RADIATION RESEARCH 181, 531–539 (2014)0033-7587/14 $15.00
Ó2014 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR13494.1

Skin Cancer Incidence among Atomic Bomb Survivors from 1958 to 1996
Hiromi Sugiyama,a,1 Munechika Misumi,b Masao Kishikawa,c Masachika Iseki,d Shuji Yonehara,e Tomayoshi
Hayashi,f Midori Soda,a Shoji Tokuoka,a,2 Yukiko Shimizu,a Ritsu Sakata,a Eric J. Grant,a Fumiyoshi Kasagi,gKiyohiko Mabuchi,h Akihiko Suyamai and Kotaro OzasaaaDepartment of Epidemiology, Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan; b Department of Statistics, Radiation Effects
Research Foundation, Hiroshima, Japan; c Nagasaki Diagnostic Pathology Clinic, Nagasaki, Japan; d Department of Pathology and Laboratory
Medicine, Sasebo Kyosai Hospital, Nagasaki, Japan; e Department of Pathology and Research Laboratory, Welfare Association Onomichi General
Hospital, Hiroshima, Japan; f Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan; g Institute of Radiation Epidemiology,
Radiation Effects Association, Tokyo, Japan; h Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, Maryland; and i Department of General Internal Medicine, Prefecture Osaka Saiseikai Izuo Hospital, Osaka, JapanINTRODUCTION
Sugiyama, H., Misumi, M., Kishikawa, M., Iseki, M.,
Yonehara, S., Hayashi, T., Soda, M., Tokuoka, S., Shimizu,
Y., Sakata, R., Grant, E. J., Kasagi, F., Mabuchi, J., Suyama,
A. and Ozasa, K. Skin Cancer Incidence among Atomic Bomb
Survivors from 1958 to 1996. Radiat. Res. 181, 531–539 (2014).

An increased risk of skin cancer associated with exposure
to ionizing radiation has been reported in various exposed
populations, including the atomic bomb (A-bomb) survivors(1–3), uranium miners (4), radiologists and individuals
treated with radiation in childhood for tinea capitis (5, 6)
and malignant tumors (7, 8). The first report among the Abomb survivors in Hiroshima and Nagasaki by the Atomic
Bomb Casualty Committee (ABCC) was 26 years after the
A-bombs were dropped. Johnson et al. (9) reported thatmalignancy of the skin was observed in only one of the
10,650 subjects of the Adult Health Study (AHS), a subcohort of the Life Span Study (LSS) that were clinicallyfollowed since 1958. An increased risk of skin cancer
associated with A-bomb radiation exposure was firstreported by Sadamori et al. who found a significant linear
dose-response relationship among the LSS cohort members
who resided in Nagasaki using the Nagasaki Tumor
Registry for the period 1958–1985 (10). Subsequently,
Ron et al. reported a significant radiation-related excess riskof incident basal cell carcinoma (BCC), but not squamouscell carcinoma (SCC), in both Hiroshima and Nagasaki
subjects of the LSS cohort for the period 1958–1987 with asuggestion of a nonlinear dose response (1). Analyzing thesame data, Kishikawa et al. reported that the excess absoluterisk of BCC attributable to radiation exposure, expressed
per unit skin surface area, did not significantly differ
between ultraviolet (UV) radiation exposed and shieldedparts of the body (2). This finding was consistent with theuniform distribution of the radiation-related excess risk overthe body, implying an additive nature of the radiationrelated risk above the background BCC rate. However therisk estimates had wide statistical confidence intervals dueto the small number of BCC cases. These findings
motivated us to update the skin cancer incidence data.
The current analysis was based on pathologicallyreviewed skin cancer incidence data through 1996, adding
10 years of follow up. Age at exposure is one of the mostThe radiation risk of skin cancer by histological types has
been evaluated in the atomic bomb survivors. We examined
80,158 of the 120,321 cohort members who had theirradiation dose estimated by the latest dosimetry system(DS02). Potential skin tumors diagnosed from 1958 to 1996
were reviewed by a panel of pathologists, and radiation riskof the first primary skin cancer was analyzed by histologicaltypes using a Poisson regression model. A significant excess
relative risk (ERR) of basal cell carcinoma (BCC) (n ¼ 123)
was estimated at 1 Gy (0.74, 95% confidence interval (CI):0.26, 1.6) for those age 30 at exposure and age 70 at
observation based on a linear-threshold model with athreshold dose of 0.63 Gy (95% CI: 0.32, 0.89) and a slopeof 2.0 (95% CI: 0.69, 4.3). The estimated risks were 15, 5.7,
1.3 and 0.9 for age at exposure of 0–9, 10–19, 20–39, over 40
years, respectively, and the risk increased 11% with each oneyear decrease in age at exposure. The ERR for squamous cell
carcinoma (SCC) in situ (n ¼ 64) using a linear model was
estimated as 0.71 (95% CI: 0.063, 1.9). However, there wereno significant dose responses for malignant melanoma (n ¼10), SCC (n ¼ 114), Paget disease (n ¼ 10) or other skincancers (n ¼ 15). The significant linear radiation risk for BCC
with a threshold at 0.63 Gy suggested that the basal cells of
the epidermis had a threshold sensitivity to ionizing
radiation, especially for young persons at the time of
exposure. Ó 2014 by Radiation Research Society

1 Address for correspondence: Department of Epidemiology,
Radiation Effects Research Foundation, 5-2, Hijiyama park, Minami-ku, Hiroshima City, Hiroshima Prefecture, Japan; e-mail: sugi@
rerf.or.jp.
2 Deceased.

531

532

SUGIYAMA ET AL.

significant modifiers of dose response for skin and manyother cancers (1, 5, 7). The LSS subjects who were exposedin childhood have now reached cancer-prone ages. The
updated data allow us to examine the effects of age at
exposure and temporal patterns of the radiation-related risk
for skin cancer up to 50 years after exposure to A-bombradiation.

persons who were not living in the catchment area of the Hiroshima
or Nagasaki cancer registry (9 cases) were also excluded. Out of theremaining 561 cases, secondary cancers were excluded as treatment
for a preceding cancer could cause a subsequent cancer or increase
the chances of detecting other cancers, leaving 451 cases of firstprimary cancer and carcinoma in situ (including SCC in situ).
Finally, 39 cases for which individual doses were not available and76 cases that occurred among NIC cohort members were excluded
leaving 336 first primary skin cancer cases diagnosed from 1958 to
1996 for analyses.

MATERIALS AND METHODS
Study Cohort
The LSS cohort comprises 120,321 people who were selected fromthe 1950 National Census that had a supplementary questionnaire
about A-bomb radiation exposure along with 26,000 persons who
were not in either city (NIC) at the time of the bombing. The detailed
sampling methods were previously described by Preston et al. (11).
The current study population comprises 80,158 LSS subjects withknown individual dose estimates based on the Dosimetry System 2002
(DS02) (12, 13), who were alive and not known to have had cancer asof January 1, 1958, when both the Hiroshima and Nagasaki Cancer
Registries began operations. NIC people were excluded because ofconcerns about the comparability of their baseline cancer rates to thosefor other zero-dose cohort members, likely due to sociodemographic(urban/rural) or other differences (14–16). The distributions of total
subjects by city and gender were 32,399 men (40.4%) and 47,759
women (59.6%) and 54,159 in Hiroshima (67.6%) and 26,002 in
Nagasaki (32.4%).
Individual radiation dose to the skin was estimated as the DS02
shielded kerma dose (12). To correct for dose uncertainties due torandom measurement error, unadjusted DS02 estimates were replacedby expected survivor dose estimates using the method developed by
Pierce et al. (17) and assuming 35% measurement error in individual
doses. Weighted skin dose was given as the sum of gamma dose plus
10 times the neutron dose. Estimated doses above 4 Gy were truncatedto 4 Gy.
Case Ascertainment
Potential cancer cases of the skin and related sites that occurred
after 1958 were identified from the Hiroshima City Cancer Registry,
Hiroshima Prefecture Tumor Registry, Nagasaki Prefecture Cancer
Registry including Tissue Registries, as well as autopsy and surgicalpathology records at Radiation Effects Research Foundation (RERF)
and other medical institutions. One of the study pathologists (SY)
reviewed the records of all potential skin tumor cases, including
benign tumor and tumor with uncertain malignancy cases from thefollowing sources: tumor registry records (3,070 reports); pathology
reports (1,097); autopsy reports (46); surgical pathology reports (133);and death certificates (283). After the first screening, a total of 896
tumor cases (820 persons) were identified as skin cancers, including insitu cancers. Using the same protocol, three pathologists (MK, MI andSY) then reviewed the pathology reports, slides and available clinicalrecords that were not rejected by the first screening. When a pathology
slide was not available or in poor condition, the tissue block wascollected and a new slide was prepared. As a last step, the three
original pathologists along with an additional pathologist (TH)examined the slides together to reach a final diagnosis. All tumors
were coded using ICD-O-2 topography code (C44.0-C44.9, C510,
C51.9, C60.9 and C63.2) and the World Health Organization,
Histological Typing of Skin Tumors, second edition (18). Finally,
642 individuals with 700 tumors were diagnosed as having skincancers. The percentage of death certificate only (DCO) cases was
3.4% (24 cases among 700 cases).
Tumors diagnosed before 1958 and after 1997 were excluded fromthe initial 700 tumors (130 cases) identified. Those occurring among

Statistical Analysis
Excess relative risk (ERR) and excess absolute risk (EAR) were
estimated using the Poisson regression method. The general ERR
model was written as:
Expected rate ¼ background rate½1 þ ERRExpected rate ¼ k0 ðc; s; p; a; paÞ½1 þ qðdÞeðc; s; a; pa; e; tÞ;and the general EAR model was written as:
Expected rate ¼ background rate þ EAR
Expected rate ¼ k0 ðc; s; p; a; paÞ þ qðdÞeðc; s; a; pa; e; tÞ:In these models, k0 (.) represents the background rate of skin cancer
as a logarithmic function of potential determinant variables, including
city (c), sex (s), period at diagnosis (p), attained age (a) and an
indicator of participating in the biennial health examination of the
AHS at least once or not (pa). City, sex and attained age wereroutinely included in the background function, but birth year was notincluded in this study because it is co-linear with p and a. Period atdiagnosis was included to evaluate the temporal trend of skin cancer
incidence. The AHS is a subset of the LSS cohort that has been
followed by biennial clinical examinations at RERF. AHS subjects
may have had a higher chance of skin cancer detection due to thebiennial exams. Potential variables were included in the functions if
they were found to be significant (P , 0.1), and the backgroundmodels of each histological type were compared with the nonparametric models consisting of the categorical variables of potential
variables to check the model fit. The functions q(.) and e(.) describedthe dose-response function and effect modification, respectively, ande(.) was modeled as log-linear functions. Potential effect modifiers
included c, s, a and pa, as well as age at exposure (e) and time since
exposure (t).
Model assessments of the radiation dose-response were carried out
as follows. First, a linear ERR model with potential backgroundparameters was estimated for all skin cancer cases and then for eachhistological type. If there was a significant response, effect modifiers
were included as potential variables. Once the background parametersand effect modifiers were determined, the shape of dose response was
explored. The best-fit dose-response curves were selected using the
Akaike’s information criteria (AIC) from among linear, linearquadratic, linear-spline, threshold and pure quadratic dose-responsemodels with the selected background function and effect modifiers.
The linear spline model was described as:b1 dðd , d0 Þ;qðdÞ ¼
b2 dðd  d0 Þðd. ¼ d0 Þ:
In the threshold model b1 was set to be equal to 0 and d0 is the dose atthreshold. Appropriate knots in linear spline and threshold models
were determined using the selected background parameters and effectmodifiers. The best-fit threshold and the 95% confidence bounds were
empirically determined from the likelihood profile.

RADIATION AND SKIN CANCER INCIDENCE AMONG LSS

To examine the interaction between radiation and UV radiation
exposures, ERRs and EARs were adjusted for the nominal areas ofskin surface that were likely or unlikely to be exposed to the sunlight.
The skin areas that were likely to be exposed to UV radiation were
defined by the ICD-2nd topography codes of C44.0 (lip), C44.1(eyelid), C44.3 (face), C44.6 (arm and shoulder: only hand), C44.2(external ear) and C44.4 (scalp and neck). Areas that were unlikely to
be exposed to UV radiation included C44.5 (trunk), C44.6 (arm andshoulder other than hand), C44.7 (leg and hip) and C44.8 (overlapping
lesion of skin)(2). We assumed the total skin surface area for the
average Japanese to be 1.6 m2 (19), with proportions of UV radiation
likely to be exposed and unlikely to be exposed areas being 0.12 m2(7.5%) and 1.48 m2 (92.5%) , respectively (20). Adjustment was madeto the incidence rate denominator by multiplying the observed persontime by the nominal surface area (m2) (2).
The analytical data file consisted of tabulation of person–time andnumbers of cases by city (Hiroshima or Nagasaki), gender (male orfemale), age at exposure (14 five-year categories from 0 to 69 and 70
to ,100), attained age (17 five-year categories from 0 to 84 and theother of 85 to ,110), time period of cancer diagnosis (9 categories:
1958–1960, 1961–1965, 1966–1970, 1971–1975, 1976–1980, 1981–
1985, 1986–1987, 1988–1990 and 1991–1996), DS02 adjusted
shielded kerma dose (23 categories including cut points and larger:
0, 0.005, 0.02, 0.04, 0.06, 0.08, 0.1, 0.125, 0.150, 0.175, 0.2, 0.25,
0.3, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5 and 3 Gy, and another categoryof unknown dose) and AHS (participant or not).
Person-years (PYs) of observation were computed from January 1,
1958, until the earliest date of diagnosis of any tumor, date of death orDecember 31, 1996, whichever occurred first. Since tumors that werediagnosed outside the catchment area were excluded from the analysis,
PYs were adjusted for the estimated migration rates in and out of thearea based on the AHS migration data.(21) Estimated parameters,
likelihood ratio tests, and likelihood-based 95% confidence intervals(CI) were computed with the AMFIT computer program from the
Epicure risk regression software.(22) CIs for attributable fractions
were based on an asymptotic variance estimators based on a delta
method.
This study was approved by the Human Investigation Committee ofRadiation Effects Research Foundation (RERF).

533

Crude Incidence Rates of Skin Cancer

Crude incidence rates of skin cancer were calculated byhistological types (Table 2). The crude incidence rates for
BCC and SCC in situ were high in the highest dose category(.1 Gy) but were similarly low in the two lower dose
categories. The rates for SCC and Paget disease weresimilar for the three dose categories. There was nodifference of crude incidence rates of BCC between males
and females exposed to less than 1 Gy. However, the crude
incidence rate for males exposed to more than 1 Gy (35.7
per 105 person-years) is 1.8 times higher than that for
females (20.1 per 105 person-years).
Dose Response by Histological Types

A significant dose response was found for total skincancer based on a linear ERR model without effectmodifiers, with an ERR at 1 Gy (ERR1Gy) of 0.74, 95%
confidence interval (CI): 0.37, 1.2. A significant doseresponse was observed for non-melanoma skin cancer as agroup (ERR1Gy ¼ 0.72, 95% CI: 0.36, 1.2), and especiallyfor BCC (ERR1Gy ¼ 2.2, 95% CI: 0.78, 2.9) and SCC in situ
(ERR1Gy ¼ 0.71, 95% CI: 0.063, 1.9). There was no
association for melanoma (ERR1Gy ¼ 0.86, 95% CI: 1.4,
7.3) and for Paget disease (ERR1Gy ¼ 1.3, 95% CI: , 1.3,
9.2). SCC showed a negative point estimate that was notstatistically significant (ERR1Gy ¼0.12, 95% CI: , 0.12,0.25). Because of the small number of the cases, further
analyses were not conducted for either melanoma or Paget
disease.
Basal Cell Carcinoma
ERR Model

RESULTS

Distribution of Histological Types of Skin Cancer by
Various Factors

We analyzed 336 eligible cases with first primary skincancer, adding 128 new cases to the previous 1958–1986
series. Of these, 320 cases (95.2%) were diagnosed bypathological review, 8 (2.4%) based on clinical records and
8 (2.4%) were based on death certificates only.
There were 10 malignant melanomas, 301 epidermal
tumors (123 BCCs, 114 SCCs and 64 SCC in situ), 10 Paget
disease tumors and 15 other tumors (5 adnexal tumors, 3cutaneous lymphoproliferative tumors, 3 vascular tumors, 3cutaneous fibrohistiocytic tumors and 1 miscellaneoustumor) (Table 1). There were more female than male cases
for skin cancers combined, largely due to the higher female
frequency of cases with SCC in situ, BCC and SCC. The
higher proportion of Hiroshima cases (72.9% vs. 35.1% forNagasaki) reflected the larger number of Hiroshima subjects
in the cohort. The ratio of BCC to SCC was 1.08, which wasslightly lower than the previous study (1.2) (1).

Several possible modifiers of the ERR for BCC were
examined (Table 3). The ERRs of age at exposure group of
0–9, 10–19, 20–39 and over 40 years were 15 (95% CI: 4.2,43), 5.7 (95% CI: 2.2, 13), 1.3 (95% CI: 0.35, 2.9), 0.19
(95% CI: ,–0.32, 1.2), respectively, and age at exposure
was the most significant modifier with a coefficient estimate¼ 0.11 (95% CI: 0.17, 0.070). That is, the ERR
decreased 11% (95% CI: 6.7%, 15%, P , 0.001) with each
one year increase in age at exposure. Attained age did not
significantly modify the ERR after allowance for the effectof age at exposure. With the exception of the earliest
calendar period (1958–1965), the ERR remained stablethrough the last follow-up period, with no significant
temporal trend. The ERR was estimated to be 1.3 (95% CI:
0.44, 2.8, P ¼ 0.046) for people who were exposed to 1 Gyof radiation at age 30.
The shape of the dose response was examined using fivemodels with effect modification. First, was a linear spline
function with a knot between 0.5–1.5 Gy (incrementing
0.01 Gy with each iteration) with effect modification by age
at exposure (fixed to age at exposure of 30). A model with a

534

SUGIYAMA ET AL.

TABLE 1
Distribution of Histological Type of Skin Cancer among Atomic-Bomb Survivors, 1958–1996
BCCa

Melanoma

SCCb

SCCb in situ Paget disease

No. ofNo. ofNo. ofNo. of
Person- No. ofcases (%) cases (%) cases (%) cases (%) cases
years
GenderMale
756,536
5
Female1,265,140
5City
Hiroshima
1,398,540
5
Nagasaki
623,128
5
AHSc
Participants
329,7881
Non-participants
1,691,890
9
Age at diagnosis (years),50
891,4172
50 , 60
417,829060 , 70368,2684
70 , 80
240,7422
80þ
103,4152
Age at exposure (years),10505,4210
10 , 20502,2532
20 , 40
655,0763
40þ
358,922
5
Year of diagnosis
1958–1965
550,5832
1966–1975
582,3684
1976–1987
561,8554
1988–1996
326,865
0
Anatomical site
Face
1
Scalp and neck0
Trunk, limbs and other
9
External genitals
0
Total
2,021,670 10
(%)
(3%)

Other

Total

No. of(%) cases (%)

No. of Percentage
cases
(%)

(50.0)(50.0)

49 (39.8)
74 (60.2)

46 (40.4)
68 (59.6)

1450(21.9)(78.1)

3
7(30.0)(70.0)

7
8(46.7)(53.3)

124212(36.9)(63.1)(50.0)(50.0)

83 (67.5)
40 (32.5)

83 (72.8)
31 (27.2)

56
8(87.5)(12.5)

7
3(70.0)(30.0)

114(73.3)(26.7)

245
91(72.9)(27.1)(10.0)(90.0)

42 (34.1)
81 (65.9)30 (26.3)
84 (73.7)

18
46(28.1)(71.9)

1
9(10.0)(90.0)

2
13(13.3)(86.7)

94242(28.0)(72.0)(20.0)(0.0)(40.0)(20.0)(20.0)

6
17
27
40
33

(4.9)
(13.8)(22.0)(32.5)(26.8)

11 (9.6)
11 (9.6)
19 (16.7)
29 (25.4)
44 (38.6)

0
3
14
22
25

(0.0)
(4.7)
(21.9)(34.4)(39.1)

0
2
1
5
2

(0.0)
(20.0)(10.0)(50.0)(20.0)

1
1
2
7
4

(6.7)
(6.7)
(13.3)(46.7)(26.7)

20
34
67
105
110

(6.0)
(10.1)(19.9)(31.3)(32.7)(0.0)(20.0)(30.0)(50.0)

6 (4.9)18 (14.6)
52 (42.3)
47 (38.2)

3 (2.6)12 (10.5)
40 (35.1)
59 (51.8)

1
6
34
23

(1.6)
(9.4)
(53.1)(35.9)

1
1
3
5(10.0)(10.0)(30.0)(50.0)

1
1
8
5

(6.7)
(6.7)
(53.3)(33.3)

12
40
140
144

(3.6)
(11.9)(41.7)(42.9)(20.0)(40.0)(40.0)(0.0)

9 (7.3)19 (15.4)
55 (44.7)
40 (32.5)

20
21
35
38

3
4
23
34

(4.7)
(6.3)
(35.9)(53.1)

1
1
2
6(10.0)(10.0)(20.0)(60.0)

2
2
5
6(13.3)(13.3)(33.3)(40.0)

37
51
124
124

(11.0)(15.2)(36.9)(36.9)(10.0)(0.0)(90.0)(0.0)(17.5)(18.4)(30.7)(33.3)

67 (54.5) 32 (28.1) 12 (18.8)0(0.0)
6 (40.0) 118
15 (12.2) 12 (10.5)
0
(0.0)
0
(0.0)
2 (13.3)
29
33 (26.8) 54 (47.4) 51 (79.7)
1 (10.0)
7 (46.7) 155
8 (6.5) 16 (14.0)
1(1.6)
9 (90.0)
0
(0.0)
34
123
114
64
10
15
336
(37%)
(34%)
(19%)
(3%)
(4%)
(100%)(35.1)(8.6)(46.1)(10.1)aBasal cell carcinoma.
Squamous cell carcinoma.
c
Adult Health Study.
b

TABLE 2
Crude Skin Cancer Incidence Rates by Histological Types, Radiation Dose and Gender
Male

FemaleBoth sexes

Weighted skin dose (DS02, Gy)

Weighted skin dose (DS02, Gy)

Weighted skin dose (DS02, Gy),0.005,0.005,0.0050.005-0.99

1þ

0.005-0.99

1þ

0.005-0.99

1þCase Ratea Case Ratea Case Ratea Case Ratea Case Ratea Case Ratea Case Ratea Case Ratea Case Ratea
Melanoma
Nonmelanoma
skin cancer
BCCb
SCCc
SCCc in situ
Paget disease
Other
Migration-adjusted
person-years
a

5

1

0.3

3

0.7

1

2.6

2

0.4

3

0.4

1

0.0

3

0.4

6

0.6

1

1.0

44
13
22
5
3
1

13.9
4.1
7.0
1.6
0.9
0.3

57
22
22
7
0
6

14.2
5.5
5.5
1.7
0.0
1.5

18
14
2
2
0
0

45.9
35.7
5.1
5.1
0.0
0.0

84
27
30
24
1
2

16.1
5.2
5.7
4.6
0.2
0.4

99
35
35
20
5
4

14.5
5.1
5.1
2.9
0.7
1.5

24
12
3
6
1
2

40.3
20.1
5.0
10.1
1.7
3.4

128
40
52
29
4
3

15.3
4.8
6.2
3.5
0.5
0.4

156
57
57
27
5
10

14.4
5.3
5.3
2.5
0.5
0.9

42
26
5
8
1
2

42.5
26.3
5.1
8.1
1.0
2.0

316,032

Rate per 10 persons per year.
Basal cell carcinoma.
c
Squamous cell carcinoma.
b

401,308

39,196

522,793682,725

59,617

838,825

1,084,030

98,813

535

RADIATION AND SKIN CANCER INCIDENCE AMONG LSSTABLE 3
Basal Cell Carcinoma Fitted Linear Risk Estimates by Age at Exposure, Age at Diagnosis, Period at Diagnosis, City,
Gender and AHS Participant; Atomic-Bomb Survivors
Variables
Age at exposure (years)
0–9
10–19
20–39
40þ
Age at diagnosis (years),50
50 , 60
60 , 70
70 , 8080þ
Period at diagnosis
1958–1965
1966–1975
1976–1987
1988–1996
City
Hiroshima
Nagasaki
GenderMale
FemaleAHS
Participant
Non-participant

No. of cases

Person-years

ERR1Gya

95% CIb

Heterogeneityc P

Trendd P

6
18
52
47

505,421502,253655,076
358,922

15
5.7
1.3
0.19

(4.2, 43)
(2.2, 13)(0.35, 2.9)(,–0.32,e 1.2)

,0.001,0.001

6
17
27
40
33

891,417417,829368,268
240,742
103,415

11
7.5
1.6
0.7
0.02

(2.3, 36)
(3.1, 17)(0.28, 4.2)
(0.014, 2.1)(,–0.49,e 1.1)

,0.001,0.001919
55
40

550,582
582,368
561,855
326,865

,0
2.2
1.3
2.5

(,0.1,e 2.1)
(0.40, 6.8)
(0.41, 3.0)
(0.83, 6.2)

0.11

0.21

83
40

1,398,540
623,1281.2
3.0(0.48, 2.9)
(1.2, 6.2)

0.054

49
74

756,536
1,265,140

2.4
1.1(0.97, 5.5)
(0.33, 2.5)

0.17

42
81

329,788
1,691,890

2.3
0.9(0.93, 5.3)
(0.35, 2.6)

0.22

a

Excess relative risk at 1 Gy.
Confidence interval.
cTest of hypothesis that effects differ across categories.
d
Test of log-linear trend across categories.
e
The lower confidence bounds were described as the limit to be estimated.
bknot at 0.63 (95% CI: 0.3, 0.9) was selected as the best (AIC
¼ 1,086.0). The slope was estimated to be 2.0 (95% CI: ,0,4.3) at doses over 0.63 Gy and 0.05 (95% CI: ,–0.05,
1.2) below the knot of 0.63 Gy. Second, among linear
threshold models with a knot in the same range, a modelwith a knot at 0.63 Gy fit best (95% CI: 0.3, 0.9, AIC ¼
1,084.3). The slope over 0.63 Gy was estimated to be 2.0(95% CI: 0.69, 4.3). Third, the best-fit linear model
estimated an ERR1Gy of 1.3 (95% CI: 0.44, 2.8, AIC ¼
1,089.6). Fourth, the best-fit linear quadratic model (AIC ¼
1,088.8) showed that the coefficient estimate of the linear
term was 0.40 (95% CI: ,0, 2.0) and that the quadratic term
was 0.31 (95% CI: 0.059, 0.87). The best-fit quadraticmodel (AIC ¼ 1,087.8) showed a coefficient estimate of
0.43 (95% CI: 0.14, 0.97). Comparing those five models
based on the AIC, the best-fit model was the thresholdmodel and a slope over the threshold of 2.0 (95% CI: 0.69,
4.3), with an 11% increase of effect modification with a
one-year decrease in age at exposure (95% CI: 6.9%, 16%)
(Figs. 1 and 2).
EAR Model

The excess absolute risk (EAR) of radiation effects wasestimated using the selected variables in the linear threshold

ERR model with a knot at 0.63. When effect modification
by age at exposure, time since exposure and attained age
were examined simultaneously, the effect of time since
exposure was found to be significant (P , 0.001), but notage at exposure or attained age. The EAR1Gy was estimatedto be 0.059 cases per 104 PYs (95% CI: ,0, 0.30). The
background cases, excess cases and attributable fractions ofradiation were estimated for each category of radiation dose
based on the above ERR model. The attributable fraction
was 19.9% (95% CI: 13.6, 26.2) for total BCC (Table 4).
While there were no excess cases under the threshold of
0.63 Gy, the attributable fraction rapidly increased in thedose category of 0.5 Gy or higher.
Interaction Between UV Radiation and Radiation

The number of BCC cases observed on the face or neck
(likely to be exposed to UV radiation) was 65, and with an
ERR1Gy of 0.6 (95% CI: ,0, 2.1) based on the linear model
including background parameters of city, period of
diagnosis and attained age, with age at exposure as aneffect modifier. The number of the BCC cases observed on
the rest of body (unlikely to be exposed to UV radiation)
was 58 with in an ERR1Gy of 2.3 (95% CI: 0.61, 6.7). The
difference in ERRs was not statistically significant (likeli-

536

SUGIYAMA ET AL.

FIG. 1. Basal cell carcinoma radiation dose-response curves forvarious excess relative models; Atomic bomb survivors (Japan)
diagnosed between 1958 and 1996. The excess relative models include
variables; gender, period at diagnosis and log age 70 as the
background parameters, and age at the time of bombing as the effectmodifier. The 95% Wald confidence bounds were also estimated.

hood ratio test, P ¼ 0.15) based on the joint analysis
proposed by Pierce and Preston (17, 23). For BCC in thearea likely to be exposed to UV radiation, the backgroundrate and the EAR (cases per m2 105 years Gy) were
estimated to be 23 and 40 (95% CI: ,0, 106), respectively.
The comparable rates in the area unlikely to be exposed to
UV radiation were estimated to be 1.0 and 5.7 (95% CI: 1.9,
11), respectively. These were based on a linear model withbackground parameters (city, gender, period at diagnosis
and attained age) and effect modifier (age at exposure andattained age).
SCC In Situ

There was a significant dose response for SCC in situ
using a linear model (ERR1Gy ¼ 0.71, 95% CI: 0.063, 1.9).
Also, there was a statistically significant city difference indose-response slopes between Hiroshima and Nagasaki(likelihood ratio test, P , 0.001). The ERR1Gy in Hiroshima
was 0.28 (95% CI: ,0, 1.9), which was not statisticallysignificant, while that in Nagasaki was 17.6 (95% CI: 3.0,149), which was statistically significant. Although the ERR
slope for Nagasaki was steep, the 95% CI was extremely
wide and the number of cases in Nagasaki was only 8,
which included no cases with high radiation dose (morethan 2 Gy).
DISCUSSION

We extended the follow-up period by 10 years since theprevious study of skin cancer incidence among the LSS
adding 128 new cases, which is a 60% increase. As in theprevious study, we found a significant dose relationship for

FIG. 2. Solid line shows excess relative risk at 1 Gy with age at
exposure modification for basal cell carcinoma based on the linear
model with a threshold at 0.63 Gy. Dots show excess relative risk
point estimates by age at exposure categories, 0–9, 10–19, 20–39, over
40 years old at the time of bombing and the 95% confidence bounds
were also estimated.

BCC but not for invasive SCC. The updated BCC data
strengthened the results of the previous 1958–1987 results(1), and the trend indicates that elevated risks of radiationfor BCC remains more than 50 years after exposure. The
number of melanoma cases oddly remained the same andwas quite small with no evidence of a dose response. The
significantly elevated ERR for SCC in situ, an intraepidermal lesion of SCC, was surprising, but the evidenceof radiation causality is uncertain, as discussed below.
Skin cancer is rare among Asian populations, for instance,
incidence rates of melanoma were highest in the Oceania
region (range 41.1 to 55.8 per 100,000 population, age
standardized by Segi’s world standard population), while
they were 0.5 in Hiroshima in 1995–2000 as well as
Nagasaki in 1997–2002 (24). The rates of non-melanoma
skin cancer were high in Central and South America and inEurope (range 12.6 to 19.8 per 100,000 population, age
standardized by above population), while they were 6.2 and5.9 in Hiroshima and Nagasaki, respectively (24). As thenumber of skin cancer cases is so small in Japan with avariety in histological types and good prognoses, cancer
incidence data with pathological review are crucial for skincancer studies. Both the Hiroshima and Nagasaki cancer
registries include data from tumor and tissue registries,
which record histological diagnoses directly from pathologists. These independent reports were major sources for thehistological diagnoses in our study.
The estimates of ERRs1Gy for different age-at-exposure
strata (Table 3) were almost 10 times greater than theestimates that were reported for medical radiation exposures(5–7, 25). The ERR/Gy estimates for LSS subjects exposed
at ages 0–9 years, 10–19 years, 20–39 years and more than

537

RADIATION AND SKIN CANCER INCIDENCE AMONG LSSTABLE 4
Observed and Fitted Cases of Basal Cell Carcinoma by Dose Category with Attributable Fraction Estimates
Dose categorya

Subjects

Cases

Backgroundb

Excessb

Attributable fractionc,0.0050.005–0.1
0.1–0.2
0.2–0.5
0.5–1
1–2
2–3
3þ
Total

33,456
26,879
5,618
6,412
3,757
2,540
766
730
80,158

40
31
10
10
6
8
8
10
123

40.6
31.6
7.2
8.7
5.1
3.5
1.0
0.8
98.5

0.0
0.0
0.0
0.0
1.5
8.1
5.3
9.6
24.5

0%
0%
0%
0%
22.7%
69.7%
84.6%
92.6%
19.9%

a

Weighted skin dose (shielded kerma) in Gy.
Estimates of background and fitted excess cases are based on an ERR model with threshold dose response and a knot at 0.63, effectmodification by time since exposure.
c
Attributale fraction among cohort members.
b

40 years were estimated to be 15, 5.7, 1.3 and 0.19,
respectively, while the corresponding estimates among
patients with total body irradiation (TBI) for hematopoietic
cell transplantation were 1.49, 0.55, 0.11 and 0.02,
respectively (7). Also the EAR1Gy of 0.053 cases per 104
PYs for LSS subjects was much lower than the estimatesthat were reported among medical exposures, such as 55.6
cases per 104 PYs for TBI exposure patients (7), 1.1 cases
per 104 PYs for New York tinea capitis study series (5) and
0.31 cases per 104 PYs for Israel tinea capitis study(6). Thismay be partially explained by three reasons. First, the Abomb survivors had acute whole-body radiation exposure
whereas most of the medical exposures were fractionatedand more localized. Second, the TBI cohort members didn’t
include any patients with doses less than 7.5 Gy. Schwartz
et al. hypothesized that the dose responses, which are muchsteeper at the lower doses received by A-bomb survivors,
may flatten out at the much higher doses received by TBIconditioned patients. Third, the LSS cohort only included
Japanese whose background rate of skin cancer is lower
than rates among Caucasians, and pigmentation characteristics might have modified the radiation risk of BCC asreported in either the Israel or New York tinea capitis study
or the U.S. radiologic technologists study (26).
In the tinea capitis study, the skin cancer radiation risk
was 10 times lower among African-Americans than among
Caucasians.(5) The difference in the magnitude of radiation
risk estimates may be due to the lower background risk ofskin cancer in the Japanese population compared with
Caucasian populations. Although the radiation risk estimates for the different age-at-exposure categories among
the A-bomb survivors were greater than those of medical
exposure, the magnitude of effect modification by age at
exposure was similar [11% increase with each one-year
decrease in age at exposure among A-bomb survivors vs.
10.9% increase among patients who were irradiated for
medical reasons (7)].
Using an ERR model, the best-fit knot for a thresholddose was determined to be 0.63 Gy according to the AIC.

Previous studies have reported that the threshold may be as
high as 1 Gy for BCC (1, 3). A significant dose response atdoses greater than 1 Gy and nonsignificant at doses lessthan 1 Gy were reported in a case-control study ofchildhood cancer survivors who has received radiotherapy
in the U.S. (27). The current study provides data with doses
comparable to those observed in radiotherapy (,1 Gy) andallows for an analysis to estimate a threshold dose forradiation-induced skin cancer. Additional data that will becollected in later years will be valuable for this and otherpurposes in the future.
In regards to the interaction between UV radiation andradiation for BCC, the ERR estimated for skin areas
unlikely to be exposed to UV radiation was 2.3, but was 0.6
in skin areas likely to be exposed to UV radiation. A skincancer case-control study among New Hampshire residents
found that radiotherapy risk was statistically high in thesubjects who had not experience sunburn and the risk inthose who had experience sunburn did not increase,although the difference in the risks between those twogroups was not significant (28). These two reportssuggested that radiation effects were stronger on skin thatwas unlikely to be exposed to UV radiation.
On an absolute risk scale, the New York tinea capitis
study reported higher risks for excess BCC on the sunexposed margin of the scalp (EAR ¼ 21/100 cm2 Gy)compared with the relatively sun-shielded scalp (EAR ¼
4.7/100 cm2 Gy). In the previous report by Kishikawa et al.
the BCC EAR/105 m2 years Sv for skin areas likely to be
exposed to UV radiation was slightly, but not significantly,
higher than those for areas unlikely to be exposed to UV
radiation, suggesting that the uniform distribution of theradiation risks are additive to the background rates. A
different pattern is observed in the current study where theEAR was 40/105 m2 years Gy for areas likely to be exposed
to UV radiation compared with 5.7/105 m2 years Gy forareas unlikely to be exposed to UV radiation. The current
EAR was markedly higher than the previous report fromthis cohort (9.1/105 m2 years Gy). Given that the baseline

538

SUGIYAMA ET AL.

BCC rates were more than 20 times higher in UV radiationexposed areas than in UV radiation-shielded areas and all
estimates had wide confidence intervals due to the small
number of cases, the present EAR estimate for BCC on UV
radiation-exposed body parts cannot rule out either an
additive or multiplicative interaction between ionizing
radiation and UV radiation exposure. Therefore, a further
follow-up is needed to assess the nature of the UV radiationand ionizing radiation interaction more precisely.
BCC is rarely metastatic or fatal (29–31), but can beinvasive and prone to multiple lesions (32). Among 123
patients, 8.1% (10 cases) had a second skin cancer (SCC ¼
3, BCC ¼ 6 and SCC in situ ¼ 1) after having suffered a firstprimary BCC. This proportion was lower than that observed
among Caucasian subjects in the tinea capitis treatment
study [38% of the irradiated cases and 24% of the control
BCC cases (5)]. However, people who were exposed at a
young age have reached a cancer-prone age and are also at ahigher risk for skin cancer due to their radiation exposure.
Thus, second skin cancers may occur with greater frequency
in the subsequent follow-up period. The city difference inthe dose-response relationship for SCC in situ was large. To
further explore this finding, we calculated the ERR
including NIC people to increase the number of persons
in the reference group. However, the city difference
persisted after this analysis. We then calculated the agestandardized incidence rates of SCC in situ in Hiroshima
and Nagasaki City based on the population-based cancer
registries. The rates were nearly the same (1.2 and 1.0 per
100,000 population, respectively). Finally, since the numberof cases in Nagasaki was very small, we reviewed the tissue
registry reports of the LSS cases in Nagasaki who had been
diagnosed as ‘‘Bowen type of actinic keratosis’’, which issimilar to SCC in situ (Bowen’s disease). Out of 65 actinic
keratosis cases, 11 cases were found to be similar to SCC in
situ but were not registered in the Nagasaki Cancer Registrybecause actinic keratosis was not considered a cancer andwere therefore not included in this study. Thus, there may
be city differences in diagnoses and reporting. In light ofthese difficulties, it is hard to determine the dose-response
relationship for SCC in situ.
There may be a concern for our choice of a relative
biological effectiveness (RBE) of 10 for the neutron dose. A
publication by Preston et al. stated the purpose of an RBE
assumption for analysis of the LSS data was to adjust forneutron effects at higher doses where the cancer risks aresubstantial, which is the reason that the assumption of RBE¼ 10 is ordinarily used for the LSS data (13). They also
compared the results of solid cancer ERR to consider theconfidence of the RBE assumption. If a dose constant RBEof 20 was assumed, the solid cancer ERR estimate
decreased from 0.41/Sv (RBE ¼ 10) to 0.39/Sv. Finallythey concluded that the neutron component accounted for
only a small fraction of the total dose received by LSS
cohort members, (especially for the organ doses most
relevant to risk estimation in the LSS) and this fraction will

be virtually impossible to make useful inference about theeffect of neutron exposure on LSS cancer risks directly fromthe LSS data. To examine the effect of the RBE assumption
for BCC threshold estimation in this study, we performed asensitivity analysis. When the RBE was assumed to be 5
and 20, the threshold was estimated to be 0.63 (95%
confidence interval: 0.35, 0.84) and 0.80 (95% CI: 0.32,
1.1), respectively. Therefore the neutron RBE fraction
played only a small role on the BCC risk estimation on the
LSS members.
In conclusion, the current analysis showed a significant
linear dose-response with a threshold association between
BCC and exposure to A-bomb radiation. Significant effectmodification by age at exposure was observed and theradiation-related risk of BCC persisted throughout thefollow-up period, 50 years after the bombs. These findings
suggested that the response of the basal cells of theepidermis to ionizing radiation had a threshold shape andthe overall risks were especially high for those who wereyoung at the age of exposure. No association was observed
for malignant melanoma, SCC or Paget disease. An
association of SCC in situ with radiation was implied but
the unusual results in Nagasaki and significant city
difference make the finding difficult to interpret.
ACKNOWLEDGMENTS
We would like to thank the Hiroshima City Cancer Registry, theHiroshima Prefecture Tumor Registry and the Nagasaki Prefecture Cancer
Registry for approval to use the data, and also thank the staff of theregistries for their efforts. The assistance of Ms. Sachiyo Funamoto andstaff of the pathology laboratory are gratefully acknowledged. Special
thanks are expressed to the late Dr. Elaine Ron for her advice. This paper
is dedicated to Dr. Shoji Tokuoka, a key leader and pathologist of the sitespecific cancer study program in A-bomb survivors for 25 years at RERF.
His untimely death during final preparation of this paper, took from us a
dedicated researcher. The Radiation Effects Research Foundation (RERF),
Hiroshima and Nagasaki, Japan is a private, nonprofit foundation fundedby the Japanese Ministry of Health, Labour and Welfare (MHLW) and the
U.S. Department of Energy (DOE), the latter in part through DOE Award
DE-HS0000031 to the National Academy of Sciences that supported EJG.
This publication was supported by RERF Research Protocol(s) RP 2–91
and 2-02, and with additional support from U.S. National Cancer Institute(NCI) contract number N01-CP-31012. The views of the authors do notnecessarily reflect those of the two governments.
Received: July 31, 2013; accepted: February 3, 2014; published online:
April 22, 2014

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