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Melanoma Screening and Mortality

Melanoma Screening and Mortality The incidence of melanoma has increased steadily, yet mortality has risen to a much lesser extent. This can be explained at least in part by the concept of “overdiagnosis,” where lesions are diagnosed as cancers that would not have caused mortality even if they had not been removed. Overdiagnosis (which is not “misdiagnosis”) occurs when there is a pool of asymptomatic lesions—and screening efforts to detect them (1). The rationale is to reduce mortality by removing lesions that would have progressed at an early, curable stage. If there is a large pool of nonprogressing lesions that are indistinguishable from those with potential to progress, then the apparent incidence of “cancer” will increase while mortality will be affected less or not at all. This situation exists not only in relation to melanoma but also to breast, thyroid, renal, prostate, and other cancers (1). Population-based screening for melanoma has not been proven to be beneficial overall (2) and is generally not recommended. The current advice is to offer screening only to individuals at high risk, such as those with a strong family or personal history of melanoma, and/or with many risk factors such as numerous nevi including dysplastic nevi. In this issue, Olson et al. describe a strategy for selective screening based on stratification of a population for melanoma risk to identify those for whom early detection activities might be appropriate (3). The study is derived from a 3.4 year follow-up of a population-based cohort in Queensland, Australia. A prediction model for invasive plus in situ melanoma included 13 attributes related to risk, most of them related to sun susceptibility and other known risk factors such as number of nevi. Some of these criteria relate to medical utilization (eg, skin checks by a doctor), which has been shown to encourage overdiagnosis (4). Using this model, the “number needed to screen” to detect 82% of future melanomas was 39 people. If patients were screened only once per year, the number of office visits to detect each melanoma would be 39 x 3.4 = 133, and no doubt these examinations would generate many false-positive and irrelevant results. This meticulous study is an excellent example of prediction model development in a population, albeit one in which the incidence is one of the highest in the world, likely limiting global generalizability. It is also worth considering what would be the effect on mortality, and whether there could be adverse effects even when only screening this subpopulation of high-risk individuals. Mortality is rising only slightly, if at all, in populations in which screening activity is intense, while at the same time the incidence is rising rapidly (1). This “screening pressure” results not only from organized campaigns, but also from the activities of practitioners (and patients) who strongly believe that these activities are life-saving. It is clear from the mismatch between incidence and mortality figures that most of the lesions removed by screening are cured by excision; however, these procedures (which can sometimes be elaborate) add materially to medical costs and also have adverse effects on patients, including anxiety, which is sometimes taken to extremes, and impaired insurability. This epidemic of “melanoma” will likely be exacerbated when artificial intelligence (eg, cell phone programs to assess moles) becomes widely used to screen skin lesions. It has long been known that there are subsets of melanoma for which the predicted probability of long-term survival is 100% or very close to it (5,6). Prognostic attributes such as tumor thickness, mitogenicity, patient age, and the absence of ulceration and of “vertical growth phase” (VGP) can be used to identify “zero-risk” melanomas. Almost all melanoma mortality occurs in lesions with VGP, which is a mass or tumor-forming lesion that usually arises in an antecedent “radial growth phase” (RGP), patch, or plaque lesion. This suggests that removal of RGP lesions could reduce mortality by preventing the development of VGP, a concept that is challenged although not entirely refuted by the overdiagnosis hypothesis. Most of the criteria used to identify melanomas in practice (Asymmetry, Border irregularity, Color variegation, and Diameter—the ABCDs) are attributes primarily of the RGP. Some VGP lesions, termed nodular melanomas (NMs), lack RGP and present as a growing pigmented or pink papule/nodule that stretches the epidermis, making it thin and glistening. These papules may be only a few millimeters in diameter, yet they account for disproportionate mortality risk (6). A risk prediction model for recognition of persons at risk of VGP melanomas, and for earlier diagnosis of these, would have a more focused effect on mortality than a generalized risk prediction model as developed by Olsen et al. (3), but would be difficult and perhaps impossible to develop. If the overdiagnosis epidemic is to be reduced, one or both of two strategies could be used. One of these, as has been done with a subset of thyroid tumors (8), would be to rename RGP (including in situ) melanomas using a less “malignant” term such as “severe melanocytic dysplasia.” Fifty years ago, these lesions were often called “active junctional (or compound) nevi” (9). Lesions of this type, which have atypia but do not progress lethally, are “intermediate lesions” of cancer development (10). Recent studies have identified that their genetic basis is the presence of two or a few oncogenic mutations, as compared with only one driver mutation for benign nevi, and multiple genomic “hits” for invasive melanomas (11). It seems unlikely that this renaming will be easily achieved in the present state of screening pressure. The other approach would be to more convincingly educate patients, practitioners, health systems, and insurers that a predictable and substantial subset of melanomas pose very little risk to life, analogous to basal cell carcinomas, and to focus on the identification of “rapidly growing” melanomas with VGP (7). Emphasizing “history of change” as a criterion for biopsy (12) and discouraging biopsy of small asymptomatic patch lesions discovered in surveillance (13) are strategies that could reverse the overdiagnosis epidemic and lower mortality rates. Notes Affiliation of author: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA. The author discloses serving as a consultant for SciBase and Myriad Genetics. References 1 Welch HG , Black WC. Overdiagnosis in cancer . J Natl Cancer Inst. 2010 ; 102 9 : 605 – 613 . Google Scholar Crossref Search ADS PubMed 2 Johnson MM , Leachman SA , Aspinwall LG , et al. . Skin cancer screening: Recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy . Melanoma Manag. 2017 ; 4 1 : 13 – 37 . Google Scholar Crossref Search ADS PubMed 3 Olsen CM , Pandeya N , Thompson BS , et al. . Risk stratification for melanoma: Models derived and validated in a purpose-designed prospective cohort . J Natl Cancer Inst . 2018 ; 110 10 : 1075 – 1083 . 4 Welch HG , Woloshin S , Schwartz LM. Skin biopsy rates and incidence of melanoma: Population based ecological study . BMJ. 2005 ; 331 7515 : 481 . Google Scholar Crossref Search ADS PubMed 5 Gimotty PA , Elder DE , Fraker DL , et al. . Identification of high-risk patients among those diagnosed with thin cutaneous melanomas . J Clin Oncol. 2007 ; 25 9 : 1129 – 1134 . Google Scholar Crossref Search ADS PubMed 6 Guerry D 4th , Synnestvedt M , Elder DE , Schultz D. Lessons from tumor progression: The invasive radial growth phase of melanoma is common, incapable of metastasis, and indolent . J Invest Dermatol. 1993 ; 100 3 : 342S – 345S . Google Scholar Crossref Search ADS PubMed 7 Cicchiello M , Lin MJ , Pan Y , McLean C , Kelly JW. An assessment of clinical pathways and missed opportunities for the diagnosis of nodular melanoma versus superficial spreading melanoma . Australas J Dermatol. 2016 ; 57 2 : 97 – 101 . Google Scholar Crossref Search ADS PubMed 8 Nikiforov YE , Seethala RR , Tallini G , et al. . Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: A paradigm shift to reduce overtreatment of indolent tumors . JAMA Oncol. 2016 ; 2 8 : 1023 – 1029 . Google Scholar Crossref Search ADS PubMed 9 Munro DD. Multiple active junctional naevi with family history of malignant melanoma . Proc R Soc Med. 1974 ; 67 7 : 594 – 595 . Google Scholar PubMed 10 Clark WH Jr. The nature of cancer: Morphogenesis and progressive (self)-disorganization in neoplastic development and progression . Acta Oncol. 1995 ; 34 1 : 3 – 21 . Google Scholar Crossref Search ADS PubMed 11 Shain AH , Yeh I , Kovalyshyn I , et al. . The genetic evolution of melanoma from precursor lesions . N Engl J Med. 2015 ; 373 20 : 1926 – 1936 . Google Scholar Crossref Search ADS PubMed 12 Truong A , Strazzulla L , March J , et al. . Reduction in nevus biopsies in patients monitored by total body photography . J Am Acad Dermatol. 2016 ; 75 1 : 135 – 143 . Google Scholar Crossref Search ADS PubMed 13 Soltani-Arabshahi R , Sweeney C , Jones B , et al. . Predictive value of biopsy specimens suspicious for melanoma: Support for 6-mm criterion in the ABCD rule . J Am Acad Dermatol. 2015 ; 72 3 : 412 – 418 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Melanoma Screening and Mortality

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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0027-8874
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1460-2105
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10.1093/jnci/djy056
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Abstract

The incidence of melanoma has increased steadily, yet mortality has risen to a much lesser extent. This can be explained at least in part by the concept of “overdiagnosis,” where lesions are diagnosed as cancers that would not have caused mortality even if they had not been removed. Overdiagnosis (which is not “misdiagnosis”) occurs when there is a pool of asymptomatic lesions—and screening efforts to detect them (1). The rationale is to reduce mortality by removing lesions that would have progressed at an early, curable stage. If there is a large pool of nonprogressing lesions that are indistinguishable from those with potential to progress, then the apparent incidence of “cancer” will increase while mortality will be affected less or not at all. This situation exists not only in relation to melanoma but also to breast, thyroid, renal, prostate, and other cancers (1). Population-based screening for melanoma has not been proven to be beneficial overall (2) and is generally not recommended. The current advice is to offer screening only to individuals at high risk, such as those with a strong family or personal history of melanoma, and/or with many risk factors such as numerous nevi including dysplastic nevi. In this issue, Olson et al. describe a strategy for selective screening based on stratification of a population for melanoma risk to identify those for whom early detection activities might be appropriate (3). The study is derived from a 3.4 year follow-up of a population-based cohort in Queensland, Australia. A prediction model for invasive plus in situ melanoma included 13 attributes related to risk, most of them related to sun susceptibility and other known risk factors such as number of nevi. Some of these criteria relate to medical utilization (eg, skin checks by a doctor), which has been shown to encourage overdiagnosis (4). Using this model, the “number needed to screen” to detect 82% of future melanomas was 39 people. If patients were screened only once per year, the number of office visits to detect each melanoma would be 39 x 3.4 = 133, and no doubt these examinations would generate many false-positive and irrelevant results. This meticulous study is an excellent example of prediction model development in a population, albeit one in which the incidence is one of the highest in the world, likely limiting global generalizability. It is also worth considering what would be the effect on mortality, and whether there could be adverse effects even when only screening this subpopulation of high-risk individuals. Mortality is rising only slightly, if at all, in populations in which screening activity is intense, while at the same time the incidence is rising rapidly (1). This “screening pressure” results not only from organized campaigns, but also from the activities of practitioners (and patients) who strongly believe that these activities are life-saving. It is clear from the mismatch between incidence and mortality figures that most of the lesions removed by screening are cured by excision; however, these procedures (which can sometimes be elaborate) add materially to medical costs and also have adverse effects on patients, including anxiety, which is sometimes taken to extremes, and impaired insurability. This epidemic of “melanoma” will likely be exacerbated when artificial intelligence (eg, cell phone programs to assess moles) becomes widely used to screen skin lesions. It has long been known that there are subsets of melanoma for which the predicted probability of long-term survival is 100% or very close to it (5,6). Prognostic attributes such as tumor thickness, mitogenicity, patient age, and the absence of ulceration and of “vertical growth phase” (VGP) can be used to identify “zero-risk” melanomas. Almost all melanoma mortality occurs in lesions with VGP, which is a mass or tumor-forming lesion that usually arises in an antecedent “radial growth phase” (RGP), patch, or plaque lesion. This suggests that removal of RGP lesions could reduce mortality by preventing the development of VGP, a concept that is challenged although not entirely refuted by the overdiagnosis hypothesis. Most of the criteria used to identify melanomas in practice (Asymmetry, Border irregularity, Color variegation, and Diameter—the ABCDs) are attributes primarily of the RGP. Some VGP lesions, termed nodular melanomas (NMs), lack RGP and present as a growing pigmented or pink papule/nodule that stretches the epidermis, making it thin and glistening. These papules may be only a few millimeters in diameter, yet they account for disproportionate mortality risk (6). A risk prediction model for recognition of persons at risk of VGP melanomas, and for earlier diagnosis of these, would have a more focused effect on mortality than a generalized risk prediction model as developed by Olsen et al. (3), but would be difficult and perhaps impossible to develop. If the overdiagnosis epidemic is to be reduced, one or both of two strategies could be used. One of these, as has been done with a subset of thyroid tumors (8), would be to rename RGP (including in situ) melanomas using a less “malignant” term such as “severe melanocytic dysplasia.” Fifty years ago, these lesions were often called “active junctional (or compound) nevi” (9). Lesions of this type, which have atypia but do not progress lethally, are “intermediate lesions” of cancer development (10). Recent studies have identified that their genetic basis is the presence of two or a few oncogenic mutations, as compared with only one driver mutation for benign nevi, and multiple genomic “hits” for invasive melanomas (11). It seems unlikely that this renaming will be easily achieved in the present state of screening pressure. The other approach would be to more convincingly educate patients, practitioners, health systems, and insurers that a predictable and substantial subset of melanomas pose very little risk to life, analogous to basal cell carcinomas, and to focus on the identification of “rapidly growing” melanomas with VGP (7). Emphasizing “history of change” as a criterion for biopsy (12) and discouraging biopsy of small asymptomatic patch lesions discovered in surveillance (13) are strategies that could reverse the overdiagnosis epidemic and lower mortality rates. Notes Affiliation of author: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA. The author discloses serving as a consultant for SciBase and Myriad Genetics. References 1 Welch HG , Black WC. Overdiagnosis in cancer . J Natl Cancer Inst. 2010 ; 102 9 : 605 – 613 . Google Scholar Crossref Search ADS PubMed 2 Johnson MM , Leachman SA , Aspinwall LG , et al. . Skin cancer screening: Recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy . Melanoma Manag. 2017 ; 4 1 : 13 – 37 . Google Scholar Crossref Search ADS PubMed 3 Olsen CM , Pandeya N , Thompson BS , et al. . Risk stratification for melanoma: Models derived and validated in a purpose-designed prospective cohort . J Natl Cancer Inst . 2018 ; 110 10 : 1075 – 1083 . 4 Welch HG , Woloshin S , Schwartz LM. Skin biopsy rates and incidence of melanoma: Population based ecological study . BMJ. 2005 ; 331 7515 : 481 . Google Scholar Crossref Search ADS PubMed 5 Gimotty PA , Elder DE , Fraker DL , et al. . Identification of high-risk patients among those diagnosed with thin cutaneous melanomas . J Clin Oncol. 2007 ; 25 9 : 1129 – 1134 . Google Scholar Crossref Search ADS PubMed 6 Guerry D 4th , Synnestvedt M , Elder DE , Schultz D. Lessons from tumor progression: The invasive radial growth phase of melanoma is common, incapable of metastasis, and indolent . J Invest Dermatol. 1993 ; 100 3 : 342S – 345S . Google Scholar Crossref Search ADS PubMed 7 Cicchiello M , Lin MJ , Pan Y , McLean C , Kelly JW. An assessment of clinical pathways and missed opportunities for the diagnosis of nodular melanoma versus superficial spreading melanoma . Australas J Dermatol. 2016 ; 57 2 : 97 – 101 . Google Scholar Crossref Search ADS PubMed 8 Nikiforov YE , Seethala RR , Tallini G , et al. . Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: A paradigm shift to reduce overtreatment of indolent tumors . JAMA Oncol. 2016 ; 2 8 : 1023 – 1029 . Google Scholar Crossref Search ADS PubMed 9 Munro DD. Multiple active junctional naevi with family history of malignant melanoma . Proc R Soc Med. 1974 ; 67 7 : 594 – 595 . Google Scholar PubMed 10 Clark WH Jr. The nature of cancer: Morphogenesis and progressive (self)-disorganization in neoplastic development and progression . Acta Oncol. 1995 ; 34 1 : 3 – 21 . Google Scholar Crossref Search ADS PubMed 11 Shain AH , Yeh I , Kovalyshyn I , et al. . The genetic evolution of melanoma from precursor lesions . N Engl J Med. 2015 ; 373 20 : 1926 – 1936 . Google Scholar Crossref Search ADS PubMed 12 Truong A , Strazzulla L , March J , et al. . Reduction in nevus biopsies in patients monitored by total body photography . J Am Acad Dermatol. 2016 ; 75 1 : 135 – 143 . Google Scholar Crossref Search ADS PubMed 13 Soltani-Arabshahi R , Sweeney C , Jones B , et al. . Predictive value of biopsy specimens suspicious for melanoma: Support for 6-mm criterion in the ABCD rule . J Am Acad Dermatol. 2015 ; 72 3 : 412 – 418 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

JNCI: Journal of the National Cancer Institute – Oxford University Press

Published: Oct 1, 2018

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