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Figure.
Patient with lentigo maligna treated with imiquimod. A, Before therapy. B, After 20 days of twice-daily imiquimod application. C, Fourteen days after imiquimod treatment was stopped. D, Twelve weeks after imiquimod treatment was stopped.

Patient with lentigo maligna treated with imiquimod. A, Before therapy. B, After 20 days of twice-daily imiquimod application. C, Fourteen days after imiquimod treatment was stopped. D, Twelve weeks after imiquimod treatment was stopped.

Table. 
Patient Characteristics
Patient Characteristics
1.
Weinstock  MASober  AJ The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 1987;116 (3) 303- 310
PubMedArticle
2.
Arlette  JPTrotter  MJTrotter  TTemple  CL Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol 2004;86 (4) 179- 186
PubMedArticle
3.
Osborne  JEHutchinson  PE A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision. Br J Plast Surg 2002;55 (8) 611- 615
PubMedArticle
4.
Rajpar  SFMarsden  JR Imiquimod in the treatment of lentigo maligna. Br J Dermatol 2006;155 (4) 653- 656
PubMedArticle
5.
Naylor  MFCrowson  NKuwahara  R  et al.  Treatment of lentigo maligna with topical imiquimod. Br J Dermatol 2003;149 ((suppl 66)) 66- 70
PubMedArticle
6.
Fisher  GHLang  PG Treatment of melanoma in situ on sun-damaged skin with topical 5% imiquimod cream complicated by the development of invasive disease. Arch Dermatol 2003;139 (7) 945- 947
PubMedArticle
7.
Fleming  CJBryden  AMEvans  ADawe  RSIbbotson  SH A pilot study of treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol 2004;151 (2) 485- 488
PubMedArticle
8.
van Meurs  Tvan Doorn  RKirtschig  G Recurrence of lentigo maligna after initial complete response to treatment with 5% imiquimod cream. Dermatol Surg 2007;33 (5) 623- 627
PubMed
9.
Gilchrest  BAFitzpatrick  TBAnderson  RRParrish  JA Localization of melanin pigmentation in the skin with Wood's lamp. Br J Dermatol 1977;96 (3) 245- 248
PubMedArticle
Research Letter
July 21, 2008

Imiquimod Treatment of Lentigo Maligna: An Open-Label Study of 34 Primary Lesions in 32 Patients

Arch Dermatol. 2008;144(7):943-945. doi:10.1001/archderm.144.7.943

Lentigo maligna (LM) is an in situ lesion with a 2% to 50% risk of progression to LM melanoma.1 Currently, surgery or radiotherapy is usually recommended as the primary treatment for LM. In the literature, the recurrence rates reported for radiotherapy range from 0% to 19%, with a mean recurrence rate of approximately 7%; in addition, radiotherapy carries the risk of causing chronic radiodermatitis or radiation-induced malignant neoplasm.2 A margin-controlled excision using “slow Mohs” (rush permanent sections) and Mohs micrographic surgery has the lowest recurrence rate, perhaps as low as 3%.3

Methods

Thirty-two patients with 34 histologically confirmed facial LM lesions were enrolled in an open-label trial of imiquimod, 5%, cream (Aldara; 3M Pharma, Rueschlikon, Switzerland). No patient had been treated by other methods previously. The diagnosis was based on clinical examination including dermoscopy and histologic evaluation of a 3-mm punch biopsy specimen. Informed consent was obtained from all patients.

Topical imiquimod, 5%, cream was applied to the pigmented areas of the LM lesions, excluding the surrounding margin, for 2 to 20 weeks. Patients were examined every 3 or 4 weeks. The cream was applied with or without occlusion (Tegaderm; 3M, St Paul, Minnesota) until a weeping erosion of the whole pigmented skin area developed. In 2 cases, inflammation was triggered by 2 × 2 liquid nitrogen cryotherapy (2 freeze-thaw cycles with a freezing time of 2 seconds each). The patient used a topical antimicrobial solution 2 to 3 times daily. A follow-up examination was performed every 3 months. If complete clinical clearance was not achieved, lesion biopsy specimens were taken again with a 3-mm punch.

Results

The clinical details of the patients are listed in the Table. Thirty-two patients, 13 men and 19 women (mean age, 75 years) with 34 LM lesions were enrolled in the study. All lesions were on the face, the most common site being the cheeks (14 of 34). All 34 LM lesions completely cleared as assessed clinically (Figure). Six lesions showed a reappearance of pigmentation at follow-up. Biopsy specimens were taken of these 6 lesions for histologic and immunohistochemical analysis, the results of which confirmed complete response in all 6 cases; only melanophages and melanin were found within the dermis. No other patient showed recurrences (mean follow-up time, 17.2 months; follow-up range, 5-31 months).

The median time of imiquimod application was 7 weeks (range, 2-20 weeks). In most patients (30 of 34), the cream was applied once or twice daily. The median time to induce an inflammatory response was 4 weeks (range, 1-16 weeks). Clinical evidence of an inflammatory response was seen in all lesions. Six lesions had no clinical evidence of an inflammatory response initially, so the therapy was intensified either by increasing the application frequency of the cream to twice daily or by occlusion or triggering an inflammation with 2 × 2 cryotherapy. Three lesions were successfully treated with imiquimod under occlusion from the beginning.

Apart from irritation of the treatment area, no severe local or systemic reactions were seen. In 4 patients, persisting telangiectasia or a turgid redness remained for at least 3 months after therapy. Histologically, a residual cell infiltrate with ectatic vessels was seen in the upper dermis. No patient had clinical evidence of scarring after treatment. One patient developed persistent vitiligolike white patches on the dorsal surfaces of the hands.

Comment

All 34 LM lesions treated with imiquimod completely cleared (for 6 lesions, clearance was histologically confirmed). Only 1 lesion recurred after 30 months, and this was successfully retreated with imiquimod. This patient had immunodeficiency caused by a B-cell lymphoma, which indicates that immunocompetence is important for a complete clearance of LM lesions.

In a review of LM cases,4 15 reports were found to describe the successful treatment of LM with imiquimod (11 case reports and 4 open-label studies). Taken together with the data reported herein, the response rates in the open-label studies ranged from 66% to 100%. The mean LM clearance rate was 91% (58 of 64). Clearance was histologically confirmed in 52 lesions.

The factors responsible for a complete clearance of LM lesions are not yet clearly defined. In the case series,4 4 of the 6 nonresponders showed no inflammation. In our opinion, the lack of clinical efficacy is most probably due to insufficient inflammatory reaction of the treated skin area. In contrast to reports in the literature, all of our patients showed strong local inflammatory reactions characterized by weeping erosions. The frequency and duration of imiquimod application required to induce this inflammatory reaction differed from patient to patient. Based on our experience, we started the therapy with imiquimod every other day or daily. While a daily application for 2 weeks was sufficient for 1 patient, in some patients, a twice-daily application did not induce a sufficient reaction. We therefore increased the efficacy of the cream by occlusion and/or triggering an inflammation with 2 × 2 cryotherapy. The inflammation in our patients always extended beyond the border of cream application, which suggests that cream application peripheral to the lesion may not be necessary.

Of concern, invasive melanoma has occurred in a patient after 1 month of imiquimod treatment5 as well as progression of longstanding LM lesions to amelanotic LM melanoma following imiquimod therapy.6 In 1 case an LM lesion almost cleared clinically but did not change histologically,7 and in another case an LM lesion with a small hyperpigmented area recurred 9 months after the original clearance.8 Owing to these possibilities, frequent clinical controls and a long follow-up are necessary. A Wood lamp illumination could be helpful to increase clinical sensitivity.9

The major advantage of imiquimod therapy is the excellent cosmetic result. Furthermore, to our knowledge, this is the first report of repeated imiquimod application in the treatment LM. The use of topical imiquimod therapy postoperatively might also be discussed to help prevent recurrences after conventional or Mohs micrographic surgery.

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Article Information

Correspondence: Dr Hunger, Department of Dermatology, University of Bern, Inselspital, CH-3010 Bern, Switzerland (Robert.Hunger@insel.ch).

Author Contributions:Study concept and design: Buettiker, Braathen, and Hunger. Acquisition of data: Buettiker and Hunger. Analysis and interpretation of data: Buettiker, Yawalkar, Braathen, and Hunger. Drafting of the manuscript: Buettiker and Hunger. Critical revision of the manuscript for important intellectual content: Buettiker, Yawalkar, Braathen, and Hunger. Statistical analysis: Buettiker and Hunger. Obtained funding: Buettiker and Hunger. Administrative, technical, and material support: Buettiker and Hunger. Study supervision: Buettiker, Yawalkar, Braathen, and Hunger.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part with funds from the Department of Dermatology, University of Berne, Inselspital (Drs Buettiker and Hunger).

Previous Presentation: This study was presented in lecture format at the Immunotherapy Session of the 11th World Congress on Cancers of the Skin; June 8-11, 2007; Amsterdam, the Netherlands.

References
1.
Weinstock  MASober  AJ The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 1987;116 (3) 303- 310
PubMedArticle
2.
Arlette  JPTrotter  MJTrotter  TTemple  CL Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol 2004;86 (4) 179- 186
PubMedArticle
3.
Osborne  JEHutchinson  PE A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision. Br J Plast Surg 2002;55 (8) 611- 615
PubMedArticle
4.
Rajpar  SFMarsden  JR Imiquimod in the treatment of lentigo maligna. Br J Dermatol 2006;155 (4) 653- 656
PubMedArticle
5.
Naylor  MFCrowson  NKuwahara  R  et al.  Treatment of lentigo maligna with topical imiquimod. Br J Dermatol 2003;149 ((suppl 66)) 66- 70
PubMedArticle
6.
Fisher  GHLang  PG Treatment of melanoma in situ on sun-damaged skin with topical 5% imiquimod cream complicated by the development of invasive disease. Arch Dermatol 2003;139 (7) 945- 947
PubMedArticle
7.
Fleming  CJBryden  AMEvans  ADawe  RSIbbotson  SH A pilot study of treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol 2004;151 (2) 485- 488
PubMedArticle
8.
van Meurs  Tvan Doorn  RKirtschig  G Recurrence of lentigo maligna after initial complete response to treatment with 5% imiquimod cream. Dermatol Surg 2007;33 (5) 623- 627
PubMed
9.
Gilchrest  BAFitzpatrick  TBAnderson  RRParrish  JA Localization of melanin pigmentation in the skin with Wood's lamp. Br J Dermatol 1977;96 (3) 245- 248
PubMedArticle
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