Lentiginous Melanoma In Situ Treatment With Topical Imiquimod: Need for Individualized Regimens

Melanoma in situ, lentiginous type (LM), is a precursor lesion for invasive malignant melanoma, lentiginous type (LMM). Already the most prevalent subtype of in situ melanoma, LM has been shown to be increasing in incidence.¹ Currently, nonsurgical patients with LM have no treatment alternative but irradiation and so must endure the associated adverse effects of this treatment. In addition, recurrence following standard therapies is unacceptably high (8%-20%).² For these reasons, a new effective therapy for LM that provides local control, prevents progression to LMM, and decreases morbidity and mortality is clinically desirable.

Small studies have reported successful treatment of LM with imiquimod, 5%, cream. The present case series highlights 15 LM lesions in 14 patients treated with topical imiquimod. Histologic tissue specimens obtained before, during, and after treatment were evaluated to assist in directing patient management and in providing objective posttreatment histopathologic response.

This study was approved by the Saint Louis University institutional review board. After diagnostic biopsy, patients were offered surgical excision or treatment with topical imiquimod, 5%. The risks of each treatment were thoroughly discussed. Patients began imiquimod therapy with topical application 5 to 7 times each week, and this regimen was altered based on clinical response. Patients kept a log of treatment days and were observed closely during treatment. Pretreatment and posttreatment assessments were performed histologically and clinically in all patients. Intratreatment 4-mm punch biopsy specimens were obtained in 6 of the 14 patients. Imiquimod treatment was discontinued only after the tumor clinically resolved with no remaining inflammatory response and biopsy specimens showed no residual tumor histologically.

We report 15 LM lesions in 14 patients treated effectively with imiquimod, 5%, cream as determined by clinical and histopathologic assessment. The patient demographics, treatment applications, and histologic and clinical findings are summarized in the Table. Patients were treated over 12 to 20 weeks with a range of 47 to 106 treatment applications (average, 79.5). All patients agreed to posttreatment biopsies, and 6 of the 14 agreed to intratreatment biopsies. Biopsies were performed during treatment in patients 6, 9, 10, 11, 12, and 14. While no residual tumor was present in patients 6, 9, 10, and 11, patients 12 and 14 showed histologic evidence of remaining LM during treatment. Posttreatment biopsy specimens were obtained from all patients and demonstrated histologic clearance of LM. We report successful clearing of LM clinically in all 14 of these patients, with an average clinical follow-up of 15.9 months (range, 0-32 months).

Many case reports and open-label studies have recently shown imiquimod to be effective for LM treatment. By assessing patients histologically during and after treatment with imiquimod, we observed a variation in the duration of imiquimod treatment needed to histologically clear LM. For example, while the intratreatment biopsy specimen obtained from patient 12 after 84 treatments revealed residual tumor, 10 of the 15 lesions in this study cleared both clinically and histologically after fewer than 84 treatments. This variation is likely due to multiple factors, including genetic heterogeneity, immune status of patients, and the size and location of the lesions.

It is important to note the limitations of histologic evaluation by sampling biopsies. Sampling error is inherent in scouting biopsies, and only total excision would allow a complete histologic evaluation, but follow-up cannot be assessed in a study design involving complete excision. We recognized this limitation of sampling biopsies and discussed it with our patients.

Based on combined clinical and histologic findings, we strongly believe that a predetermined protocol for imiquimod treatment is not likely to be effective for all patients. We did not encounter any patients who could not mount a clinical response to imiquimod, but we observed differences in the timing of that response among patients. In addition, we noted differences in the total number of applications needed for clinical and histologic clearance of LM. The timing of the immune response induced by imiquimod appears to be unique for each patient, and therefore the ability of this immune response to effectively clear LM may be specific. We not only agree with Powell and colleagues³ that treatment should be adjusted to achieve an effective immune response but also recommend that each patient be observed closely to ensure resolution of the inflammatory reaction and clearance of tumor both clinically and histologically.

The continued reporting of case series from multiple institutions with longer follow-up periods monitoring patients both clinically and histologically will be invaluable in providing more complete data regarding the potential efficacy of imiquimod treatment and the duration of therapy required in LM management. These studies may identify novel patient and/or lesion characteristics that will predict the efficacy of imiquimod therapy for each specific clinical situation.

Correspondence: Dr Missall, Department of Dermatology, Saint Louis University School of Medicine, 1755 S Grand Blvd, St Louis, MO 63104 (missalta@slu.edu).

Accepted for Publication: June 22, 2010.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Missall and Fosko. Acquisition of data: Missall, Hurley, and Fosko. Analysis and interpretation of data: Missall, Hurley, and Fosko. Drafting of manuscript: Missall. Critical revision of the manuscript for important intellectual content: Missall, Hurley, and Fosko. Obtained funding: Missall. Administrative, technical, and material support: Hurley and Fosko. Study supervision: Hurley and Fosko.

Financial Disclosure: None

Funding/Support: This study was supported in part by a Saint Louis University Cancer Center seed grant (Dr Missall).

Additional Contributions: Summer Youker, MD, participated in the development of the protocol and patient enrollment. Edward Prodanovic, MD, and Mark Doig, PA-C, managed the patients' therapy. Members of the Saint Louis University Melanoma Group, including Nicole Burkemper, MD, Eddy Hsueh, MD, Sarah Jensen, MD, Frank Johnson, MD, John Richart, MD, Sarah Smith, MD, and Summer Youker, MD, stimulated discussions regarding melanoma management.