What are the most effective treatment/management interventions to improve outcomes in patients with lentigo maligna?
Lentigo maligna (LM), historically known as Hutchinson’s melanotic freckle, is a subtype of melanoma in situ characterised by atypical intraepidermal melanocytes that usually occurs in sun damaged skin. If left untreated LM can develop into invasive melanoma, term lentigo maligna melanoma (LMM), which shares the same prognosis as other types of invasive melanoma. LM usually occurs in the elderly population and is most commonly found on the head or neck region on severely sun damaged skin. However particularly in Australia, LM is occasionally found on the trunk and extremities. The diagnosis of LM is based on clinical and dermoscopic features, and confirmed through biopsy and histopathological assessment. The most effective treatment of LM is complete surgical excision with at least 5mm margins, however the often sensitive anatomical location of the lesion, the age of the patient and size of the lesion can present challenges for surgical intervention. There are multiple non-surgical treatment alternatives currently used including radiotherapy, cryotherapy, laser ablation, and topical immunomodulatory therapies such as imiquimod. These procedures have the advantage of reduced morbidity and cosmetic impact, however they have not achieved the same level of complete clearance and recurrence rates over surgical removal of lesions.
Systematic review evidence
To date there have been no randomised controlled trials that have compared the outcomes of surgical and non-surgical treatment methods for LM. One RCT on the off-label use of Imiquimod, 5% cream with vs without Tazarotene, 0.1% gel for the treatment of LM has been published by Hyde et al (2012). This study concluded that the complete response rate of LM may be improved with the combined use of tazarotene with imiquimod, however it did not report statistically significant results. A Cochrane Systematic Review was conducted by Tzellos et al (2014) to compare all treatments of LM, though only the aforementioned Imiquimod trial met the RCT inclusion criteria. The Cochrane review further concluded that whilst the addition of tazarotene to imiquimod as an adjuvant therapy may increase inflammatory response, it also may result in early cessation of treatment due to treatment-related side effects.
Three cohort studies comparing the outcomes of conventional excision vs staged or Mohs micrographic surgery were identified for this review. Conventional excision has historically been the treatment method of choice when achieving 5mm margins LM location is not complicated by anatomical site of the LM. However, the studies reviewed suggested that 5mm margins, originally recommended by the National Institutes of Health (NIH) consensus statement in 1992, may be inadequate due to indistinct peripheral tumour borders often associated with LM, attributing to reported recurrence rates of between 6% and 20% As a result, Mohs micrographic surgery (MMS) has become increasingly used as a surgical method for LM removal. Mohs micrographic surgery has the advantage of intraoperative assessment of tumour margins, conserving the amount of healthy tissue removed and furthermore achieving lower recurrence rates (0.5% to 6.3%). The primary disadvantage of MMS remains the reliance on frozen sections and immunohistochemical staining for the challenging visualisation of epidermal melanocytes. However, techniques such as Slow MMS that use paraffin-embedded sections have been shown to improve the visualisation of melanocytes. Slow MMS or Delayed Reconstruction After Primary Excision (DRAPE) involves leaving an open wound with regular dressings while a carefully oriented FFPE sample is assessed and a pathology report issued. If close or positive margins are encountered, these can be re-excised. A definitive reconstruction is delayed until a satisfactory excision margin is achieved.
In addition to the 2014 Cochrane Review described above, three other systematic reviews were identified that assessed outcomes of non-surgical therapeutic treatment of LM. Mora and Tio both assessed outcomes for patients treated with imiquimod by reviewing 45 and 41 studies, respectively. Both authors concluded that while surgical removal remains the gold standard for the treatment of LM, imiquimod is a potential option for those patients not eligible or willing to undergo surgery and/or radiotherapy. Both reviews also recommended an intensive treatment regime of greater than 60 applications, with a frequency of six to seven applications per week. The clearance rates reported by Mora and Tio were 76–77% for histopathological clearance and 78% for clinical clearance, although these reviews were hindered by varying treatment protocols, short-term follow-up, and risk of publication bias in the case reports reviewed. In the systematic review by Read et al (2016), three non-surgical methods were evaluated; radiotherapy, imiquimod and laser therapy. Read et al evaluated 29 studies and likewise concluded that while surgical removal of LM remains the preferred treatment; radiotherapy and imiquimod are both alternative treatment options, with radiotherapy achieving superior complete response rates and fewer recurrences than imiquimod. Read et al also reported that the evidence available for the effective use of laser therapy was weak. A cohort study published by Hedblad and Mallbris (2011), describes the treatment of LM and early LMM with superficial energy radiotherapy in 593 patients. The study assesses outcomes for three types of managements including primary treatment with radiotherapy; partial surgical removal followed by radiotherapy; and radical surgical excision followed by postoperative radiotherapy as a recurrence prophylactic, with reported complete clearance rate of 83%, 90% and 97%, respectively. While radiotherapy has the advantage of being non-invasive, easy to perform, is well tolerated and is associated with positive cosmetic outcome, it does not achieve the same clearance and recurrence rates as surgical excision. Lee et al (2011) conducted a retrospective review comparing outcomes in treating LM though surgical excision, radiotherapy and carbon dioxide laser ablation. The authors found lower recurrence rates with surgical excision and carbon dioxide laser ablation, however the results were not statistically significant. Carbon dioxide laser ablation may have a role in treatment of LM when standard treatments are refused or unsuitable, however there is currently only weak evidence of its efficacy.
All publications reviewed resolved that the surgical removal of LM remains the reference standard treatment, however there remains a lack of quality evidence available to infer the most effective non-surgical treatment. Currently a multi-site, multi-country RCT (RADICAL) is underway by ANZMTG to compare outcomes of radiotherapy vs Imiquimod for complex LM where surgery is not suitable or refused. This trial is expected to produce a strong level of evidence that may influence future guidelines for the non-surgical treatment of LM.
Evidence summary and recommendations
|There have been no RCTs to date comparing the efficacy of all lentigo maligna (LM) treatments.||N/A|
|Mohs micrographic surgery (MMS) has shown to improve complete clearance rates and reduced recurrences over conventional surgical removal of LM.||III-2||, , |
|Superficial radiotherapy is a suitable alternative to surgical excision of LM or as adjuvant therapy after surgical excision especially for treatment of large lesions.||III-1|||
|Radiotherapy has shown to have superior complete clearance rates and few recurrences over imiquimod therapy for LM.||IV|||
|The addition of tazarotene to imiquimod as an adjuvant therapy can increase the inflammatory response for LM.||IV|||
|There is currently a lack of sufficient evidence available to determine the efficacy of laser therapy.||III-1, IV||, |
Diagnosis of lentigo maligna should be obtained by biopsy and histopathology.
|Complete surgical removal of lentigo maligna lesion with 5-10mm margins is the preferred management, when possible.||C|
|When surgical removal of lentigo maligna is not possible or refused, radiotherapy is recommended.||C|
|When both surgery and radiotherapy of lentigo maligna are not appropriate or refused, imiquimod is recommended.||D|
|Cryotherapy is not recommended for the treatment of lentigo maligna.||C|
|Laser therapy is not recommended for the treatment of lentigo maligna.||C|
Issues requiring more clinical research study
It is recommended that further RCTs on LM patients are performed. Currently a multi-site, multi-country RCT (RADICAL) is underway by ANZMTG to compare outcomes of radiotherapy vs Imiquimod for complex LM where surgery is not suitable or refused. This trial is expected to produce a strong level of evidence that may influence future guidelines for the non-surgical treatment of LM.
- Read T, Noonan C, David M, Wagels M, Foote M, Schaider H, et al. A systematic review of non-surgical treatments for lentigo maligna. J Eur Acad Dermatol Venereol 2016 May;30(5):748-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26299846.
- Hyde MA, Hadley ML, Tristani-Firouzi P, Goldgar D, Bowen GM. A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions. Arch Dermatol 2012 May;148(5):592-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22431716.
- Tzellos T, Kyrgidis A, Mocellin S, Chan AW, Pilati P, Apalla Z. Interventions for melanoma in situ, including lentigo maligna. Cochrane Database Syst Rev 2014 Dec 19;12:CD010308 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25526608.
- Walling HW, Scupham RK, Bean AK, Ceilley RI. Staged excision versus Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol 2007 Oct;57(4):659-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17870430.
- Hilari H, Llorca D, Traves V, Villanueva A, Serra-Guillén C, Requena C, et al. Conventional surgery compared with slow Mohs micrographic surgery in the treatment of lentigo maligna: a retrospective study of 62 cases. Actas Dermosifiliogr 2012 Sep;103(7):614-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22572575.
- Hou JL, Reed KB, Knudson RM, Mirzoyev SA, Lohse CM, Frohm ML, et al. Five-year outcomes of wide excision and Mohs micrographic surgery for primary lentigo maligna in an academic practice cohort. Dermatol Surg 2015 Feb;41(2):211-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25590473.
- Hedblad MA, Mallbris L. Grenz ray treatment of lentigo maligna and early lentigo maligna melanoma. J Am Acad Dermatol 2012 Jul;67(1):60-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22030019.
- Mora AN, Karia PS, Nguyen BM. A quantitative systematic review of the efficacy of imiquimod monotherapy for lentigo maligna and an analysis of factors that affect tumor clearance. J Am Acad Dermatol 2015 Aug;73(2):205-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26088690.
- Tio D, van der Woude J, Prinsen CAC, Jansma EP, Hoekzema R, van Montfrans C. A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures. J Eur Acad Dermatol Venereol 2017 Apr;31(4):616-624 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27987308.
- Lee H, Sowerby LJ, Temple CL, Yu E, Moore CC. Carbon dioxide laser treatment for lentigo maligna: a retrospective review comparing 3 different treatment modalities. Arch Facial Plast Surg 2011 Nov;13(6):398-403 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22106185.