifying patients at risk for NSLN involvement remains clinically important
  • Tumor burden in the SLN, ulceration, and number of positive SLNs are key predictors
  • This information is essential for prognostication, risk-adapted surveillance, and selecting candidates for adjuvant therapy

• 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

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