doi: 10.1111/j.1346-8138.2011.01495.

Journal of Dermatology 2012; 39: 541544

ORIGINAL ARTICLE

Risk of second cancers after the diagnosis of non-melanoma skin cancer in Korean patients
Mi Ryung ROH,1 Hyun Joon SHIN,2 Soo Hyun LEE,1 Kee Yang CHUNG1
1 2

Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

ABSTRACT
Individuals with a personal history of non-melanoma skin cancer (NMSC) are known to have an increased risk of subsequent cancers. However, most of the studies regarding this fact were done on Caucasian populations. We investigated whether Korean patients with NMSC have an increased risk of developing second cancers compared to the general Korean population. Five hundred and thirty-two patients diagnosed with NMSC at the Department of Dermatology of Yonsei University Health System from 1999 to 2008 were assessed for development of second cancers. The overall second cancer incidence was increased among patients diagnosed with NMSC compared with the general population in Korea: 37 second cancer total (standardized incidence ratio [SIR] 1.38, 95% condence interval [CI] 1.101.90); 23 second cancers in males (SIR 4.24, 95% CI 2.696.36); and 14 second cancers in females (SIR 2.28, 95% CI 1.253.83). There were signicantly increased incidence ratios for NMSC (eight second cancers [SIR 9.52, 95% CI 4.1118.77]), bladder cancer (four second cancers [SIR 4.21, 95% CI 1.1510.78]) and nasopharyngeal cancer (one second cancer [SIR 20.00, 95% CI: 1.5125.33]). Korean patients diagnosed with NMSC had more second cancers, particularly other skin cancers. This study provides additional evidence that NMSC may be a clinically signicant and substantial risk factor for second cancers even in a Korean population, in which the incidence of NMSC is much lower than Caucasians.

Key words:

cancer risk, epidemiology, Korean, non-melanoma skin cancer, second primary cancer.

INTRODUCTION
Non-melanoma skin cancer (NMSC), which refers to basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), are by far the most common form of malignancy in Caucasians and Asians. Skin cancer represents approximately 2030% of all neoplasms in Caucasians, but only 24% of all neoplasms in Asians.1 Since the 1960s, incidences of NMSC among Caucasians have increased at a rate of 58% annually.2 In Asians, although the overall incidence of NMSC is much lower, the incidence of NMSC has increased between the 1970s and 1990s and is steadily increasing.3,4 The major predisposing factor for the development of NMSC is ultraviolet (UV) light exposure.5 Individual risk factors for NMSC are known to be determined by the combination of sun exposure and individual susceptibility such as skin types with a propensity for sunburn. A personal history of NMSC is known to be a predictive factor of subsequent new primary NMSC or recurrent NMSC. A history of NMSC is also known as a risk factor for malignant melanoma,69 probably due to the shared risk of exposure to UV radiation. In addition, individuals with a personal history of NMSC are known to have an increased risk of subsequent non-cutaneous malignancies.6 Also, a personal history of NMSC was associated with increased overall

cancer mortality and poorer prognosis in surviving other cancer diagnoses.10 Therefore, such relationships should inuence the routines of follow up, promote early detection of second cancers and possibly reveal unknown risk factors. However, most of the previous reports showing increased second cancers were from cancer registries mainly composed of Caucasians. In the present study, we investigated whether a previous NMSC diagnosis was associated with an increased risk of second cancers in Korean patients in the period 19992008.

METHODS
Study population and data collection
Patients with a rst primary cutaneous NMSC were identied from the computerized database from the Yonsei Cancer Registry of Yonsei University Health System in Seoul, Korea. The study includes all persons diagnosed with a primary BCC or SCC over the calendar period of 19992008. The follow up started on the date of diagnosis of NMSC and ended on the date of death, emigration or the closing date of the study (31 December 2008), whichever occurred rst. Cancers occurring within 6 months of NMSC diagnosis were excluded from the analysis. Also, patients were excluded if they had

Correspondence: Kee Y. Chung, M.D., Ph.D., Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, 120-752, Seoul, Korea. Email: kychung@yuhs.ac Conict of interest: none. Received 5 October 2011; accepted 14 December 2011.

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a genetic disease that predisposed them to accelerated development of BCC or SCC (i.e. basal cell nevus syndrome or xeroderma pigmentosum), congenital lesions such as nevus sebaceous that predisposed them to development of BCC, previous arsenical exposure history that predisposed them to development of various cutaneous malignancies or treatment with radiation at the site of tumor occurrence. These cases were excluded from the study because the conditions are characterized by inherent etiologic factors that place these patients at high risk for the development of NMSC at an early age by mechanisms different from those of the general population. The medical records of these patients were reviewed and the data such as age and sex of the subject, body mass index (BMI), history of cigarette smoking, skin type, diagnosis and date of the rst NMSC, diagnosis and date of second cancers and prognosis of the patient were acquired.

Table 1. Baseline characteristics of study participants. NMSC with second cancer (n = 34) Age (years), mean (SD) Sex (%) Male Female Mean BMI, kg m2 (SD) Cigarette smoking (%) Never Former Current Unknown Skin type (%) Blistering sunburn Sunburn without blisters Mild sunburn turns tan Tan without sunburn No change in skin color 64.1 (10.29) NMSC without second cancer (n = 498) 65.29 (13.54)

P-value* >0.05

22 (64.7) 12 (35.3) 22.1 (2.77)

236 (47.4) 262 (52.6) 22.65 (2.67)

>0.05

Statistical analysis
The observed subsequent primary cancers, occurring at least 6 months after NMSC diagnosis, were compared with those expected by incidence rates among the national Korean populations. To estimate the expected number of cancers, the age-, sex-, period- and site-specic incidence rates (extracted from Korea Central Cancer Registry [KCCR])11 were multiplied by the respective numbers of accumulated person-years at risk. The ratios of the observed-to-expected number of cases were expressed as the standardized incidence ratio (SIR). Risks were also estimated stratied by sex. Ninety-ve percent condence intervals (CI) of the SIR were computed assuming a Poisson distribution for observed cases. The baseline characteristics of participants according to second cancer status (conrmed second cancer vs no second cancer) were compared by use of Students t-test for continuous variables and Fishers exact test for categorical variables. Findings were considered signicant for a two-tailed test with signicance level P < 0.05.

17 9 6 2 0 1 21 10 2

278 107 78 35 0 27 389 74 8

>0.05

>0.05

*P-value compared with NMSC patients without second cancer using Students t-test for continuous variables and v2-test for categorical variables. All statistical tests were two-sided. Age in both groups is age at diagnosis of NMSC. BMI, body mass index; NMSC, non-melanoma skin cancer; SD, standard deviation.

Table 2. Number of patients diagnosed with NMSC and the personyears at risk for a second cancer stratied by age and sex Age at diagnosis (years) <30 3044 4559 6074 >75 Total No. of subjects diagnosed with NMSC Males 2 13 71 137 35 258 Females 6 17 53 103 95 274 Total 8 30 124 240 130 532 Person-years at risk following NMSC diagnosis 16.8 95.1 530.7 1269.5 862.6 2774.7

RESULTS
A total of 547 individuals were diagnosed with NMSC, of which 532 had NMSC as a rst cancer (Table 1). Six subjects had NMSC detected simultaneously with another cancer and four subjects had NMSC after another cancer. Five subjects had a genetic disease that predisposed them to accelerated development of BCC or SCC (one patient with basal cell nevus syndrome, one patient with xeroderma pigmentosum, two patients with BCC arising in nevus sebaceous and one patient with previous arsenical exposure). All NMSC diagnoses were based on histological examination. Baseline characteristics of the study participants according to second cancer status are shown in Table 1. The patient group with second cancer showed no statistical difference in age, BMI, history of cigarette smoking and skin type compared to patients without second cancer. Thirty-eight patients were younger than 45 years at the time of the diagnosis, whereas 130 patients were 75 years of age or older. There were 274 females and 258 males, resulting in a female to male ratio of 1.1:1. The mean follow-up time after the diagnosis of NMSC was 4.4 years. The cumulative post-diagnosis follow-up time yielded 2774.7 person-years at risk (Table 2).

NMSC, non-melanoma skin cancer.

Following a diagnosis of NMSC, 34 patients developed second cancer. In these patients, a total of 37 second primary cancers were diagnosed. The mean age of the patients was 64.1 years (range 3178). The mean age did not differ signicantly between the BCC and SCC groups. Male patients were signicantly predominant in both groups numbering 22 in a total of 34 patients. The head and neck (79.4%) were the most common sites where NMSC occurred.

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NMSC and risk of second primary cancers

Table 3. Specic characteristics of NMSC patients diagnosed with second cancer Total No. of patients Age (years), mean (range) Sex (%) Male Female Involved anatomic sites (%) Head and neck Trunk Upper extremity Lower extremity Genitalia No. of BCC SCC No. of second cancer Time until diagnosis of 0.51 >1 BCC SCC

34 27 7 64.1 (3178) 63.3 (4776) 65.6 (3178)

22 (64.7) 12 (25.3)

18 (66.7) 9 (33.3)

4 (57.1) 3 (42.9)

27 (79.4) 18 (90) 4 (57.1) 1 (2.9) 1 (5) 0 3 (8.9) 0 1 (14.3) 1 (2.9) 0 1 (14.3) 2 (5.9) 1 (5) 1 (14.3) 34 20 7 37 28 9 second primary malignancies (years) 22 17 5 15 11 4

The duration until the diagnosis of second cancer varied among patients. In 22 cases, second cancer was diagnosed within 6 months to 1 year of skin cancer diagnosis and after 1 year in 15 cases (Table 3). The most frequent second cancer was NMSC followed by colorectal cancer, hepatocellular carcinoma, bladder cancer and lung cancer. Patients diagnosed with NMSC had a greater risk for a second primary cancer than expected in a sex- and age-matched general population. The overall SIR for any subsequent cancer at any site was 1.38 (95% CI 1.101.90). Female NMSC patients were diagnosed with 14 subsequent cancers (SIR 2.28, 95% CI 1.253.83) and male patients with 23 cancers (SIR 4.24, 95% CI 2.696.36) (Table 4). The most frequent second primary cancer was NMSC (n = 8; SIR 9.52, 95% CI 4.1118.77). The risks of bladder cancer (n = 4; SIR 4.21, 95% CI 1.1510.78) and nasopharyngeal cancers (n = 1; SIR 20.00, 95% CI 1.5191.43) were also signicantly increased (Table 5).

DISCUSSION
We found that Korean patients diagnosed with NMSC were at increased risk of second primary cancers, in particular for NMSC, bladder cancer and nasopharyngeal cancers. Previously, in several epidemiological studies, a history of conrmed NMSC was associated with statistically signicant increase in the risk of developing a subsequent cancer.6,1216 However, because the incidence of skin cancer is much lower in persons of Asian origin, the data on regarding the occurrence of second cancer in this population is rare. In Korea, BCC and SCC are the two most common forms of skin malignancy.3 However, the incidence is much lower consisting of approximately 24% of all malignancies,1 but their incidence steadily is rising.17 Therefore, in our retrospective study, we investigated whether this pattern of association could be applied to Korean patients and investigated whether these patients have other risktaking behaviors of malignancies. Among the 532 NMSC patients, we identied 34 patients with 37 second primary cancers. In the present study, we discovered a 1.38-fold risk of second primary cancer in Korean NMSC patients. The group diagnosed with second cancer showed no statistical difference in age, BMI, history of cigarette smoking and skin type compared to the group without second cancer which suggests that these patients did not have any other risk-taking behaviors related to their risk of a second primary cancer. In previous studies on second occurrences of cancers after NMSC, the increase has been explained by common risk factors such as UV exposure and a coexistent intrinsic susceptibility among NMSC patients to develop cancer.6,12 Two potential pathways that may relate NMSC risk to overall cancer risks are UV-induced immune response and DNA repair pathways. In human studies, both BCC and SCC patients have been shown to be more prone to UV-induced immune suppression than healthy controls.18 Because UV-induced immune suppression is systemic in nature,19,20 it may be plausible to speculate that a person with susceptibility to UVinduced immune suppression may end up with an increased risk for multiple malignancies, including NMSC. UV radiation can cause skin cancer by inducing mutations in the cellular DNA of skin cells.21

BCC, basal cell carcinoma; NMSC, non-melanoma skin cancer; SCC, squamous cell carcinoma.

Table 4. Overall second cancers stratied by sex Sex Male Female Observed 23 14 Expected 5.43 6.14 SIR 4.24 2.28 95% CI 2.696.36 1.253.83

CI, condence interval; SIR, standardized incidence ratio.

Table 5. Second cancers occurring at least 6 months after NMSC diagnosis Cancer site All types NMSC Colorectal Hepatocellular carcinoma Bladder Gastric Lung Female breast Thyroid Esophageal Nasopharyngeal Renal cell carcinoma Retroperitoneal schwannoma Cervix cancer Ovarian cancer Observed 37 8 5 4 4 3 3 2 2 1 1 1 1 1 1 Expected 26.81 0.84 5.27 3.25 0.95 6.31 5.56 0.89 1.61 0.61 0.05 0.58 0.22 0.45 0.22 SIR 1.38 9.52 0.95 1.23 4.21 0.48 0.54 2.25 1.24 1.64 20.00 1.72 4.55 2.22 4.55 95% CI 1.11.9 4.1118.77 0.312.21 0.343.15 1.1510.78 0.11.39 0.111.58 0.278.12 0.154.49 0.049.13 1.5191.43 0.049.61 0.1225.33 0.0612.38 0.1225.33

CI, condence interval; NMSC, non-melanoma skin cancer; SIR, standardized incidence ratio.

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Defective nucleotide excision repair has been strongly linked to NMSC risk and an intrinsic deciency in the nucleotide excision repair capability may also put cells in all tissues at risk for various environmental carcinogens.6 Also, individuals with a personal history of NMSC may be more likely than those without such history to get far more medical attention including whole skin examination that enhanced the likelihood of cancer detection which could explain increased second cancer detection in NMSC patients. This study has limitations in that the study population is limited to a single institution which is a referral hospital and, thus, it may not be the best source to reect the general Korean population. Also, the number of patients is limited due to the fact that the incidence of NMSC is low compared to Caucasians. Further investigation by multicenter prospective cohort studies are needed to validate the relationship between increased risk of subsequent cancer and NMSC diagnosis in the Korean population. We conclude that this study may provide additional evidence that occurrence of NMSC may be a clinically signicant and substantial risk factor for second cancer even in Korean patients where skin cancer is much less common than Caucasians.

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