Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy.

We report a case of major regression of multiple atypical melanocytic nevi with a vitiligoid reaction in a patient with metastatic melanoma who achieved long-lasting complete remission after ipilimumab therapy. In 2008, a 54-year-old man presented with a dysplastic nevus syndrome. The patient was diagnosed with a scalp ulcerated melanoma (Breslow index 5.1 mm and Clark level IV), which was removed surgically. Four years later in April 2012, the patient was diagnosed with a right parietal skin metastasis, brain, lymph nodes, and bilateral lung metastases. The patient was first treated with vemurafenib, which had to be stopped because of renal toxicity. Disease stabilization was achieved after the second line of treatment with immunotherapy (ipilimumab, four infusions). However, 6 months later, the lung metastases had progressed. The patient was treated with pulmonary stereotactic radiotherapy associated with a second cycle of ipilimumab. After 6 months, he achieved complete remission. Simultaneously, the patient presented a generalized regression of his nevi with a vitiligoid reaction, or halo nevus, associated with a vitiligo located on the hands and inguinal areas. Vitiligo is a frequent immune-related adverse event of immunotherapy. Immunotherapy-induced halo nevus reaction is much less frequent than vitiligo. It was associated in the two case reports from the literature and in our patient with a quick and long-lasting complete remission of nodes and visceral metastases. Therefore, it might correspond to a stronger antimelanocyte immune reaction, associated with a favorable prognosis. The generalized halo nevi reaction in our patient could be more important because of the two cycles of ipilimumab compared with a single one. In conclusion, this case report suggests that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response.

Role of Tip60 in human melanoma cell migration, metastasis, and patient survival.

The tumor suppressor Tip60 regulates gene transcription, DNA damage response, apoptosis, and cancer development, but its role in melanoma is unknown. In this study, we investigated the expression pattern of Tip60 in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 448 cases of melanomas (201 for the training set and 247 for the validation set) and 105 cases of nevi, we found that Tip60 expression was significantly reduced in metastatic melanoma compared to common nevi (P=0.045), dysplastic nevi (P=0.047), and primary melanoma (P=0.001). Kaplan-Meier survival curve and univariate Cox regression analyses showed that reduced Tip60 expression was associated with a poorer 5-year disease-specific survival in primary melanoma (P=0.016) and metastatic melanoma patients (P=0.027). Multivariate Cox regression analyses indicated that Tip60 expression was an independent prognostic marker for primary (P=0.024) and metastatic melanomas (P=0.035). In vitro wound healing assay showed that enforced Tip60 expression inhibited but Tip60 knockdown enhanced melanoma cell migration, suggesting that Tip60 might regulate melanoma metastasis. Finally, we showed that overexpression of Tip60 in melanoma cells resulted in significantly increased chemosensitivity. Our data indicate that Tip60 may serve as a potential biomarker for melanoma patient outcome as well as a potential therapeutic target.

Epidermolysis bullosa nevus-like lesions in a pediatric patient with pyoderma gangrenosum.

Epidermolysis bullosa-associated nevi are recently described dysplastic nevi found in patients with epidermolysis bullosa. These lesions display clinical features of unusual nevi suggestive of malignancy but thus far cases with malignant transformation have not been reported. We describe a case of epidermolysis bullosa-type nevi developing in a child with pyoderma gangrenosum. The nevi in our patient were found in areas previously affected by pyoderma gangrenosum and were clinically concerning for malignancy. However, they were only moderately atypical on light and confocal microscopy. This case demonstrates that pediatric patients with cutaneous inflammation, bullae formation, or both, are at risk for developing unusual nevi at previous sites of skin involvement. Considering the absence of malignant change in these nevi, we suggest that close observation can be employed in cases where this diagnosis can be confirmed both clinically and microscopically.

Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) harbor gain-of-function mutations of the c-kit tyrosine kinase receptor. Imatinib mesylate is an inhibitor of c-kit and is indicated in the treatment of chronic myeloid leukemia and GISTs. Reported adverse effects of imatinib include hypopigmentation, depigmentation, and hyperpigmentation. Although the exact mechanism by which these occur is unclear, it is likely that inhibition of c-kit leads to downstream inhibition of the tyrosinase gene promoter and thus to inhibition of pigment production. OBSERVATIONS: A 45-year-old woman with a history of multiple dysplastic nevi and lentigines was diagnosed as having familial GIST syndrome. Treatment with imatinib mesylate was started in an attempt to decrease the tumor load. Three months after treatment initiation, the patient noted a decrease in the number of pigmented lesions, lightening of the skin in her genital area, and graying of her terminal hair. CONCLUSIONS: The potential association between a specific genetic mutation and pigmentation changes secondary to imatinib therapy may account for the variety in presentation of this potential side effect. Further genetic studies paired with melanocyte-specific or c-kit-specific stains of affected tissue are warranted to better understand the relationship between the genetic mutation and the effect of imatinib on pigmentation.

Beta-carotene in dermatology: Does it help?

UV irradiation of the skin leads to the induction of free radicals, carcinogenesis, and skin aging, and thus the use of beta-carotene in humans as a chaperoning agent is discussed. In the photohemolysis model, beta-carotene protects against the phototoxic effects of porphyrins. Beta-carotene should be used in erythropoietic protoporphyria, photosensitive diseases, and to reduce the effects of phototoxic drugs. Its effects on aging skin and on actinic keratosis have not yet been sufficiently studied.

Treatment of dysplastic nevi with 5% imiquimod cream, a pilot study.

OBJECTIVE: To assess the clinical and histologic effects of topical imiquimod therapy on dysplastic nevi, and to determine the feasibility of using in vivo confocal microscopy (CSLM) to non-invasively monitor histological response of dysplastic nevi to imiquimod therapy. DESIGN: Single-blinded pilot study with patients not blinded as to treatment status. SETTING: Dermatology Outpatient Clinic, Memorial Sloan-Kettering Cancer Center, New York, NY. PATIENTS: The study population comprised of 10 patients with clinically dysplastic (atypical) nevi and at least 8 large nevi, (> or =5 mm) on their trunk. INTERVENTION: Sixteen weeks of imiquimod 5% cream applied to treatment lesions 3 times per week. MAIN OUTCOME MEASURE: Clinical response as gauged by comparison of baseline and week 20 1:1 standardized photographs for all study nevi and histological assessment of each patient's 4 largest study nevi at completion of therapy. RESULTS: There were no obvious clinical changes in the size and morphology of the study nevi. Subtle changes in nevus color could not be assessed due to imperfect spectral registration of images over the course of the study. Histologically, 4 of 14 treated nevi and 0 of 14 untreated nevi p=0.03 showed a significant relative reduction of junctional and intraepidermal nevocytes accompanied by papillary dermal fibroses and variable inflammation suggestive of partial regression. Non-invasive CSLM imaging of study nevi demonstrated previously reported in vivo features of dysplastic nevi. but the imaging equipment and protocol utilized proved inconsistent across lesions and time. CONCLUSIONS: The histological changes seen in a subset of treated nevi suggest a possible role for the use of topical immune response modifiers for the treatment of dysplastic nevi with the intent of melanoma chemoprevention. The dose regimen of topical imiquimod utilized in this study failed to induce sufficient clinical or histological responses to warrant further study. Targeting of dysplastic nevi and intermediate endpoints for melanoma chemoprevention with more intense and/or prolonged treatment regimens with imiquimod or the use of other immune response modifiers seems promising. Technical improvements are required for the use of non-invasive CSLM imaging in lieu of invasive histology for the study of topical nevus therapies.

A three-year randomized trial in patients with dysplastic naevi treated with oral beta-carotene.

Ultraviolet irradiation provokes the development of new melanocytic naevi, or changes in existing naevi, leading to repeated surgery of atypical naevi and becoming a continual burden for individuals with many of these lesions. To determine the influence of long-term medication with the radical scavenger beta-carotene on newly developing atypical naevi, a single-centre, randomized, placebo-controlled study, prospective over 3 years, was started double-blind in 62 patients with numerous clinically atypical naevi. Beta-carotene (25 mg) was given twice daily for 36 months in the treatment group (n = 30) and saccharose capsules as placebo in the control group (n = 32). The total number of newly developed naevi in the beta-carotene group (n = 18) was 68 versus 88 in the placebo group (n=21) (not significant). Of 12 different locations on the human body evaluated separately, only in two, the lower arm (p = 0.03) and the feet (p = 0.03), was there a difference for the beta-carotene group in the quantification of naevi. Overall, it is concluded that beta-carotene does not reduce the development of new naevi in patients with numerous atypical naevi.

Effects of topical tretinoin on dysplastic nevi.

PURPOSE: As potential precursors of melanoma and markers of increased melanoma risk, dysplastic nevi are suitable targets of strategies for melanoma chemoprevention. We report the results of a pilot study of topical retinoic acid in patients with dysplastic nevi. PATIENTS AND METHODS: Five male patients with dysplastic nevi applied tretinoin to half of the back for 6 months. Baseline photographs of dysplastic nevi were compared with posttreatment photographs and assessed for morphologic change. At study completion, each subject had four nevi excised from the treated side and four from the untreated side of the back. Biopsies were histologically evaluated for the presence of dysplasia. RESULTS: All patients developed signs of irritation as a result of treatment. One patient was not compliant with treatment due to skin irritation. The four compliant patients showed significant decreases in the clinical atypia of treated lesions, with concomitant fading and even disappearance of many treated nevi. Histologically, only four of 16 treated nevi met histologic criteria for dysplasia, in comparison to 13 of 16 untreated nevi. CONCLUSION: These results suggest that there is concomitant clinical and histologic improvement in a significant percentage of dysplastic nevi treated with topical tretinoin. However, the utility of topical tretinoin for chemoprevention of melanoma is limited by difficulty of application and associated inflammation. While new strategies in chemoprevention of melanoma are explored, sun protection and assiduous avoidance of sunburn must remain the mainstay of melanoma prevention.

The prevention of cutaneous malignant melanoma: high-risk groups, chemoprevention, education, and screening.

Melanoma is a disease that need not be deadly. Advances in our understanding of the etiology and biology of melanoma over the past 20 years have brought us to the brink of a new era in which the twin goals of primary and secondary prevention may be within our grasp. There is ample reason to be optimistic that this can and will be accomplished.

The effect of topical tretinoin on dysplastic nevi. A preliminary trial.

Twenty-one patients were enrolled in a randomized, double-blind study that examined the effects of topical 0.05% tretinoin (all-trans-retinoic acid; vitamin A acid; Retin-A) solution on dysplastic nevi. Following histologic confirmation of the diagnosis of dysplastic nevus in three representative lesions, patients applied either tretinoin or a placebo containing 50% alcohol to selected dysplastic nevi once a day under tape occlusion, or twice a day unoccluded, for 4 months. Immediate posttreatment comparative photographs showed marked fading or elimination of some dysplastic nevi clinically, and histologic examination of excisional biopsy specimens showed disappearance or reversion to benign nevi in many of the treated lesions. There were no clinical or histologic changes in those dysplastic nevi treated with placebo. This study shows a definite biological effect of topical tretinoin on some dysplastic nevi.

Effect of oral isotretinoin on dysplastic nevi.

We previously reported a favorable histologic response of dysplastic nevi to topical tretinoin in three patients. To investigate the anticancer and cancer preventive effects of retinoids we have examined the effect of systemic isotretinoin on dysplastic nevi. After confirmatory baseline biopsies, eleven patients with the dysplastic nevus syndrome were treated with oral isotretinoin, 40 mg twice a day for 4 months. At completion of therapy, at least three previously identified and photographed clinically typical dysplastic nevi were rephotographed and removed for histologic evaluation. Eight patients completed the full course of medication. There were no clinical changes in the dysplastic nevi in these patients. Posttherapy biopsy specimens in six volunteers revealed most of the remaining lesions to be dysplastic nevi. The majority of lesions biopsied in two subjects showed normal, benign nevi only. This proportion of clinically typical dysplastic nevi that prove to be normal nevi histologically (28%) is not significantly different from that reported by others. Oral isotretinoin does not appear to have a significant biologic effect on the clinical or histologic appearance of dysplastic nevi in the treatment schedule employed.

Role of topical tretinoin in melanoma and dysplastic nevi.

The retinoids have been investigated extensively as chemopreventive and therapeutic agents in a variety of neoplasms. They have been shown to inhibit the proliferation of transformed cell lines in vitro and transplanted tumors in vivo. In cultured murine melanoma cells, retinoids inhibit proliferation and induce differentiation. Human melanoma cell lines have shown a mixed response. The clinical experience with retinoids in melanoma has been limited. Previously we investigated the activity of topical B-all-trans-retinoic acid (Retin-A, vitamin A acid, retinoic acid, and tretinoin) against intracutaneous metastases from malignant melanoma. We saw complete remission of multiple lesions in one individual and regression of several lesions in a second patient. This experience led us to conduct the present pilot trial of topical tretinoin in dysplastic nevus syndrome. The latter is a precursor of malignant melanoma. We saw regression of some of the treated lesions to benign nevi showing minimal or no dysplasia. Thus topical tretinoin appears to possess some activity against melanoma and at least one of its precursor conditions. In view of these preliminary results, more extensive trials are warranted to better define the role of tretinoin in the chemoprevention of malignant melanoma in high-risk lesions.