Amelanotic lentigo maligna managed with topical imiquimod as immunotherapy

Clinically amelanotic lentigo maligna often resembles an inflammatory lesion rather than a melanoma in situ. We present two cases of extensive amelanotic lentigo maligna presenting as gradually enlarging erythematous patches on the faces of women following incomplete excisions of lentigo maligna. Because of their site and size, therapeutic options were limited; the lesions have, however, resolved (clinically and histologically) following the topical application of 5% imiquimod cream. We discuss the rationale for the use of imiquimod in the treatment of lentigo maligna.     

Immunocryosurgery as monotherapy for lentigo maligna or combined with surgical excision for lentigo maligna melanoma

The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results.     

Immunocryosurgery ‐ an effective combinational modality for Bowen's disease

Bowen's disease (BD) is widely treated with topical imiquimod or cryosurgery. The present single‐center retrospective study reports on the application of standardized immunocryosurgery (cryosurgery during ongoing topical imiquimod) for the treatment of BD. Daily imiquimod 5% cream was applied on BD lesion and a 5 mm rim around it in 5‐week treatment cycles; cryosurgery (liquid N₂, open spray; 2 cycles, 15 second each) was performed at the end of the second week of each treatment cycle. Between 1/1/2009 and 31/12/2014 21 patients (mean age ± SD: 74.4 ± 8.0 years; 12 males) with 24 lesions (mean maximum diameter ± SD: 45.8 ± 50.9 mm; range: 9–200 mm) completed the protocol. The anatomic distribution of the lesions included face/scalp (Ν = 14), neck/trunk (Ν = 6), and extremities (Ν = 4). Twenty‐one out of twenty‐four lesions with diameter <80 mm cleared after one immunocryosurgery cycle, while the rest three tumors (with the largest diameters: 100, 180, 200 mm) required two treatment cycles for complete response (clearance rate: 100%). After a median follow‐up of 24 months (range: 6–60 months) the overall effectiveness was 91.7%: 22/24 lesions remained in sustained complete remission. With the exception of a variable degree of hypopigmentation, the cosmetic outcome was satisfactory even for extensive lesions. Immunocryosurgery, is feasible and highly efficacious minimally‐invasive treatment alternative for BD.     

Clinical usefulness of dermoscopy in the management of lentigo maligna melanoma treated with topical imiquimod: A case report

The importance of dermoscopy for diagnosing lentigo maligna melanoma (LMM) is well known. More recently, dermoscopy has been proposed as a useful tool also for the treatment choice and monitoring. Herein, we present an 87‐year‐old woman, who was successfully treated with imiquimod 5% cream after surgical persistence of residual LMM and for whom dermoscopy was helpful to assist diagnosis and assess tumor persistence after surgery and its response to topical treatment with imiquimod.     

Mucosal side effects in patients treated with topical imiquimod—A scoping review of the literature

Imiquimod 5% is approved for topical treatment of actinic keratosis (AKs), superficial basal cell carcinoma and condylomata acuminata, the 3.75% formulation for the treatment of AKs and genital warts. Imiquimod has also been used off‐label in various other skin conditions (eg, Bowen's disease, lentigo maligna, vulvar intraepithelial neoplasia). As a toll‐like receptor 7/8 (TLR7/8) agonist imiquimod induces a local inflammatory response by increased production of cytokines, co‐stimulatory molecules, activation of Nk‐cells and antigen‐specific T‐cells. In addition to imiquimod‐associated adverse effects at non‐application sites such as fever, vertigo or myalgia there have been anecdotal reports of distant inflammatory mucosal reactions—a side effect not declared in the medicinal product information. In this scoping review we collected a total of seven cases of patients with lesions of the oral mucosa and lips and summarized pathophysiological hypotheses to explain this type of side effect. The review is complemented with an illustrated report of a 87‐year‐old female patient of ours suffering from chronic lymphocytic leukemia (CLL) who developed severe oral mucosal and labial reactions following application of imiquimod 3.75% for treatment of AKs. She denied accidental transfer of imiquimod and was tested negative for herpes simplex virus (PCR) and bacteria (culture) from lesional swabs.     

Imiquimod enhances the systemic immunity attained by local cryosurgery destruction of melanoma lesions

Melanoma lesions can be frozen in vivo, resulting in necrotic death of malignant cells and in tumor antigen release suitable for cross-presentation by professional antigen-presenting cells. Imiquimod is a small molecule with adjuvant pro-inflammatory effects that can be topically delivered as a cream. Local cryosurgery of B16/ovalbumin (OVA)-derived subcutaneous tumor nodules leads to curative destruction of the lesions. If imiquimod is repeatedly applied on the cryo-treated lesion, a conspicuous, leukocyte-rich inflammatory infiltrate appears during the days following treatment. Mice treated by cryosurgery plus imiquimod rejected rechallenges of B16/OVA in 90% of the cases, whereas cryosurgery alone failed to prevent tumor grafting in 70% of the cases. The combination treatment of B16/OVA tumors was also able to protect 60% of the mice against outgrowth of a lethal dose of non-transfected B16 tumor cells. Addition of imiquimod to cryosurgery results in increases of the cellular immune response against tumor antigens as measured by in vitro IFN-gamma production and T-cell proliferation in response to OVA. The potent memory response is not only directed against the OVA epitope, but also toward a broader range of B16 antigens. Our data indicate that these combined treatments turn the treated tumor lesion into an autologous tumor vaccine, which is even able to cause vitiligo in several cases. These preclinical data and the simplicity of the procedures warrant the design of a pilot clinical trial.     

Cryosurgery is more effective in the treatment of primary, non-superficial basal cell carcinomas when applied during and not prior to a five week imiquimod course: a randomized, prospective, open-label study

Combinational cryosurgery during daily imiquimod application ('immunocryosurgery') efficiently cures invading basal cell carcinoma (BCC). Since timing of the cryosurgery is considered crucial for effectiveness, our aim was to compare efficacy of two different timing schemes of the combination of cryosurgery and topical imiquimod: Cryosurgery (a) 2 weeks after (Arm I) vs (b) prior to the initiation of a 5 week daily imiquimod course (Arm II). 16 patients with 21 BCC were recruited in this prospective, randomized, open-label trial. 14 patients with 17 BCC were evaluated (Arm I: 7 patients/10 tumors vs Arm II: 7 patients/7 tumors) during scheduled interim analysis at 6 month follow-up (two patients dropped out, one non-compliant and one lost to follow up). The trial was revoked because study Arm I ('immunocryosurgery') was significantly superior to Arm II (adjuvant imiquimod) in achieving tumor clearance (10/10 vs 3/7 tumors; p=0.0147) and by overall treatment efficacy (9/10 vs 2/7 relapse-free tumors; p=0.0345). The same overall efficacy persisted after at least 18 months follow-up for those patients with tumor clearance after the trial treatment. The timing of cryosurgery during imiquimod application substantially determines the efficacy of this combinational approach in the treatment of BCC.     

Increased number of mast cells in the dermis in actinic keratosis lesions effectively treated with imiquimod

Actinic keratosis (AK) is a cutaneous cancer in situ which develops as a result of excessive exposure to ultraviolet (UV). Toll‐like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non‐melanoma skin cancers. Recently, the diagnostic role of the dermatoscope has been reported in the course of treatment of AK. In addition, mast cells are now considered to contribute to both the innate and adaptive immune systems in topical imiquimod therapy. We assessed the effect of imiquimod treatment by dermatoscopic and immunohistochemical findings in 14 patients with a total of 21 AK lesions. With the dermatoscope, though the mean erythema score was not significantly different between the cured lesions and the unresponsive lesions, the erythema/red pseudo‐network (“strawberry”) pattern was decreased significantly in the cured lesions. By immunohistochemistry, the number of Ki‐67‐positive proliferative cells in the epidermis was decreased and that of CD117‐positive mast cells in the dermis was increased in the responding lesions. To the best of our knowledge, this is the first study demonstrating that the number of mast cells in the dermis was increased in AK lesions effectively treated with imiquimod. Our present result suggests that mast cells may contribute an antitumor effect in human skin treated with topical imiquimod.     

A systematic review of non‐surgical treatments for lentigo maligna

Lentigo maligna (LM) is the most common melanocytic malignancy of the head and neck. If left untreated, LM can progress to lentigo maligna melanoma (LMM). Complete surgical excision is the gold standard for treatment, however, due to the location, size, and advanced age of patients, surgery is not always acceptable. As a result, there is ongoing interest in alternative, less invasive treatment modalities. The objective was to provide a structured review of key literature reporting the use of radiotherapy, imiquimod and laser therapy for the management of LM in patients where surgical resection is prohibited. An independent review was conducted following a comprehensive search of the National Library of Medicine using MEDLINE and PubMed, Embase, Scopus, ScienceDirect and Cochrane Library databases. Data were presented in tabular format, and crude data pooled to calculate mean recurrence rates for each therapy. 29 studies met the inclusion criteria: radiotherapy 10; topical imiquimod 10; laser therapies 9. Radiotherapy demostrated recurrence rates of up to 31% (mean 11.5%), with follow‐up durations of 1–96 months. Topical imiquimod recurrence rates were up to 50% (mean 24.5%), with follow‐up durations of 2–49 months. Laser therapy yielded recurrence rates of up to 100% (mean 34.4%), and follow‐up durations of 8–78 months. in each of the treatment series the I² value measuring statistical heterogeneity exceeded the accepted threshold of 50% and as such a meta‐analysis of included data were inappropriate. For non‐surgical patients with LM, radiotherapy and topical imiquimod were efficacious treatments. Radiotherapy produced superior complete response rates and fewer recurrences than imiquimod although both are promising non‐invasive modalities. There was no consistent body of evidence regarding laser therapy although response rates of up to 100% were reported in low quality studies. A prospective comparative trial is indicated and would provide accurate data on the long‐term efficacy and overall utility of these treatments.     

Series of Fourteen Cases of Topical Imiquimod 5% in Lentigo Maligna: Treatment Modalities and Clues for Detecting Recurrences

Topical imiquimod has been used off-label as monotherapy or adjuvant treatment for lentigo maligna. Our aim is to describe treatment modalities, clinical outcomes, and management of recurrence in patients receiving imiquimod for lentigo maligna.Patients from our unit with lentigo maligna or lentigo maligna melanoma treated with imiquimod 5% as monotherapy or in combination with surgery were included in this study.Fourteen cases were recruited (85.7% lentigo maligna and 14.3% lentigo maligna melanoma). Eight patients (57.1%) received imiquimod without surgery, and six (42.9%) underwent narrow excision before beginning treatment. During the follow-up period, pigmentation reappeared in 6 patients (4 postinflammatory hyperpigmentation and 2 relapses). Relapses were managed with very narrow excision (1 mm margin) and retreatment with imiquimod 5%.All imiquimod modalities showed well-tolerated side effects and low recurrence rates, with long periods of follow-up. Imiquimod appears to be a versatile option for treating LM in suitable candidates.     

Immunomodulation by imiquimod in patients with high-risk primary melanoma

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.     

Treatment options in melanoma in situ: topical and radiation therapy,excision and Mohs surgery

Background The treatment of melanoma in situ (MIS), particularly the lentigo maligna (LM) subtype, has been a controversial subject in the literature for over a decade. Surgical excision with 5 mm margins is the standard of care in the USA, while several variations of Mohs surgery are frequently used to treat clinically ill‐defined lesions. Radiation is much less frequently used. Topical imiquimod has also been more recently proposed, in small case reports in the literature, as a therapy for MIS. However, controversies exist with all approaches. Objective To review the current literature regarding topical imiquimod, radiation therapy, surgical excision, and the various forms of Mohs surgery for MIS, focusing on the LM subtype. Methods A literature search was performed in the PubMed database using the following terms: “melanoma in situ,”“lentigo maligna,”“excisional surgery,”“Mohs micrographic surgery,”“radiation therapy,” and “imiquimod.” Articles relevant to the treatment of MIS were reviewed and reported herein. Results Studies of imiquimod therapy for MIS are hampered by small study numbers and short follow‐up periods. The few, better‐designed studies reveal relatively low cure rates. In addition, literature review reveals that a significant percentage of cases of MIS that are initially diagnosed as in situ disease by biopsy subsequently prove to have an invasive component upon complete excision. This finding suggests that topical therapy of any kind may be problematic. Studies of radiation therapy for MIS have relatively small numbers of patients and short follow‐up. Multiple studies of excisional surgery have shown that 5 mm margins are often insufficient to clear the LM subtype of MIS due to unseen subclinical extension, accounting for this treatment’s reported 8–20% recurrence rate. Finally, a number of variants of traditional frozen section Mohs surgery have been utilized to try and achieve complete peripheral margin assessment of clinically ill‐defined LM lesions. All studies are retrospective, and most are single‐institution and frequently single‐operator, limiting the meaningfulness of their results. Nevertheless, they involve moderate numbers of patients, and many have at least a five year follow‐up. Collectively, they suggest recurrence rates in the range of 0.5–3.0%. Conclusion Topical imiquimod therapy appears to provide relatively low cure rates for MIS, and because some of these lesions contain an unrecognized invasive component, should be used with extreme caution to treat this disease. Radiation therapy may be a useful second‐line therapy if surgery is contraindicated. Excisional surgery is an appropriate therapy for clinically well‐defined MIS; however, margins larger than 5 mm may be required when treating larger or indistinct lesions. Finally, for clinically ill‐defined LM arising on sun‐damaged skin, especially in regions of aesthetic concern, some form of complete peripheral margin assessment – one of the various forms of Mohs surgery – may provide the highest cure rate and create the smallest surgical defect.     

Die solare Keratose: Von der Präkanzerose zum präinvasiven Plattenepithelkarzinom – Therapeutischer Ansatz nach dem Bioinduktionsverfahren

Background: Solar keratoses are precancerous lesions in chronically UV‐damaged skin with histological features consistent with pre‐invasive squamous cell carcinoma. They require therapeutic intervention in order to prevent progression towards invasive carcinoma. Treatment options include topical medications and destructive methods. We report on a new approach – topical bioinductive therapy with imiquimod 5 % cream. Patients and methods: In a prospective case series, 7 patients with solar keratoses have been treated with topical imiquimod 5 %. The cream was applied 5 days/week over 2 weeks. After end of treatment, the outcome was assessed at regular control visits and, in some cases, histologically confirmed. One patient was followed up as untreated control. Results: In 6 of the 7 treated patients, the lesions cleared completely; one patient did not respond. The patients did not show new solar keratoses during a follow‐up period of about 2 years. The untreated patient showed spontaneous clearance of his keratoses. Local skin reactions during treatment included erythema, oedema and erosions in varying degrees, all of which completely resolved. Conclusions: Bioinductive therapy with imiquimod 5 % cream represents a promising therapeutic approach for cutaneous precancerous lesions such as solar keratoses.     

Mechanism of pathogenesis of imiquimod‐induced skin inflammation in the mouse: A role for interferon‐alpha in dendritic cell activation by imiquimod

Topical application of imiquimod (IMQ), a Toll‐like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ‐induced psoriasis‐like skin inflammation, T‐helper (Th)17 cells and interleukin (IL)‐17/IL‐22‐producing γδ‐T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis‐like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ‐induced psoriasis‐like skin inflammation in mice. We first confirmed that, together with an increase in IL‐17 and IL‐22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro‐inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7^?/? mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)‐α, IL‐23, IL‐6 and tumor necrosis factor (TNF)‐α. Furthermore, when we analyzed in vitro‐generated bone marrow‐derived DCs with features similar to TNF‐α and inducible nitric oxide synthase (iNOS)‐producing DCs, IL‐23, IL‐6, IL‐1β, TNF‐α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co‐stimulation with IMQ and IFN‐α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN‐α was suggested to be caused by upregulation of TLR7 expression by IFN‐α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis‐like skin inflammation are induced by IMQ and IFN‐α in a mouse model.     

Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod

BACKGROUND: Patients with seborrheic keratoses frequently desire an effective topical therapy for seborrheic keratoses. OBJECTIVE: To compare topical calcipotriene, topical tazarotene, and topical imiquimod with standard cryosurgery in the treatment of seborrheic keratoses. METHODS: Fifteen patients with numerous seborrheic keratoses were enrolled in an open-label study comparing cryosurgery with topical agents. Eight separate seborrheic keratoses were selected to be treated with topical medications. One lesion was treated with cryosurgery. RESULTS: One treatment with cryosurgery led to clinical and histological improvement of all lesions treated. Neither scarring nor recurrence resulted in cryosurgery. In seven of 15 patients, tazarotene 0.1% cream applied BID caused clinical improvement in lesions within 16 weeks. CONCLUSION: Cryosurgery produces clinical and histological improvement of seborrheic keratoses. The result with cryosurgery was cosmetically acceptable to all patients. Responders to tazarotene cream 0.1% found it cosmetically acceptable.     

Lentigo maligna treated with 5% imiquimod cream

Lentigo maligna (LM) is considered to be an in-situ stage of lentigo maligna melanoma. Clinically, it presents as a pigmented macule, irregular in shape and tone. 30% to 35% of untreated lentigo malignas can progress into lentigo maligna melanoma. The treatment of choice for this pathology is surgical excision with margins of 0.5 cm. of clinically normal skin around the lesion, or Mohs microsurgery. Imiquimod is a topical immunomodulator that stimulates both acquired and innate immunity. We present the case of a patient with LM, treated with 5% imiquimod cream, with an excellent therapeutic response.     

Effective induction of melanoma‐antigen‐specific CD8+ T cells via Vγ9γδT cell expansion by CD56high+ Interferon‐α‐induced dendritic cells

Dendritic cells (DCs) can be differentiated from CD14⁺ monocytes in the presence of interferon‐α (IFNα) and granulocyte/macrophage‐colony stimulating factor (GM‐CSF) in vitro and are known as IFN‐DCs. Circulating blood CD56⁺ cells expressing high levels of CD14, HLA‐DR and CD86 have been shown to spontaneously differentiate into DC‐like cells in vitro after their isolation from blood. We show here that IFN‐DCs expressing high levels of CD56 (hereafter, CD56^high+ IFN‐DCs) can be differentiated in vitro from monocytes obtained as adherent cells from healthy donors and patients with metastatic melanoma. These cells expressed high levels of CD14, HLA‐DR and CD86 and possessed many pseudopodia. These CD56^high+ IFN‐DCs may be an in vitro counterpart of the circulating CD56⁺ CD14⁺ CD86⁺ HLA‐DR⁺ cells in blood. Conventional mature DCs differentiated from monocytes as adherent cells in the presence of GM‐CSF, IL‐4 and TNF‐α (hereafter, mIL‐4DCs) did not express CD56 or CD14. In contrast to mIL‐4DCs, the CD56^high+ IFN‐DCs exhibited a stronger capacity to stimulate autologous CD56⁺ Vγ9γδT cells highly producing IFNγ in the presence of zoledronate and IL‐2. The CD56^high+ IFN‐DCs possessing HLA‐A*0201 effectively induced Mart‐1‐modified melanoma peptide (A27L)‐specific CD8⁺ T cells through preferential expansion of CD56⁺ Vγ9γδT cells in the presence of A27L, zoledronate and IL‐2. Vaccination with CD56^high+ IFN‐DCs copulsed with tumor antigens and zoledronate may orchestrate the induction of various CD56⁺ immune cells possessing high effector functions, resulting in strong immunological responses against tumor cells. This study may be relevant to the design of future clinical trials of CD56^high+ IFN‐DCs‐based immunotherapies for patients with melanoma.     

Lentigo Maligna: Review of Salient Characteristics and Management

Lentigo maligna is a melanocytic neoplasm, often regarded as ‘melanoma in situ,’ which may progress to lentigo maligna melanoma. Lentigo maligna clinically presents as a pigmented, asymmetric macule that originates on the head and neck and spreads slowly. The preferred method for diagnosing lentigo maligna is excisional biopsy. Histology shows proliferation of atypical melanocytes at the epidermal–dermal junction in small nests or single cells. The differential diagnosis includes solar lentigo, seborrheic keratosis, lichen planus-like keratosis, pigmented actinic keratosis, and melanocytic nevus. Stains used in diagnosis include hematoxylin and eosin, HMB-45, MART-1/Melan-A, Mel-5, and S-100. Surgical excision is the preferred treatment for lentigo maligna. Second-line techniques include medical (topical imiquimod) and destructive therapy.     

Kontrollierte schichtweise Abtragung anogenitaler Warzen mittels Argon‐Plasma‐Koagulation

Background: According to guidelines of the German STD Association, appropriate treatment of extensive anogenital warts with comparable recurrence rates includes cryotherapy, surgical excision, electrosurgery, CO₂‐ and Nd:YAG‐laser vaporisation. All these procedures are associated with varying degrees of risk for bleeding, release of potentially infectious aerosol, deep thermal destruction, slow wound healing, and scarring. Methods: Using argon‐plasma coagulation anogenital warts can be removed in layers in a controlled manner. High frequency current flows through the argon plasma to the tissue, allowing well‐controlled, superficial tissue destruction. Results: From January 2001 to March 2003, 54 patients with extensive genital, anal or anogenital warts were treated. After one treatment, 66 % of the patients remained disease‐free in the following 4 months. Thirteen patients (24 %) showed early recurrence after 4 weeks, five patients (9 %) at a later date. In these patients, further treatment, in 9 cases combined with topical imiquimod cream, were necessary for complete remission. Conclusion: Compared to other therapeutic procedures, argon‐plasma coagulation is a better controlled, quick and low‐risk option for the treatment of anogenital warts. Depending on the type of involvement and individual risk factors, postoperative treatment with topical imiquimod cream may be useful.