Cutaneous melanoma in situ: translational evidence from a large population-based study.

Department of Oncological Sciences, University of Padova, Padova, Italy.
The Oncologist (Impact Factor: 4.54). 06/2011; 16(6):896-903. DOI: 10.1634/theoncologist.2010-0340
Source: PubMed

ABSTRACT Cutaneous melanoma in situ (CMIS) is a nosologic entity surrounded by health concerns and unsolved debates. We aimed to shed some light on CMIS by means of a large population-based study.
Patients with histologic diagnosis of CMIS were identified from the Surveillance Epidemiology End Results (SEER) database.
The records of 93,863 cases of CMIS were available for analysis. CMIS incidence has been steadily increasing over the past 3 decades at a rate higher than any other in situ or invasive tumor, including invasive skin melanoma (annual percentage change [APC]: 9.5% versus 3.6%, respectively). Despite its noninvasive nature, CMIS is treated with excision margins wider than 1 cm in more than one third of cases. CMIS is associated with an increased risk of invasive melanoma (standardized incidence ratio [SIR]: 8.08; 95% confidence interval [CI]: 7.66-8.57), with an estimated 3:5 invasive/in situ ratio; surprisingly, it is also associated with a reduced risk of gastrointestinal (SIR: 0.78, CI: 0.72-0.84) and lung (SIR: 0.65, CI: 0.59-0.71) cancers. Relative survival analysis shows that persons with CMIS have a life expectancy equal to that of the general population.
CMIS is increasingly diagnosed and is often overtreated, although it does not affect the life expectancy of its carriers. Patients with CMIS have an increased risk of developing invasive melanoma (which warrants their enrollment in screening programs) but also a reduced risk of some epithelial cancers, which raises the intriguing hypothesis that genetic/environmental risk factors for some tumors may oppose the pathogenesis of others.

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    ABSTRACT: Background Malignant melanoma is a form of skin cancer associated with significant mortality once it has spread beyond the skin. Melanoma in situ (MIS) is the earliest histologically recognisable stage of malignant melanoma and represents a precursor of invasive melanoma. Lentigo maligna (LM) represents a subtype of pre-invasive intraepidermal melanoma associated specifically with chronic exposure to ultraviolet (UV) radiation. Over the past two decades, the incidence of MIS has increased significantly, even more than the invasive counterpart. There are several treatment options for MIS, but no consensus exists on the best therapeutic management of this condition. Objectives To assess the effects of all available interventions, surgical and non-surgical, for the treatment of melanoma in situ, including LM. Search methods We searched the following databases up to November 2014: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 10), MEDLINE (from 1946), Embase (from 1974), LILACS (from 1982), African Index Medicus (from inception), IndeMED of India (from inception), and Index Medicus for the South-East Asia Region (IMSEAR) (from inception). We scanned the references of included and excluded studies for further references to relevant trials and searched five trials registries. We checked the abstracts of major dermatology and oncology conference proceedings, and we shared our lists of included and excluded studies with industry contacts and other experts in the field of melanoma to try to identify further relevant trials. Selection criteria We included randomised controlled trials (RCT) on the management of MIS, including LM, that compared any intervention to placebo or active treatment. We included individuals, irrespective of age and sex, diagnosed with MIS, including LM, based on histological examination. Data collection and analysis Two authors independently evaluated possible studies for inclusion; extracted data from the included study using a standard data extraction form modified for our review; assessed risk of bias; and analysed data on efficacy, safety, and tolerability. They resolved any disagreements by discussion with a third author. We collected adverse effects information from included studies. Main results Our search identified only 1 study eligible for inclusion (and 1 ongoing study in active recruitment stage), which was a single centre, open label, parallel group, 2-arm RCT with 90 participants, who had 91 histologically proven LM lesions. Forty-four participants, with 44 LM lesions, were treated with imiquimod 5% cream 5 days per week plus tazarotene 0.1% gel 2 days/ week for 3 months, and 46 participants, with 47 LM lesions, were treated with imiquimod 5% cream 5 days per week for 3 months. Two months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision. This study was open label, and analysis was not intention-to-treat, leading to a high risk of incomplete outcome data. Our primary outcome 'Histological or clinical complete response' was measured at 5 months in 29/44 participants (66%) treated with imiquimod plus tazarotene (combination therapy) and 27/46 participants (59%) treated with imiquimod (monotherapy). The difference was not statistically significant (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.81 to 1.55, P value = 0.48). With regard to our secondary outcomes on recurrence and inflammation, after amean follow up of 42 months, no local recurrences were observed among complete responders. Difference in overall inflammation score between the 2 groups was significant (mean difference (MD) 0.6, 95% CI 0.2 to 1, P value = 0.004), with the mean overall inflammation score being significantly higher in the combination group. The study authors did not clearly report on side-effects. Because of adverse effects, there was a dropout rate of 6/44 participants (13.7%) in the combination group compared with 1/46 (2.2%) in the imiquimod monotherapy group (due to excessive inflammation) before the cessation of topical treatment (first 3 months), but this was not statistically significant (RR 6.27, 95% CI 0.79 to 50.02, P value = 0.08). Authors' conclusions There is a lack of high-quality evidence for the treatment of MIS and LM. For the treatment of MIS, we found no RCTs of surgical interventions aiming to optimise margin control (square method, perimeter technique, 'slowMohs', staged radial sections, staged "mapped" excisions, or Mohs micrographic surgery), which are the mostwidely used interventions recommended as first-line therapy. The use of non-surgical interventions in selected cases (patients with contraindications to surgical interventions) may be effective and may be considered preferable for experienced providers and under close and adequate follow up. For the treatment of LM, we found no RCTs of surgical interventions, which remain the most widely used and recommended available treatment. The use of non-surgical interventions, such as imiquimod, as monotherapy may be effective and may be considered in selected cases where surgical procedures are contraindicated and used preferentially by experienced providers under close and adequate follow up. The use of topical therapies, such as 5-fluorouracil and imiquimod, as neoadjuvant therapies warrants further investigation. There is insufficient evidence to support or refute the addition of tazarotene to imiquimod as adjuvant therapy; the current evidence suggests that it can increase topical inflammatory response and withdrawal of participants because of treatment-related side-effects.
    Cochrane database of systematic reviews (Online) 12/2014; 12(12):CD010308. DOI:10.1002/14651858.CD010308.pub2 · 5.70 Impact Factor
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    ABSTRACT: The incidence of malignant melanoma has increased markedly among white populations in the recent decades. This may suggest that the incidence of melanoma in situ (MIS), the precursor of malignant melanoma, has also increased; however, few studies have assessed the incidence of MIS drawing on large population-based data sets. The present study aimed to assess MIS incidence trends in Denmark from 1997 to 2011. Data on MIS overall and on the histological subtypes superficial spreading MIS (SSM) and lentigo maligna (LM) were obtained from the Danish Nationwide Registry of Pathology. We calculated overall and age-specific incidence rates for both sexes, age-adjusted according to the world standard population. The average annual percentage change (AAPC) and 95% confidence intervals were calculated using log-linear Poisson models. Among both sexes, a high continued increase in MIS incidence rates overall and in that of the histological subtypes SSM and LM were observed during the period from 1997 to 2011. During this period, the age-adjusted MIS incidence rate increased from 2.6 to 8.1 cases among women and from 1.4 to 5.6 cases among men per 100 000 person-years. For both sexes, the highest AAPC in MIS incidence was observed during the most recent 5-year calendar period. A markedly higher AAPC was observed for SSM than for LM during the most recent 5-year calendar period for both sexes. The marked increase in incidence of MIS during the last 5 years of the period may indicate a growing awareness of skin cancer among the general Danish population and more frequent excision of suspicious skin lesions.
    Melanoma Research 06/2014; 24(5). DOI:10.1097/CMR.0000000000000092 · 2.10 Impact Factor
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    ABSTRACT: The incidence of melanoma in situ (MIS) is growing significantly. Detection at the MIS stage provides the highest cure rate for melanoma, but reliable detection of MIS with dermoscopy alone is not yet possible. Adjunct dermoscopic instrumentation using digital image analysis may allow more accurate detection of MIS. Gray areas are a critical component of MIS diagnosis, but automatic detection of these areas remains difficult because similar gray areas are also found in benign lesions. This paper proposes a novel adaptive thresholding technique for automatically detecting gray areas specific to MIS. The proposed model uses only MIS dermoscopic images to precisely determine gray area characteristics specific to MIS. To this aim, statistical histogram analysis is employed in multiple color spaces. It is demonstrated that skew deviation due to an asymmetric histogram distorts the color detection process. We introduce a skew estimation technique that enables histogram asymmetry correction facilitating improved adaptive thresholding results. These histogram statistical methods may be extended to detect any local image area defined by histograms.
    IEEE Transactions on Instrumentation and Measurement 07/2012; 61(7):1839-1847. DOI:10.1109/TIM.2012.2192349 · 1.71 Impact Factor


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