Management of lentiginous melanoma with imiquimod assessed by reflectance confocal microscopy.

Lentiginous melanoma (LM) has poorly defined margins and may be subject to inaccurate assessment by traditional methods, including clinical evaluation and dermoscopy.1 Imiquimod, a topical immunomodulatory agent, has been used as an alternative to surgical treatment for LM, but concern for incomplete tumour clearance limits its widespread adoption. Reflectance confocal microscopy (RCM) is a high-resolution, non-invasive imaging technique and a reliable diagnostic tool to identify LM, with a sensitivity of 85% and specificity of 76%.2 Given LM often presents on cosmetically sensitive regions such as the face, non-invasive therapy and monitoring techniques, such as imiquimod and RCM, respectively, may be preferred. We systematically reviewed the literature on LM treated with imiquimod and assessed by RCM. We identified 10 relevant publications and graded the evidence using the Joanna Briggs Institute (JBI) critical appraisal tool (Table 1, Supplementary Figure S1). Across all studies, there was a total of 168 participants, of which 114 were female and 54 were male. Participants' ages ranged from 33 to 90. Facial LM was the most common type of LM evaluated in all publications reviewed. In 7/10 publications, a treatment regimen of imiquimod 5% daily, five times per week was utilised. The average length of imiquimod treatment in the evaluated studies was approximately 10 weeks. Studies reproducibly demonstrated imiquimod as a potential treatment alternative to traditional surgical excision. Furthermore, RCM margin evaluation had high concordance with gold standard histopathology (Table 1). For the studies that specified evaluation time points, RCM assessment was performed four or more weeks after treatment with imiquimod. One prospective study (n = 20) reported LM histopathologic clearance with imiquimod in 75% of patients. RCM identified 93% of the responders with no false negatives (compared to histopathology) at 12 weeks and 12 months after treatment. Responders continued to have histopathological clearance for a mean of 34 months3 Several retrospective studies demonstrated imiquimod to be an adequate treatment for LM with concurrent RCM monitoring. In one study (n = 18) evaluating 5-year recurrence rates of LM after imiquimod treatment, all 18 patients had histopathologically clear margins 3 months post-treatment. Long-term tumour clearance (mean follow-up 7.4 years) measured by RCM revealed no evidence of recurrence in any patient.9 In another retrospective study (n = 34), 33/34 patients demonstrated initial therapeutic response with imiquimod as measured by RCM and histopathology. Seven patients had LM recurrence within a mean of 3.07 years. RCM measurements significantly correlated with histopathology results (r = 0.7335, p = 0.0001).5 Another retrospective study detected recurrence in 1/7 patients treated with imiquimod at 1-year follow-up (tumour had previously recurred five times). This patient was treated with a subsequent course of imiquimod, and no recurrence was detected via RCM evaluation at 40 months following this second treatment.1 A subsequent retrospective study (n = 28) demonstrated complete clearance in 25/28 participants treated with imiquimod. In comparison to histopathological evaluation for tumour recurrence, RCM had a specificity of 94% and a sensitivity of 100%.7 In a case series of three participants treated with imiquimod for LM, two achieved complete clearance and had no recurrence after an 18-month follow-up period, evaluated by RCM and histopathology concordantly. One patient achieved partial clearance at initial evaluation by RCM, but was lost to follow-up.6 An additional case series included two patients with LM treated with imiquimod. One patient achieved complete clearance after 3 months of therapy and remained disease-free 2 years after treatment. The other patient failed 7 months of treatment and required surgical excision. RCM was concordant with histopathological evaluation in both cases.10 A randomized controlled trial evaluated imiquimod as a neoadjunvant treatment prior to surgery. Researchers compared the pre-surgical treatment of LM with imiquimod versus placebo. Prior to surgery, pre-determined RCM features, such as non-edged dermal papillae, were significantly decreased in the imiquimod arm (n = 21) versus placebo (n = 19) after 1 month of treatment (p < 0.001). RCM was concordant with histology in 19 of 21 patients (90%) with no false negatives.11 Current data demonstrate that imiquimod can be effectively utilised in the treatment of LM. This review is limited by varying follow-up times for long-term tumour recurrence monitoring. Prior data have shown that the median time to LM recurrence after treatment is 3.8 years12 Two of the included publications had a follow-up period greater than 3.8 years. In these studies, a tumour recurrence was detected in 10/34 patients. Given that, imiquimod alone may not be sufficient for complete LM clearance and may be more suitable as an adjunctive therapy. Larger prospective studies are warranted to explore the limitations of and an appropriate clinical scenario for imiquimod as monotherapy for LM treatment. RCM demonstrated margin evaluation concordance or significant positive correlation with histopathology in 9/10 publications. Of particular clinical importance, in the 8 studies that reported concordance rates, there were no false negatives when RCM was used to evaluate for residual LM following imiquimod treatment. This supports its potential use as a non-invasive and reliable method to monitor imiquimod treatment of LM. This letter received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare that there is no conflict of interest. Joseph Han: Conceptualization (Lead); Data curation (Lead); Formal analysis (Lead); Investigation (Lead); Methodology (Lead); Project administration (Lead); Validation (Lead); Visualization (Lead); Writing – original draft (Lead); Writing – review & editing; Lead. Hansen Tai: Conceptualization (Lead); Data curation (Lead); Formal analysis (Lead); Investigation (Lead); Methodology (Lead); Project administration (Lead); Validation (Lead); Visualization (Lead); Writing – original draft (Lead); Writing – review & editing (Lead). Dina Poplausky: Data curation (Equal); Formal analysis (Equal); Investigation (Equal); Methodology (Equal); Project administration (Equal); Validation (Equal); Visualization (Equal); Writing – original draft (Equal); Writing – review & editing (Equal). Jade Young: Data curation (Equal); Formal analysis (Equal); Investigation (Equal); Methodology (Equal); Project administration (Equal); Validation (Equal); Visualization (Equal); Writing – original draft (Equal); Writing – review & editing; Equal. Rishab Revankar: Data curation (Equal); Investigation (Equal). Peter Baek: Data curation (Equal); Investigation (Equal); Samantha Walsh: Data curation (Lead); Methodology (Lead); Nicholas Gulati: Conceptualization (Lead); Methodology (Lead); Project administration (Lead); Supervision (Lead); Writing – review & editing (Lead). This article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Not applicable. The data that supports the findings of this study are available in the supplementary material of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.