Twenty years of imiquimod taking its toll on lentigo maligna — Where are we?

By Warren R. Heymann, MD
February 12, 2020
Vol. 2, No. 6

Although Y2K never amounted to much, a solitary case report that year changed the dynamic in treating a vexing problem — melanoma in situ of the lentigo maligna (LM) subtype. Ahmed and Berth Jones reported treating an 88-year old man with a large lentigo maligna of his scalp with imiquimod 5% cream. The authors initially treated a test area and then the whole lesion for 7 months. Imiquimod resulted in complete clinical and histological cure. The patient was followed up to 9 months without evidence of recurrence. (1) Since the inaugural report there have been at least 125 PubMed references discussing imiquimod for managing LM — what have we learned?

LM occurs primarily on exposed sun-damaged skin of the elderly, many of whom may be poor candidates for surgical excision including Mohs. As the populace ages, LM rates have increased in the United States. There is an estimated 5% lifetime risk of progression from LM to invasive melanoma, although true rates are unknown as most LMs are treated. (2) Most authorities agree that surgical excision of LM, either by conventional excision with 0.5 to 1-cm margins or staged surgery, including Mohs micrographic surgery, is the preferred therapeutic option. Recent data suggest that the surgical excision of melanoma in situ subtypes, including LM, should include at least 9 mm of normal-appearing skin, which is similar to the amount recommended for early invasive melanoma. (3) Patients may choose other options to treat LM for a variety of reasons, ranging from a concern of tolerating the procedure, cosmetic issues, advanced age and co-morbid conditions, and/or potential functional impairment. I recently tried to encourage a “young” healthy 70-year-old patient to opt for Mohs surgery for a LM of his left ear. “Look Doc, I was not even aware that I had this problem until you found it. I don’t want a scarred ear. Period.” We discussed other options — including radiation and cryosurgery. He agreed to apply imiquimod 5% cream, which clinically cleared the lesion after three months of treatment.

Imiquimod binds to Toll-like receptors (TLR) 7 and 8. TLR7 activates the T-helper 1 response and increases the production of pro-inflammatory cytokines such as interferon-alpha, tumor necrosis factor-alpha, and interleukin (IL)-12. Additionally, imiquimod directly increases the expressions of pro-inflammatory cytokines such as IL-6, IL-8, and IL-10, and pro-apoptotic molecules. (4) Although the precise mechanisms for imiquimod’s efficacy for LM are yet to be determined, it is assumed that a combination of these immunologic effects are responsible.

There is now ample literature to assess imiquimod’s utility for LM and its attendant risks. Mora et al, in a meta-analysis of 347 tumors from 45 studies, found that histologic and clinical clearance rates were 76.2% and 78.3%, respectively. The incidence of clinical recurrence was 2.3%, with a mean follow-up of 34.2 ± 11.8 months. Treatment with > 60 total applications, or with > 5 applications per week, was associated with a higher likelihood of histologic clearance. (5) Tio et al reviewed their experience of 57 patients with lentigo maligna who were treated with off-label topical imiquimod once daily for 12 weeks. Complete clinical clearance was observed in 48 patients (84.2%) and partial clearance in 3 patients (5.3%). Three patients (5.3%) showed no response and another 3 patients (5.3%) stopped treatment due to side-effects (flu-like symptoms, lymphedema of the cheek, headache, and a sterile conjunctivitis). After 4.5 years of follow-up, one patient developed a lentigo maligna melanoma which was subsequently excised. (6) Papanikolaou and Lawrence retrospectively analyzed 33 patients treated with imiquimod cream for biopsy-proven LM. Doses of applied imiquimod 5% cream were escalated as necessary to produce a brisk local inflammatory response. An inflammatory response developed in 29 (88%) of the 33 patients, and of these, 4 patients stopped treatment earlier than planned because they could not tolerate the inflammatory reaction, while 3 patients reported systemic side effects (muscle aches, fatigue and nausea). There was lesional clearance in 21 (72%) of the 29 patients; they remained clear after a mean follow-up of 4.1 years. Eight failed to clear; in 5 of those patients the lesion was excised, while the remaining 3 were managed expectantly. Importantly, the authors observed that a clinical response is more likely if there is a brisk inflammatory response, and LM was less likely to resolve if there was no inflammatory response. (7) However, it is critical to evaluate these studies in the context of imiquimod as primary treatment (for surgically unresected or incompletely resected LM) versus imiquimod as an adjuvant therapy after optimal surgical excision, in which case lack of inflammatory response may not correlate with outcomes.

Even though the possibility of developing lentigo maligna melanoma in imiquimod-treated LM may be small, the risk is real. Most published series in which invasive melanoma developed following the use of imiquimod for LM have showed thin melanoma, which was subsequently excised, without adverse patient outcomes. However, following treated patients is crucial and may be assisted by dermoscopy, Woods lamp exam, and/or reflectance confocal microscopy. There may also be advantages in using imiquimod as adjuvant therapy following surgery or as neoadjuvant therapy before surgery. In the adjuvant setting (defined as histologically transected or narrowly excised LM without clinical residual pigmentation), Swetter et al showed >94% clearance in 41 patients with mean follow-up of 43 months. (8) Donigan et al demonstrated that neoadjuvant imiquimod 5% cream administered prior to conservatively staged excisions allowed for negative histologic margins with a median final margin of 2 mm and a rate of recurrence similar to standard staged excisions by Mohs surgery or en face permanent sections. (9) In an accompanying editorial, Fosko et al proposed personalized treatment plans for patients with LM, with imiquimod being utilized in some cases — either adjunctively (to treat LM extending beyond suspected clinical margins) or as monotherapy. (10)

The past 20 years have brought imiquimod to the forefront of LM therapy. While the lack of prospective randomized trials has designated its use for LM as off-label, from my vantage point, it is the second option if surgery is contraindicated or declined. There is still no standardized dosing schedule, but it is apparent that an inflammatory response needs to be observed in the primary treatment setting. Perhaps a “Goldilocks” approach is best — increase the dosing schedule if there is minimal (or no) inflammation and cut back if the inflammatory response is too great. Astorino et al suggest shortening the course of therapy by using imiquimod under occlusion, and topical tazarotene gel may be added to induce inflammation. (10) Given its rise to prominence in managing LM, there is ample need for more research focusing on proper dosing, adjuvant/neoadjuvant use, and in elucidating the precise molecular anti-tumor effects of imiquimod for LM. Such knowledge will refine imiquimod’s use for LM, in the personalized manner envisioned by Fosko et al.

Point to Remember: For those patients with lentigo maligna who cannot, or will not, have definitive surgery, consider off-label topical imiquimod, but understand its limitations and the need for close patient follow-up.  

Our Expert’s Viewpoint

Susan M. Swetter, MD
Director, Pigmented Lesion/Melanoma and Cutaneous Oncology Programs
Stanford University Medical Center and Cancer Institute  

For increasing rates of melanoma in situ, lentigo maligna (LM) type in elderly individuals in whom surgical excision may be less feasible, topical imiquimod presents a reasonable alternative “first-line” therapy for primary treatment in selected cases. It may also be used as “second-line,” adjuvant therapy in cases where surgery has been optimized (usually when histologically transected MIS/LM is evident without clinical correlation). Most LM occurs in elderly light-complexioned individuals with significant sun damage, further complicating the ability of pathologists to distinguish actinic melanocytic hyperplasia from true LM. While imiquimod remains off-label for LM, it should be considered as a therapeutic option, although limitations regarding its use must be discussed with the patient and close clinical follow-up arranged. Further investigation (including prospective clinical trials) regarding its use in the adjuvant and neoadjuvant settings is warranted. 

1. Ahmed I, Berth-Jones. Imiquimod: A novel treatment for lentigo maligna. Br J Dermatol 2000; 143: 843-845.  

2. Fogarty GB, Hong A, Economides A, Guitera P. Experience treating lentigo maligna with definitive radiotherapy.

3. Kunishige JH, Doan L, Brodland DG, Zitelli JA. Comparison of surgical margins for lentigo maligna versus melanoma in situ. J Am Acad Dermatol 2019; 81: 204-212.  

4. Kim NH, Lee JB, Yun SJ. Development of vitiligo-like depigmentation after treatment of lentigo maligna melanoma with 5% imiquimod cream. Ann Dermatol 2018; 30: 454-457. 

5. Mora AN, Karia PS, Nguyen BM. A quantitative systemic review of the efficacy of imiquimod monotherapy for lentigo maligna and an analysis of factors that affect tumor clearance. J Am Acad Dermatol 2015; 73: 205-212.  

6. Tio DCKS, Van Montfrans C, Ruijter CGH, Hoekzema R, Bekkenk MW. Effectiveness of 5% topical imiquimod for lentigo maligna treatment. Acta Dermatol Venereol 2019 Jun 24 [Epub ahead of print]. 

7. Papanikolaou M, Lawrence CM. Long-term outcomes of imiquimod-treated lentigo maligna. Clin Exp Dermatol 2019; 44: 631-636. 

8. Swetter S, Chen FW, Kim DD, Egbert BM. Imiquimod 5% cream as primary or adjuvatn therapy for melanoma in situ, lentigo maligna type. J Am Acad Dermatol 2015; 72: 1047-1053. 

9. Donigan JM, Hyde MA, Goldgar DE, Hadley ML, et al. Rate of recurrence of lentigo maligna treated with off-label neoadjuvant topical imiquimod, 5%, cream prior to conservatively staged excision. JAMA Dermatol 2018; 154: 885-889.  

10. Fosko SW, Navarettte-Dechent CP, Nehal KS. Lentigo maligna- challenges, observations, imiquimod, confocal microscopy, and personalized treatment. JAMA Dermatol 2018; 154: 879-881.  

11. Astorino S, Astorre P, Pasquini P, DiNunno D, et al. Imiquimod 5% cream in occlusion, for the treatment of lentigo maligna: A new scheme of short cycles and the need for clinical trials. Dermatologic Therapy 2019; 32e12757.