What is the appropriate treatment of macroscopic (i.e. detectable clinically or by ultrasound) nodal metastases?
At the time of writing of this guideline, surgery remains the standard of care for patients with symptomatic or imaging detected lymph node field relapse of melanoma. In a small proportion of patients (typically <5%), the extent of the disease is such as to preclude complete surgical resection. In this situation radiotherapy is an option, however systemic therapy with targeted therapies or immune checkpoint inhibitors are increasingly an option. The possibility of a neoadjuvant approach to these patients with extensive disease has been proposed but at the present time must remain an investigational approach.
Notwithstanding the enormous strides that have been made with targeted therapies and immune checkpoint inhibitors for patients with metastatic disease, there is currently no evidence that these agents have a definitive role in the management of patients with lymph node field relapse. Numerous studies investigating a role for these agents are currently underway and where appropriate patients should be referred for possible participation in these studies.
Even with the widespread use of sentinel node biopsy (SNB) approximately 50% of patients with Stage III disease present with symptomatic, usually palpable or imaging detected lymph node field recurrence. These patients include those who did not undergo SNB, patients who had a false negative SNB and patients presenting with lymph node field relapse and no known primary lesion. Lymph node field recurrence is the commonest and usually first site of recurrence of melanoma in patients not undergoing a SLNB. Patients with thick melanomas who did not undergo a SNB have a median time to presentation with a lymph node field recurrence of 9 months and for patients with intermediate thickness melanoma and no sentinel node biopsy around 19 months. However lymph node filed recurrence many years after treatment of a primary lesion are a well-recognised but uncommon phenomenon. Surgical management of patients presenting with macroscopic nodal disease results in a lymph node field results in long term control in nearly 50% of patients, however this varies widely depending on a number of factors including time since treatment of the primary lesion and features of the primary melanoma including thickness and ulceration. The reported ten year survival of patients in the AJCC database is approximately 45% for patients with Stage III B disease (1-3 nodes involved)and approximately 25% for patients with Stage III C disease (more than 3 nodes involved). As there is still a high risk of failure with surgical therapy there is great interest in the addition of effective systemic therapies to the management of these patients either in the adjuvant or neoadjuvant setting and clinical trials are currently underway.
The diagnosis should be confirmed pre-operatively preferably, by ultrasound guided fine needle aspirate (FNAC)) even for palpable lymphadenopathy rather than open biopsy (or core needle biopsy) which may potentially contaminate the operative site.
The risk for patients with clinical stage 3B/C disease of occult disseminated disease at presentation is approximately 20%. Preoperative staging preferably by PET-CT and MRI brain is therefore indicated. Alternatively CT may be used. PET/CT however has superior sensitivity and specificity for staging compared to other imaging modalities. MRI brain is superior to standard CT brain.
Tumour markers (LDH, S100 etc) have not been shown to be particularly sensitive or specific in staging patients with stage III B/C disease nor useful in planning treatment or predicting outcome and are not recommended.
Patients with macroscopic nodal disease should have the diagnosis confirmed preoperatively by image guided fine needle aspiration cytology and undergo staging with whole body PET-CT and MRI brain or CT Brain, Chest Abdomen and Pelvis.
Systematic review evidence
Extensive observational data indicates surgical management of the lymph node field by radical lymphadenectomy results in long term control in up to 50% of patients. There is limited data available as to the extent of the surgery. Limited and indirect evidence favours radical comprehensive surgical procedures over less aggressive approaches. Special situations include patients presenting with lymphadenopathy and no prior history of a primary lesion (unknown primary). These patients achieve results comparable or better to those with a recognised primary lesion with standard surgical management.
Complete clearance of the involved lymph node field is indicated. There is little data available comparing radical clearance with lesser procedures. Higher rates of local recurrence and potentially worse survival have been noted following inadequate surgery. In a number of retrospective studies, the adequacy of the surgical procedure as determined by the number of lymph nodes removed and performance of the surgery in a high volume institution were associated with reduced risk of lymph nodes field relapse and distant relapse. More recently the Lymph Node Ratio (the number of involved to uninvolved nodes) has been shown to be related to both survival and regional recurrence presumably reflecting the completeness of the lymphadenectomy.
The surgical options for management of cervical lymphadenopathy include radical neck dissection (removal of all nodes in levels I-V including sterno mastoid muscle, accessory nerve and internal jugular vein), extended radical (includes a superficial parotidectomy in addition), modified radical neck dissection (removal of all nodes in levels I-V with preservation of all or some of sterno mastoid muscle, accessory nerve and internal jugular vein) or selective node dissection (removal of less than levels I-V usually with preservation of major structures). In addition resection of occipital/retro-auricular nodes is indicated for primary melanomas located behind the plane of the external auditory canal, patients who had lymphatic mapping to the area but no SLNB found or patients with involved lymph nodes in this region.
Patients with a parotid lymph node field recurrence have a risk of upper cervical lymph node involvement of up to 20%. Surgical management of parotid lymphadenopathy should include parotidectomy and an upper level cervical lymphadenectomy (levels 1B, 2, 3, and upper 5 and possibly 1a).
Patients with a parotid lymph node recurrence should undergo a superficial parotidectomy and upper neck dissection (levels 1B, 2, 3, and upper 5 and possibly 1a).
In principle the sterno mastoid muscle, accessory nerve or internal jugular vein should only be removed if involved with tumour or to facilitate complete resection. The role of selective lymphadenectomy is undetermined. At present for limited volume disease it appears to offer similar rates of regional and distant control to more aggressive procedures however for patients with more extensive disease i.e. N2, N3 disease higher rates of local recurrence in particular have been noted.
The standard procedure for axillary lymph node involvement is a complete level 1-3 lymphadenectomy which may include resection of the pectoralis minor muscle (to facilitate clearance of the superior axilla), intercosto-brachial nerve(s) and usually medial pectoral nerve dependent on the extent of disease and body habitus. Less extensive procedures may be associated with higher rates of regional recurrence.
The surgical management of inguinal lymph node field relapse is controversial with proponents arguing for inguinal lymphadenectomy or combined inguinal and pelvic lymphadenectomy. Pre-operative staging should involve a CT scan or PET / CT scan of the inguinal and pelvic lymph node fields to exclude the presence of pelvic lymph node involvement as 25 to 50% of patients undergoing combined inguinal and pelvic lymphadenectomy will have pelvic lymph node involvement. Unfortunately the sensitivity and specificity of CT scanning in this situation is limited and there is limited data on the effectiveness of PET / CT scanning. Intraoperative assessment of the risk of pelvic lymph node involvement based on femoral canal or Cloquet’s node status is unreliable. Tumour volume as determined by increasing number and size of inguinal nodes is associated with an increased risk of pelvic lymph node involvement but is of limited practical value for most cases.
Hesitation around recommending combined inguinal and pelvic lymphadenectomy reflects concerns about undertaking a more extensive and possibly more morbid procedure in the absence of a definite survival advantage. Unproven concerns about worse lymphoedema and poorer quality of life with the combined procedure has led most authorities to recommend inguinal and pelvic lymphadenectomy only for proven pelvic involvement or the presence of extensive inguinal disease. A prospective long term evaluation of symptoms, quality of life and limb volumes found no differences between inguinal and combined inguinal and pelvic lymphadenectomy. There is an ongoing randomised controlled trial evaluating the role of inguinal versus ilio-inguinal lymphadenectomy in this situation. This study is a proof of principle study that less extensive surgery is safe when the PET / CT scan is negative in the pelvic area. It is a lead into other surgical extent de-escalation studies, especially relevant in the era of impending effective neoadjuvant and / or adjuvant therapy.
Unknown primary melanoma
In approximately 10-15% of patients with palpable lymphadenopathy the site of the primary lesion cannot be identified. Possible explanations include a regressed primary melanoma or a melanoma arising within the lymph node itself. A complete skin examination should be performed and the pathology of any previous skin lesions reviewed.These patients should be worked up and treated in a similar fashion to patients with a recognised primary lesion. The outcomes for these patients is at least as good as for patients with an identifiable primary lesion.
Uncommon lymph node recurrences
Occasionally patients may present with disease in the epi-trochlear or popliteal fossae. Palpable disease in these lymph node fields may be associated with involvement of the inguinal or axillary lymph node fields and should be investigated prior to resection. In a small number of cases patients may present with disease just outside the axillary or inguinal lymph node fields. Consideration should be given to resecting the palpable recurrence, the adjacent lymph node field and the intervening tissue (in continuity resection).
Patients at high risk of lymph node field relapse after lymphadenectomy (at least 25%) include those with multiple nodes involved (1 parotid, >2 cervical or >3 axillary or inguinal), large lymph nodes (>3 cm) or extensive extra-capsular spread of tumour. Adjuvant radiotherapy reduces the risk of lymph node field relapse by approximately 50% but does not improve survival. In addition radiotherapy is associated with worse long term regional symptoms and increased lymphoedema in the lower limb. Patients who develop an isolated lymph node field relapse after lymphadenectomy alone can often be managed successfully by a combination of surgery and radiotherapy.
Adjuvant systemic therapy
The use of adjuvant systemic therapies at the present time is highly controversial. Currently routine systemic therapy after lymphadenectomy cannot be recommended. Interferon alpha 2B (four week high dose induction therapy followed by 11 months maintenance therapy) is associated with a small improvement in survival (3% at five years) but with potential significant toxicity. Initial results from a trial of ipilimumab (10 mg/kg) resulted in a modest improvement in survival but again at the risk of significant toxicity. Early data from a number of studies of BRAF and MEK inhibition and anti-PD-1 immunotherapy are encouraging but mature data is not yet available.
Evidence summary and recommendations
|Lymphadenectomy provides long term control in up to 50% of patients with Stage III B and III C disease.||II|||
|Complete lymphadenectomy is recommended for patients with palpable or imaging detected lymph node field recurrence.||C|
Complete lymphadenectomy results in improved regional control over lesser procedures.
All patients with Stage III B/C disease should be presented at a multidisciplinary management meeting.
These high risk patients should be offered the opportunity to enrol in systemic adjuvant or neoadjuvant therapy trials.
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