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Metastatic Melanoma of Unknown Primary Site

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Approximately 1% to 8% of patients with melanoma:
    • Present with metastatic disease from melanoma of unknown primary (MUP) site
  • The most common presentation is:
    • In the axillary lymph node basin (> 50%):
      • Followed by the cervical lymph node basin
  • Various reasons have been proposed for the phenomenon of MUP site:
    • Anbari et al. suggested the following possibilities for primary lesions:
      • An unrecognized melanoma
      • A treated melanoma that had been initially misdiagnosed
      • A spontaneously regressed melanoma
      • Malignant transformation of a melanocyte that had traveled to a metastatic location
  • For metastatic melanoma to be classified as MUP site:
    • The histologic diagnosis must be confirmed
    • Previous biopsies and / or excisions, if any, should be evaluated for a possible diagnosis of melanoma
    • Less common primary sites for melanoma should be thoroughly evaluated
  • A thorough history may also identify prior lesion that was excised or destroyed:
    • But never pathologically examined
  • If the metastatic lesion is to a lymph node basin:
    • The drainage areas of that basin should be rigorously examined
    • Furthermore, patients should undergo staging evaluation with:
      • CT of the chest, abdomen, and pelvis (also including neck CT if anatomically appropriate), and MRI of the brain
      • PET / CT can also be considered, particularly in the setting of extremity soft tissue metastasis associated with unknown primary
  • Several studies have compared the survival of these patients to similar cohorts having equivalent nodal status and a known primary site:
    • Although patients with unknown primary tumors were historically believed to have worse prognoses:
      • Recent studies have contradicted earlier findings by demonstrating that patients with MUP have a natural history that is similar to (if not better than) the survival of many patients with stage III disease:
        • Given their survival profile, such patients with nodal disease should be staged as stage III and treated like stage III patients with a known primary melanoma, including consideration for stage III clinical trials

Dissection of the Iliac and Obturator Nodes in Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • General:
    • I generally perform a deep groin dissection (dissection of the iliac and obturator nodes) for the following indications:
      • Known involvement of the nodes revealed by preoperative imaging studies
      • More than three grossly positive nodes in the superficial lymph node dissection specimen
      • Metastatic disease in Cloquet node:
        • If performed
  • Incision:
    • To gain access to the deep nodes, we extend the skin incision superiorly if performed concomitantly with a superficial groin dissection
    • If a deep groin dissection only is to be performed:
      • I generally use a dedicated right lower quadrant incision
  • Lymph Node Dissection:
    • The external oblique muscle:
      • Is split from a point superomedial to the anterior superior iliac spine to the lateral border of the rectus sheath
    • The internal oblique and transversus abdominis muscles:
      • Are divided, and the peritoneum is retracted superiorly
    • An alternative approach:
      • Sometimes used when extensive disease populates this region:
        • Is to split the inguinal ligament vertically:
          • Medial to the femoral vein
    • The ureter is exposed:
      • As it courses over the iliac artery
    • The inferior epigastric artery and vein are divided, if necessary
    • The bifurcation of the common iliac artery marks the cephalad extent of the dissection:
      • All nodes are taken along the external iliac artery to the inguinal ligament caudally
    • Nodes overlying the external iliac vein:
      • Are dissected to the point at which the internal iliac vein courses under the internal iliac artery
    • The plane of the peritoneum is traced along the wall of the bladder:
      • The fatty tissues and lymph nodes are dissected off the perivesical fat starting at the internal iliac artery
    • Dissection is completed on the medial wall of the external iliac vein, and the nodal chain is further separated from the pelvic fascia until the obturator nerve is seen
    • Obturator nodes:
      • Are located in the space between the external iliac vein and the obturator nerve (in an anteroposterior direction) and between the internal iliac artery and the obturator foramen (in a cephalad–caudad direction)
    • The obturator artery and vein usually need not be disturbed
  • Wound Closure:
    • The transversus abdominis, internal oblique, and external oblique muscles:
      • May be closed with running sutures
    • The inguinal ligament, if previously divided:
      • Is approximated with interrupted nonabsorbable sutures to Cooper ligament medially and to the iliac fascia lateral to the femoral vessels
    • A closed suction drain is placed in the deep pelvic space exiting through a separate small incision
  • Postoperative Management:
    • Suction drainage is continued until output is less than 20 mL to 30 mL per day for 2 consecutive days
    • The pelvic drain is usually removed prior to hospital discharge
    • Ambulation is encouraged the day after surgery
    • Patients are hospitalized postoperatively for expectant management of potential ileus after deep pelvic surgery and for pain control, usually for a duration of 2 to 3 days

ASCO 2025 Guidelines for Head and Neck Cancer

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:

Superficial (Inguinal) Groin Dissection for Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
Figure 1: Skin Incisions for Superficial Groin Dissection
Technique of inguinal lymph node dissection.
A: The borders of the femoral triangle are the inguinal ligament superiorly, the sartorius laterally, and the adductor longus medially.
B: The lymphatic contents removed during a superficial inguinal lymphadenectomy include the lymphatic contents of the femoral triangle as well as nodal tissue that lies superficial to the external oblique superior to the inguinal ligament.
C: The lazy-S incision used for an inguinal lymphadenectomy.
D: The anatomy visualized during an inguinal lymphadenectomy. (From Balch CM, Milton GW, Shaw HM, et al., eds. Cutaneous Melanoma. Lippincott; 1985.)
A: Lymphatic anatomy of the inguinal and iliac-obturator area demonstrating the superficial and deep lymphatic chains. Cloquet node lies at the transition between the superficial and deep inguinal nodes. It is located beneath the inguinal ligament in the femoral canal.
B: The iliac-obturator nodes include those distal to the common iliac bifurcation, and around the external and internal iliac vessels, and the obturator nodes. Obturator nodes should be excised as part of an iliac-obturator nodal dissection. (From Balch CM, Milton GW, Shaw HM, et al., eds. Cutaneous Melanoma. Lippincott; 1985.)
Transection of the sartorius muscle at its origin on the anterior superior iliac spine in preparation for transposition over the femoral vessels and nerves. (From Balch CM, Milton GW, Shaw HM, et al., eds. Cutaneous Melanoma. Lippincott; 1985, with permission.)

ASCO 2025 Head and Neck Cancer Updates

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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:

Axillary Dissection

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
Lymphatic anatomy of the axilla showing the three groups of axillary lymph nodes defined by their relationship to the pectoralis minor muscle. The highest axillary nodes (level III) medial to the pectoralis minor muscle should be included in an axillary lymph node dissection for melanoma.
Access to the upper axilla. The arm is draped so that it can be brought over the chest wall during the operation. This facilitates retraction of the pectoralis muscles upward to reveal the level III axillary lymph nodes. (From Balch CM, Milton GW, Shaw HM, et al., eds. Cutaneous Melanoma. Lippincott; 1985.)

Management of Clinically Detectable Lymph Node Disease at Presentation in Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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:
Rodrigo Arrangoiz, MD (Oncology Surgeon)

Current Practice Guidelines for the Use of Sentinel Lymph Node Biopsy

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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:
Current Practice Guidelines for the Use of Sentinel Lymph Node Biopsy. Who Should get a SLNB?
Reference: NCCN Guidelines for Melanoma, Version 2.2024
  • 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

Identifying Additional Disease in Nonsentinel Nodes in Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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

Role of Completion Lymph Node Dissection (CLND) for Patients With a Melanoma-Involved Sentinel Lymph Node (SLN)

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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

Benefits and Risks of CLND.
  • 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