Clinical Review & Education
From The JAMA Network
Risk-Stratified Screening for Detection of Melanoma Vernon K. Sondak, MD; L. Frank Glass, MD; Alan C. Geller, MPH, RN
JAMA DERMATOLOGY Detection of Primary Melanoma in Individuals at Extreme High Risk: A Prospective 5-Year Follow-up Study
EXPOSURES Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (ⱖ6 months), following established criteria, was performed. Atypical lesions were excised.
Fergal J. Moloney, MD; Pascale Guitera, MD, PhD; Elliot Coates, MB, BS; Nikolas K. Haass, MD, PhD; Kenneth Ho, MB, BS; Ritta Khoury, BMedSci; Rachel L. O’Connell, PhD; Leo Raudonikis; Helen Schmid, MPH; Graham J. Mann, MB, BS, PhD; Scott W. Menzies, MB, BS, PhD
MAIN OUTCOMES AND MEASURES New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup; effect of diagnostic aids on new melanoma identification.
IMPORTANCE The clinical phenotype and certain predisposing
genetic mutations that confer increased melanoma risk are established; however, no consensus exists regarding optimal screening for such individuals. Early identification remains the most important intervention in reducing melanoma mortality. OBJECTIVE To evaluate the impact of full-body examinations
every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation.
The incidence of cutaneous melanoma continues to increase worldwide; in the next 10 to 15 years, melanoma is expected to become one of the most common cancers in the United States, with a projected incidence of 150 000 cases by 2030. 1 Even though melanoma is amenable to early detection, the mortality for melanoma has continued to increase and currently is estimated to result in 9710 deaths in the United States in 2014.2 However, screening for melanoma is not currently supported by US Preventive Services Task Force skin cancer screening guidelines.3 Uncertainty about the benefits of population-based screening for melanoma in terms of reducing deaths, concerns about the large number of unnecessary biopsies that might result, and the perception that screening programs would expend resources on many individuals at very low risk are among the most commonly cited reasons why skin screening for early detection of cutaneous melanoma is not supported in the United States. It is time to reexamine this issue and begin the process of 616
RESULTS In 311 patients with a median (interquartile range
[IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic; the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74]; P = .002). CONCLUSIONS AND RELEVANCE Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial. JAMA Dermatol. 2014;150(8):819-827. doi:10.1001/jamadermatol.2014.514.
adopting risk-stratified screening to detect cutaneous melanoma at its earliest, most curable stages. In JAMA Dermatology, Moloney et al4 report findings from a 5-year prospective observational study in which 311 Australian patients at “extreme high risk” for melanoma development (based on known genetic predisposition, personal and family history of melanoma, dysplastic nevus syndrome, or a combination of multiple factors) were subjected to intensive skin screenings every 6 months. Patients underwent full skin examinations by expert dermatologists and total body photography, to assist in detecting changing or new skin lesions, and examination of individual lesions was augmented by digital dermoscopy when appropriate. After a median follow-up of 3.5 years, 75 primary melanomas were detected in this very high-risk cohort—and 70 of 75 were either in situ or 1 mm or thinner invasive melanomas. (The remaining 5 were difficult-to-detect melanoma variants: 3 were of desmoplastic histology, while the other 2 were amela-
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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From The JAMA Network Clinical Review & Education
notic nodular primaries.) This high rate of detection of early and potentially curable melanomas required a significant investment of patient and dermatologist time and effort but did not come at a cost of a prohibitively high number of biopsies. In fact, a total of 770 skin lesions were removed during the course of the study, 38% of which were malignant (including 143 basal cell carcinomas and 66 squamous cell cancers of various types along with the 75 melanomas).4 Although this study was not designed to determine the relationship between intensive skin screening and survival, the results constitute “proof of principle” that a risk-stratified approach to skin cancer screening can be effective in diagnosing new melanomas (and nonmelanoma skin cancers) at an early and curable stage with a very acceptable ratio of benign-to-malignant skin biopsies. Other reports have also provided evidence that skin screening is effective. In a German study evaluating population-based screening, Katalinic et al5 demonstrated a 48% reduction in melanomarelated deaths in a state (Schleswig-Holstein) that instituted a comprehensive skin cancer screening program, whereas the melanoma mortality rate remained stable in the rest of the country and neighboring Denmark, where screening did not take place. The German screening program involved 1673 general practitioners and 116 dermatologists who received a day-long training program in skin cancer detection using a standardized whole body examination. The first examination was performed by the general practitioner in 72% of instances, with referral to a dermatologist if a suspicious skin lesion was identified. For the remainder of screened patients, dermatologists provided the first examination. Individuals throughout the state were encouraged to participate in the screening program through mass media campaigns. As a result of this study, population-based skin cancer screening is now taking place throughout Germany, with millions of individuals aged 35 years and older receiving screening to date. Although government-funded screening is available to all German adults 35 years or older, there were some notable differences in the implications of screening based on age in the Schleswig-Holstein campaign: 20 excisions were performed to detect 1 melanoma in men 65 years and older, but 55 excisions were required to detect 1 melanoma in men aged 20 to 49 years.6 This lends credence to the notion that risk-stratified approaches, such as emphasizing screenARTICLE INFORMATION Author Affiliations: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida (Sondak, Glass); Harvard School of Public Health, Boston, Massachusetts (Geller). Corresponding Author: Vernon K. Sondak, MD, Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612 ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030. Cancer Res. 2014;74 (11):2913-2921.
ing middle-aged and older individuals, perhaps along with additional training and increased use of diagnostic aids such as total body photography and dermoscopy, can be more cost-effective than screening individuals of all ages. In the United States, the Surgeon General has issued a call to action to prevent skin cancer,7 but this stops short of recommending any type of screening to detect those cancers that cannot be prevented. However, it is time to embrace the opportunity to decrease melanoma mortality through risk-stratified education and screening. Geller et al8 have provided suggestions for such an approach. Educational efforts need to be increased substantially, ranging from population-wide education about skin cancer prevention particularly focused on children and young adults, to education of minority groups about their risk of specific types of melanomas, to education of all physicians in performance of skin examination and recognition and early diagnosis of melanoma. High-risk populations for delayed presentation with thick melanomas, particularly middle-aged and older men, need specific and properly targeted education and screening approaches but in return offer the greatest opportunity to decrease melanoma-related mortality through physician screening and education about skin self-examination.9 In addition, as Moloney et al4 have demonstrated, extremely highrisk populations should be provided with comprehensive screening programs by experienced dermatologists, ideally before their first invasive melanoma is diagnosed rather than after (as was the case for most of the patients in their study). However, their experience also points out the need for improved strategies, such as an emphasis on evolving lesions, to identify the nodular and desmoplastic melanomas (frequently clinically amelanotic) that can remain undetected with current screening approaches and present as thick and dangerous lesions.4 As noted by Halpern et al10 in an editorial accompanying the report by Moloney et al, managing the increasing number of melanoma (and nonmelanoma skin cancer) cases that are expected regardless of whether screening efforts are increased will require the engagement of a broad segment of physicians and other health care professionals—not just dermatologists—and likely will require new diagnostic and therapeutic strategies. In addition to the call to action to prevent melanoma,7 it is time for a call to action to detect those skin cancers that cannot be prevented.
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
/calls/prevent-skin-cancer/call-to-action-prevent -skin-cancer.pdf. Accessed September 4, 2014.
3. Screening for skin cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(3):188-193.
8. Geller AC, Miller DR, Swetter SM, Demierre MF, Gilchrest BA. A call for the development and implementation of a targeted national melanoma screening program. Arch Dermatol. 2006;142(4): 504-507.
4. Moloney FJ, Guitera P, Coates E, et al. Detection of primary melanoma in individuals at extreme high risk. JAMA Dermatol. 2014;150(8):819-827. 5. Katalinic A, Waldmann A, Weinstock MA, et al. Does skin cancer screening save lives? Cancer. 2012;118(21):5395-5402. 6. 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(8):903-910.
9. Swetter SM, Johnson TM, Miller DR, Layton CJ, Brooks KR, Geller AC. Melanoma in middle-aged and older men. Arch Dermatol. 2009;145(4):397404. 10. Halpern AC, Marchetti MA, Marghoob AA. Melanoma surveillance in “high-risk” individuals. JAMA Dermatol. 2014;150(8):815-816.
7. The Surgeon General’s call to action to prevent skin cancer. http://www.surgeongeneral.gov/library
jama.com
(Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
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617
From The JAMA Network
Risk-Stratified Screening for Detection of Melanoma Vernon K. Sondak, MD; L. Frank Glass, MD; Alan C. Geller, MPH, RN
JAMA DERMATOLOGY Detection of Primary Melanoma in Individuals at Extreme High Risk: A Prospective 5-Year Follow-up Study
EXPOSURES Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (ⱖ6 months), following established criteria, was performed. Atypical lesions were excised.
Fergal J. Moloney, MD; Pascale Guitera, MD, PhD; Elliot Coates, MB, BS; Nikolas K. Haass, MD, PhD; Kenneth Ho, MB, BS; Ritta Khoury, BMedSci; Rachel L. O’Connell, PhD; Leo Raudonikis; Helen Schmid, MPH; Graham J. Mann, MB, BS, PhD; Scott W. Menzies, MB, BS, PhD
MAIN OUTCOMES AND MEASURES New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup; effect of diagnostic aids on new melanoma identification.
IMPORTANCE The clinical phenotype and certain predisposing
genetic mutations that confer increased melanoma risk are established; however, no consensus exists regarding optimal screening for such individuals. Early identification remains the most important intervention in reducing melanoma mortality. OBJECTIVE To evaluate the impact of full-body examinations
every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation.
The incidence of cutaneous melanoma continues to increase worldwide; in the next 10 to 15 years, melanoma is expected to become one of the most common cancers in the United States, with a projected incidence of 150 000 cases by 2030. 1 Even though melanoma is amenable to early detection, the mortality for melanoma has continued to increase and currently is estimated to result in 9710 deaths in the United States in 2014.2 However, screening for melanoma is not currently supported by US Preventive Services Task Force skin cancer screening guidelines.3 Uncertainty about the benefits of population-based screening for melanoma in terms of reducing deaths, concerns about the large number of unnecessary biopsies that might result, and the perception that screening programs would expend resources on many individuals at very low risk are among the most commonly cited reasons why skin screening for early detection of cutaneous melanoma is not supported in the United States. It is time to reexamine this issue and begin the process of 616
RESULTS In 311 patients with a median (interquartile range
[IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic; the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74]; P = .002). CONCLUSIONS AND RELEVANCE Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial. JAMA Dermatol. 2014;150(8):819-827. doi:10.1001/jamadermatol.2014.514.
adopting risk-stratified screening to detect cutaneous melanoma at its earliest, most curable stages. In JAMA Dermatology, Moloney et al4 report findings from a 5-year prospective observational study in which 311 Australian patients at “extreme high risk” for melanoma development (based on known genetic predisposition, personal and family history of melanoma, dysplastic nevus syndrome, or a combination of multiple factors) were subjected to intensive skin screenings every 6 months. Patients underwent full skin examinations by expert dermatologists and total body photography, to assist in detecting changing or new skin lesions, and examination of individual lesions was augmented by digital dermoscopy when appropriate. After a median follow-up of 3.5 years, 75 primary melanomas were detected in this very high-risk cohort—and 70 of 75 were either in situ or 1 mm or thinner invasive melanomas. (The remaining 5 were difficult-to-detect melanoma variants: 3 were of desmoplastic histology, while the other 2 were amela-
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/11/2015
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From The JAMA Network Clinical Review & Education
notic nodular primaries.) This high rate of detection of early and potentially curable melanomas required a significant investment of patient and dermatologist time and effort but did not come at a cost of a prohibitively high number of biopsies. In fact, a total of 770 skin lesions were removed during the course of the study, 38% of which were malignant (including 143 basal cell carcinomas and 66 squamous cell cancers of various types along with the 75 melanomas).4 Although this study was not designed to determine the relationship between intensive skin screening and survival, the results constitute “proof of principle” that a risk-stratified approach to skin cancer screening can be effective in diagnosing new melanomas (and nonmelanoma skin cancers) at an early and curable stage with a very acceptable ratio of benign-to-malignant skin biopsies. Other reports have also provided evidence that skin screening is effective. In a German study evaluating population-based screening, Katalinic et al5 demonstrated a 48% reduction in melanomarelated deaths in a state (Schleswig-Holstein) that instituted a comprehensive skin cancer screening program, whereas the melanoma mortality rate remained stable in the rest of the country and neighboring Denmark, where screening did not take place. The German screening program involved 1673 general practitioners and 116 dermatologists who received a day-long training program in skin cancer detection using a standardized whole body examination. The first examination was performed by the general practitioner in 72% of instances, with referral to a dermatologist if a suspicious skin lesion was identified. For the remainder of screened patients, dermatologists provided the first examination. Individuals throughout the state were encouraged to participate in the screening program through mass media campaigns. As a result of this study, population-based skin cancer screening is now taking place throughout Germany, with millions of individuals aged 35 years and older receiving screening to date. Although government-funded screening is available to all German adults 35 years or older, there were some notable differences in the implications of screening based on age in the Schleswig-Holstein campaign: 20 excisions were performed to detect 1 melanoma in men 65 years and older, but 55 excisions were required to detect 1 melanoma in men aged 20 to 49 years.6 This lends credence to the notion that risk-stratified approaches, such as emphasizing screenARTICLE INFORMATION Author Affiliations: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida (Sondak, Glass); Harvard School of Public Health, Boston, Massachusetts (Geller). Corresponding Author: Vernon K. Sondak, MD, Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612 ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030. Cancer Res. 2014;74 (11):2913-2921.
ing middle-aged and older individuals, perhaps along with additional training and increased use of diagnostic aids such as total body photography and dermoscopy, can be more cost-effective than screening individuals of all ages. In the United States, the Surgeon General has issued a call to action to prevent skin cancer,7 but this stops short of recommending any type of screening to detect those cancers that cannot be prevented. However, it is time to embrace the opportunity to decrease melanoma mortality through risk-stratified education and screening. Geller et al8 have provided suggestions for such an approach. Educational efforts need to be increased substantially, ranging from population-wide education about skin cancer prevention particularly focused on children and young adults, to education of minority groups about their risk of specific types of melanomas, to education of all physicians in performance of skin examination and recognition and early diagnosis of melanoma. High-risk populations for delayed presentation with thick melanomas, particularly middle-aged and older men, need specific and properly targeted education and screening approaches but in return offer the greatest opportunity to decrease melanoma-related mortality through physician screening and education about skin self-examination.9 In addition, as Moloney et al4 have demonstrated, extremely highrisk populations should be provided with comprehensive screening programs by experienced dermatologists, ideally before their first invasive melanoma is diagnosed rather than after (as was the case for most of the patients in their study). However, their experience also points out the need for improved strategies, such as an emphasis on evolving lesions, to identify the nodular and desmoplastic melanomas (frequently clinically amelanotic) that can remain undetected with current screening approaches and present as thick and dangerous lesions.4 As noted by Halpern et al10 in an editorial accompanying the report by Moloney et al, managing the increasing number of melanoma (and nonmelanoma skin cancer) cases that are expected regardless of whether screening efforts are increased will require the engagement of a broad segment of physicians and other health care professionals—not just dermatologists—and likely will require new diagnostic and therapeutic strategies. In addition to the call to action to prevent melanoma,7 it is time for a call to action to detect those skin cancers that cannot be prevented.
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
/calls/prevent-skin-cancer/call-to-action-prevent -skin-cancer.pdf. Accessed September 4, 2014.
3. Screening for skin cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(3):188-193.
8. Geller AC, Miller DR, Swetter SM, Demierre MF, Gilchrest BA. A call for the development and implementation of a targeted national melanoma screening program. Arch Dermatol. 2006;142(4): 504-507.
4. Moloney FJ, Guitera P, Coates E, et al. Detection of primary melanoma in individuals at extreme high risk. JAMA Dermatol. 2014;150(8):819-827. 5. Katalinic A, Waldmann A, Weinstock MA, et al. Does skin cancer screening save lives? Cancer. 2012;118(21):5395-5402. 6. 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(8):903-910.
9. Swetter SM, Johnson TM, Miller DR, Layton CJ, Brooks KR, Geller AC. Melanoma in middle-aged and older men. Arch Dermatol. 2009;145(4):397404. 10. Halpern AC, Marchetti MA, Marghoob AA. Melanoma surveillance in “high-risk” individuals. JAMA Dermatol. 2014;150(8):815-816.
7. The Surgeon General’s call to action to prevent skin cancer. http://www.surgeongeneral.gov/library
jama.com
(Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/11/2015
617
