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by other methods previously. The diagnosis was based Imiquimod Treatment of Lentigo Maligna:
on clinical examination including dermoscopy and his- An Open-Label Study of 34 Primary Lesions
tologic evaluation of a 3-mm punch biopsy specimen. In- in 32 Patients
formed consent was obtained from all patients.
Topical imiquimod, 5%, cream was applied to the pig- L entigomaligna(LM)isaninsitulesionwitha mentedareasoftheLMlesions,excludingthesurround-
2% to 50% risk of progression to LM mela- ing margin, for 2 to 20 weeks. Patients were examined noma.1 Currently, surgery or radiotherapy is usu- every 3 or 4 weeks. The cream was applied with or with- ally recommended as the primary treatment for LM. In out occlusion (Tegaderm; 3M, St Paul, Minnesota) until the literature, the recurrence rates reported for radio- a weeping erosion of the whole pigmented skin area de- therapy range from 0% to 19%, with a mean recurrence veloped. In 2 cases, inflammation was triggered by 2 ϫ2 rate of approximately 7%; in addition, radiotherapy car- liquid nitrogen cryotherapy (2 freeze-thaw cycles with a ries the risk of causing chronic radiodermatitis or radia- freezing time of 2 seconds each). The patient used a topi- tion-induced malignant neoplasm.2 A margin- cal antimicrobial solution 2 to 3 times daily. A fol- controlled excision using “slow Mohs” (rush permanent low-up examination was performed every 3 months. If sections) and Mohs micrographic surgery has the low- complete clinical clearance was not achieved, lesion bi- est recurrence rate, perhaps as low as 3%.3 opsy specimens were taken again with a 3-mm punch.
Methods. Thirty-two patients with 34 histologically con-
Results. The clinical details of the patients are listed in
firmed facial LM lesions were enrolled in an open-label the Table. Thirty-two patients, 13 men and 19 women
trial of imiquimod, 5%, cream (Aldara; 3M Pharma, (mean age, 75 years) with 34 LM lesions were enrolled Rueschlikon, Switzerland). No patient had been treated in the study. All lesions were on the face, the most com- Table. Patient Characteristics
Patient No./
Duration,
Application
Inflammatory
Follow-up,
Sex/Age, y
Location
Frequency, No.
Response
Abbreviations: CCC, complete clinical clearance; HC, histologically confirmed; PCC, partial clinical clearance (residual pigmentation).
a Duration of treatment (duration to the point of skin reaction).
b Liquid nitrogen cryotherapy using 2 freeze-thaw cycles with a freezing time of 2 seconds each.
(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 7), JULY 2008 2008 American Medical Association. All rights reserved.
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.
mon site being the cheeks (14 of 34). All 34 LM lesions Comment. All 34 LM lesions treated with imiquimod com-
completely cleared as assessed clinically (Figure). Six
pletely cleared (for 6 lesions, clearance was histologi- lesions showed a reappearance of pigmentation at cally confirmed). Only 1 lesion recurred after 30 months, follow-up. Biopsy specimens were taken of these 6 and this was successfully retreated with imiquimod. This lesions for histologic and immunohistochemical analy- patient had immunodeficiency caused by a B-cell lym- sis, the results of which confirmed complete response phoma, which indicates that immunocompetence is im- in all 6 cases; only melanophages and melanin were portant for a complete clearance of LM lesions.
found within the dermis. No other patient showed In a review of LM cases,4 15 reports were found to de- recurrences (mean follow-up time, 17.2 months; scribe the successful treatment of LM with imiquimod (11 case reports and 4 open-label studies). Taken to- The median time of imiquimod application was 7 gether with the data reported herein, the response rates weeks (range, 2-20 weeks). In most patients (30 of 34), in the open-label studies ranged from 66% to 100%. The the cream was applied once or twice daily. The median mean LM clearance rate was 91% (58 of 64). Clearance time to induce an inflammatory response was 4 weeks was histologically confirmed in 52 lesions.
(range, 1-16 weeks). Clinical evidence of an inflamma- The factors responsible for a complete clearance of LM tory response was seen in all lesions. Six lesions had no lesions are not yet clearly defined. In the case series,4 4 clinical evidence of an inflammatory response initially, of the 6 nonresponders showed no inflammation. In our so the therapy was intensified either by increasing the opinion, the lack of clinical efficacy is most probably due application frequency of the cream to twice daily or by to insufficient inflammatory reaction of the treated skin occlusion or triggering an inflammation with 2 ϫ 2 area. In contrast to reports in the literature, all of our pa- cryotherapy. Three lesions were successfully treated tients showed strong local inflammatory reactions char- with imiquimod under occlusion from the beginning.
acterized by weeping erosions. The frequency and du- Apart from irritation of the treatment area, no severe ration of imiquimod application required to induce this local or systemic reactions were seen. In 4 patients, per- inflammatory reaction differed from patient to patient.
sisting telangiectasia or a turgid redness remained for at Based on our experience, we started the therapy with imi- least 3 months after therapy. Histologically, a residual quimod every other day or daily. While a daily applica- cell infiltrate with ectatic vessels was seen in the upper tion for 2 weeks was sufficient for 1 patient, in some pa- dermis. No patient had clinical evidence of scarring af- tients, a twice-daily application did not induce a sufficient ter treatment. One patient developed persistent vitiligo- reaction. We therefore increased the efficacy of the cream like white patches on the dorsal surfaces of the hands.
by occlusion and/or triggering an inflammation with 2ϫ2 (REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 7), JULY 2008 2008 American Medical Association. All rights reserved.
cryotherapy. The inflammation in our patients always ex- treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol. 2004; tended beyond the border of cream application, which 8. van Meurs T, van Doorn R, Kirtschig G. Recurrence of lentigo maligna after suggests that cream application peripheral to the lesion initial complete response to treatment with 5% imiquimod cream. Dermatol 9. Gilchrest BA, Fitzpatrick TB, Anderson RR, Parrish JA. Localization of mela- Of concern, invasive melanoma has occurred in a pa- nin pigmentation in the skin with Wood’s lamp. Br J Dermatol. 1977;96(3): tient after 1 month of imiquimod treatment5 as well as progression of longstanding LM lesions to amelanotic LMmelanoma following imiquimod therapy.6 In 1 case an COMMENTS AND OPINIONS
LM lesion almost cleared clinically but did not changehistologically,7 and in another case an LM lesion with asmall hyperpigmented area recurred 9 months after theoriginal clearance.8 Owing to these possibilities, fre- Topical Tretinoin, Lung Cancer,
quent clinical controls and a long follow-up are neces- and Lung-Related Mortality
sary. A Wood lamp illumination could be helpful to in-crease clinical sensitivity.9 The major advantage of imiquimod therapy is the ex- A midcontinuingcontroversiesoverdrugsafety,1,2
results of a trial of topical tretinoin—a com- cellent cosmetic result. Furthermore, to our knowl- edge, this is the first report of repeated imiquimod ap- wrinkles, hyperpigmentation, and roughness4—raise se- plication in the treatment LM. The use of topical rious concerns for the public health. The Veterans Affairs imiquimod therapy postoperatively might also be dis- Topical Tretinoin Chemoprevention (VATTC) trial5,6 was cussed to help prevent recurrences after conventional or a vehicle-controlled randomized controlled trial (RCT) that studied whether topical tretinoin, 0.1%, cream applied tothe face and ears could prevent nonmelanoma skin can- cer. As reported in an abstract published in 2005,6 the study observed 1131 subjects for at least 2 years. After 6 years, and about 6 months prior to the study’s scheduled con- clusion, a safety monitoring committee stopped the studybecause of excess mortality among subjects who applied Correspondence: Dr Hunger, Department of Dermatol-
tretinoin (n=82 deaths [14%]) compared with those who ogy, University of Bern, Inselspital, CH-3010 Bern, Swit- applied vehicle (n=53 [9%]) (P=.01). Differences in mor- tality from pulmonary disease (12 vs 4) and non–small cell Author Contributions: Study concept and design: Buettiker,
lung cancer (NSCLC) (11 vs 4) were reported.5 Braathen, and Hunger. Acquisition of data: Buettiker and A causal link between tretinoin and mortality due to Hunger. Analysis and interpretation of data: Buettiker, lung cancer or other lung diseases is consistent with pre- Yawalkar, Braathen, and Hunger. Drafting of the manu- vious RCT data. Specifically, the Alpha-Tocopherol, Beta script: Buettiker and Hunger. Critical revision of the manu- Carotene Cancer Prevention Trial7 and the Beta- script for important intellectual content: Buettiker, Yawalkar, Carotene and Retinol Efficacy Trial8 both linked vitamin Braathen, and Hunger. Statistical analysis: Buettiker and A–related compounds to lung cancer. Ironically, both trials Hunger. Obtained funding: Buettiker and Hunger. Admin- were intended to demonstrate that these compounds could istrative, technical, and material support: Buettiker and prevent lung cancer. In both studies, however, lung can- Hunger. Study supervision: Buettiker, Yawalkar, Braathen, cer rates in subjects taking vitamin A–related substances were, unexpectedly, significantly higher than in subjects Financial Disclosure: None reported.
taking placebo, leading to early discontinuation of the vi- Funding/Support: This study was supported in part with
tamin A–related interventions in both trials.
funds from the Department of Dermatology, University A link between tretinoin and lung-related mortality of Berne, Inselspital (Drs Buettiker and Hunger).
is biologically plausible, with the putative culprit not treti- Previous Presentation: This study was presented in lec-
noin itself but harmful tretinoin metabolites. This line ture format at the Immunotherapy Session of the 11th of association begins with the finding that topically ap- World Congress on Cancers of the Skin; June 8-11, 2007; plied tretinoin can be absorbed systemically9 and there- fore can reach lung tissue. Once inside cells, tretinoin 1. Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to len- can induce its own metabolism; continuous dosing with tigo maligna melanoma. Br J Dermatol. 1987;116(3):303-310.
tretinoin may lead not to higher levels of tretinoin but 2. Arlette JP, Trotter MJ, Trotter T, Temple CL. Management of lentigo maligna to higher levels of tretinoin metabolites.10 It is those treti- and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol.
2004;86(4):179-186.
noin metabolites that may injure lung tissue, particu- 3. Osborne JE, Hutchinson PE. A follow-up study to investigate the efficacy of larly in the presence of cigarette smoke. This was dem- initial treatment of lentigo maligna with surgical excision. Br J Plast Surg. 2002;55(8):611-615.
onstrated in a study that exposed ferrets to beta carotene 4. Rajpar SF, Marsden JR. Imiquimod in the treatment of lentigo maligna. Br J (a vitamin A precursor) or cigarette smoke or both or nei- Dermatol. 2006;155(4):653-656.
ther for 6 months; lungs of all ferrets exposed to beta caro- 5. Naylor MF, Crowson N, Kuwahara R, et al. Treatment of lentigo maligna with topical imiquimod. Br J Dermatol. 2003;149(suppl 66):66-70.
tene showed a strong proliferative response and squa- 6. Fisher GH, Lang PG. Treatment of melanoma in situ on sun-damaged skin mous metaplasia that was enhanced by exposure to with topical 5% imiquimod cream complicated by the development of inva- cigarette smoke.11 A hypothesis linking lung cancer to sive disease. Arch Dermatol. 2003;139(7):945-947.
7. Fleming CJ, Bryden AM, Evans A, Dawe RS, Ibbotson SH. A pilot study of adverse effects of tretinoin metabolites is also supported (REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 7), JULY 2008 2008 American Medical Association. All rights reserved.

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