Subsequent primary cancers among men and women with in situ and invasive melanoma of the skin

Subsequent primary cancers among men and women with in situ and invasive melanoma of the skin Appathurai Balamurugan, MD, MPH,a Judy R. Rees, BM, BCh, MPH, PhD,b Carol Kosary, PhD,c Sun Hee Rim, MPH,d Jun Li, MD, MPH, PhD,d and Sherri L. Stewart, PhDd Little Rock, Arkansas; Hanover, New Hampshire; Bethesda, Maryland; and Atlanta, Georgia CME INSTRUCTIONS Please note this is one article that is part of a 16-article CME supplement. CME credit should only be claimed after reading the entire supplement which can be accessed via the ‘‘Melanoma Supplement’’ tab under the ‘‘Collections By Type’’ pulldown menu on http://www.jaad.org. This journal supplement is a CME activity (enduring material) co-sponsored by the American Academy of Dermatology and the Centers for Disease Control and Prevention and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading all the articles in this supplement 3. Achievement of a 70% or higher on the online Post Test 4. Completion of the CME Evaluation

CME INFORMATION AND DISCLOSURES Statement of Need: Healthcare providers continue to underreport melanoma even though cancer reporting requirements mandate such reporting. Additionally, providers may be unaware of recent trends and descriptive epidemiology regarding melanoma which includes the fact that nonwhites have a higher mortality rate from melanoma than do whites. Target Audience: Dermatologists, dermatopathologists, general physicians, and public health professionals. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this enduring material for a maximum of 7 AMA PRA Category 1 CreditsÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This CME activity is recognized by the American Academy of Dermatology for 7 AAD Recognized Credits and may be used toward the American Academy of Dermatology’s Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statement or opinions expressed in this activity reflect the views of the author(s) and do not reflect the official policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for independent medical judgment of a health provider relative to the diagnostic, management and treatment options of a specific patient’s medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors of this CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this CME activity have reported no relevant financial relationships with commercial interest(s). Resolutions of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and mitigate conflits of interest for all individuals in a position to control the content of this CME activity. Learning Objectives After completing this learning activity, participants should be able to describe recent trends in the epidemiologic patterns of melanoma, including ethnic disparities in

melanoma mortality; identify when a private practice dermatologist is required to report melanoma cases to a cancer registry; locate and access central cancer reporting registries (http://apps.nccd.cdc.gov/cancercontacts/npcr/contacts.asp); and recognize and access national and state-based sources on surveillance systems for sun protection behaviors. Date of release: November 2011 Expiration date: November 2014 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2011.04.033 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site user’s computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the user’s efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacypolicy

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Background: An estimated 750,000 melanoma survivors in the United States are at increased risk of subsequent primary cancers. Objective: We sought to assess the risk of developing subsequent primary cancers among people with cutaneous melanoma. Methods: Using 1992 to 2006 data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program, 40,881 people with in situ melanoma and 76,041 people with invasive melanoma were followed up (mean of 5.6 years) for the development of subsequent primary cancers. The observed number of subsequent cancers was compared with those expected based on age-/race-/year-/site-specific rates in the Surveillance, Epidemiology, and End Results population. Standardized incidence ratios (SIRs) (SIR = observed number/expected number) were considered statistically significant if they differed from 1, with an alpha level of 0.05. Results: After a first primary in situ melanoma, risk was significantly elevated for subsequent invasive melanoma and chronic lymphocytic leukemia among men (SIRs = 8.43 and 1.44, respectively) and women (SIRs = 12.33 and 1.79, respectively). After a first primary invasive melanoma, risk was significantly elevated for subsequent invasive melanoma, thyroid cancer, non-Hodgkin lymphoma, and chronic lymphocytic leukemia among both men (SIRs = 12.50, 2.67, 1.56, and 1.57, respectively) and women (SIRs = 15.67, 1.77, 1.42, and 1.63, respectively). Limitations: Case ascertainment issues particularly affecting in situ melanoma cases could affect results. The role of detection bias in the diagnoses of some subsequent cancers cannot be completely eliminated. Conclusions: The findings of the study should guide the development of strategies such as posttreatment surveillance, screening, and ultraviolet exposure education among melanoma survivors to improve cancer survivorship. ( J Am Acad Dermatol 2011;65:S69.e1-9.) Key words: melanoma; posttreatment surveillance; screening; subsequent primary cancer; survivors.

Based on recent estimates, there are approximately 750,000 melanoma survivors in the United States.1 The role of ultraviolet (UV) radiation in the development of primary and subsequent melanoma has been well established.2-7 Other factors such as dysplastic nevi, family or personal history of melanoma, fair skin, severe blistering sunburns, and weakened immune system have also been implicated in the development of melanoma in various studies. Prior studies have shown that melanoma survivors have increased risk of developing subsequent primary cancers of the esophagus, non-Hodgkin lymphoma (NHL), soft

tissue sarcoma, subsequent melanoma, and thyroid, prostate, female breast, and kidney cancers.8-15 It is possible that some of these primary cancers may have coexisted before the melanoma diagnosis and/or have been diagnosed subsequently or appeared after treatment with radiotherapy.16 Characterizing the burden and risk of developing a subsequent primary cancer among in situ and invasive melanoma survivors, particularly among in situ melanoma survivors, has been limited.17 The objectives of this study are to: (1) assess the risk of subsequent primary cancers among men and

From the Department of Family and Preventive Medicine, University of Arkansas for Medical Sciencesa; New Hampshire State Cancer Registry, Department of Community and Family Medicine (Biostatistics and Epidemiology Section), Dartmouth Medical Schoolb; National Cancer Institute, Bethesdac; and Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta.d Publication of this supplement to the JAAD was supported by the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC). Conflicts of interest: None declared. The opinions or views expressed in this supplement are those of the authors and do not necessarily reflect the opinions,

recommendations, or official position of the journal editors or the Centers for Disease Control and Prevention. Accepted for publication April 30, 2011. Some of the results on invasive melanoma from this manuscript were presented as a poster at the 2010 American Academy of Family Physicians Scientific Assembly held in Denver, CO, September 29-October 2, 2010. Reprint requests: Appathurai Balamurugan, MD, MPH, Department of Family and Preventive Medicine, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 530, Little Rock, AR 72205. E-mail: [email protected]. 0190-9622/$36.00

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women with in situ and invasive melanoma of the melanoma and melanoma, not otherwise specified skin, and (2) stratify and ascertain the risk of subseand other subtypes) were included. quent primary cancers among men and women with melanoma by gender and age at diagnosis. The Subsequent primary cancers findings of this study could help shed light on We defined subsequent primary cancers as those possible common causes of different cancer forms, reported after the index melanoma diagnosis date. and assist in formulating preventive strategies such To assess detection bias caused by more intensive as posttreatment surveilscreening of patients with lance, screening, and UV excancer during the initial medCAPSULE SUMMARY posure reduction education ical workup, we assessed the among melanoma survivors. risk of developing subseMen and women with in situ and quent primary cancers durinvasive melanoma are at increased risk METHODS ing each of several time of subsequent primary cancers such as Data intervals after melanoma disubsequent invasive melanoma, thyroid We analyzed 1992 to 2006 agnosis.18 The subsequent cancer, non-Hodgkin lymphoma, and primary cancers included cancer incidence data from chronic lymphocytic leukemia. those reported to the SEER 13 population-based cancer incidence registry and death registries participating in the The risk of subsequent primary cancers is certificate or autopsy-only National Cancer Institute higher among those given the diagnosis cases. Detailed guidelines Surveillance, Epidemiology, of melanoma at a younger age, although on identifying subsequent and End Results (SEER) the overall burden is larger among older primary cancers are provided Program, covering 14% of persons. in the SEER Program code the US population. These Preventive strategies such as manual.18 Stage at diagnosis registries are Atlanta, GA; posttreatment surveillance, screening, was classified according to Connecticut; Detroit, MI; and risk factor reduction education the SEER summary stage (hisHawaii; Iowa; New Mexico; among melanoma survivors are required toric stage A). In an effort to San Francisco-Oakland, CA; to improve survivorship. assess the potential effects of Los Angeles, CA; San Josegender and age at diagnosis Monterey, CA; Seattle-Puget on subsequent development of primary cancers, the Sound, WA; Utah; Alaska Native Tumor Registry; and analyses were repeated after stratification by gender 10 counties in rural Georgia. The SEER data are a and age at diagnosis. Because of the relatively small public domain that can be obtained by the general number of subsequent primary cancers, we did not public including the researchers without needing restrict our analysis to specific histology subtypes, institutional review board approval because all the stage, and race/ethnicity. personal identifiers are removed from the data set. The primary data sources include hospital medical records, pathology and radiotherapy reports, outpaStatistical analysis tient surgical center records, and death certificates. The analysis was conducted using the personyears (PY) and indirect standardization methods. Cancer incidence rates were calculated for the 13 Index cases SEER areas combined by age, race, and calendarIndex cases of primary in situ or invasive melayear group, and were multiplied by the PY acnoma of the skin were defined as those diagnosed crued by the index cases to estimate the expected during the period 1992 through 2006 with no prior number of subsequent cancers for each stratum. reported cancers of any site. We excluded individStandardized incidence ratio (SIR) equals the ratio uals (N = 18,708) for whom in situ or invasive of the observed number divided by the expected melanoma was not the first diagnosed cancer, to number of subsequent cancers, and as such, remove cancers for which a common cause or describes the risk of development of subsequent previous treatment for these primary cancers may primary cancers. To assess the actual burden of have contributed to the development of subsequent subsequent cancers in the population, the absolute cancers. The remaining cohort of index cases was excess risk (AER) per 10,000 PY was computed followed up from the date of diagnosis of the first in using the formula: [(observed number e expected situ or invasive melanoma. Microscopic confirmation number) O PY] 3 10,000. SEER*Stat software rates were over 97% for the eligible index cases. All (National Cancer Institute, Bethesda, MD) was histologic subtypes of melanoma (superficial spreadused for data analysis. ing melanoma, nodular melanoma, acral lentiginous d

d

d

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Abbreviations used: AER: CLL: NHL: PY: SEER: SIR: UV:

absolute excess risk chronic lymphocytic leukemia non-Hodgkin lymphoma person-years Surveillance, Epidemiology, and End Results standardized incidence ratio ultraviolet

Bidirectional association A unidirectional association between melanoma and a subsequent cancer at a given site may suggest an artifactual association or a treatment effect. A bidirectional association between two cancers suggests shared risk factors (genetic or environmental) between the two cancers.19 To assess bidirectional relationships, we determined associations between first primary invasive nonmelanomatous cancer to subsequent primary invasive melanoma.

RESULTS Characteristics of index cases We analyzed 40,881 index cases of in situ melanoma and 76,041 index cases of invasive melanoma of the skin followed up in the SEER registries for a mean of 5.6 PY. Among the index patients with in situ melanoma, 53.9% were male and 46.1% were female (Table I). In all, 94% were non-Hispanic whites, and 2.3% were Hispanics. A total of 53% were aged 35 to 64 years, and 40.0% were 65 years or older at the time of diagnosis. Melanoma not otherwise specified (85.2%) and superficial spreading melanoma (14.0%) constituted the majority of histologic types. Among index patients with invasive melanoma, 54.9% were male and 45.1% were female (Table I). In all, 92% were non-Hispanic whites, and 3.2% were Hispanics. A total of 56% were 35 to 64 years of age, and 31.6% were 65 years and older at the time of diagnosis. Similar to in situ cases, melanoma not otherwise specified (50.6%) and superficial spreading melanoma (40.4%) constituted most of the histologic types. The index cases were largely either localized (82.2%) or regional stage (10.5%) at the time of diagnosis. Risk and burden of subsequent primary cancers among those with in situ melanoma During the follow-up period, 3004 subsequent primary cancers were identified among men with in situ melanoma (Table II). The SIRs over the total follow-up period were significantly elevated for invasive melanoma, NHL, chronic lymphocytic leukemia (CLL), and prostate cancer (SIRs 8.43, 1.21,

NOVEMBER 2011

Table I. Characteristics of index cases of in situ and invasive melanoma, Surveillance, Epidemiology, and End Results Program 1992 through 2006 In situ (N = 40,881) Characteristic

Gender Male Female Race/ethnicity White White, Hispanic White, nonHispanic Black API AI/AN Hispanic* Age at diagnosis, y 0-14 15-34 35-64 $ 65 Histology Superficial spreading melanoma Nodular melanoma Acral lentiginous melanoma Melanoma, NOS and other Stage of diagnosis Localized Regional Distant Unstaged Mean person-years at risk

Invasive (N = 76,041)

N

%

N

%

22,013 18,868

53.9 46.1

41,715 34,326

54.9 45.1

848 37,093

2.2 94.2

2292 69,838

3.0 92.3

137 327 57 912

0.4 0.8 0.1 2.3

365 671 125 2380

0.5 0.9 0.2 3.2

55 2951 21,543 16,332

0.1 7.2 52.7 40.0

191 8996 42,829 24,025

0.3 11.8 56.3 31.6

3612

14.0

28,384

40.4

7 211

0.0 0.8

5489 863

7.8 1.2

21,910

85.2

35,524

50.6

65,522 8014 2576 2929 5.61

82.2 10.5 3.4 3.9

NA

5.57

Data are from 13 population-based cancer registries that participate in Surveillance, Epidemiology, and End Results Program and meet high-quality data criteria. These registries cover approximately 14% of US population. AI/AN, American Indian/Alaska Native; API, Asian/Pacific Islander; NA, not applicable; NOS, not otherwise specified. *Hispanic ethnicity is not mutually exclusive from race.

1.44, and 1.24, respectively) (Table II). The AERs of subsequent invasive melanoma, NHL, CLL, and prostate cancer were 58.82, 1.64, 1.03, and 14.35 per 10,000 PY, respectively. During the same follow-up period, 1448 subsequent primary cancers were identified among women with in situ melanoma (Table III). The SIRs over the total follow-up period were significantly elevated for invasive melanoma, CLL, and thyroid cancer (SIRs 12.33, 1.79, and 1.58, respectively) (Table III). The AERs of subsequent invasive

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Table II. Subsequent primary cancers among men with in situ and invasive melanoma, all races, Surveillance, Epidemiology, and End Results Program 1992 through 2006 Follow-up time since diagnosis, mo Subsequent primary invasive cancer

Among men with in situ melanoma All sites Invasive melanoma Non-Hodgkin lymphoma Chronic lymphocytic leukemia Colon and rectum Lung and bronchus Thyroid Prostate Kidney Among men with invasive melanoma All sites Invasive melanoma Non-Hodgkin lymphoma Chronic lymphocytic leukemia Colon and rectum Lung and bronchus Thyroid Prostate Kidney

0-1 O

2-11 SIR

O

154 90 e 0

2.50* 441 36.31* 117 e 18 e e

14 e e 29 e

2.07* 38 e 37 e e 1.42 137 e 8

SIR

12-59 O

SIR

$ 120

60-119 O

SIR

O

SIR

Total O

SIR

1.50* 1398 1.28* 9.85* 338 7.41* 1.54 55 1.24 e 23 1.71*

834 215 32 12

1.24* 177 1.19* 3004 7.31* 52 7.45* 812 1.14 7 1.09 113 1.38 e e 41

1.32* 8.43* 1.21* 1.44*

1.18 0.86 e 1.41* 1.05

53 68 6 249 15

0.72* 0.69* 1.71 1.17* 0.83

0.87* e2.75 0.68 e8.73 1.27 0.26 1.24* 14.35 1.20 0.97

102 108 6 447 42

0.84 0.67* 1.07 1.26* 1.46*

9 12 0 44 6

0.56 0.55* 0.00 0.97 1.46

216 227 15 906 72

594 6.23* 839 1.89* 2210 1.43* 1316 1.31* 320 1.20* 5279 1.57* 403 102.06* 312 16.81* 665 9.93* 390 8.54* 80 6.21* 1850 12.50* 25 6.50* 47 2.61* 72 1.13 55 1.30 18 1.58 217 1.56* 9 8.02* 12 2.28* 23 1.24 15 1.20 e e 64 1.57* 12 23 7 47 9

1.15 47 1.66* 45 12.91* 18 1.51* 180 3.60* 30

AER

0.97 0.70* 7.09* 1.24* 2.56*

175 171 20 591 48

1.04 0.76* 2.19* 1.18* 1.14

95 99 7 351 39

0.89 0.69* 1.12 1.08* 1.37

28 29 2 85 10

1.02 357 0.77* 367 1.13 54 1.01 1254 1.28 136

60.07 58.82 1.64 1.03

84.66 75.13 3.43 1.02

0.98 e0.27 0.76* e5.10 2.67* 1.49 1.15* 7.37 1.47* 1.93

Data are from 13 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program and meet high quality data criteria. These registries cover approximately 14% of the U.S. population. Dashes indicate that data are suppressed if there are \ 6 observed cancers. AER, Absolute excess risk; O, observed number; SIR, standardized incidence ratio. *SIR differs significantly from 1 (P \ 0.05).

melanoma, CLL, and thyroid cancer were 37.96, 0.75, and 1.11 per 10,000 PY, respectively. When the index cases of in situ cancers were stratified by age at diagnosis (0-14, 15-34, 35-64, and $ 65 years) and assessed for the risk of subsequent primary cancer, men (Table IV) (SIRs for ages 15-34 years = 25.98, 35-64 = 9.35, and $ 65 = 7.71, respectively) and women (Table V) (SIRs for ages 15-34 years = 14.22, 35-64 = 10.41, and $ 65 = 14.39, respectively) with in situ melanoma had a significantly elevated risk of subsequent invasive melanoma in all age groups 15 years and older. Significantly elevated risk of subsequent CLL was observed among men (SIR = 2.11) and women (SIR = 2.88) with in situ melanoma among those 35 to 64 years of age alone. Risk and burden of subsequent primary cancers among those with invasive melanoma During the follow-up period, 5279 subsequent primary cancers were identified among men with

invasive melanoma (Table II). The SIRs over the total follow-up period were significantly elevated for invasive melanoma, NHL, CLL, and thyroid, prostate, and kidney cancer (SIRs 12.50, 1.56, 1.57, 2.67, 1.15, and 1.47, respectively) (Table II). The AERs of subsequent invasive melanoma, NHL, CLL, and thyroid, prostate, and kidney cancer were 75.13, 3.43, 1.02, 1.49, 7.37, and 1.93 per 10,000 PY, respectively. During the same follow-up period, 2761 subsequent primary cancers were identified among women with invasive melanoma (Table III). The SIRs over the total follow-up period were significantly elevated for invasive melanoma, NHL, CLL, and thyroid and breast cancer (SIRs 15.67, 1.42, 1.63, 1.77, and 1.18, respectively) (Table III). The AERs of subsequent invasive melanoma, NHL, CLL, and thyroid and breast cancer were 44.99, 1.49, 0.43, 1.46, and 4.79 per 10,000 PY, respectively. When the index cases of invasive cancers were stratified by age at diagnosis and assessed for the risk of subsequent primary cancer, men (Table IV) (SIRs

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Table III. Subsequent primary cancers among women with in situ and invasive melanoma, all races, Surveillance, Epidemiology, and End Results Program 1992 through 2006 Follow-up time since diagnosis, mo Subsequent primary invasive cancer

0-1 O

2-11 SIR

O

SIR

12-59 O

SIR

$ 120

60-119 O

SIR

O

SIR

Total O

SIR

AER

Among women with in situ melanoma All sites 97 3.46* 204 1.52* 617 1.20* 440 1.35* 90 1.20 1448 1.35* 35.08 Invasive melanoma 72 77.17* 72 16.19* 170 10.02* 106 9.94* 18 7.19* 438 12.33* 37.96 Non-Hodgkin lymphoma e e 7 1.25 23 1.05 22 1.53 e e 57 1.23 1.00 Chronic lymphocytic 0 e e e 12 2.56* e e e e 18 1.79* 0.75 leukemia Colon and rectum e e 19 1.20 53 0.86 38 0.95 7 0.77 121 0.93 e0.81 Lung and bronchus e e 13 0.72 56 0.80 39 0.85 9 0.83 120 0.81* e2.69 Thyroid e e e e 17 1.76* 6 1.00 e e 32 1.58* 1.11 Female breast 10 1.16 47 1.15 150 0.97 106 1.12 22 1.04 335 1.05 1.44 Kidney 0 e e e 8 0.82 e e e e 17 1.82 e0.36 Among women with invasive melanoma All sites 269 6.12* 421 2.04* 1157 1.52* 730 1.39* 184 1.23* 2761 1.64* 53.97 Invasive melanoma 198 127.59* 162 22.09* 357 13.00* 189 9.85* 51 9.24* 957 15.67* 44.99 Non-Hodgkin lymphoma e e 16 1.89* 44 1.40* 30 1.35 7 1.07 100 1.42* 1.49 0.43 Chronic lymphocytic e e 6 3.39* 8 1.23 e e e e 24 1.63* leukemia Colon and rectum e e 32 1.34 90 1.04 61 1.03 15 0.89 203 1.06 0.57 Lung and bronchus 9 1.59 28 1.05 95 0.96 57 0.83 19 0.94 208 0.94 e0.61 Thyroid e e 22 4.94* 21 1.25 14 1.16 e e 67 1.77* 1.46 Female breast 24 1.76* 70 1.09 288 1.21* 193 1.19* 43 0.96 618 1.18* 4.79 Kidney 0 e e e 21 1.48 16 1.54 e e 44 1.36 0.59 Data are from 13 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program and meet high quality data criteria. These registries cover approximately 14% of the U.S. population. Dashes indicate that data are suppressed if there are \ 6 observed cancers. AER, Absolute excess risk; O, observed number; SIR, standardized incidence ratio. *SIR differs significantly from 1 (P \ 0.05).

for ages 15-34 years = 34.24, 35-64 = 13.98, and $ 65 = 10.48, respectively) and women (Table V) (SIRs for ages 15-34 years = 23.12, 35-64 = 14.15, and $ 65 = 16.08, respectively) with invasive melanoma had a significantly elevated risk of subsequent invasive melanoma for all age groups 15 years and older. Significantly elevated risk of subsequent NHL was observed among men (SIR = 1.65) and women (SIR = 1.58) with invasive melanoma among those 65 years of age and older, and among men aged 35 to 64 years (SIR = 1.46). There was also an elevated risk of CLL among men aged 35 to 64 years (SIR = 2.12) and women aged 65 years and older (SIR = 1.85) Bidirectional association Bidirectional association was assessed between first primary invasive nonmelanomatous cancer (NHL and CLL) to subsequent primary invasive melanoma. Significantly elevated risks for subsequent invasive melanoma were observed among

men after a NHL and CLL (SIRs 1.31 and 2.33, respectively). Significantly elevated risk for subsequent invasive melanoma was observed among women after NHL alone (SIR 1.70).

Sensitivity analysis We conducted sensitivity analyses to assess the impact of change in the index case definition on the risk and burden of development of subsequent primary cancers. We performed one sensitivity analysis to account for detection bias, by excluding subsequent primary cancers diagnosed 2 months or sooner after the index melanoma diagnosis. This yielded similar results with the exception that the risk of subsequent thyroid cancer after an in situ melanoma among females was no longer significantly elevated (SIR = 1.47). In other sensitivity analysis, we expanded the index case definition to combine both in situ and invasive melanoma. The

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Table IV. Subsequent primary cancers among men with in situ and invasive melanoma by age at diagnosis, all races, Surveillance, Epidemiology, and End Results Program 1992 through 2006 Subsequent primary cancer Invasive melanoma Characteristics of index case

In situ Age at diagnosis, y 0-14 15-34 35-64 $ 65 Invasive Age at diagnosis, y 0-14 15-34 35-64 $ 65

O

SIR

0 16 330 466

e 80 963 805

Non-Hodgkin lymphoma

AER

O

e 25.98* 9.35* 7.71*

e 27.6 45.5 79.3

e 34.24* 13.98* 10.48*

e 36.2 64.7 109.5

Chronic lymphocytic leukemia

SIR

AER

O

SIR

AER

0 0 37 76

e e 1.29 1.19

e e 1.3 2.4

0 0 16 25

e e 2.11* 1.20

e e 1.3 0.8

0 e 81 135

e e 1.46* 1.65*

e e 1.8 8.0

0 e 30 33

e e 2.12* 1.24

e e 1.2 1.0

Dashes indicate that data are suppressed if there are \ 6 observed cancers. AER, Absolute excess risk; O, observed number; SIR, standardized incidence ratio. *SIR differs significantly from 1 (P \ 0.05).

Table V. Subsequent primary cancers among women with in situ and invasive melanoma by age at diagnosis, all races, Surveillance, Epidemiology, and End Results Program 1992 through 2006 Subsequent primary cancer Invasive melanoma Characteristics of index case

In situ Age at diagnosis, y 0-14 15-34 35-64 $ 65 Invasive Age at diagnosis, y 0-14 15-34 35-64 $ 65

Non-Hodgkin lymphoma

Chronic lymphocytic leukemia

O

SIR

AER

O

SIR

AER

O

SIR

AER

0 29 190 219

e 14.22* 10.41* 14.39*

e 21.7 28.8 60.1

0 0 23 34

e e 1.44 1.14

e e 1.2 1.2

0 0 8 10

e e 2.88* 1.38

e e 0.9 0.8

0 139 492 326

e 23.12* 14.15* 16.08*

e 36.2 39.4 67.0

0 e 35 63

e e 1.22 1.58*

e e 0.5 5.1

0 0 6 18

e e 1.22 1.85*

e e 0.1 1.8

Data are from 13 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program and meet high quality data criteria. These registries cover approximately 14% of the U.S. population. Dashes indicate that data are suppressed if there are \ 6 observed cancers. AER, Absolute excess risk; O, observed number; SIR, standardized incidence ratio. *SIR differs significantly from 1 (P \ 0.05).

analysis yielded no significantly different results (data not shown).

DISCUSSION Our findings are consistent with previous studies that have shown an elevated risk for subsequent primary cancers among invasive melanoma survivors.8-15 However, to our knowledge, this is the first study to report the risk and burden of subsequent primary cancers among such a large number of in

situ melanoma survivors (N = 40,881) using a population-based registry. The only other study by Wassberg et al17 using the Swedish Cancer Register had a much smaller sample size of in situ melanoma survivors (N = 3766). Of the 3004 men with subsequent primary cancers among in situ melanoma survivors, there was a 32% increased risk of subsequent primary cancers of all sites. Similarly, of the 1448 women with subsequent primary cancers among in situ

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melanoma survivors, there was a 35% increased risk of subsequent primary cancers of all sites. Elevated risk was found for subsequent invasive melanoma in age groups 15 years and older; and throughout the follow-up period with the risk ranging from over 8-fold in men to over 12-fold in women, confirming that in situ melanoma is a strong risk factor for later development of invasive melanoma. This could be attributed to higher risk or continued UV exposure among these survivors. The risk of subsequent invasive melanoma decreased with age particularly among men; however, the AER is much higher among older individuals suggesting an increasing burden of subsequent invasive melanoma among older individuals. Elevated risk for subsequent CLL was observed among both men and women with in situ melanoma, particularly after the first year of index case diagnosis. This is less likely a result of increased medical surveillance, and the role of impaired immunologic status should be considered. Less than 0.1% (N = 28) of those with in situ melanoma received radiation therapy as a form of treatment, hence it is unlikely to have contributed to the elevated risk. Also, elevated risk for prostate cancer among men and thyroid cancer among women particularly after 12 months of index case diagnosis diminishes the possibility that detection bias accounts for these findings, and suggests instead that common risk factors such as genetic or environmental exposures may be responsible. Of the 5279 men with subsequent primary cancers among invasive melanoma survivors, there was a 57% increased risk of subsequent primary cancers of all sites. Similarly, of the 2761 women with subsequent primary cancers among invasive melanoma survivors, there was a 64% increased risk of subsequent primary cancers of all sites. Elevated risk was observed for subsequent invasive melanoma age groups 15 years and older; and throughout the follow-up period with the risk ranging close to 13-fold in men to over 16-fold in women, suggesting that invasive melanoma is a strong risk factor for later development of additional melanomas. This could again be a result of higher risk or continued UV exposure among these survivors. The risk of subsequent invasive melanoma decreased with age particularly among men; however, the AER is much higher among older individuals, just as it was after in situ melanoma. Elevated risk for subsequent NHL was observed particularly among women after the first year of index melanoma diagnosis. This could be a result of shared risk factors such as age and UV exposure, impaired immunologic status, or genetic susceptibility. Prior genetic studies have shown deletion of a region of chromosome 9p21 in both

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melanoma and NHL suggesting shared susceptibility.20,21 Elevated risk observed for CLL and kidney cancers among men and women and thyroid cancer among men during the first 12 months of index case diagnosis could be a result of increased medical surveillance. Less than 2% (N = 1501) of those with invasive melanoma received radiation therapy as a form of treatment, hence it is unlikely to have contributed to the elevated risk. Persistent elevated risk for prostate cancer in men and breast cancer among women after a 12-month follow-up period could be a result of increased awareness and screening among general population or a result of possible shared risk factors with melanoma. Two cancer sites showed some evidence of reduced risk after melanoma: colon/rectum and lung/bronchus. Among women, the only significantly reduced rates were of cancer of the lung and bronchus after in situ melanoma. Among men, there was a significantly reduced risk of colorectal cancer after in situ melanoma, despite a significantly increased risk during the first 2 months that was presumably attributable to detection bias. The same pattern was not seen among men after invasive melanoma. Also among men, cancers of the lung and bronchus were significantly less common after invasive melanoma, and after in situ melanoma; the association was also statistically significant among those with longer follow-up times since the index melanoma diagnosis. The decreased risk for cancers of lung and bronchus among men with invasive melanoma may be related to their higher socioeconomic status and lower smoking prevalence, but this hypothesis could be investigated only with individual exposure data that are not generally available through cancer registries. Although there is no general consensus for follow-up after initial melanoma diagnosis, several entities advocate for intensified skin surveillance and follow-up after a first melanoma.22-25 A study by Uliasz and Lebwohl26 found that earlier diagnosis of the first melanoma along with patient education and follow-up was associated with significantly thinner subsequent melanoma and hence an opportunity for curative treatment. Patient education on selfexamination based on the ABCDE mnemonic (asymmetry, borders, color, diameter, and evolution),27 proper sun protection, posttreatment surveillance, and vigilant screening for subsequent primary cancers and follow-up are necessary. There are a few potential limitations with this study. First, there may be inconsistency or underreporting of melanoma particularly in situ lesions because of variation in the interpretation of pathologic specimens by different individuals, and

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difficulties in case ascertainment when pathologic confirmation is made by a dermatologist outside the larger pathology laboratory setting. Second, the role of detection bias in the diagnoses of some of subsequent cancers cannot be completely eliminated; it is possible that some of the cancers detected as a result of increased medical surveillance may never have come to light under other circumstances. Third, the small numbers of subsequent primary cancers limited further subgroup analysis, particularly by type of treatment as predominant form of treatment was surgery. Fourth, some of the patients with melanoma may have moved out of the SEER areas during the follow-up period, resulting in underreporting of subsequent cancers. Finally, the ability of an individuals’ immune system to identify and destroy nascent cancers (tumor immune surveillance and immunoediting) and hence function as a primary defense against melanoma or any other subsequent cancer varies, however, this is beyond the scope of this study. The study findings shed new light on the development of subsequent primary cancers among melanoma survivors, particularly among those with in situ melanoma. The findings could help formulate strategies such as posttreatment surveillance, screening, and UV exposure education among melanoma survivors to improve survivorship. REFERENCES 1. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, et al. SEER cancer statistics review, 1975-2006. Available from: URL: http://seer.cancer.gov/csr/1975_2006/. Accessed April 9, 2011. 2. Elwood JM, Hislop TG. Solar radiation in the etiology of cutaneous malignant melanoma in Caucasians. Natl Cancer Inst Monogr 1982;62:162-71. 3. Lee JAH. Melanoma and exposure to sunlight. Epidemiol Rev 1982;4:110-36. 4. Holman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenic types. J Natl Cancer Inst 1984; 73:75-82. 5. Gallagher RP, Elwood JM, Hill GB. Risk factors for cutaneous malignant melanoma: the Western Canada melanoma study. In: Gallagher RP, editor. Epidemiology of malignant melanoma. Berlin: Springer-Verlag; 1986. pp. 38-55. 6. Kricker A, Armstrong BK, Goumas C, Litchfield M, Begg CB, Hummer AJ, et al. Ambient UV, personal sun exposure and risk of multiple primary melanomas. Cancer Causes Control 2007; 18:295-304. 7. Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancer: vitamin D as a possible explanation. Eur J Cancer 2007;43:1701-12. 8. Hayat MJ, Howlander N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) program. Oncologist 2007;12:20-37.

Balamurugan et al S69.e9

9. Freedman DM, Miller BA, Tucker MA. New malignancies following melanoma of the skin, eye melanoma, and non-melanoma eye cancer. SEER cancer registries, 1973-2000. NIH publication No. 05-5302. Bethesda (MD): National Cancer Institute; 2006. p. 339-62. 10. Bradford PT, Freedman DM, Goldstein AM, Tucker MA. Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol 2010;146:265-72. 11. Crocetti E, Guzzinati S, Paci E, Falcini F, Zanetti R, Vercelli M, et al. The risk of developing a second, different, cancer among 14560 survivors of malignant cutaneous melanoma: a study by AIRTUM (the Italian network of cancer registries). Melanoma Res 2008;18:230-4. 12. Cantwell MM, Murray LJ, Catney D, Donnelly D, Autier P, Boniol M, et al. Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland. Br J Cancer 2009;100:174-7. 13. Hall P, Rosendahl I, Mattsson A, Einhorn S. Non-Hodgkin’s lymphoma and skin malignancieseshared etiology? Int J Cancer 1995;62:519-22. 14. Bhatia S, Estrad-Batres L, Maryon T, Bogue M, Chu D. Second primary tumors in patients with cutaneous malignant melanoma. Cancer 1999;86:2014-20. 15. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 2003;97:639-43. 16. Guerin S, Dupuy A, Anderson H, Shamsaldin A, Svahn-Tapper G, Moller T, et al. Radiation dose as a risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003;39: 2379-86. 17. Wassberg C, Thorn M, Yuen J, Hakulinen T, Ringborg U. Cancer risk in patients with earlier diagnosis of cutaneous melanoma in situ. Int J Cancer 1999;83:314-7. 18. Johnson CH, editor. SEER program coding and staging manual 2004, revision 1. NIH publication No. 04-5581. Bethesda (MD): National Cancer Institute; 2004. 19. Ahmed F, Goodman MT, Kosary C, Ruiz B, Wu X, Chen VW, et al. Excess risk of subsequent primary cancers among colorectal carcinoma survivors, 1975-2001. Cancer 2006; 107(Suppl):1162-71. 20. Fountain JW, Karajiorgou M, Ernstoff MS, Kirkwood JM, Vlock DR, Titus-Ernstoff L, et al. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Nat Acad Sci 1992;89:10557-61. 21. Pollack C, Hagemeijer A. Abnormalities of the short arm of chromosome 9 with partial loss of materials in hematological disorders. Leukemia 1987;1:541-8. 22. National Comprehensive Cancer Network. Melanoma: clinical practice guidelines in oncology. Available from: URL: http:// www.nccn.org. Accessed March 23, 2011. 23. Francken AB, Bastiaannet E, Heokstra HJ. Follow-up in patients with localized primary cutaneous melanoma. Lancet Oncol 2005;6:608-21. 24. Poo-Hwu WJ, Ariyan S, Lamb L, Papac R, Zelterman D, Hu GL, et al. Follow-up recommendations for patients with American Joint Committee on Cancer stages I-III malignant melanoma. Cancer 1999;86:2252-8. 25. Brobreil A, Rapaport D, Wells K, Cruse CW, Glass F, Fenske N, et al. Multiple primary melanomas: implications for screening and follow-up programs for melanoma. Ann Surg Oncol 1997;4:19-23. 26. Uliasz A, Lebwohl M. Patient education and regular surveillance results in earlier diagnosis of second primary melanoma. Int J Dermatol 2007;46:575-7. 27. Abbasi NR, Shaw HM, Rigel DS, Friedman RJ, McCarthy WH, Osman I, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA 2004;292:2771-6.