CONTINUING
MEDICAL EDUCATION
Melanoma in situ Part I. Epidemiology, screening, and clinical features H. William Higgins II, MD, MBE,a Kachiu C. Lee, MD, MPH,a Anjela Galan, MD,c and David J. Leffell, MDb Providence, Rhode Island, and New Haven, Connecticut
Learning objectives Describe the current epidemiologic trends in MIS, the role of screening, and the evidence on prevention. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Reviewer Dr Laura Ferris served as a reviewer and reported the following financial relationships: Abbott Laboratories, Principal Investigator, Other Financial Benefit; Abbott Laboratories, Consultant, Honorarium; Amgen, Principal Investigator, Other Financial Benefit; Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Institution); Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Self); Castle Biosciences, Inc, Consultant, Honorarium; Castle Biosciences, Inc, Principal Investigator, Other Financial Benefit; Celgene Corporation, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc, Consultant, Honorarium; DermTech International, Principal Investigator, Other Financial Benefit; Eli Lilly and Company, Principal Investigator, Other Financial Benefit; Janssen Pharmaceuticals, Inc, Consultant, Honorarium; LEO Pharma, US, Principal Investigator, Other Financial Benefit; Medimmune, Principal Investigator, Other Financial Benefit; MelaSciences, Consultant, Honorarium; and Pfizer, Inc, Principal Investigator, Other Financial Benefit.
The incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ comprising a disproportionately high percentage of the rising incidence. Our understanding of melanoma in situ has been shaped by epidemiologic and clinical studies. Central to a review of melanoma in situ is a focus on its epidemiology, pathology, biologic behavior, treatment, and clinical outcome, which may differ significantly from that of malignant melanoma. Part I of this continuing medical education article reviews the epidemiology, risk factors, and clinical features of melanoma in situ; part II covers the histopathology, treatment options, and clinical management. ( J Am Acad Dermatol 2015;73:181-90.) Key words: lentigo maligna; melanoma; melanoma in situ.
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he incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ (MIS) comprising a disproportionately high percentage of the rising incidence.1-4 According to the American Joint Committee on Cancer, MIS is defined as melanomas that are limited to the epidermis.5 Lentigo maligna is a subtype of MIS, and is defined histologically when atypical melanocytes are present in the basal layer with a background of solar elastosis. Comparatively, From the Department of Dermatology,a Brown University School of Medicine, Providence, and the Departments of Dermatologyb and Pathology,c Yale University School of Medicine, New Haven. Funding sources: None. Conflicts of interest: None declared. Accepted for publication April 1, 2015. Correspondence to: H. William Higgins II, MD, MBE, Brown University School of Medicine, Department of Dermatology,
Abbreviations used: MIS: MM: PPV: SCREEN: SEER: SPF:
melanoma in situ malignant melanoma positive predictive value Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany Surveillance, Epidemiology, and End Results sun protective factor
593 Eddy St, APC 10th fl, Providence, RI 02903. E-mail: [email protected]. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.014 Date of release: August 2015 Expiration date: August 2018
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invasive melanomas represent tumors that have invaded the dermis. The combined incidence of MIS and invasive melanoma has been increasing by 2.6% annually over the last decade, with MIS constituting the majority of this increase.6 MIS has increased 9.5% annually, representing one of the fasting growing malignancies in the Surveillance, Epidemiology, and End Results (SEER) database.7 Some clinicians question whether this is a true increase in tumor burden or a result of overdiagnosis of MIS because of its complex histopathologic nuance. Increased rates of obtaining a skin biopsy specimen between 1968 and 2001 were also associated with an increased incidence of melanoma during the same time period, further fueling this controversy.8-10 MIS is considered stage 0 and as such has no associated direct mortality. However, there is an association with an increased risk of developing second primary tumors.5,11-14 Specifically, patients with MIS are at much higher risk of developing a subsequent primary malignant melanoma (MM), leading dermatologists to recommend regular screening of patients with pigmented lesions.13,15,16 Despite these recommendations, the evidence for early detection through screening and prevention of MIS by sun avoidance and protection strategies is indeterminate, in part because of the difficulty of performing controlled trials. In order for screening to be a successful tool, physicians must be able to accurately diagnose MIS based on a clinical examination. These tumors can be challenging to distinguish from benign pigmented lesions, especially in sun-exposed areas. The use of dermoscopy may be a helpful tool in the diagnosis of MIS, although biopsy is always required for definitive diagnosis. We review the epidemiologic evidence for an increase in the incidence of MIS and address the controversy about whether there is in fact a true increase in incidence or simply an overdiagnosis of MIS. We discuss the increased risk of secondary tumors after a diagnosis of MIS and the studies examining the effect of screening and sunscreen usage. A significant limitation in this review is that much of the literature addresses MM, and not MIS. Therefore, a major assumption is made when applying the findings of these studies on screening and sunscreen use to MIS. Clinical and dermoscopic features of MIS will also be reviewed, highlighting differences between benign nevi, MIS, and MM.
INCIDENCE Key points d
The incidence of melanoma in situ has been increasing steadily over the past decade,
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with a faster rate of increase in younger patients (20-49 years of age) than older patients and in men compared to women The annual percentage change in incidence is the highest of any tumor in the Surveillance, Epidemiology, and End Results database
An increase in the incidence of cutaneous melanoma (MIS and MM) over the past 3 decades is well documented.17 In Europe, Australia (Queensland), and the United States, MIS makes up a disproportionate amount of the annual increase in melanoma.18-20 In Queensland, the incidence of MIS between 1982 and 2002 increased at a rate of 10.6% for men and 8.5% for women, whereas invasive melanoma increased at a rate of 2.6% for men and 1.2% for women.21 In the United States, the incidence of MIS has risen from \1 case per 100,000 patients in 1973 to 14 cases per 100,000 patients in 2006.11 This rapid increase amounts to an annual percent change of 9.5%, which is higher than that of invasive melanomas (annual percent change over the past decade, 2.6%).11 The annual percent change of MIS is the highest of any tumor recorded by the SEER database, which indexes leukemia, bladder, breast, colon, endometrial, renal, lung, pancreatic, prostate, and thyroid cancers, and non-Hodgkin’s lymphoma.7 Younger patients (20-49 years of age) have a faster rate of increase for MIS than older patients.7 Men are also more commonly diagnosed with MIS than women (men, 55.7%; women, 44.3%). The mean age of those diagnosed with MIS was 61.2 years, with whites making up 93.1% of the affected population. Comparatively, the mean age of patients diagnosed with MM is 54 years; men make up 53.4% of this population.22 Fig 1 shows locations of MIS, with head and neck being the most common location. In contrast, head and neck is the fourth most common location of MM (18.2%) after the trunk (32%), upper extremities (23.4%), and lower extremities (20.3%).7,22 Fig 2 shows subtypes of MIS, as categorized by the SEER study.7 The rapid increase in the incidence of MIS—if real and not related to overdiagnosis—warrants public health efforts to address the disease. Such steps are predicated on understanding the basis of the increase.
CONTROVERSY ABOUT INCIDENCE Key points d
There is controversy about whether there is in fact a true increase in incidence or simply an increase in diagnosis of melanoma in situ
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Fig 1. Locations of melanoma in situ recorded by the Surveillance, Epidemiology, and End Results study between 1973 and 2006. Total numbers of melanoma in situ in each area shown.7
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Improved screening, increased reporting, or changes in histologic criteria may be the cause of increased diagnosis and the apparent increase in incidence
Because of the growing incidence of MIS, some clinicians have raised questions about whether there is indeed an epidemic of increased tumor burden or whether it represents an apparent increase related to improved screening and reporting or changes in histologic criteria. Welch et al10 conducted a population-based study of the SEER-Medicare linked data and found a 2.5-fold increase in biopsy rates in the Medicare population between 1986 and 2001. Over the same time period, the incidence of MM also had a 2.4-fold increase, suggesting an association between increased biopsy rates and invasive melanoma diagnosis. For MIS, each 1000 biopsy specimens were estimated to result in 4.4 diagnoses of MIS.10 Studies exploring the incidence of MM based on tumor thickness and demographic factors have suggested that increased screening and biopsy alone cannot account for the dramatic increase in the incidence of this tumor, especially because incidence increased without regard to socioeconomic status, which functioned as a surrogate marker for access to care and screening.8,23 In addition, others have suggested that the increase in incidence of MIS is related to a general trend toward overdiagnosing melanocytic lesions as malignant. In 1 study, slides that were previously diagnosed as dysplastic nevi and radial growth phase melanoma between 1988 and 1990 were reevaluated by dermatopathologists in 2008 and 2009. Diagnoses rendered in 1988 to 1990 resulted in a mean number of 11 melanomas; diagnoses of the same slides rendered in 2008 to 2009 resulted in a mean number of 18 melanomas.24 These studies did not address MIS specifically, which makes it difficult to interpret whether the
Fig 2. Pathology of melanoma in situ recorded by the Surveillance, Epidemiology, and End Results study between 1973 and 2006.
incidence of MIS is truly increasing or whether it is a reflection of increased diagnostic scrutiny (ie, more vigilant biopsy and screening efforts and more aggressive interpretation by dermatopathologists).
RISK OF SECONDARY TUMORS AND MORTALITY Key points d
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Patients diagnosed with melanoma in situ have a higher risk of developing secondary tumors Malignant melanoma (a second primary) is the most common secondary tumor diagnosed Patients with melanoma in situ have the same life expectancy as the general population
Similar to MM, MIS is associated with a higher risk of developing secondary tumors (standardized incidence ratio [SIR], 1.2 [95% confidence interval {CI}, 1.2-1.3]), especially MM (SIR, 8.1 [95% CI, 7.7-8.6]).11,22 Other secondary tumors diagnosed after MIS included tumors of the lip (SIR, 1.7 [95% CI, 1.1-2.6]), lymphocytic leukemia (SIR, 1.6 [95% CI, 1.3-2]), non-Hodgkin’s lymphoma (SIR, 1.2 [95% CI, 1-1.4]), and hematologic tumors (SIR, 1.1 [95% CI, 1-1.3]).11 A lower risk of malignancy was found for tumors of the digestive system (SIR, 0.8 [95% CI, 0.7-0.8]), colon/rectum/anus (SIR, 0.8 [95% CI, 0.7-0.9]), pancreas (SIR, 0.8 [95% CI, 0.6-0.9]), liver/gallbladder/biliary ducts (SIR, 0.7 [95% CI, 0.5-0.9]), respiratory system (SIR, 0.7 [95% CI, 0.6-0.7]), lung/bronchus (SIR, 0.7 [95% CI, 0.6-0.7]), and larynx (SIR, 0.4 [95% CI, 0.2-0.7]).11 The mean time to diagnosis of a second tumor of any type was 14 years. While additional evaluation is needed, this association could reflect genetic or environmental factors that predispose individuals diagnosed with
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MIS to developing additional malignancies or even decrease the likelihood of others.11 Patients with MIS have the same life expectancy as the general population. In contrast, the 5-year mortality of patients with MM is higher than that of the general population, although this trend has been improving over the past 3 decades.7
SCREENING RECOMMENDATIONS Key points d
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There is limited evidence to support the usefulness of full body skin examinations in screening for melanoma in situ by primary care physicians Some evidence suggests that screening for melanoma in situ by dermatologists may be beneficial, particularly in higher-risk populations
The issue of the value of screening for MIS is complicated by the fact that most studies either focused on MM or, if MIS was included, it was not distinguished from MM. Nonetheless, it is reasonable to conclude that guidance regarding screening practices and outcomes for MM would be applicable to the clinical aspects of screening diagnosis if not to alterations in patient mortality. Currently, the United States Preventative Task Force (USPTF) reports limited evidence to support the utility of full body skin examinations in screening for melanoma/skin cancer by primary care physicians.25,26 As such, it is silent on the usefulness of full body skin examinations in the asymptomatic patient without specific risk factors. This recommendation, published in 2009, was based on an English-language search of relevant articles examining the evidence for and against full body skin examinations.25,26 Before this 2009 recommendation, the 2001 USPTF report also reported limited evidence to recommend for or against skin screening in asymptomatic individuals. Both reports specifically point out 2 practice gaps, including the lack of quality evidence demonstrating improved outcomes with screening and the lack of information about a primary care physician’s ability to perform full body skin examinations in a regular office visit.25,26 There are substantial challenges to conducting a screening study that seeks to ascertain a benefit to screening. Importantly, these recommendations do not address screening by specialists (ie, dermatologists, specialty midlevel providers). In addition, these recommendations specifically apply to the general adult population with an average risk of skin cancer
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and may not pertain to those with an already established history of skin cancer or those with a higher risk than the general public.25,26 Because most studies do not distinguish MIS from MM, the closest approximation to analyzing the value of screening is derived from large prospective studies of population screening for melanoma. The Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany (SCREEN) project was a population-wide skin cancer screening study using both primary care physicians and dermatologists. In this study, residents in the German state of Schleswig-Holstein received full body skin examinations and those in the state of Saarland did not. Based on comparisons between MIS incidence before, during, and after the full body skin examination intervention, the population receiving skin examinations showed an increase in the incidence of MIS, with the greatest differences noted in women. After the conclusion of the study intervention, MIS incidence decreased in women. The SCREEN study was one of the first to show the impact that screening can have on improved MIS diagnosis.27,28 The incidence of nonmelanoma skin cancer also increased during the screening intervention period of the SCREEN study. Specifically, incidence rates increased from 81.5 per 100,000 people to 111.5 per 100,000 people during the screening period. Therefore, increased screening of melanoma also results in increased detection of nonmelanoma skin cancer and related morbidity and health care costs.29 In the SCREEN study, 1 in 23 individuals receiving full body skin examinations underwent excision for treatment of malignant skin tumors.30 Other studies have examined the positive predictive value (PPV) for the diagnosis of melanoma through screening by both general practitioners and dermatologists. One of the reasonable conclusions that can be drawn from the literature is that MIS can be diagnosed in a fashion similar to invasive MM. The remaining issue is whether early diagnosis of MIS has any impact on morbidity. One Australian study examined community-based general practitioners conducting full body skin examinations. Of 16,383 skin examinations conducted, 2302 patients were referred for suspicious lesions. The specificity of finding a lesion histologically confirmed as melanoma was 86.1%, with a 2.5% PPV. The specificity of detecting melanoma in patients $50 years of age was comparable to the specificity of mammography in this high-risk Australian population.20 Other studies conducted in the late 1990s found PPVs ranging from 6% to 24%. Higher
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PPVs were associated with general practitioners that had previously received some type of training as part of the study.31,32 When screening for melanoma was performed by a plastic surgeon or dermatologist in Australia, the PPV was found to be approximately 10%, with a specificity of 95% to 99% and a sensitivity of 64% to 82%.33 In the United States, participants who self-selected for skin cancer screening were also studied in the late 1990s. Of 132 patients, the PPV for melanoma ranged from 6% to 15%. A major limitation to this study was the diagnosis of only 2 melanomas in this population.32 Other screening studies conducted during this time found similar PPVs for melanoma in self-selecting populations.34-36 An analysis of the American Academy of Dermatology’s screening program in the 1990s found a PPV of 11% for melanoma. When this population was restricted to patients $50 years of age, the PPV rose to 21%.37-39 The age at which to begin screening is unclear. Because there are few studies examining the impact of screening on MIS, it is hard to extrapolate from their data what the target age group for screening should encompass. Based on SEER incidence data, MIS is increasing at a faster rate in younger patients (ie, those 20-49 years of age), although the mean age of those diagnosed with MIS is still 61.2 years.7 Screening should ideally encompass both of these age groups. When considering the benefits of screening for MIS and its potential impact on morbidity, the harms of screening are also worth considering. Namely, the number needed to screen for melanoma is estimated to be 25,000 patients to prevent 1 melanoma-related mortality.40 When examining the number needed to screen for detection of melanoma, this number drops to 1 in 620, based on data from the SCREEN study.27 These numbers apply to a calculation for all melanomas, including MIS and MM. Therefore, the cost and burden of screening for MIS may differ significantly.
SUNSCREEN USE Key points d
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Sunscreen use has been shown to prevent invasive melanoma in some studies It is unknown whether sunscreen is effective in specifically preventing melanoma in situ
Sunscreen use can prevent or mitigate sunburn by reducing the impact of ultraviolet radiation on the skin. Laboratory studies on animal models confirm this role for sunscreens.41 Sunscreens are one of the most common forms of sun protection used by the general public, although its application
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is frequently suboptimal.42-44 The sun protective factor (SPF) is tested at an application thickness on the skin surface of 2 mg/cm2. Several studies have shown that users routinely apply an inadequate amount of sunscreen, ranging from 0.3 to 1 mg/ cm2. This thin application considerably decreases the amount of ultraviolet protection afforded by the sunscreen.45 The use of high SPF ($70) compositions with frequent reapplication or double-layered applications may compensate for thin or uneven applications.46,47 Because sun exposure is considered a major risk factor for melanoma, the use of sunscreen can theoretically decrease the incidence of melanoma. A randomized trial of sunscreens in children noted reductions in the development of melanocytic nevi, a strong predictor of melanoma. This effect was strongest in children with freckles. However, these studies did not investigate the effects on MIS and MM.48,49 Evidence for the use of sunscreen in prevention of melanoma is sparse, with few randomized controlled trials. Data from case control studies have produced conflicting results. Some studies demonstrated decreased melanoma risk with routine use of SPF 151 sunscreen and other sun protection methods (eg, long-sleeved shirts, staying in the shade) while other studies showed no association.50-52 A metaanalysis of 9067 patients from 11 case controlled studies showed a relative risk of 1.01, indicating a lack of association between sunscreen use and melanoma.51 Other studies have suggested that sunscreen use may actually increase a person’s risk for melanoma because individuals using sunscreen have longer sun exposures.53,54 Before 2011, the lack of randomized controlled trials left the effect of sunscreen on melanoma unanswered. In 2011, Green et al published data from a randomized skin cancer prevention trial investigating the effect of sunscreen use in a community in Queensland, Australia. This study of 1621 adults randomized individuals to the use of SPF 16 sunscreen. Experimental group subjects were asked to apply sunscreen to sun-exposed areas (ie, the head, neck, arms, and hands) daily, with reapplication after water exposure, long sun exposure, and heavy sweating. Control group subjects were asked to use sunscreen at their normal frequency, which could have included no use of sunscreen. During the 5-year trial period, compliance with sunscreen use was recorded based on the weight of sunscreen bottles returned and by surveys querying subjects’ weekly use of sunscreen. Ten years after conclusion of the trial, a
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Fig 3. A, Melanoma in situ (MIS) [6 mm of the nose. B, Macular presentation of MIS. C, Variegate coloration of MIS; both brown and black portions are present. D and E, Superficial spreading melanoma variant of MIS. F-H, Lentigo maligna variant of MIS.
reduction in the number of melanomas diagnosed was observed in the trial group compared to control group, suggesting a preventative role for use of sunscreen in preventing invasive melanoma. Despite the reduction in invasive melanomas, it is notable that there were no significant differences between both groups with respect to MIS.55 Therefore, the question of the efficacy of sunscreen use in prevention of MIS still remains. To the extent that the effect was not unequivocally answered, questions about the etiology or behavior of MIS may be raised. While the evidence for sunscreen use in the prevention of MIS is indeterminate, dermatologists still often recommend use of these products to the general public. The other benefits of sunscreen, including reducing actinic keratoses, prevention of squamous cell carcinoma, and delay in appearance of sunburn-related erythema, warrant its use in at-risk populations.56-61 In patients with a history of MM, there is an increase in sunscreen use immediately after diagnosis. Over time, this use becomes inconsistent and comparable to the use in those without a history of melanoma.62 These behavioral patterns may shed light on those patients diagnosed with MIS, although additional investigation is necessary to definitively assess sun-protective habits in those with a history of MIS.
CLINICAL FEATURES Key points d
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Melanoma in situ has clinical and dermoscopic features that may aid in its distinction from common nevi Lentigo maligna is considered by the World Health Organization as melanoma in situ
MIS can vary in size, shape, and color. In a study of 121 MIS lesions, 77% of lesions were [6 mm (Fig 3, A), 92% were macular (Fig 3, B), and 75% were asymmetric (Figure 3, F-H). Although the border was irregular in the majority of lesions, it was not thought to be poorly defined. The most common color present in the tumor was black (48%), followed by brown (41%), tan (16%), grey (85), and pink (3%). The majority of lesions (98%) had [1 color present in the lesion (Fig 3, C-E ).63 Amelanotic MIS presents as an erythematous macule or plaque and may initially be misdiagnosed as an inflammatory disorder.64-66 Lentigo maligna (LM) subtype typically occurs on chronically sun-exposed skin. LM can act as a precursor to LM melanoma (Fig 3, F-H ). Roughly 5% of LMs progress to invasive melanoma.67 LM occurs most commonly on the face of elderly individuals and has a predilection for the nose and cheek. This slow-growing lesion typically presents as an asymmetric, brown-black macule with
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color variation and irregular borders. LM can be difficult to distinguish histologically from the atypical melanocytic hyperplasia seen in severely sun-damaged skin.68 This distinction will be discussed in part II of this continuing medical education article. Some advocate that the current concept of LM69,70 actually embodies 2 distinct histologic entities, with LM recognized as atypical melanocytic hyperplasia and MIS, LM type showing confluence and nesting of atypical melanocytes at various layers of the epidermis.68,71 Despite this controversy, most studies have not made this distinction. The World Health Organization and national registries, such as SEER, recognize LM and MIS as the same entity, allowing reporting of both under the category of MIS.72 Dermoscopy can be used to clinically diagnose melanomas. While nevi, MIS, and MM have many overlapping features, certain characteristics can help to distinguish MIS. Compared to typical nevi, MIS frequently has an atypical pigment network involving [50% of the lesion or the presence of multiple different pigment networks. Grey-blue regression is also more commonly observed in MIS lesions.73 The comparison between atypical nevi and MIS is more difficult, because both can share similar features. In a study of 38 MIS and 136 atypical nevi, no distinguishing features could be found between the 2 entities in terms of geometry, color, textures, and islands of color, such as a grey-blue veil.74 MIS and MM share several common dermoscopic features, making these lesions difficult to distinguish. Light brown areas are more common in MIS; grey-blue veils are more common in MM. When blue areas are present in MIS, they are more likely to show a reticular grey-blue pattern, compared to a more disorganized pattern in MM. This reticular pattern can serve as a distinguishing characteristic of MIS.75 The distribution of blue areas (center vs. periphery) is similar in MIS and MM. Peppering, or scattered blue-gray granules within an area of hypopigmentation, can be seen in similar proportions in both types of lesions. Both types of lesions can have a combination of the aforementioned features.75,76 When considering MIS only, 8 different dermoscopic subtypes have been proposed: reticular greyblue, reticular, multicomponent, island, spitzoid, inverse network, net-blue globules, and globular. Of these, the reticular grey-blue is the most common.77 Other studies have also suggested various dermoscopic features that may be helpful in distinguishing MIS from other pigmented lesions.
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These include the dermoscopic island, a well-circumscribed area with a uniform dermoscopic pattern that differs from the rest of the lesion.78 The ‘‘mushroom-cloud sign’’ and ‘‘mistletoe sign’’ have also been described. The ‘‘mushroom-cloud sign’’ consists of a hyperpigmented area extending in one direction. Once past the border, a faint stalk-like projection can be seen.79 The ‘‘mistletoe sign’’ represents well-circumscribed areas with nonuniform structures resembling branching pseudopods. This pattern arises from reticular or homogenous background patterns, which are reminiscent of mistletoe.80 When specifically examining the LM subtype of MIS, LM features hyperpigmented follicular openings, rhomboidal structures, and irregular pigmented perifollicular dots.81,82 In conclusion, the incidence of MIS has been steadily rising over the past 3 decades, with little impact on mortality or life expectancy. There is controversy as to whether this rising incidence in MIS represents overdiagnosis related to better screening methods and more biopsies or if it represents a true increase in incidence. Given the risk of a second primary tumor after a diagnosis of MIS, this condition still warrants close surveillance. Full body skin examinations are currently not recommended by the USPTF in the general population. This group does not address screening recommendations in the high-risk population, such as those with a strong family history or those with a personal history of skin cancer. Sunscreen use can help to decrease the incidence of MM, although its effect on MIS may be minimal. This area of research has proven difficult due to the large sample sizes required to detect differences in MIS incidence. Part II of this continuing medical education article will explore treatment, surveillance tools, and genetic considerations. We thank John Kawaoka, Jennie Muglia, Jayne Bird, and Newsha Lajevardi for contributing clinical photographs for this manuscript.
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25. Wolff T, Tai E, Miller T. Screening for skin cancer: an update of the evidence for the US Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality; 2009. 26. Wolff T, Tai E, Miller T. Screening for skin cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;150:194-198. 27. Waldmann A, Nolte S, Weinstock MA, et al. Skin cancer screening participation and impact on melanoma incidence in Germany—an observational study on incidence trends in regions with and without population-based screening. Br J Cancer. 2012;106:970-974. 28. Breitbart EW, Waldmann A, Nolte S, et al. Systematic skin cancer screening in Northern Germany. J Am Acad Dermatol. 2012;66:201-211. 29. Eisemann N, Waldmann A, Geller AC, et al. Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence. J Invest Dermatol. 2014;134: 43-50. 30. Waldmann A, Nolte S, Geller AC, et al. Frequency of excisions and yields of malignant skin tumors in a population-based screening intervention of 360,288 whole-body examinations. Arch Dermatol. 2012;148:903-910. 31. Burton RC, Howe C, Adamson L, et al. General practitioner screening for melanoma: sensitivity, specificity, and effect of training. J Med Screen. 1998;5:156-161. 32. Jonna BP, Delfino RJ, Newman WG, Tope WD. Positive predictive value for presumptive diagnoses of skin cancer and compliance with follow-up among patients attending a community screening program. Prev Med. 1998;27: 611-616. 33. Fritschi L, Dye SA, Katris P. Validity of melanoma diagnosis in a community-based screening program. Am J Epidemiol. 2006;164:385-390. 34. de Rooij MJ, Rampen FH, Schouten LJ, Neumann HA. Volunteer melanoma screenings. Follow-up, compliance, and outcome. Dermatol Surg. 1997;23:197-201. 35. de Rooij MJ, Rampen FH, Schouten LJ, Neumann HA. Skin cancer screening focusing on melanoma yields more selective attendance. Arch Dermatol. 1995;131:422-425. 36. Engelberg D, Gallagher RP, Rivers JK. Follow-up and evaluation of skin cancer screening in British Columbia. J Am Acad Dermatol. 1999;41:37-42. 37. Geller AC, Zhang Z, Sober AJ, et al. The first 15 years of the American Academy of Dermatology skin cancer screening programs: 1985-1999. J Am Acad Dermatol. 2003;48:34-41. 38. Geller AC, Sober AJ, Zhang Z, et al. Strategies for improving melanoma education and screening for men age [or= 50 years: findings from the American Academy of Dermatological National Skin Cancer Sreening Program. Cancer. 2002;95:1554-1561. 39. Koh HK, Norton LA, Geller AC, et al. Evaluation of the American Academy of Dermatology’s National Skin Cancer Early Detection and Screening Program. J Am Acad Dermatol. 1996;34:971-978. 40. Gelfand J. Behind the numbers: number needed to screen. NEJM Journal Watch. December 22, 2011. Available at: http:// www.targetportraits.com/products/images-cd. Accessed May 11, 2015. 41. Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354: 723-729.
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42. Stanton WR, Janda M, Baade PD, Anderson P. Primary prevention of skin cancer: a review of sun protection in Australia and internationally. Health Promot Int. 2004;19: 369-378. 43. Weiss J, Kirsner RS, Hu S. Trends in primary skin cancer prevention among US Hispanics: a systematic review. J Drugs Dermatol. 2012;11:580-586. 44. Buller DB, Cokkinides V, Hall HI, et al. Prevalence of sunburn, sun protection, and indoor tanning behaviors among Americans: review from national surveys and case studies of 3 states. J Am Acad Dermatol. 2011;65(5 suppl 1): S114-S123. 45. Petersen B, Wulf HC. Application of sunscreen—theory and reality. Photodermatol Photoimmunol Photomed. 2014;30: 96-101. 46. Ou-Yang H, Stanfield J, Cole C, Appa Y, Rigel D. High-SPF sunscreens (SPF $70) may provide ultraviolet protection above minimal recommended levels by adequately compensating for lower sunscreen user application amounts. J Am Acad Dermatol. 2012;67:1220-1227. 47. Teramura T, Mizuno M, Asano H, Naito N, Arakane K, Miyachi Y. Relationship between sun-protection factor and application thickness in high-performance sunscreen: double application of sunscreen is recommended. Clin Exp Dermatol. 2012;37:904-908. 48. Lee TK, Rivers JK, Gallagher RP. Site-specific protective effect of broad-spectrum sunscreen on nevus development among white schoolchildren in a randomized trial. J Am Acad Dermatol. 2005;52:786-792. 49. Gallagher RP, Rivers JK, Lee TK, Bajdik CD, McLean DI, Coldman AJ. Broad-spectrum sunscreen use and the development of new nevi in white children: a randomized controlled trial. JAMA. 2000;283:2955-2960. 50. Dennis LK, Beane Freeman LE, VanBeek MJ. Sunscreen use and the risk for melanoma: a quantitative review. Ann Intern Med. 2003;139:966-978. 51. Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am J Public Health. 2002;92: 1173-1177. 52. Lazovich D, Vogel RI, Berwick M, Weinstock MA, Warshaw EM, Anderson KE. Melanoma risk in relation to use of sunscreen or other sun protection methods. Cancer Epidemiol Biomarkers Prev. 2011;20:2583-2593. 53. Autier P, Dore JF, Cattaruzza MS, et al. Sunscreen use, wearing clothes, and number of nevi in 6- to 7-year-old European children. European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Natl Cancer Inst. 1998;90:1873-1880. 54. Autier P. Sunscreen abuse for intentional sun exposure. Br J Dermatol. 2009;161(suppl 3):40-45. 55. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29:257-263. 56. Pissavini M, Diffey B. The likelihood of sunburn in sunscreen users is disproportionate to the SPF. Photodermatol Photoimmunol Photomed. 2013;29:111-115. 57. Liu W, Wang X, Lai W, et al. Sunburn protection as a function of sunscreen application thickness differs between high and low SPFs. Photodermatol Photoimmunol Photomed. 2012;28: 120-126. 58. Gordon LG, Scuffham PA, van der Pols JC, McBride P, Williams GM, Green AC. Regular sunscreen use is a cost-effective approach to skin cancer prevention in subtropical settings. J Invest Dermatol. 2009;129:2766-2771.
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59. van der Pols JC, Williams GM, Pandeya N, Logan V, Green AC. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546-2548. 60. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993;329: 1147-1151. 61. Dupuy A, Dunant A, Grob JJ. Randomized controlled trial testing the impact of high-protection sunscreens on sun-exposure behavior. Arch Dermatol. 2005;141: 950-956. 62. Idorn LW, Datta P, Heydenreich J, Philipsen PA, Wulf HC. A 3-year follow-up of sun behavior in patients with cutaneous malignant melanoma. JAMA Dermatol. 2014;150: 163-168. 63. Bartoli C, Bono A, Clemente C, Del Prato ID, Zurrida S, Cascinelli N. Clinical diagnosis and therapy of cutaneous melanoma in situ. Cancer. 1996;77:888-892. 64. Andre J, Moulonguet I, Goettmann-Bonvallot S. In situ amelanotic melanoma of the nail unit mimicking lichen planus: report of 3 cases. Arch Dermatol. 2010;146: 418-421. 65. Cliff S, Otter M, Holden CA. Amelanotic lentigo maligna melanoma of the face: a case report and review of the literature. Clin Exp Dermatol. 1997;22:177-179. 66. Pichler E, Fritsch P. Macular amelanotic melanoma in situ. Dermatologica. 1988;177:313-316. 67. Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol. 1987; 116:303-310. 68. Tannous ZS, Lerner LH, Duncan LM, Mihm MC Jr, Flotte TJ. Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type. Hum Pathol. 2000;31: 705-708. 69. Cohen LM. Lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol. 1997;36:913. 70. Dubow BE, Ackerman AB. Ideas in pathology. Malignant melanoma in situ: the evolution of a concept. Mod Pathol. 1990;3:734-744. 71. Flotte TJ, Mihm MC Jr. Lentigo maligna and malignant melanoma in situ, lentigo maligna type. Hum Pathol. 1999; 30:533-536. 72. World Health Organization Classification of Tumours. In: LeBoit PE, Burg G, Weedon D, Sarasain A, eds. Pathology and Genetics of Skin Tumours. 2006. Lyon, France: IARC Press. 73. Seidenari S, Ferrari C, Borsari S, et al. The dermoscopic variability of pigment network in melanoma in situ. Melanoma Res. 2012;22:151-157. 74. Burroni M, Sbano P, Cevenini G, et al. Dysplastic naevus vs. in situ melanoma: digital dermoscopy analysis. Br J Dermatol. 2005;152:679-684. 75. Seidenari S, Ferrari C, Borsari S, et al. Reticular grey-blue areas of regression as a dermoscopic marker of melanoma in situ. Br J Dermatol. 2010;163:302-309. 76. Silva VP, Ikino JK, Sens MM, Nunes DH, Di Giunta G. Dermoscopic features of thin melanomas: a comparative study of melanoma in situ and invasive melanomas smaller than or equal to 1mm. An Bras Dermatol. 2013; 88:712-717. 77. Seidenari S, Bassoli S, Borsari S, et al. Variegated dermoscopy of in situ melanoma. Dermatology. 2012;224:262-270. 78. Borsari S, Longo C, Ferrari C, et al. Dermoscopic island: a new descriptor for thin melanoma. Arch Dermatol. 2010;146: 1257-1262.
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79. Mahlberg MJ, Hwa C, Kopf AW, Stein JA. Letter: ‘‘mushroomcloud sign’’ of melanoma. Dermatol Surg. 2011;37:1546-1548. 80. Kaminska-Winciorek G, Wlaszczuk P, Wydmanski J. ‘‘Mistletoe sign’’: probably a new dermoscopic descriptor for melanoma in situ and melanocytic junctional nevus in the inflammatory stage. Postepy Dermatol Alergol. 2013;30:316-319.
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81. Stante M, Giorgi V, Stanganelli I, Alfaioli B, Carli P. Dermoscopy for early detection of facial lentigo maligna. Br J Dermatol. 2005;152:361-364. 82. Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol. 2003;48:679-693.
MEDICAL EDUCATION
Melanoma in situ Part I. Epidemiology, screening, and clinical features H. William Higgins II, MD, MBE,a Kachiu C. Lee, MD, MPH,a Anjela Galan, MD,c and David J. Leffell, MDb Providence, Rhode Island, and New Haven, Connecticut
Learning objectives Describe the current epidemiologic trends in MIS, the role of screening, and the evidence on prevention. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Reviewer Dr Laura Ferris served as a reviewer and reported the following financial relationships: Abbott Laboratories, Principal Investigator, Other Financial Benefit; Abbott Laboratories, Consultant, Honorarium; Amgen, Principal Investigator, Other Financial Benefit; Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Institution); Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Self); Castle Biosciences, Inc, Consultant, Honorarium; Castle Biosciences, Inc, Principal Investigator, Other Financial Benefit; Celgene Corporation, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc, Consultant, Honorarium; DermTech International, Principal Investigator, Other Financial Benefit; Eli Lilly and Company, Principal Investigator, Other Financial Benefit; Janssen Pharmaceuticals, Inc, Consultant, Honorarium; LEO Pharma, US, Principal Investigator, Other Financial Benefit; Medimmune, Principal Investigator, Other Financial Benefit; MelaSciences, Consultant, Honorarium; and Pfizer, Inc, Principal Investigator, Other Financial Benefit.
The incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ comprising a disproportionately high percentage of the rising incidence. Our understanding of melanoma in situ has been shaped by epidemiologic and clinical studies. Central to a review of melanoma in situ is a focus on its epidemiology, pathology, biologic behavior, treatment, and clinical outcome, which may differ significantly from that of malignant melanoma. Part I of this continuing medical education article reviews the epidemiology, risk factors, and clinical features of melanoma in situ; part II covers the histopathology, treatment options, and clinical management. ( J Am Acad Dermatol 2015;73:181-90.) Key words: lentigo maligna; melanoma; melanoma in situ.
T
he incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ (MIS) comprising a disproportionately high percentage of the rising incidence.1-4 According to the American Joint Committee on Cancer, MIS is defined as melanomas that are limited to the epidermis.5 Lentigo maligna is a subtype of MIS, and is defined histologically when atypical melanocytes are present in the basal layer with a background of solar elastosis. Comparatively, From the Department of Dermatology,a Brown University School of Medicine, Providence, and the Departments of Dermatologyb and Pathology,c Yale University School of Medicine, New Haven. Funding sources: None. Conflicts of interest: None declared. Accepted for publication April 1, 2015. Correspondence to: H. William Higgins II, MD, MBE, Brown University School of Medicine, Department of Dermatology,
Abbreviations used: MIS: MM: PPV: SCREEN: SEER: SPF:
melanoma in situ malignant melanoma positive predictive value Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany Surveillance, Epidemiology, and End Results sun protective factor
593 Eddy St, APC 10th fl, Providence, RI 02903. E-mail: [email protected]. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.014 Date of release: August 2015 Expiration date: August 2018
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invasive melanomas represent tumors that have invaded the dermis. The combined incidence of MIS and invasive melanoma has been increasing by 2.6% annually over the last decade, with MIS constituting the majority of this increase.6 MIS has increased 9.5% annually, representing one of the fasting growing malignancies in the Surveillance, Epidemiology, and End Results (SEER) database.7 Some clinicians question whether this is a true increase in tumor burden or a result of overdiagnosis of MIS because of its complex histopathologic nuance. Increased rates of obtaining a skin biopsy specimen between 1968 and 2001 were also associated with an increased incidence of melanoma during the same time period, further fueling this controversy.8-10 MIS is considered stage 0 and as such has no associated direct mortality. However, there is an association with an increased risk of developing second primary tumors.5,11-14 Specifically, patients with MIS are at much higher risk of developing a subsequent primary malignant melanoma (MM), leading dermatologists to recommend regular screening of patients with pigmented lesions.13,15,16 Despite these recommendations, the evidence for early detection through screening and prevention of MIS by sun avoidance and protection strategies is indeterminate, in part because of the difficulty of performing controlled trials. In order for screening to be a successful tool, physicians must be able to accurately diagnose MIS based on a clinical examination. These tumors can be challenging to distinguish from benign pigmented lesions, especially in sun-exposed areas. The use of dermoscopy may be a helpful tool in the diagnosis of MIS, although biopsy is always required for definitive diagnosis. We review the epidemiologic evidence for an increase in the incidence of MIS and address the controversy about whether there is in fact a true increase in incidence or simply an overdiagnosis of MIS. We discuss the increased risk of secondary tumors after a diagnosis of MIS and the studies examining the effect of screening and sunscreen usage. A significant limitation in this review is that much of the literature addresses MM, and not MIS. Therefore, a major assumption is made when applying the findings of these studies on screening and sunscreen use to MIS. Clinical and dermoscopic features of MIS will also be reviewed, highlighting differences between benign nevi, MIS, and MM.
INCIDENCE Key points d
The incidence of melanoma in situ has been increasing steadily over the past decade,
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with a faster rate of increase in younger patients (20-49 years of age) than older patients and in men compared to women The annual percentage change in incidence is the highest of any tumor in the Surveillance, Epidemiology, and End Results database
An increase in the incidence of cutaneous melanoma (MIS and MM) over the past 3 decades is well documented.17 In Europe, Australia (Queensland), and the United States, MIS makes up a disproportionate amount of the annual increase in melanoma.18-20 In Queensland, the incidence of MIS between 1982 and 2002 increased at a rate of 10.6% for men and 8.5% for women, whereas invasive melanoma increased at a rate of 2.6% for men and 1.2% for women.21 In the United States, the incidence of MIS has risen from \1 case per 100,000 patients in 1973 to 14 cases per 100,000 patients in 2006.11 This rapid increase amounts to an annual percent change of 9.5%, which is higher than that of invasive melanomas (annual percent change over the past decade, 2.6%).11 The annual percent change of MIS is the highest of any tumor recorded by the SEER database, which indexes leukemia, bladder, breast, colon, endometrial, renal, lung, pancreatic, prostate, and thyroid cancers, and non-Hodgkin’s lymphoma.7 Younger patients (20-49 years of age) have a faster rate of increase for MIS than older patients.7 Men are also more commonly diagnosed with MIS than women (men, 55.7%; women, 44.3%). The mean age of those diagnosed with MIS was 61.2 years, with whites making up 93.1% of the affected population. Comparatively, the mean age of patients diagnosed with MM is 54 years; men make up 53.4% of this population.22 Fig 1 shows locations of MIS, with head and neck being the most common location. In contrast, head and neck is the fourth most common location of MM (18.2%) after the trunk (32%), upper extremities (23.4%), and lower extremities (20.3%).7,22 Fig 2 shows subtypes of MIS, as categorized by the SEER study.7 The rapid increase in the incidence of MIS—if real and not related to overdiagnosis—warrants public health efforts to address the disease. Such steps are predicated on understanding the basis of the increase.
CONTROVERSY ABOUT INCIDENCE Key points d
There is controversy about whether there is in fact a true increase in incidence or simply an increase in diagnosis of melanoma in situ
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Fig 1. Locations of melanoma in situ recorded by the Surveillance, Epidemiology, and End Results study between 1973 and 2006. Total numbers of melanoma in situ in each area shown.7
d
Improved screening, increased reporting, or changes in histologic criteria may be the cause of increased diagnosis and the apparent increase in incidence
Because of the growing incidence of MIS, some clinicians have raised questions about whether there is indeed an epidemic of increased tumor burden or whether it represents an apparent increase related to improved screening and reporting or changes in histologic criteria. Welch et al10 conducted a population-based study of the SEER-Medicare linked data and found a 2.5-fold increase in biopsy rates in the Medicare population between 1986 and 2001. Over the same time period, the incidence of MM also had a 2.4-fold increase, suggesting an association between increased biopsy rates and invasive melanoma diagnosis. For MIS, each 1000 biopsy specimens were estimated to result in 4.4 diagnoses of MIS.10 Studies exploring the incidence of MM based on tumor thickness and demographic factors have suggested that increased screening and biopsy alone cannot account for the dramatic increase in the incidence of this tumor, especially because incidence increased without regard to socioeconomic status, which functioned as a surrogate marker for access to care and screening.8,23 In addition, others have suggested that the increase in incidence of MIS is related to a general trend toward overdiagnosing melanocytic lesions as malignant. In 1 study, slides that were previously diagnosed as dysplastic nevi and radial growth phase melanoma between 1988 and 1990 were reevaluated by dermatopathologists in 2008 and 2009. Diagnoses rendered in 1988 to 1990 resulted in a mean number of 11 melanomas; diagnoses of the same slides rendered in 2008 to 2009 resulted in a mean number of 18 melanomas.24 These studies did not address MIS specifically, which makes it difficult to interpret whether the
Fig 2. Pathology of melanoma in situ recorded by the Surveillance, Epidemiology, and End Results study between 1973 and 2006.
incidence of MIS is truly increasing or whether it is a reflection of increased diagnostic scrutiny (ie, more vigilant biopsy and screening efforts and more aggressive interpretation by dermatopathologists).
RISK OF SECONDARY TUMORS AND MORTALITY Key points d
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Patients diagnosed with melanoma in situ have a higher risk of developing secondary tumors Malignant melanoma (a second primary) is the most common secondary tumor diagnosed Patients with melanoma in situ have the same life expectancy as the general population
Similar to MM, MIS is associated with a higher risk of developing secondary tumors (standardized incidence ratio [SIR], 1.2 [95% confidence interval {CI}, 1.2-1.3]), especially MM (SIR, 8.1 [95% CI, 7.7-8.6]).11,22 Other secondary tumors diagnosed after MIS included tumors of the lip (SIR, 1.7 [95% CI, 1.1-2.6]), lymphocytic leukemia (SIR, 1.6 [95% CI, 1.3-2]), non-Hodgkin’s lymphoma (SIR, 1.2 [95% CI, 1-1.4]), and hematologic tumors (SIR, 1.1 [95% CI, 1-1.3]).11 A lower risk of malignancy was found for tumors of the digestive system (SIR, 0.8 [95% CI, 0.7-0.8]), colon/rectum/anus (SIR, 0.8 [95% CI, 0.7-0.9]), pancreas (SIR, 0.8 [95% CI, 0.6-0.9]), liver/gallbladder/biliary ducts (SIR, 0.7 [95% CI, 0.5-0.9]), respiratory system (SIR, 0.7 [95% CI, 0.6-0.7]), lung/bronchus (SIR, 0.7 [95% CI, 0.6-0.7]), and larynx (SIR, 0.4 [95% CI, 0.2-0.7]).11 The mean time to diagnosis of a second tumor of any type was 14 years. While additional evaluation is needed, this association could reflect genetic or environmental factors that predispose individuals diagnosed with
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MIS to developing additional malignancies or even decrease the likelihood of others.11 Patients with MIS have the same life expectancy as the general population. In contrast, the 5-year mortality of patients with MM is higher than that of the general population, although this trend has been improving over the past 3 decades.7
SCREENING RECOMMENDATIONS Key points d
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There is limited evidence to support the usefulness of full body skin examinations in screening for melanoma in situ by primary care physicians Some evidence suggests that screening for melanoma in situ by dermatologists may be beneficial, particularly in higher-risk populations
The issue of the value of screening for MIS is complicated by the fact that most studies either focused on MM or, if MIS was included, it was not distinguished from MM. Nonetheless, it is reasonable to conclude that guidance regarding screening practices and outcomes for MM would be applicable to the clinical aspects of screening diagnosis if not to alterations in patient mortality. Currently, the United States Preventative Task Force (USPTF) reports limited evidence to support the utility of full body skin examinations in screening for melanoma/skin cancer by primary care physicians.25,26 As such, it is silent on the usefulness of full body skin examinations in the asymptomatic patient without specific risk factors. This recommendation, published in 2009, was based on an English-language search of relevant articles examining the evidence for and against full body skin examinations.25,26 Before this 2009 recommendation, the 2001 USPTF report also reported limited evidence to recommend for or against skin screening in asymptomatic individuals. Both reports specifically point out 2 practice gaps, including the lack of quality evidence demonstrating improved outcomes with screening and the lack of information about a primary care physician’s ability to perform full body skin examinations in a regular office visit.25,26 There are substantial challenges to conducting a screening study that seeks to ascertain a benefit to screening. Importantly, these recommendations do not address screening by specialists (ie, dermatologists, specialty midlevel providers). In addition, these recommendations specifically apply to the general adult population with an average risk of skin cancer
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and may not pertain to those with an already established history of skin cancer or those with a higher risk than the general public.25,26 Because most studies do not distinguish MIS from MM, the closest approximation to analyzing the value of screening is derived from large prospective studies of population screening for melanoma. The Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany (SCREEN) project was a population-wide skin cancer screening study using both primary care physicians and dermatologists. In this study, residents in the German state of Schleswig-Holstein received full body skin examinations and those in the state of Saarland did not. Based on comparisons between MIS incidence before, during, and after the full body skin examination intervention, the population receiving skin examinations showed an increase in the incidence of MIS, with the greatest differences noted in women. After the conclusion of the study intervention, MIS incidence decreased in women. The SCREEN study was one of the first to show the impact that screening can have on improved MIS diagnosis.27,28 The incidence of nonmelanoma skin cancer also increased during the screening intervention period of the SCREEN study. Specifically, incidence rates increased from 81.5 per 100,000 people to 111.5 per 100,000 people during the screening period. Therefore, increased screening of melanoma also results in increased detection of nonmelanoma skin cancer and related morbidity and health care costs.29 In the SCREEN study, 1 in 23 individuals receiving full body skin examinations underwent excision for treatment of malignant skin tumors.30 Other studies have examined the positive predictive value (PPV) for the diagnosis of melanoma through screening by both general practitioners and dermatologists. One of the reasonable conclusions that can be drawn from the literature is that MIS can be diagnosed in a fashion similar to invasive MM. The remaining issue is whether early diagnosis of MIS has any impact on morbidity. One Australian study examined community-based general practitioners conducting full body skin examinations. Of 16,383 skin examinations conducted, 2302 patients were referred for suspicious lesions. The specificity of finding a lesion histologically confirmed as melanoma was 86.1%, with a 2.5% PPV. The specificity of detecting melanoma in patients $50 years of age was comparable to the specificity of mammography in this high-risk Australian population.20 Other studies conducted in the late 1990s found PPVs ranging from 6% to 24%. Higher
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PPVs were associated with general practitioners that had previously received some type of training as part of the study.31,32 When screening for melanoma was performed by a plastic surgeon or dermatologist in Australia, the PPV was found to be approximately 10%, with a specificity of 95% to 99% and a sensitivity of 64% to 82%.33 In the United States, participants who self-selected for skin cancer screening were also studied in the late 1990s. Of 132 patients, the PPV for melanoma ranged from 6% to 15%. A major limitation to this study was the diagnosis of only 2 melanomas in this population.32 Other screening studies conducted during this time found similar PPVs for melanoma in self-selecting populations.34-36 An analysis of the American Academy of Dermatology’s screening program in the 1990s found a PPV of 11% for melanoma. When this population was restricted to patients $50 years of age, the PPV rose to 21%.37-39 The age at which to begin screening is unclear. Because there are few studies examining the impact of screening on MIS, it is hard to extrapolate from their data what the target age group for screening should encompass. Based on SEER incidence data, MIS is increasing at a faster rate in younger patients (ie, those 20-49 years of age), although the mean age of those diagnosed with MIS is still 61.2 years.7 Screening should ideally encompass both of these age groups. When considering the benefits of screening for MIS and its potential impact on morbidity, the harms of screening are also worth considering. Namely, the number needed to screen for melanoma is estimated to be 25,000 patients to prevent 1 melanoma-related mortality.40 When examining the number needed to screen for detection of melanoma, this number drops to 1 in 620, based on data from the SCREEN study.27 These numbers apply to a calculation for all melanomas, including MIS and MM. Therefore, the cost and burden of screening for MIS may differ significantly.
SUNSCREEN USE Key points d
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Sunscreen use has been shown to prevent invasive melanoma in some studies It is unknown whether sunscreen is effective in specifically preventing melanoma in situ
Sunscreen use can prevent or mitigate sunburn by reducing the impact of ultraviolet radiation on the skin. Laboratory studies on animal models confirm this role for sunscreens.41 Sunscreens are one of the most common forms of sun protection used by the general public, although its application
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is frequently suboptimal.42-44 The sun protective factor (SPF) is tested at an application thickness on the skin surface of 2 mg/cm2. Several studies have shown that users routinely apply an inadequate amount of sunscreen, ranging from 0.3 to 1 mg/ cm2. This thin application considerably decreases the amount of ultraviolet protection afforded by the sunscreen.45 The use of high SPF ($70) compositions with frequent reapplication or double-layered applications may compensate for thin or uneven applications.46,47 Because sun exposure is considered a major risk factor for melanoma, the use of sunscreen can theoretically decrease the incidence of melanoma. A randomized trial of sunscreens in children noted reductions in the development of melanocytic nevi, a strong predictor of melanoma. This effect was strongest in children with freckles. However, these studies did not investigate the effects on MIS and MM.48,49 Evidence for the use of sunscreen in prevention of melanoma is sparse, with few randomized controlled trials. Data from case control studies have produced conflicting results. Some studies demonstrated decreased melanoma risk with routine use of SPF 151 sunscreen and other sun protection methods (eg, long-sleeved shirts, staying in the shade) while other studies showed no association.50-52 A metaanalysis of 9067 patients from 11 case controlled studies showed a relative risk of 1.01, indicating a lack of association between sunscreen use and melanoma.51 Other studies have suggested that sunscreen use may actually increase a person’s risk for melanoma because individuals using sunscreen have longer sun exposures.53,54 Before 2011, the lack of randomized controlled trials left the effect of sunscreen on melanoma unanswered. In 2011, Green et al published data from a randomized skin cancer prevention trial investigating the effect of sunscreen use in a community in Queensland, Australia. This study of 1621 adults randomized individuals to the use of SPF 16 sunscreen. Experimental group subjects were asked to apply sunscreen to sun-exposed areas (ie, the head, neck, arms, and hands) daily, with reapplication after water exposure, long sun exposure, and heavy sweating. Control group subjects were asked to use sunscreen at their normal frequency, which could have included no use of sunscreen. During the 5-year trial period, compliance with sunscreen use was recorded based on the weight of sunscreen bottles returned and by surveys querying subjects’ weekly use of sunscreen. Ten years after conclusion of the trial, a
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Fig 3. A, Melanoma in situ (MIS) [6 mm of the nose. B, Macular presentation of MIS. C, Variegate coloration of MIS; both brown and black portions are present. D and E, Superficial spreading melanoma variant of MIS. F-H, Lentigo maligna variant of MIS.
reduction in the number of melanomas diagnosed was observed in the trial group compared to control group, suggesting a preventative role for use of sunscreen in preventing invasive melanoma. Despite the reduction in invasive melanomas, it is notable that there were no significant differences between both groups with respect to MIS.55 Therefore, the question of the efficacy of sunscreen use in prevention of MIS still remains. To the extent that the effect was not unequivocally answered, questions about the etiology or behavior of MIS may be raised. While the evidence for sunscreen use in the prevention of MIS is indeterminate, dermatologists still often recommend use of these products to the general public. The other benefits of sunscreen, including reducing actinic keratoses, prevention of squamous cell carcinoma, and delay in appearance of sunburn-related erythema, warrant its use in at-risk populations.56-61 In patients with a history of MM, there is an increase in sunscreen use immediately after diagnosis. Over time, this use becomes inconsistent and comparable to the use in those without a history of melanoma.62 These behavioral patterns may shed light on those patients diagnosed with MIS, although additional investigation is necessary to definitively assess sun-protective habits in those with a history of MIS.
CLINICAL FEATURES Key points d
d
Melanoma in situ has clinical and dermoscopic features that may aid in its distinction from common nevi Lentigo maligna is considered by the World Health Organization as melanoma in situ
MIS can vary in size, shape, and color. In a study of 121 MIS lesions, 77% of lesions were [6 mm (Fig 3, A), 92% were macular (Fig 3, B), and 75% were asymmetric (Figure 3, F-H). Although the border was irregular in the majority of lesions, it was not thought to be poorly defined. The most common color present in the tumor was black (48%), followed by brown (41%), tan (16%), grey (85), and pink (3%). The majority of lesions (98%) had [1 color present in the lesion (Fig 3, C-E ).63 Amelanotic MIS presents as an erythematous macule or plaque and may initially be misdiagnosed as an inflammatory disorder.64-66 Lentigo maligna (LM) subtype typically occurs on chronically sun-exposed skin. LM can act as a precursor to LM melanoma (Fig 3, F-H ). Roughly 5% of LMs progress to invasive melanoma.67 LM occurs most commonly on the face of elderly individuals and has a predilection for the nose and cheek. This slow-growing lesion typically presents as an asymmetric, brown-black macule with
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color variation and irregular borders. LM can be difficult to distinguish histologically from the atypical melanocytic hyperplasia seen in severely sun-damaged skin.68 This distinction will be discussed in part II of this continuing medical education article. Some advocate that the current concept of LM69,70 actually embodies 2 distinct histologic entities, with LM recognized as atypical melanocytic hyperplasia and MIS, LM type showing confluence and nesting of atypical melanocytes at various layers of the epidermis.68,71 Despite this controversy, most studies have not made this distinction. The World Health Organization and national registries, such as SEER, recognize LM and MIS as the same entity, allowing reporting of both under the category of MIS.72 Dermoscopy can be used to clinically diagnose melanomas. While nevi, MIS, and MM have many overlapping features, certain characteristics can help to distinguish MIS. Compared to typical nevi, MIS frequently has an atypical pigment network involving [50% of the lesion or the presence of multiple different pigment networks. Grey-blue regression is also more commonly observed in MIS lesions.73 The comparison between atypical nevi and MIS is more difficult, because both can share similar features. In a study of 38 MIS and 136 atypical nevi, no distinguishing features could be found between the 2 entities in terms of geometry, color, textures, and islands of color, such as a grey-blue veil.74 MIS and MM share several common dermoscopic features, making these lesions difficult to distinguish. Light brown areas are more common in MIS; grey-blue veils are more common in MM. When blue areas are present in MIS, they are more likely to show a reticular grey-blue pattern, compared to a more disorganized pattern in MM. This reticular pattern can serve as a distinguishing characteristic of MIS.75 The distribution of blue areas (center vs. periphery) is similar in MIS and MM. Peppering, or scattered blue-gray granules within an area of hypopigmentation, can be seen in similar proportions in both types of lesions. Both types of lesions can have a combination of the aforementioned features.75,76 When considering MIS only, 8 different dermoscopic subtypes have been proposed: reticular greyblue, reticular, multicomponent, island, spitzoid, inverse network, net-blue globules, and globular. Of these, the reticular grey-blue is the most common.77 Other studies have also suggested various dermoscopic features that may be helpful in distinguishing MIS from other pigmented lesions.
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These include the dermoscopic island, a well-circumscribed area with a uniform dermoscopic pattern that differs from the rest of the lesion.78 The ‘‘mushroom-cloud sign’’ and ‘‘mistletoe sign’’ have also been described. The ‘‘mushroom-cloud sign’’ consists of a hyperpigmented area extending in one direction. Once past the border, a faint stalk-like projection can be seen.79 The ‘‘mistletoe sign’’ represents well-circumscribed areas with nonuniform structures resembling branching pseudopods. This pattern arises from reticular or homogenous background patterns, which are reminiscent of mistletoe.80 When specifically examining the LM subtype of MIS, LM features hyperpigmented follicular openings, rhomboidal structures, and irregular pigmented perifollicular dots.81,82 In conclusion, the incidence of MIS has been steadily rising over the past 3 decades, with little impact on mortality or life expectancy. There is controversy as to whether this rising incidence in MIS represents overdiagnosis related to better screening methods and more biopsies or if it represents a true increase in incidence. Given the risk of a second primary tumor after a diagnosis of MIS, this condition still warrants close surveillance. Full body skin examinations are currently not recommended by the USPTF in the general population. This group does not address screening recommendations in the high-risk population, such as those with a strong family history or those with a personal history of skin cancer. Sunscreen use can help to decrease the incidence of MM, although its effect on MIS may be minimal. This area of research has proven difficult due to the large sample sizes required to detect differences in MIS incidence. Part II of this continuing medical education article will explore treatment, surveillance tools, and genetic considerations. We thank John Kawaoka, Jennie Muglia, Jayne Bird, and Newsha Lajevardi for contributing clinical photographs for this manuscript.
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