What is the appropriate treatment for macroscopic (i.e. detectable clinically or by ultrasound) nodal metastasis?

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Introduction

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.[1] 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.[1] 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.[1] 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).[2] 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.[3] 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.


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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.

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Summary of systematic review results

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.[2] 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.[4] 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.

Surgical treatment

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.[4] 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.[5][6][7][8] 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.[7][9][10][11]

Cervical 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).


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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.[12][13]

Axillary lymphadenectomy

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.[14]

Inguinal lymphadenectomy

The surgical management of inguinal lymph node field relapse is controversial with proponents arguing for inguinal lymphadenectomy or combined inguinal and pelvic lymphadenectomy.[15][16] 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.[15][17]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.[18][15] 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.[19] 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.[20][21][22][23][24][25]

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).

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Adjuvant therapy

Adjuvant radiotherapy

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.[26] 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.[17] Patients who develop an isolated lymph node field relapse after lymphadenectomy alone can often be managed successfully by a combination of surgery and radiotherapy.[17][27]

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 (Mocellin 2012). 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. Results from a number of other trials of BRAF and MEK inhibition, anti PD-1 immune modulation therapy as well as combinations of different agents are awaited.

Evidence summary and recommendations

Evidence summary Level References
Lymphadenectomy provides long term control in up to 50% of patients with Stage III B and III C disease. II [2]

Recommendations

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Complete lymphadenectomy is recommended for patients with palpable or imaging detected lymph node field recurrence.
C



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Complete lymphadenectomy results in improved regional control over lesser procedures.


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All patients with Stage III B/C disease should be presented at a multidisciplinary management meeting.


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These high risk patients should be offered the opportunity to enrol in systemic adjuvant or neoadjuvant therapy trials.

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References

  1. 1.0 1.1 1.2 Spillane AJ, Pasquali S, Haydu LE, Thompson JF. Patterns of recurrence and survival after lymphadenectomy in melanoma patients: clarifying the effects of timing of surgery and lymph node tumor burden. Ann Surg Oncol 2014 Jan;21(1):292-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24052314.
  2. 2.0 2.1 2.2 Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009 Dec 20;27(36):6199-206 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19917835.
  3. Rodriguez Rivera AM, Alabbas H, Ramjaun A, Meguerditchian AN. Value of positron emission tomography scan in stage III cutaneous melanoma: a systematic review and meta-analysis. Surg Oncol 2014 Mar;23(1):11-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24556310.
  4. 4.0 4.1 Balch CM, Durant JR, Bartolucci AA. The impact of surgical quality control in multi-institutional group trials involving adjuvant cancer treatments. Ann Surg 1983 Aug;198(2):164-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6347102.
  5. Rossi CR, Mozzillo N, Maurichi A, Pasquali S, Macripò G, Borgognoni L, et al. Number of excised lymph nodes as a quality assurance measure for lymphadenectomy in melanoma. JAMA Surg 2014 Jul;149(7):700-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24804856.
  6. Rossi CR, Mozzillo N, Maurichi A, Pasquali S, Quaglino P, Borgognoni L, et al. The number of excised lymph nodes is associated with survival of melanoma patients with lymph node metastasis. Ann Oncol 2014 Jan;25(1):240-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24356635.
  7. 7.0 7.1 Spillane AJ, Cheung BL, Winstanley J, Thompson JF. Lymph node ratio provides prognostic information in addition to american joint committee on cancer N stage in patients with melanoma, even if quality of surgery is standardized. Ann Surg 2011 Jan;253(1):109-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21119509.
  8. Spillane AJ, Cheung BL, Stretch JR, Scolyer RA, Shannon KF, Quinn MJ, et al. Proposed quality standards for regional lymph node dissections in patients with melanoma. Ann Surg 2009 Mar;249(3):473-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19247037.
  9. Xing Y, Badgwell BD, Ross MI, Gershenwald JE, Lee JE, Mansfield PF, et al. Lymph node ratio predicts disease-specific survival in melanoma patients. Cancer 2009 Jun 1;115(11):2505-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19309746.
  10. Berger AC, Fierro M, Kairys JC, Berd D, Sato T, Andrel J, et al. Lymph node ratio is an important and independent prognostic factor for patients with stage III melanoma. J Surg Oncol 2012 Jan;105(1):15-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21815149.
  11. Rossi CR, Mocellin S, Pasquali S, Pilati P, Nitti D. N-ratio: a novel independent prognostic factor for patients with stage-III cutaneous melanoma. Ann Surg Oncol 2008 Jan;15(1):310-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17987346.
  12. Supriya M, Narasimhan V, Henderson MA, Sizeland A. Managing regional metastasis in patients with cutaneous head and neck melanoma - is selective neck dissection appropriate? Am J Otolaryngol 2014 Sep;35(5):610-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25080830.
  13. O'Brien CJ, Petersen-Schaefer K, Ruark D, Coates AS, Menzie SJ, Harrison RI. Radical, modified, and selective neck dissection for cutaneous malignant melanoma. Head Neck 1995 May;17(3):232-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7782208.
  14. Kretschmer L, Preusser KP. Standardized axillary lymphadenectomy improves local control but not survival in patients with palpable lymph node metastases of cutaneous malignant melanoma. Langenbecks Arch Surg 2001 Nov;386(6):418-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11735014.
  15. 15.0 15.1 15.2 Allan CP, Hayes AJ, Thomas JM. Ilioinguinal lymph node dissection for palpable metastatic melanoma to the groin. ANZ J Surg 2008 Nov;78(11):982-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18959697.
  16. West CA, Saleh DB, Peach H. Combined clearance of pelvic and superficial nodes for clinical groin melanoma. J Plast Reconstr Aesthet Surg 2014 Dec;67(12):1711-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25219338.
  17. 17.0 17.1 17.2 Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol 2015 Jul 20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26206146.
  18. van Wissen J, van der Hiel B, van der Hage JA, van de Wiel BA, Wouters MW, van Akkooi AC. The Diagnostic Value of PET/CT Imaging in Melanoma Groin Metastases. Ann Surg Oncol 2016 Feb 26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26920386.
  19. ClinicalTrials.gov. Evaluation of Groin Lymphadenectomy Extent For Metastatic Melanoma (EAGLE FM).; 2017 Nov 18 Available from: https://clinicaltrials.gov/ct2/show/NCT02166788.
  20. van der Ploeg AP, Haydu LE, Spillane AJ, Scolyer RA, Quinn MJ, Saw RP, et al. Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease. Ann Surg Oncol 2014 Sep;21(9):3108-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24802907.
  21. Prens SP, van der Ploeg AP, van Akkooi AC, van Montfort CA, van Geel AN, de Wilt JH, et al. Outcome after therapeutic lymph node dissection in patients with unknown primary melanoma site. Ann Surg Oncol 2011 Dec;18(13):3586-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21611857.
  22. Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer 2006 May 1;106(9):2012-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16568458.
  23. Hughes MC, Wright A, Barbour A, Thomas J, Smithers BM, Green AC, et al. Patients undergoing lymphadenectomy for stage III melanomas of known or unknown primary site do not differ in outcome. Int J Cancer 2013 Dec 15;133(12):3000-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23754707.
  24. Rutkowski P, Nowecki ZI, Dziewirski W, Zdzienicki M, Pieñkowski A, Salamacha M, et al. Melanoma without a detectable primary site with metastases to lymph nodes. Dermatol Surg 2010 Jun;36(6):868-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20482725.
  25. Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol 2008 Feb 1;26(4):535-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18235114.
  26. Burmeister BH, Henderson MA, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol 2012 Jun;13(6):589-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22575589.
  27. Barbour S, Mark Smithers B, Allan C, Bayley G, Thomas J, Foote M, et al. Patterns of Recurrence in Patients with Stage IIIB/C Cutaneous Melanoma of the Head and Neck Following Surgery With and Without Adjuvant Radiation Therapy: Is Isolated Regional Recurrence Salvageable? Ann Surg Oncol 2015 Jan 13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25582744.

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Appendices