- Email: [email protected]
Risk of subsequent melanoma after melanoma in situ and invasive melanoma: A population-based study from 1973 to 2011
Risk of subsequent melanoma after melanoma in situ and invasive melanoma: A population-based study from 1973 to 2011 Hyemin Pomerantz, MD,a,b David Huang, BS,a,b and Martin A. Weinstock, MD, PhDa,b,c,d Providence, Rhode Island Background: Patients with melanoma in situ are at an increased risk of subsequent melanoma compared with the general population, but the risk of subsequent melanoma after initial melanoma in situ versus after initial invasive melanoma is not known. Objective: We sought to compare the risk of subsequent melanoma in the cohort whose first cancer was melanoma in situ to the risk in the cohort whose first cancer was invasive melanoma. Methods: In this cohort study, we identified individuals whose first cancer was either melanoma in situ or invasive melanoma from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2011 and used Cox proportional hazards models for comparison. Results: Compared with the invasive melanoma cohort, the melanoma in situ cohort was more likely to develop subsequent melanoma of any stage after 2 years, subsequent invasive melanoma after 10 years, and subsequent melanoma in situ at all the time points (P \ .001, P = .003, P \ .001, respectively). Limitations: Underreporting of melanomas, particularly melanoma in situ cases, and missing cases of subsequent melanomas as a result of patient migration from the SEER registry areas could affect results. Conclusion: Given the increased long-term risk of subsequent melanoma in the melanoma in situ cohort, the patients with melanoma in situ diagnosis may benefit from a long-term surveillance for subsequent melanomas. ( J Am Acad Dermatol 2015;72:794-800.) Key words: invasive melanoma; melanoma; melanoma in situ; risk comparisons; Surveillance, Epidemiology, and End Results; subsequent melanoma.
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ollow-up visits after treatment of primary cutaneous melanoma play an important role in early detection of subsequent primary, recurrent, or metastatic melanoma.1,2 Almost all recurrent or metastatic melanomas are detected in fewer than 10 years after the initial melanoma diagnosis,3-5 whereas long-term follow-up of patients with melanoma is beneficial in early detection of subsequent melanoma.6-11 Evidence suggests that follow-up visits after a melanoma result in early
diagnosis of subsequent melanoma and may reduce morbidity and mortality associated with the subsequent melanoma.8,10,12 Patients with regular clinic
From the Center for Dermatoepidemiology, Department of Veterans Affairs Medical Centera; Departments of Dermatologyb and Epidemiology,c Brown University; and Department of Dermatology, Rhode Island Hospital.d Funding sources: None. Conflicts of interest: None declared. The abstract that included part of the results reported in the manuscript was presented at the American Academy of Dermatology summer meeting in Chicago, IL on August 7, 2014.
Accepted for publication February 1, 2015. Reprint requests: Hyemin Pomerantz, MD, Center for Dermatoepidemiology, Department of Veterans Affairs Medical Center, 830 Chalkstone Ave, Providence, RI 02908. E-mail: hyemin. [email protected]. Published online March 12, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.02.006
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Abbreviations used: CI: HR: SEER:
confidence interval hazard ratio Surveillance, Epidemiology, and End Results
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visits after the first melanoma diagnosis had a second Edition. Only the individuals with the microscopimelanoma that was thinnerehence with better progcally confirmed first melanoma diagnosis with nosisethan the patients without regular follow-up known SEER summary stage were included in the schedule.12 Studies showed that the subsequent study. Whether these individuals developed subseprimary melanoma detected at a follow-up visit quent melanoma was identified from the SEER 9 were thinner than the first melanoma.8,10 database. Subsequent melanoma diagnosed within 2 The risk of subsequent melanoma after initial months after the initial melanoma was excluded, melanoma in situ or initial because subsequent melainvasive melanoma is higher nomas diagnosed within 2 CAPSULE SUMMARY than the risk in the general months after the first melapopulation.13-15 Patients with noma were considered synMelanoma in situ increases the risk of melanoma in situ have an chronous to the first one.31,32 subsequent melanoma, compared to the overall better prognosis Our study was exempt from general population. than those with invasive melinstitutional review board After 2 years, patients with melanoma in anoma,4,16 but the former oversight, because the SEER situ were more likely to develop group’s subsequent mela9 database is accessible to the subsequent melanoma than those with noma risk compared with public and the subjects in the invasive melanoma. that of the latter group is not database are de-identified. known. Although national/ These results support long-term regional melanoma guideStudy variables surveillance for subsequent melanoma lines recommend regular Sex, race, birth year, and after melanoma in situ. follow-ups of patients with SEER registry were identified invasive melanoma for a for each individual included number of years, necessity of regular follow-ups of in the analyses. SEER summary stage (in situ, patients treated for melanoma in situ is currently localized, or regional/distant), based on a combined debatable. Some guidelines do not recommend clinical and histologic assessment, were collected for additional follow-up after surgical excision of a both first and second melanomas.33 Age at diagnosis melanoma in situ or do not address follow-up and month and year of diagnosis were collected for recommendations for patients with melanoma in both first and second melanomas, and the time situ.1,2,17-21 The incidence of cutaneous melanoma in duration from the first melanoma to the second situ is rising in various countries.22-29 Therefore, melanoma was calculated. If no subsequent melabetter characterization of subsequent melanoma noma was developed, the time to follow-up was risk in the patients with melanoma in situ would defined as the time from the first melanoma to death, provide additional evidence for developing clinical loss to follow-up, or end of study. surveillance plans that will be useful for the increasing patient population. This study compared Statistical analysis the risk of subsequent melanoma in the population The baseline characteristics (sex, birth year, age at whose first primary cancer was melanoma in situ to first melanoma diagnosis, year of first melanoma the risk in the population whose first primary cancer diagnosis, and SEER registry) were compared by was invasive melanoma. Wilcoxon rank sum tests between the melanoma in situ and the invasive localized melanoma cohorts and between the melanoma in situ and the invasive METHODS regional/distant melanoma cohorts. The incidence Data source and selection criteria rate ratios of subsequent melanoma of any type, Individuals whose first primary cancer was either subsequent invasive melanoma, and subsequent in situ or invasive melanoma of the skin were melanoma in situ were calculated, comparing the identified in the Surveillance, Epidemiology, and melanoma in situ cohort with the invasive localized End Results (SEER) 9 program from 1973 to 2011. melanoma cohort or with the invasive regional/ SEER collects data on cancers, including melanoma, distant melanoma, separately. The risks of subseand SEER 9 started the data collection from 1973 quent melanoma were compared between the melto 1975 in 9 regions, which represents approximately anoma in situ cohort (whose first primary cancer was 10% of the US population.30 Melanoma of the melanoma in situ) and the invasive melanoma cohort skin was defined as cases that had the primary site (whose first primary cancer was invasive melanoma) coded as skin (C44.0-C49.0) and histology as melawith Cox proportional hazards regression models. noma (8720-8790) according to the International The hazard ratios (HR) of the invasive melanoma Classification of Diseases for Oncology, Third d
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cohort with reference to the melanoma in situ cohort were adjusted for sex, race, birth year, age at first melanoma diagnosis, and SEER registry, because these characteristics were found to be significantly different between the cohorts. The proportionality assumption in the Cox proportional hazard model was tested in a generalized linear regression of the scaled Schoenfeld residuals on functions of time. The proportionality assumption was not violated, when the model was stratified by the levels of each adjusted variable and separate models were fit to different time intervals (2 months-2 years, 2-10 years, $10 years). The risks of subsequent invasive melanoma and subsequent melanoma in situ were compared between the 2 cohorts using the same models. Cumulative probabilities of subsequent invasive melanoma were calculated using the Kaplan-Meier method. Data were analyzed using STATA SE Version 8 (StataCorp, College Station, TX).
RESULTS Identification of individuals with melanoma as their first primary cancer In the SEER 9 from 1973 to 2011, 55,661 individuals had melanoma in situ as their first primary cancer of any type and 112,613 individuals had invasive melanoma as their first primary cancer. Of these individuals with invasive melanoma as their first primary cancer, 97,614 (87%) were given a diagnosis of localized melanoma and 14,999 (13%) were given a diagnosis of regional/distant melanoma (Table I). The baseline characteristics between the melanoma in situ and invasive melanoma cohorts were significantly different (Table I). The median follow-up duration after the first melanoma diagnosis was 7 years (range 0.17-39 years) in the melanoma in situ cohort, 8.7 years (range 0.17-39 years) in the invasive localized melanoma cohort, and 2.8 years (range 0.17-39 years) in the invasive regional/distant melanoma cohort (Table II). The median follow-up duration of the invasive melanoma cohort (localized and regional/distant combined) was 7.8 years. Incidences of subsequent melanoma Of the total cohort of 168,274 individuals with the diagnosis of either in situ or invasive melanoma as their first primary cancer, 10,876 individuals (6.5%) developed at least 1 subsequent melanoma of any stage (either in situ or invasive). Nine individuals per 1000 person-years in the melanoma in situ cohort were given a diagnosis of a subsequent melanoma, whereas 6.4 individuals per 1000 person-years in the invasive melanoma cohort were given a diagnosis of a subsequent melanoma (incidence rate ratio 1.5, 95% confidence interval [CI] 1.4-1.5). The melanoma
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Table I. Baseline characteristics in Surveillance, Epidemiology, and End Results 9 from 1973 to 2011 Stage of first melanoma
Characteristics
In situ melanoma (N = 55,661) n (%)
Localized Regional/distant melanoma melanoma (N = 97,614) (N = 14,999) n (%) n (%)
Sex Male 30,097 (54) 51,108 Female 25,564 (46) 46,506 Birth year #1930 14,800 (27) 24,495 1931-1940 10,089 (18) 15,533 1941-1950 12,019 (22) 20,137 1951-1960 10,026 (18) 19,015 $1961 8727 (16) 18,434 Age at first melanoma diagnosis, y 0-19 270 (0.5) 992 20-34 3816 (7) 13,000 35-49 11,247 (20) 26,556 50-64 18,026 (32) 29,402 65-79 16,659 (30) 20,861 $80 5643 (10) 6803 Year of first melanoma diagnosis 1973-1979 666 (1) 6659 1980-1989 4791 (9) 18,014 1990-1999 14,361 (26) 26,631 2000-2011 35,843 (64) 46,310 SEER registry Atlanta, GA 5177 (9) 9933 Connecticut 8419 (15) 14,860 Detroit, MI 6584 (12) 11,814 Hawaii 2193 (4) 3856 Iowa 4852 (9) 10,712 New Mexico 3268 (6) 5626 San Francisco/ 8789 (16) 15,004 Oakland, CA Seattle, WA 11,201 (20) 17,628 Utah 5178 (9) 8181
(52) (48)
9329 (62) 5670 (38)
(25) (16) (21) (19) (19)
5370 2508 2637 2387 2097
(36) (17) (18) (16) (14)
(1) (13) (27) (30) (21) (7)
197 1404 3236 4364 3919 1879
(1) (9) (22) (29) (26) (13)
(7) (18) (27) (47)
1173 2675 4059 6922
(8) (18) (27) (46)
(10) (15) (12) (4) (11) (6) (15)
1173 2447 1934 557 1958 904 2275
(8) (16) (13) (4) (13) (6) (15)
(18) (8)
2476 (17) 1275 (9)
P \ .001 for all characteristics in comparisons between melanoma in situ and each of invasive melanoma cohorts. SEER, Surveillance, Epidemiology, and End Results.
in situ cohort had a higher incidence of subsequent melanoma than the invasive localized melanoma cohort or the invasive regional/distant melanoma cohort (incidence rate ratio 1.5, 95% CI 1.4-1.5; incidence rate ratio 1.4, 95% CI 1.3-1.5, respectively) (Table II). In the total cohort, 6067 individuals (3.6%) developed at least 1 subsequent invasive melanoma. Incidence rate of subsequent invasive melanoma was 3.7 per 1000 person-years. The incidence rates of subsequent invasive melanoma after initial melanoma in situ, initial localized, and initial regional/ distant melanoma were 4.1, 3.6, and 4.6 per 1000 person-years, respectively (Table II). The melanoma
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Table II. The number of indviduals and the incidence rates of subsequent melanoma in Surveillance, Epidemiology, and End Results 9 Stage of first melanoma
Follow-up duration, y, mean 6 SD Follow-up duration, y, median (range) Subsequent melanoma N Time at risk, y Incidence rate per 1000 person-y (95% CI) Subsequent invasive melanoma N Time at risk, y Incidence rate per 1000 person-y (95% CI) Subsequent melanoma in situ N Time at risk, y Incidence rate per 1000 person-y (95% CI)
Melanoma in situ (N = 55,661)
Localized melanoma (N = 97,614)
Regional/distant melanoma (N = 14,999)
8.5 6 6.6 7 (0.2-39)
10.9 6 8.7 8.7 (0.2-39)
5.8 6 7.1 2.8 (0.2-39)
4024 448,815 9.0 (8.7-9.2)
6300 1,024,702 6.1 (6.0-6.3)
552 84,697 6.5 (6.0-7.1)
1913 461,165 4.1 (4.0-4.3)
3764 1,041,402 3.6 (3.5-3.7)
390 85,501 4.6 (4.1-5.0)
2504 454,409 5.5 (5.3-5.7)
3104 1,042,342 3.0 (2.9-3.1)
209 85,879 2.4 (2.1-2.8)
CI, Confidence interval; N, number of individuals.
in situ cohort had a higher incidence of subsequent invasive melanoma than the invasive localized cohort (incidence rate ratio 1.2, 95% CI 1.1-1.2). The subsequent invasive melanoma incidence rate was not different between the melanoma in situ cohort and the invasive regional/distant melanoma cohort (incidence rate ratio 0.9, 95% CI 0.8-1.0). In all, 5817 individuals (3.5%) developed at least 1 subsequent melanoma in situ. Incidence rate of subsequent melanoma in situ was 3.8 per 1000 person-years, and the incidence rates of subsequent melanoma in situ after initial melanoma in situ, initial localized, and initial regional/distant melanoma were 5.5, 3.0 and 2.4 per 1000 person-years, respectively (Table II). Incidence rate of subsequent melanoma in situ was higher in the melanoma in situ cohort than the invasive localized melanoma cohort or the invasive regional/distant melanoma cohort (incidence rate ratio 1.9, 95% CI 1.8-2.0; incidence rate ratio 2.3, 95% CI 2.0-2.6, respectively). Risks of subsequent melanoma The risks of subsequent melanoma of any stage (either in situ or invasive) within 2 years after the first melanoma diagnosis were not different between the melanoma in situ cohort and the invasive melanoma cohort (HR 1.02, 95% CI 0.95-1.10) (Table III). However, after 2 years, the invasive melanoma cohort was less likely to develop subsequent melanoma than the melanoma in situ cohort (2-10 years: HR 0.84, 95% CI 0.79-0.88; [10 years: HR 0.78, 95% CI 0.71-0.85) (Table III). During the first 2 years after the first melanoma, the risk of subsequent invasive melanoma in the
invasive melanoma cohort was higher than the melanoma in situ cohort (HR 1.36, 95% CI 1.211.51) (Table III). Between 2 and 10 years, the risk of subsequent invasive melanoma in the invasive melanoma cohort remained higher than the melanoma in situ cohort (HR 1.09, 95% CI 1.01-1.18) (Table III). After 10 years, however, the risk of subsequent invasive melanoma in the invasive melanoma cohort was lower than that in the melanoma in situ cohort (HR 0.84, 95% CI 0.75-0.94) (Table III). The invasive melanoma cohort was at a lower risk of subsequent melanoma in situ than the melanoma in situ cohort, and the decreased risk remained persistent throughout the entire follow-up period after the first melanoma diagnosis (HR 0.69, 95% CI 0.66-0.73) (Table III).
Cumulative probabilities of subsequent melanoma The cumulative risk of subsequent melanoma of any stage (either in situ or invasive melanoma) at 5 years was higher in the melanoma in situ cohort than the invasive melanoma cohort (in situ 2.8% [95% CI 2.7%-3.0%], invasive 2.0% [95% CI 1.9%-2.1%]), and the cumulative risk in the melanoma in situ cohort was consistently higher than the risk in the invasive melanoma cohort during the further follow-up period (Fig 1). The cumulative risk of subsequent invasive melanoma did not differ between the in situ and invasive cohorts at 5 and 10 years after the first melanoma diagnosis (at 5 years: in situ 1.3% [95% CI 1.2%-1.4%], invasive 1.2% [95% CI 1.1%-1.3%]; at 10 years: in situ
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Table III. Risks of subsequent melanoma in the melanoma in situ cohort versus the invasive melanoma cohort 2 mo-2 y Stage of first melanoma
Adjusted HR* (95% CI)
Risks of subsequent melanoma of any stage In situ melanoma 1 (ref) All invasive melanoma 1.02 (0.95-1.10) Localized melanoma 1.02 (0.95-1.10) Regional or distant 1.01 (0.88-1.18) melanoma Risks of subsequent invasive melanoma In situ melanoma 1 (ref) All invasive melanoma 1.36 (1.21-1.51) Localized melanoma 1.30 (1.16-1.46) Regional or distant 1.76 (1.47-2.11) melanoma Risks of subsequent melanoma in situ In situ melanoma 1 (ref) All invasive melanoma 0.80 (0.73-0.89) Localized melanoma 0.83 (0.75-0.92) Regional or distant 0.59 (0.46-0.74) melanoma
[10 y
2-10 y P value
Adjusted HR* (95% CI)
P value
Adjusted HR* (95% CI)
P value
.56 .59 .79
1 0.84 0.84 0.78
(ref) (0.79-0.88) (0.80-0.89) (0.68-0.89)
\.001 \.001 \.001
1 0.78 0.79 0.64
(ref) (0.71-0.85) (0.72-0.86) (0.51-0.80)
\.001 \.001 \.001
\.001 \.001 \.001
1 1.09 1.09 1.17
(ref) (1.01-1.18) (1.01-1.18) (0.99-1.38)
.02 .04 .06
1 0.84 0.85 0.70
(ref) (0.75-0.94) (0.75-0.95) (0.53-0.93)
.003 .005 .013
\.001 \.001 \.001
1 0.64 0.66 0.48
(ref) (0.60-0.69) (0.61-0.71) (0.39-0.60)
\.001 \.001 \.001
1 0.68 0.69 0.53
(ref) (0.60-0.77) (0.61-0.78) (0.38-0.73)
\.001 \.001 \.001
CI, Confidence interval; HR, hazard ratios; ref, reference. *Adjusted by age at the first primary cancer diagnosis, sex, race, birth year, and Surveillance, Epidemiology, and End Results registry.
Fig 1. Cumulative risks of subsequent melanoma of any stage.
3.2% [95% CI 3.0%-3.4%], invasive 2.9% [95% CI 2.8%-3.1%]) (Fig 2). The cumulative risks of subsequent melanoma in situ remained higher in the melanoma in situ cohort than the invasive melanoma cohort during the entire follow-up period (Fig 3).
DISCUSSION Our study suggests that the risk of subsequent melanoma of any stage was higher in the melanoma in situ cohort than the invasive melanoma cohort after 2 years following the first melanoma, although the risks were not different between the 2 cohorts for the first 2 years. The invasive melanoma cohort, compared with the melanoma in situ cohort, was at an elevated risk for subsequent invasive melanoma
in the first 10 years. However, the melanoma in situ cohort was more likely to develop subsequent invasive melanoma after 10 years following the first melanoma and more likely to develop subsequent melanoma in situ during the entire follow-up period than the invasive melanoma cohort. The increased risk of subsequent melanomas in patients with a previous melanoma, compared with the risk in the general population, has been documented in several countries.10,13-15,34-36 Some of these studies examined the subsequent melanoma risks separately in the melanoma in situ cohort and in the invasive melanoma cohort and concluded that both cohorts were at an elevated risk of developing subsequent melanomas.13-15,35 In the United States, the risks of subsequent invasive melanoma in the melanoma in situ cohort were increased by 8-fold among men and 12-fold among women, and the risks of subsequent invasive melanoma in the invasive melanoma cohort were increased by 13-fold among men and 16-fold among women.14 However, no information on comparing the risks of subsequent melanoma between the melanoma in situ and the invasive melanoma cohorts was available before our study. Our results showed that the melanoma in situ cohort, compared with the invasive melanoma cohort, was more likely to develop subsequent melanoma of any stage after 2 years of the first melanoma and more likely to develop subsequent invasive melanoma after 10 years of the first
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Fig 2. Cumulative risks of subsequent invasive melanoma.
Fig 3. Cumulative risks of subsequent melanoma in situ.
melanoma. The explanation for the increased long-term risk of subsequent melanoma in the melanoma in situ cohort is yet to be elucidated. One possible explanation includes that the patients in the melanoma in situ cohort may produce melanomas more frequently, albeit perhaps less aggressive and thinner melanomas, than the invasive melanoma cohort. Another possibility is that the patients in the melanoma in situ cohort may have health care (eg, access to dermatologists, personal habits), which facilitates detection of melanoma at an earlier stage and more frequent melanoma diagnoses than the invasive melanoma cohort. The 5-year and 10-year cumulative risks of subsequent invasive melanoma in the invasive melanoma cohort in our study were 1.2% (95% CI 1.1-1.3) and 2.9% (95% CI 2.8-3.1), respectively. These are slightly lower than the cumulative risks in those with initial invasive melanoma previously reported by Goggins and Tsao7 using the SEER 9 from 1973 to 1997: 2.1% at 5 years and 3.2% at 10 years. DiFronzo et al28 similarly reported the cumulative probabilities of 2.8% at 5 years and 3.6% at 10 years for the 8928 patients with melanoma treated at the John Wayne Cancer Institute at St. John’s Health Center in California from 1971 to 1998. Our study extended the study period to 2011, and
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more melanomas might have been diagnosed at the in situ stage, before becoming invasive, in the last decade probably because of more vigilant surveillance. This may have contributed to the lower cumulative risks of subsequent invasive melanoma. In fact, melanoma in situ diagnoses were increased by 2.5 times from the years of 1990 to 1999 to the years of 2000 to 2011, whereas invasive melanoma diagnoses were increased by 1.7 times for the same time period (Table I). A limitation of our study is the ascertainment of melanoma cases. Underreporting of melanoma cases to the SEER registries was previously documented and was thought to be more common for early-stage disease.37 Particularly, melanoma in situ was missed more frequently than invasive melanoma in the SEER registries.38 Missing cases as a result of patient migration in and out of SEER registries’ geographic catchment area is another limitation of the study. Current recommendations for following up patients after melanoma in situ vary from not recommending skin examination by a dermatologist to an annual follow-up. Some guidelines do not have specific recommendations for following up patients with melanoma in situ.1,2,17-21 Our study highlights potential usefulness of long-term follow-up of the patients previously given a diagnosis of melanoma in situ. Not only are these patients at an increased risk of developing melanoma in situ in the future, but they are at an increased long-term risk of developing invasive melanoma compared with those who survived invasive melanoma. REFERENCES 1. Marsden JR, Newton-Bishop JA, Burrows L, et al; British Association of Dermatologists Clinical Standards Unit. Revised U.K. guidelines for the management of cutaneous melanoma 2010. Br J Dermatol. 2010;163:238-256. 2. Pflugfelder A, Kochs C, Blum A, et al, German Society of Dermatology. S3-guideline ‘‘diagnosis, therapy and follow-up of melanoma’’ e short version. J Dtsch Dermatol Ges. 2013;1:563-602. 3. Baughan CA, Hall VL, Leppard BJ, Perkins PJ. Follow-up in stage I cutaneous malignant melanoma: an audit. Clin Oncol (R Coll Radiol). 1993;5:174-180. 4. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634. 5. Leiter U, Buettner PG, Eigentler TK, et al. Hazard rate for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German Central Malignant Melanoma Registry. J Am Acad Dermatol. 2012;66:37-45. 6. Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with localized primary cutaneous melanoma. Lancet Oncol. 2005;6:608-621. 7. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer. 2003;97:639-643.
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8. Johnson TM, Hamiliton T, Lowe L. Multiple primary melanomas. J Am Acad Dermatol. 1998;39:422-427. 9. Brobeil A, Rapaport D, Wells K, et al. Multiple primary melanomas: implications for screening and follow-up programs for melanoma. Ann Surg Oncol. 1997;4:19-23. 10. DiFronzo LA, Wanek LA, Morton DL. Earlier diagnosis of second primary melanoma confirms the benefits of patient education and routine postoperative follow-up. Cancer. 2001; 91:1520-1524. 11. Kang S, Barnhill RL, Mihm MC Jr, Sober AJ. Multiple primary cutaneous melanomas. Cancer. 1992;70:1911-1916. 12. de Giorgi V, Rossari S, Papi F, et al. Multiple primary melanoma: the impact of atypical nevi and follow up. Br J Dermatol. 2010;163:1319-1322. 13. Wassberg C, Th€ orn M, Yuen J, Hakulinen T, Ringborg U. Cancer risk in patients with earlier diagnosis of cutaneous melanoma in situ. Int J Cancer. 1999;83:314-317. 14. Balamurugan A, Rees JR, Kosary C, Rim SH, Li J, Stewart SL. Subsequent primary cancers among men and women with in situ and invasive melanoma of the skin. J Am Acad Dermatol. 2011;65(Suppl):S69-77. 15. van der Leest RJ, Liu L, Coebergh JW, et al. Risk of second primary in situ and invasive melanoma in a Dutch population-based cohort: 1989-2008. Br J Dermatol. 2012;167: 1321-1330. 16. Balch CM, Buzaid AC, Atkins MB, et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer. 2000;88(6):1484-1491. 17. Coit DG, Andtbacka R, Bichakjian CK, et al; NCCN Melanoma Panel. Melanoma. J Natl Compr Canc Netw. 2009;7:250-275. 18. Dummer R, Hauschild A, Guggenheim M, Keilholz U, Pentheroudakis G; ESMO Guidelines Working Group. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii86-91. 19. Bichakjian CK, Halpern AC, Johnson TM, et al; American Academy of Dermatology. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2011;65:1032-1047. 20. Dummer R, Guggenheim M, Arnold AW, Braun R, von Moos R; Project Group Melanoma of the Swiss Group for Clinical Cancer Research. Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma. Swiss Med Wkly. 2011; 141:w13320. 21. Australian Cancer Network and New Zealand Guidelines Group. Clinical practice guidelines for the management of melanoma in Australia and New Zealand. Monograph online. 2008. Available from: URL:http://www.nhmrc.gov.au/_files_nhmrc/publications/ attachments/cp111.pdf. Accessed August 20, 2014. 22. Toender A, Kjær SK, Jensen A. Increased incidence of melanoma in situ in Denmark from 1997 to 2011: results from a nationwide population-based study. Melanoma Res. 2014;24:488-495.
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23. Jemal A, Saraiya M, Patel P, et al. Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006. J Am Acad Dermatol. 2011;65(Suppl):S17-25. 24. Criscione VD, Weinstock MA. Melanoma thickness trends in the United States, 1988-2006. J Invest Dermatol. 2010;130: 793-797. 25. Downing A, Newton-Bishop JA, Forman D. Recent trends in cutaneous malignant melanoma in the Yorkshire region of England; incidence, mortality and survival in relation to stage of disease, 1993-2003. Br J Cancer. 2006;95:91-95. 26. Coory M, Baade P, Aitken J, Smithers M, McLeod GR, Ring I. Trends for in situ and invasive melanoma in Queensland, Australia, 1982-2002. Cancer Causes Control. 2006;17:21-27. 27. Nola I, Kruslin B, M€ uller D, Oremovic L, Belicza M. The rise in melanoma incidence in Croatia. Acta Dermatovenerol Croat. 2002;10:3-7. 28. M ansson-Brahme E, Johansson H, Larsson O, Rutqvist LE, Ringborg U. Trends in incidence of cutaneous malignant melanoma in a Swedish population 1976-1994. Acta Oncol. 2002;4:138-146. 29. DiFronzo LA, Wanek LA, Elashoff R, Morton DL. Increased incidence of second primary melanoma in patients with a previous cutaneous melanoma. Ann Surg Oncol. 1999;6(7): 705-711. 30. National Cancer Institute. Surveillance, Epidemiology, and End Results program: about the SEER program. Available from: URL:http://seer.cancer.gov/about. Accessed December 5, 2014. 31. Moseley HS, Giuliano AE, Storm FK III, Clark WH, Robinson DS, Morton DL. Multiple primary melanoma. Cancer. 1979;43(3): 939-944. 32. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66(3):438-444. 33. Young Jr JL, Roffers SD, Ries LAG, Fritz AG, Hurlbut AA, eds. SEER summary staging manual e 2000: codes and coding instructions. Bethesda (MD): National Cancer Institute; 2001. NIH publication No. 01-4969. 34. Youlden DR, Youl PH, Soyer HP, Aitken JF, Baade PD. Distribution of subsequent primary invasive melanomas following a first primary invasive or in situ melanoma in Queensland, Australia, 1982-2010. JAMA Dermatol. 2014;150:526-534. 35. Siskind V, Hughes MC, Palmer JM, et al. Nevi, family history, and fair skin increase the risk of second primary melanoma. J Invest Dermatol. 2011;131:461-467. 36. Bradford PT, Freedman DM, Goldstein AM, Tuckker MA. Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol. 2010;146(3):265-272. 37. Koh HK, Geller A, Miller DR, Clapp RW, Lew RA. Underreporting of cutaneous melanoma in cancer registries nationwide. J Am Acad Dermatol. 1992;27:1035-1036. 38. Seiffert J. Stat biteeunderreporting of melanoma. J Natl Cancer Inst. 1992;84:289.
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ollow-up visits after treatment of primary cutaneous melanoma play an important role in early detection of subsequent primary, recurrent, or metastatic melanoma.1,2 Almost all recurrent or metastatic melanomas are detected in fewer than 10 years after the initial melanoma diagnosis,3-5 whereas long-term follow-up of patients with melanoma is beneficial in early detection of subsequent melanoma.6-11 Evidence suggests that follow-up visits after a melanoma result in early
diagnosis of subsequent melanoma and may reduce morbidity and mortality associated with the subsequent melanoma.8,10,12 Patients with regular clinic
From the Center for Dermatoepidemiology, Department of Veterans Affairs Medical Centera; Departments of Dermatologyb and Epidemiology,c Brown University; and Department of Dermatology, Rhode Island Hospital.d Funding sources: None. Conflicts of interest: None declared. The abstract that included part of the results reported in the manuscript was presented at the American Academy of Dermatology summer meeting in Chicago, IL on August 7, 2014.
Accepted for publication February 1, 2015. Reprint requests: Hyemin Pomerantz, MD, Center for Dermatoepidemiology, Department of Veterans Affairs Medical Center, 830 Chalkstone Ave, Providence, RI 02908. E-mail: hyemin. [email protected]. Published online March 12, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.02.006
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Abbreviations used: CI: HR: SEER:
confidence interval hazard ratio Surveillance, Epidemiology, and End Results
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visits after the first melanoma diagnosis had a second Edition. Only the individuals with the microscopimelanoma that was thinnerehence with better progcally confirmed first melanoma diagnosis with nosisethan the patients without regular follow-up known SEER summary stage were included in the schedule.12 Studies showed that the subsequent study. Whether these individuals developed subseprimary melanoma detected at a follow-up visit quent melanoma was identified from the SEER 9 were thinner than the first melanoma.8,10 database. Subsequent melanoma diagnosed within 2 The risk of subsequent melanoma after initial months after the initial melanoma was excluded, melanoma in situ or initial because subsequent melainvasive melanoma is higher nomas diagnosed within 2 CAPSULE SUMMARY than the risk in the general months after the first melapopulation.13-15 Patients with noma were considered synMelanoma in situ increases the risk of melanoma in situ have an chronous to the first one.31,32 subsequent melanoma, compared to the overall better prognosis Our study was exempt from general population. than those with invasive melinstitutional review board After 2 years, patients with melanoma in anoma,4,16 but the former oversight, because the SEER situ were more likely to develop group’s subsequent mela9 database is accessible to the subsequent melanoma than those with noma risk compared with public and the subjects in the invasive melanoma. that of the latter group is not database are de-identified. known. Although national/ These results support long-term regional melanoma guideStudy variables surveillance for subsequent melanoma lines recommend regular Sex, race, birth year, and after melanoma in situ. follow-ups of patients with SEER registry were identified invasive melanoma for a for each individual included number of years, necessity of regular follow-ups of in the analyses. SEER summary stage (in situ, patients treated for melanoma in situ is currently localized, or regional/distant), based on a combined debatable. Some guidelines do not recommend clinical and histologic assessment, were collected for additional follow-up after surgical excision of a both first and second melanomas.33 Age at diagnosis melanoma in situ or do not address follow-up and month and year of diagnosis were collected for recommendations for patients with melanoma in both first and second melanomas, and the time situ.1,2,17-21 The incidence of cutaneous melanoma in duration from the first melanoma to the second situ is rising in various countries.22-29 Therefore, melanoma was calculated. If no subsequent melabetter characterization of subsequent melanoma noma was developed, the time to follow-up was risk in the patients with melanoma in situ would defined as the time from the first melanoma to death, provide additional evidence for developing clinical loss to follow-up, or end of study. surveillance plans that will be useful for the increasing patient population. This study compared Statistical analysis the risk of subsequent melanoma in the population The baseline characteristics (sex, birth year, age at whose first primary cancer was melanoma in situ to first melanoma diagnosis, year of first melanoma the risk in the population whose first primary cancer diagnosis, and SEER registry) were compared by was invasive melanoma. Wilcoxon rank sum tests between the melanoma in situ and the invasive localized melanoma cohorts and between the melanoma in situ and the invasive METHODS regional/distant melanoma cohorts. The incidence Data source and selection criteria rate ratios of subsequent melanoma of any type, Individuals whose first primary cancer was either subsequent invasive melanoma, and subsequent in situ or invasive melanoma of the skin were melanoma in situ were calculated, comparing the identified in the Surveillance, Epidemiology, and melanoma in situ cohort with the invasive localized End Results (SEER) 9 program from 1973 to 2011. melanoma cohort or with the invasive regional/ SEER collects data on cancers, including melanoma, distant melanoma, separately. The risks of subseand SEER 9 started the data collection from 1973 quent melanoma were compared between the melto 1975 in 9 regions, which represents approximately anoma in situ cohort (whose first primary cancer was 10% of the US population.30 Melanoma of the melanoma in situ) and the invasive melanoma cohort skin was defined as cases that had the primary site (whose first primary cancer was invasive melanoma) coded as skin (C44.0-C49.0) and histology as melawith Cox proportional hazards regression models. noma (8720-8790) according to the International The hazard ratios (HR) of the invasive melanoma Classification of Diseases for Oncology, Third d
d
d
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cohort with reference to the melanoma in situ cohort were adjusted for sex, race, birth year, age at first melanoma diagnosis, and SEER registry, because these characteristics were found to be significantly different between the cohorts. The proportionality assumption in the Cox proportional hazard model was tested in a generalized linear regression of the scaled Schoenfeld residuals on functions of time. The proportionality assumption was not violated, when the model was stratified by the levels of each adjusted variable and separate models were fit to different time intervals (2 months-2 years, 2-10 years, $10 years). The risks of subsequent invasive melanoma and subsequent melanoma in situ were compared between the 2 cohorts using the same models. Cumulative probabilities of subsequent invasive melanoma were calculated using the Kaplan-Meier method. Data were analyzed using STATA SE Version 8 (StataCorp, College Station, TX).
RESULTS Identification of individuals with melanoma as their first primary cancer In the SEER 9 from 1973 to 2011, 55,661 individuals had melanoma in situ as their first primary cancer of any type and 112,613 individuals had invasive melanoma as their first primary cancer. Of these individuals with invasive melanoma as their first primary cancer, 97,614 (87%) were given a diagnosis of localized melanoma and 14,999 (13%) were given a diagnosis of regional/distant melanoma (Table I). The baseline characteristics between the melanoma in situ and invasive melanoma cohorts were significantly different (Table I). The median follow-up duration after the first melanoma diagnosis was 7 years (range 0.17-39 years) in the melanoma in situ cohort, 8.7 years (range 0.17-39 years) in the invasive localized melanoma cohort, and 2.8 years (range 0.17-39 years) in the invasive regional/distant melanoma cohort (Table II). The median follow-up duration of the invasive melanoma cohort (localized and regional/distant combined) was 7.8 years. Incidences of subsequent melanoma Of the total cohort of 168,274 individuals with the diagnosis of either in situ or invasive melanoma as their first primary cancer, 10,876 individuals (6.5%) developed at least 1 subsequent melanoma of any stage (either in situ or invasive). Nine individuals per 1000 person-years in the melanoma in situ cohort were given a diagnosis of a subsequent melanoma, whereas 6.4 individuals per 1000 person-years in the invasive melanoma cohort were given a diagnosis of a subsequent melanoma (incidence rate ratio 1.5, 95% confidence interval [CI] 1.4-1.5). The melanoma
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Table I. Baseline characteristics in Surveillance, Epidemiology, and End Results 9 from 1973 to 2011 Stage of first melanoma
Characteristics
In situ melanoma (N = 55,661) n (%)
Localized Regional/distant melanoma melanoma (N = 97,614) (N = 14,999) n (%) n (%)
Sex Male 30,097 (54) 51,108 Female 25,564 (46) 46,506 Birth year #1930 14,800 (27) 24,495 1931-1940 10,089 (18) 15,533 1941-1950 12,019 (22) 20,137 1951-1960 10,026 (18) 19,015 $1961 8727 (16) 18,434 Age at first melanoma diagnosis, y 0-19 270 (0.5) 992 20-34 3816 (7) 13,000 35-49 11,247 (20) 26,556 50-64 18,026 (32) 29,402 65-79 16,659 (30) 20,861 $80 5643 (10) 6803 Year of first melanoma diagnosis 1973-1979 666 (1) 6659 1980-1989 4791 (9) 18,014 1990-1999 14,361 (26) 26,631 2000-2011 35,843 (64) 46,310 SEER registry Atlanta, GA 5177 (9) 9933 Connecticut 8419 (15) 14,860 Detroit, MI 6584 (12) 11,814 Hawaii 2193 (4) 3856 Iowa 4852 (9) 10,712 New Mexico 3268 (6) 5626 San Francisco/ 8789 (16) 15,004 Oakland, CA Seattle, WA 11,201 (20) 17,628 Utah 5178 (9) 8181
(52) (48)
9329 (62) 5670 (38)
(25) (16) (21) (19) (19)
5370 2508 2637 2387 2097
(36) (17) (18) (16) (14)
(1) (13) (27) (30) (21) (7)
197 1404 3236 4364 3919 1879
(1) (9) (22) (29) (26) (13)
(7) (18) (27) (47)
1173 2675 4059 6922
(8) (18) (27) (46)
(10) (15) (12) (4) (11) (6) (15)
1173 2447 1934 557 1958 904 2275
(8) (16) (13) (4) (13) (6) (15)
(18) (8)
2476 (17) 1275 (9)
P \ .001 for all characteristics in comparisons between melanoma in situ and each of invasive melanoma cohorts. SEER, Surveillance, Epidemiology, and End Results.
in situ cohort had a higher incidence of subsequent melanoma than the invasive localized melanoma cohort or the invasive regional/distant melanoma cohort (incidence rate ratio 1.5, 95% CI 1.4-1.5; incidence rate ratio 1.4, 95% CI 1.3-1.5, respectively) (Table II). In the total cohort, 6067 individuals (3.6%) developed at least 1 subsequent invasive melanoma. Incidence rate of subsequent invasive melanoma was 3.7 per 1000 person-years. The incidence rates of subsequent invasive melanoma after initial melanoma in situ, initial localized, and initial regional/ distant melanoma were 4.1, 3.6, and 4.6 per 1000 person-years, respectively (Table II). The melanoma
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Table II. The number of indviduals and the incidence rates of subsequent melanoma in Surveillance, Epidemiology, and End Results 9 Stage of first melanoma
Follow-up duration, y, mean 6 SD Follow-up duration, y, median (range) Subsequent melanoma N Time at risk, y Incidence rate per 1000 person-y (95% CI) Subsequent invasive melanoma N Time at risk, y Incidence rate per 1000 person-y (95% CI) Subsequent melanoma in situ N Time at risk, y Incidence rate per 1000 person-y (95% CI)
Melanoma in situ (N = 55,661)
Localized melanoma (N = 97,614)
Regional/distant melanoma (N = 14,999)
8.5 6 6.6 7 (0.2-39)
10.9 6 8.7 8.7 (0.2-39)
5.8 6 7.1 2.8 (0.2-39)
4024 448,815 9.0 (8.7-9.2)
6300 1,024,702 6.1 (6.0-6.3)
552 84,697 6.5 (6.0-7.1)
1913 461,165 4.1 (4.0-4.3)
3764 1,041,402 3.6 (3.5-3.7)
390 85,501 4.6 (4.1-5.0)
2504 454,409 5.5 (5.3-5.7)
3104 1,042,342 3.0 (2.9-3.1)
209 85,879 2.4 (2.1-2.8)
CI, Confidence interval; N, number of individuals.
in situ cohort had a higher incidence of subsequent invasive melanoma than the invasive localized cohort (incidence rate ratio 1.2, 95% CI 1.1-1.2). The subsequent invasive melanoma incidence rate was not different between the melanoma in situ cohort and the invasive regional/distant melanoma cohort (incidence rate ratio 0.9, 95% CI 0.8-1.0). In all, 5817 individuals (3.5%) developed at least 1 subsequent melanoma in situ. Incidence rate of subsequent melanoma in situ was 3.8 per 1000 person-years, and the incidence rates of subsequent melanoma in situ after initial melanoma in situ, initial localized, and initial regional/distant melanoma were 5.5, 3.0 and 2.4 per 1000 person-years, respectively (Table II). Incidence rate of subsequent melanoma in situ was higher in the melanoma in situ cohort than the invasive localized melanoma cohort or the invasive regional/distant melanoma cohort (incidence rate ratio 1.9, 95% CI 1.8-2.0; incidence rate ratio 2.3, 95% CI 2.0-2.6, respectively). Risks of subsequent melanoma The risks of subsequent melanoma of any stage (either in situ or invasive) within 2 years after the first melanoma diagnosis were not different between the melanoma in situ cohort and the invasive melanoma cohort (HR 1.02, 95% CI 0.95-1.10) (Table III). However, after 2 years, the invasive melanoma cohort was less likely to develop subsequent melanoma than the melanoma in situ cohort (2-10 years: HR 0.84, 95% CI 0.79-0.88; [10 years: HR 0.78, 95% CI 0.71-0.85) (Table III). During the first 2 years after the first melanoma, the risk of subsequent invasive melanoma in the
invasive melanoma cohort was higher than the melanoma in situ cohort (HR 1.36, 95% CI 1.211.51) (Table III). Between 2 and 10 years, the risk of subsequent invasive melanoma in the invasive melanoma cohort remained higher than the melanoma in situ cohort (HR 1.09, 95% CI 1.01-1.18) (Table III). After 10 years, however, the risk of subsequent invasive melanoma in the invasive melanoma cohort was lower than that in the melanoma in situ cohort (HR 0.84, 95% CI 0.75-0.94) (Table III). The invasive melanoma cohort was at a lower risk of subsequent melanoma in situ than the melanoma in situ cohort, and the decreased risk remained persistent throughout the entire follow-up period after the first melanoma diagnosis (HR 0.69, 95% CI 0.66-0.73) (Table III).
Cumulative probabilities of subsequent melanoma The cumulative risk of subsequent melanoma of any stage (either in situ or invasive melanoma) at 5 years was higher in the melanoma in situ cohort than the invasive melanoma cohort (in situ 2.8% [95% CI 2.7%-3.0%], invasive 2.0% [95% CI 1.9%-2.1%]), and the cumulative risk in the melanoma in situ cohort was consistently higher than the risk in the invasive melanoma cohort during the further follow-up period (Fig 1). The cumulative risk of subsequent invasive melanoma did not differ between the in situ and invasive cohorts at 5 and 10 years after the first melanoma diagnosis (at 5 years: in situ 1.3% [95% CI 1.2%-1.4%], invasive 1.2% [95% CI 1.1%-1.3%]; at 10 years: in situ
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Table III. Risks of subsequent melanoma in the melanoma in situ cohort versus the invasive melanoma cohort 2 mo-2 y Stage of first melanoma
Adjusted HR* (95% CI)
Risks of subsequent melanoma of any stage In situ melanoma 1 (ref) All invasive melanoma 1.02 (0.95-1.10) Localized melanoma 1.02 (0.95-1.10) Regional or distant 1.01 (0.88-1.18) melanoma Risks of subsequent invasive melanoma In situ melanoma 1 (ref) All invasive melanoma 1.36 (1.21-1.51) Localized melanoma 1.30 (1.16-1.46) Regional or distant 1.76 (1.47-2.11) melanoma Risks of subsequent melanoma in situ In situ melanoma 1 (ref) All invasive melanoma 0.80 (0.73-0.89) Localized melanoma 0.83 (0.75-0.92) Regional or distant 0.59 (0.46-0.74) melanoma
[10 y
2-10 y P value
Adjusted HR* (95% CI)
P value
Adjusted HR* (95% CI)
P value
.56 .59 .79
1 0.84 0.84 0.78
(ref) (0.79-0.88) (0.80-0.89) (0.68-0.89)
\.001 \.001 \.001
1 0.78 0.79 0.64
(ref) (0.71-0.85) (0.72-0.86) (0.51-0.80)
\.001 \.001 \.001
\.001 \.001 \.001
1 1.09 1.09 1.17
(ref) (1.01-1.18) (1.01-1.18) (0.99-1.38)
.02 .04 .06
1 0.84 0.85 0.70
(ref) (0.75-0.94) (0.75-0.95) (0.53-0.93)
.003 .005 .013
\.001 \.001 \.001
1 0.64 0.66 0.48
(ref) (0.60-0.69) (0.61-0.71) (0.39-0.60)
\.001 \.001 \.001
1 0.68 0.69 0.53
(ref) (0.60-0.77) (0.61-0.78) (0.38-0.73)
\.001 \.001 \.001
CI, Confidence interval; HR, hazard ratios; ref, reference. *Adjusted by age at the first primary cancer diagnosis, sex, race, birth year, and Surveillance, Epidemiology, and End Results registry.
Fig 1. Cumulative risks of subsequent melanoma of any stage.
3.2% [95% CI 3.0%-3.4%], invasive 2.9% [95% CI 2.8%-3.1%]) (Fig 2). The cumulative risks of subsequent melanoma in situ remained higher in the melanoma in situ cohort than the invasive melanoma cohort during the entire follow-up period (Fig 3).
DISCUSSION Our study suggests that the risk of subsequent melanoma of any stage was higher in the melanoma in situ cohort than the invasive melanoma cohort after 2 years following the first melanoma, although the risks were not different between the 2 cohorts for the first 2 years. The invasive melanoma cohort, compared with the melanoma in situ cohort, was at an elevated risk for subsequent invasive melanoma
in the first 10 years. However, the melanoma in situ cohort was more likely to develop subsequent invasive melanoma after 10 years following the first melanoma and more likely to develop subsequent melanoma in situ during the entire follow-up period than the invasive melanoma cohort. The increased risk of subsequent melanomas in patients with a previous melanoma, compared with the risk in the general population, has been documented in several countries.10,13-15,34-36 Some of these studies examined the subsequent melanoma risks separately in the melanoma in situ cohort and in the invasive melanoma cohort and concluded that both cohorts were at an elevated risk of developing subsequent melanomas.13-15,35 In the United States, the risks of subsequent invasive melanoma in the melanoma in situ cohort were increased by 8-fold among men and 12-fold among women, and the risks of subsequent invasive melanoma in the invasive melanoma cohort were increased by 13-fold among men and 16-fold among women.14 However, no information on comparing the risks of subsequent melanoma between the melanoma in situ and the invasive melanoma cohorts was available before our study. Our results showed that the melanoma in situ cohort, compared with the invasive melanoma cohort, was more likely to develop subsequent melanoma of any stage after 2 years of the first melanoma and more likely to develop subsequent invasive melanoma after 10 years of the first
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Fig 2. Cumulative risks of subsequent invasive melanoma.
Fig 3. Cumulative risks of subsequent melanoma in situ.
melanoma. The explanation for the increased long-term risk of subsequent melanoma in the melanoma in situ cohort is yet to be elucidated. One possible explanation includes that the patients in the melanoma in situ cohort may produce melanomas more frequently, albeit perhaps less aggressive and thinner melanomas, than the invasive melanoma cohort. Another possibility is that the patients in the melanoma in situ cohort may have health care (eg, access to dermatologists, personal habits), which facilitates detection of melanoma at an earlier stage and more frequent melanoma diagnoses than the invasive melanoma cohort. The 5-year and 10-year cumulative risks of subsequent invasive melanoma in the invasive melanoma cohort in our study were 1.2% (95% CI 1.1-1.3) and 2.9% (95% CI 2.8-3.1), respectively. These are slightly lower than the cumulative risks in those with initial invasive melanoma previously reported by Goggins and Tsao7 using the SEER 9 from 1973 to 1997: 2.1% at 5 years and 3.2% at 10 years. DiFronzo et al28 similarly reported the cumulative probabilities of 2.8% at 5 years and 3.6% at 10 years for the 8928 patients with melanoma treated at the John Wayne Cancer Institute at St. John’s Health Center in California from 1971 to 1998. Our study extended the study period to 2011, and
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more melanomas might have been diagnosed at the in situ stage, before becoming invasive, in the last decade probably because of more vigilant surveillance. This may have contributed to the lower cumulative risks of subsequent invasive melanoma. In fact, melanoma in situ diagnoses were increased by 2.5 times from the years of 1990 to 1999 to the years of 2000 to 2011, whereas invasive melanoma diagnoses were increased by 1.7 times for the same time period (Table I). A limitation of our study is the ascertainment of melanoma cases. Underreporting of melanoma cases to the SEER registries was previously documented and was thought to be more common for early-stage disease.37 Particularly, melanoma in situ was missed more frequently than invasive melanoma in the SEER registries.38 Missing cases as a result of patient migration in and out of SEER registries’ geographic catchment area is another limitation of the study. Current recommendations for following up patients after melanoma in situ vary from not recommending skin examination by a dermatologist to an annual follow-up. Some guidelines do not have specific recommendations for following up patients with melanoma in situ.1,2,17-21 Our study highlights potential usefulness of long-term follow-up of the patients previously given a diagnosis of melanoma in situ. Not only are these patients at an increased risk of developing melanoma in situ in the future, but they are at an increased long-term risk of developing invasive melanoma compared with those who survived invasive melanoma. REFERENCES 1. Marsden JR, Newton-Bishop JA, Burrows L, et al; British Association of Dermatologists Clinical Standards Unit. Revised U.K. guidelines for the management of cutaneous melanoma 2010. Br J Dermatol. 2010;163:238-256. 2. Pflugfelder A, Kochs C, Blum A, et al, German Society of Dermatology. S3-guideline ‘‘diagnosis, therapy and follow-up of melanoma’’ e short version. J Dtsch Dermatol Ges. 2013;1:563-602. 3. Baughan CA, Hall VL, Leppard BJ, Perkins PJ. Follow-up in stage I cutaneous malignant melanoma: an audit. Clin Oncol (R Coll Radiol). 1993;5:174-180. 4. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634. 5. Leiter U, Buettner PG, Eigentler TK, et al. Hazard rate for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German Central Malignant Melanoma Registry. J Am Acad Dermatol. 2012;66:37-45. 6. Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with localized primary cutaneous melanoma. Lancet Oncol. 2005;6:608-621. 7. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer. 2003;97:639-643.
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