Review

Oxford, UK
International
IJD
Blackwell
1365-4632
45 Publishing
Journal Ltd,
Ltd
of Dermatology
2006

Predictive value of phenotypic variables for skin cancer:

Predictive
Xu
REVIEW
and Koo value of phenotypic variables for skin cancer

Risk assessment beyond skin typing

Lisa Y. Xu, MD, and John Koo, MD

From the Washington University School of Medicine, St. Louis, MO,

Department of Dermatology, University of California-San Francisco,
San Francisco, CA

Correspondence
John Koo, MD
Department of Dermatology
University of California-San Francisco
Psoriasis and Skin Treatment Center
515 Spruce Street
San Francisco
CA 94118
E-mail: john.koo@ucsfmedctr.org

However, long-term data continues to accrue and it is essential

Introduction
Assessing an individual’s risk of developing skin cancer is one
of the most common clinical scenarios faced by dermatologists.
A typical method of subjectively measuring this risk is to
evaluate an individual’s phenotypic characteristics. It is
traditionally believed that the individual most susceptible to
skin cancer has the lightest constitutional features, such as red
hair, blue eyes, and lightly pigmented skin prone to freckling
and sunburn. However, not all cases are so distinct. Many
studies have attempted to evaluate the relative importance of
various phenotypic factors in risk prediction for the three
major types of skin cancer: melanoma, basal cell carcinoma
(BCC), and squamous cell carcinoma (SCC). However, to
date, there has been no concise review prioritizing these
phenotypic variables in their order of importance for all three
types of skin cancer.
The objective of this review was to evaluate and summarize
recent data regarding major phenotypic factors that are most
important in predicting increased risk for melanoma, BCC,
and SCC. This review has wide implications both for general
dermatologic cancer screening and for monitoring patients
receiving treatments such as phototherapy. Although rare,
the development of skin cancer is a major concern for photo-
therapy. An increased risk of nonmelanoma skin cancer has
been well-documented for psoralen plus ultraviolet-light A
(PUVA) treatment while the data for melanoma remains
controversial.1–3 On the other hand, most studies do not show an
increased risk of skin cancer with UVB treatment, suggesting
that it remains one of the safest modalities available.4
to provide guidelines such that individuals susceptible to skin
cancer can be more precisely identified.
It is important to keep in mind that there are many factors
that predispose an individual to skin cancer including family
history, personal history of skin cancer, and geographic
location. Thus, when clinically evaluating an individual for
risk of skin cancer, all variables must be taken into account
for a complete assessment of risk. We limited our analysis
to phenotypic risk factors. Our goal was to reassess the
predictive value of skin type, a widely used phenotypic
factor for predicting skin cancer risk, and to determine if other
phenotypic factors are more effective measures of risk. The
phenotypic factors we focused on can be divided into several
groups: (a) pigmentary factors such as hair, skin, and eye color,
(b) sun exposure indices such as freckling, actinic keratoses,
and solar lentigines that result from a combination of personal
susceptibility and sun exposure, (c) presence of nevi that may
or may not result from sun exposure and (d) skin type.
Although it is often included as a pigmentary factor, skin type
as defined by Fitzpatrick is actually a historical account
obtained from an individual combining two measures, i.e.
tanning ability and burning susceptibility.5 Therefore, it is not
simply a visual assessment but is a measure of pigmentation
derived from information about a skin reaction to sun exposure.
Hence, it is a phenotypic measure that does not neatly fit into
any of the above categories.
Skin type is a widely used method to determine skin cancer
risk, as it was designed to predict individual variation in
sensitivity to UV light, a critical factor in pathogenesis of the 1275

© 2006 The International Society of Dermatology International Journal of Dermatology 2006, 45, 1275 –1283
1276 Review Predictive value of phenotypic variables for skin cancer
three types of skin cancer. In a prospective study of PUVA
patients, Stern et al. suggested that skin type is a better predictor
of nonmelanoma skin cancer than pigmentary traits such as
eye and hair color.6 However, recent data dispute this in that
there is considerable overlap of constitutive pigmentation
factors within each skin type, making it less reliable as a
predictive measure.7 In addition, hair and eye color seem to
carry additional information about sun reactivity not con-
tained in the Fitzpatrick classification because they have been
shown to be independent risk factors for skin cancer. So the
question remains, what are the most predictive factors for
melanoma, BCC and SCC?
Methods
This review was compiled by searching MEDLINE via the PubMed
interface from 1966–2005 for articles with the keywords:
melanoma, nonmelanoma skin cancer, BCC, SCC, pigmentary risk
factors, skin cancer risk factors, epidemiology, skin type, skin color,
hair color, eye color, race, ethnicity, non-Caucasian, blacks, and
Asian. The references contained in these articles were also
examined to identify any studies that were missed with the
MEDLINE search. Prospective studies, case–control studies,
meta-analyses, and review articles were all included. Only
studies addressing a population older than 18 years were included
because childhood cases of skin cancer are rare and often owing
to a different set of risk factors, with genetic factors being more
prominent. Prospective studies and meta-analyses were given
more weight than case–control studies.
Description of studies
The reviewed studies focus on the white population. The
incidence of skin cancer is very low in non-white people and there
has been a paucity of case–control or prospective studies
addressing risk factors in these groups. Studies commonly came
from regions such as northern-Europe (UK, Scandinavia, Ireland),
southern-Europe (Italy, Greece, Spain), Australia and the USA.
The majority of studies are case–control studies. There are only
a few prospective studies for each type of skin cancer. Results
of selected large, recent meta-analyses, prospective and case–
control studies are presented here. Furthermore, the included
studies describe susceptibility of normal skin to natural sunlight,
and not diseased skin to specific types of treatment such as
phototherapy, for the purpose of eliminating confounding variables.
In many studies, exact skin type is not specified, and data
regarding tanning or burning may be presented individually.
These measures of “skin reaction to sun” will be treated as though
they are related to skin type. In addition, some data involve
historical recollection of sunburn history by the subject. Although
these data are not purely phenotypic at the time of evaluation, they
will be included because they are measures of “skin reaction to
sun”. Note that all ratios are presented as relative risks (RRs) and
the distinction between the RRs and the odds ratio (OR) is ignored
International Journal of Dermatology 2006, 45, 1275 –1283
Xu and Koo
owing to the assumption that the incident disease is relatively rare
in the general population. Furthermore, unless otherwise noted,
only adjusted RRs are presented to minimize confounding and to
ascertain that the factors examined remain independently
significant despite adjustment. Details of these studies are
summarized in Tables 1 and 2.
Results
Melanoma
Melanoma has been rising in incidence in white people
worldwide. In 2005, Gallagher et al. published a three-part
meta-analysis reviewing the major risk factors for melanoma,
pooling data from case–control, prospective, and cross-
sectional studies from 1966–2002.8 In the first part of the
meta-analysis, the RR of common and atypical nevi for
melanoma development were reviewed from 47 datasets
including a total of 10,499 cases of histologically confirmed
melanoma and 14,256 controls. Among the datasets dealing
with common nevi, 26 presented the risk estimates for whole
body nevus count and 17 for nevi counts on the arms, and
27 datasets published the RR for atypical nevi. Most of the
data adjusted for chronic or intermittent sun exposure, while
only one study provided a crude ratio. Analysis of results
showed that the risk for individuals with a high number of
common nevi (100–120 nevi) was almost sevenfold greater
(RR = 6.89, 95% CI = 4.63–10.25) than those with only a
few nevi (0–15 nevi). Subjects with five atypical nevi had a
sixfold higher risk than those with no atypical nevi (RR = 6.52,
95% CI = 3.78–11.25). Furthermore, the risk associated with
an increase of one atypical nevus (RR = 1.51, 95% CI = 1.37–
1.67) is higher than for one common nevus (RR = 1.02,
95% CI = 1.01–1.02). These data confirm the significance of
the number of common nevi and presence of atypical nevi as
risk factors.
In another part of the meta-analysis, pigmentary risk
factors including hair, eye, skin color, skin type as well as sun
exposure indices including freckles, actinic keratoses, and
solar lentigines were assessed.9 Data were extracted from
60 studies with a total of 28,157 cases. It was found that the
pigmentary factors most predictive of melanoma in descend-
ing importance were hair color (red versus dark, unadjusted
RR = 3.64, 95% CI = 2.54–5.37), skin type (I versus IV,
RR = 2.09, 95% CI = 1.67– 2.58), skin color (light versus
dark, RR = 2.06, 95% CI = 1.68– 2.52), and eye color (blue
versus dark, RR = 1.47, 95% CI = 1.28–1.69). In reviewing
the sun exposure indices, they found that actinic indicators of
damage such as actinic keratoses (unadjusted RR = 2.02,
95% CI = 1.24–3.29) and density of freckles (high versus low,
RR = 2.1, 95% CI = 1.8–2.45) each conferred considerable
risk. When these variables were combined together in
statistical analyses, they remained significant but the predictive
value of each individual variable understandably changed
© 2006 The International Society of Dermatology
Xu and Koo Predictive value of phenotypic variables for skin cancer Review 1277

Table 1 Description of studies

Reference and Geographic region/ Number of Years of

bibliography number study population Type of study subjects (n) follow up

Melanoma
Gandini I (2005)8 Europe, North America, Meta-analysis (49 studies) 10,499 cases Varied
Australia, Argentina 14,256 controls
Gandini III (2005)9 Europe, North America, Meta-analysis (60 studies) 28,157 cases Varied
Australia, Argentina,
Brazil, Israel
Cho (2005)10 USA and Europe Three prospective studies 152,949 cases Up to 14 years
25,206 controls
Bliss (1995)11 USA, Europe, Systematic review of 3230 cases NA
Australia, Canada 10 case–control studies 3896 controls
Basal cell carcinoma
van Dam (1999)12 USA Prospective study 3273 cases 8 years
44,591 controls
Walther (2004)15 Germany Case–control 213 cases NA
411 controls
Corona (2001)16 Italy Case–control 166 cases NA
158 controls
Lock-Andersen (1999)17 Denmark Case–control 145 cases NA
174 controls
Lear (1997)14 UK Case–control 827 cases NA
502 controls
Gallagher I (1995)18 Canada Case–control 226 cases NA
406 controls
Squamous cell carcinoma
Grodstein (1995)19 USA Prospective study 197 cases 8 years
107,900 controls
English (1998)20 Australia Case–control 145 cases NA
1015 controls
Zanetti (1996)22 southern-Europe Case–control 228 cases NA
1795 controls
Gallagher II (1995)21 Canada Case–control 180 cases NA
406 controls
Kricker (1991)23 Australia Case–control 45 cases NA
1015 controls

(Table 2), suggesting that these constitutional characteristics
are highly interrelated and interact with each other in deter-
mining individual UV-sensitivity.
Other studies have mostly corroborated the findings of
Gandini et al.8,9 Cho et al. recently combined data from three
major prospective studies including a total of 152,949 women
and 25,206 men followed for up to 14 years.10 Only the white
populations of Europe and the USA were included and
535 cases of melanoma were documented from medical
records. Pooled data showed that light hair color (red versus
light brown, RR = 2.05, 95% CI = 1.49–2.83), and the number
of nevi > 3 mm (10+ vs. 0, RR = 3.08, 95% CI = 2.34–4.05)
were again significant risk factors. In addition, the number
of severe and painful sunburns also conferred increased risk
(10+ vs. 0, RR = 2.36, 95% CI = 1.74–3.19).
In another systematic review summarizing data from
10 case–control studies from Europe, Australia, Canada and
the USA comprising 3000 cases and nearly 4000 controls,
the unadjusted and adjusted RR for hair, eye, skin color,
freckling and nevus count were examined.11 The unadjusted
RR for hair color were 1.49 (95% CI = 1.31–1.70) for
light brown hair, 1.84 (95% CI = 1.54–2.21) for blond
hair and 2.38 (95% CI = 1.90–2.97) for red hair. All RRs
were obtained by comparing against dark brown/black
hair. Individuals with blue eyes compared with those with
brown eyes had an unadjusted RR of 1.55 (95% CI = 1.35–
1.78). When hair and eye color were adjusted for each
other they remained independently significant, and in
some cases the RR further increased. Furthermore, the RRs
for hair and eye color were independent of skin color and
nevus count. Light skin color had a weaker RR averaging
2.0 but with confidence intervals that were statistically
insignificant. In addition, high freckle density (high versus
none, RR = 2.25, 95% CI = 2.00–2.54) was again a signi-
ficant risk factor independent of other factors. Therefore,
the data in white populations suggest that hair color, number

© 2006 The International Society of Dermatology International Journal of Dermatology 2006, 45, 1275 –1283
 1278
Table 2 Relative risks of phenotypic variables in selected major studies
International Journal of Dermatology 2006, 45, 1275 –1283

Review Predictive value of phenotypic variables for skin cancer

Pigmentary Sun exposure
factors indices
(adjusted RR, (adjusted RR, Skin
95% CI) 95% CI) Type*
Reference and Hair color Skin color Eye color Freckles (I vs IV) or
bibliography (red vs. (fair vs. (blue vs. (high vs. Actinic Solar Other painful
number brown/black) dark) brown/black) low/none) keratoses lentigines Nevi burns

Melanoma
Gandini I (2005)8 6.89, 2.63–10.25
(100 vs. 0–15, common)
6.52, 3.78–11.25
(5 vs. 0, atypical)
Gandini III (2005)9 1.86, 1.41–2.45 1.70, 1.49–1.94 1.26, 1.11–1.43 2.05, 1.62–2.6 2.02, 1.24–3.29 1.86, 1.41–2.45
Cho (2005)10 2.05, 1.49–2.83 3.08, 2.34–4.05 2.36, 1.74–3.19
(10+ vs. 0, common) (10+ vs. 0,
severe burns)

Bliss (1995)11 2.38, 1.88–3.02 ∼2.0, 0.76 – 3.28 1.53, 1.32–1.77 2.18, 1.92–2.47
(adjusted for nevi) (adjusted for (adjusted for
nevi) nevi)
2.17,1.71–2.77 1.48, 1.27–1.72 2.08, 1.83–2.35
(adjusted for skin color) (adjusted for (adjusted for
skin color) skin color)
2.10, 1.62–2.72 1.46, 1.23–1.74 2.13, 1.83–2.47
(adjusted for freckling) (adjusted for (adjusted for
freckling) hair color)
Basal cell carcinoma
van Dam (1999)12 1.46, 1.15–1.86 1.10, 0.98 –1.22 1.20, 1.00–1.45 2.13, 1.93–2.38
(painfully burn vs.
© 2006 The International Society of Dermatology

tan) 1.69, 1.32–2.18

(10+ vs. 0, painful
burns)
Walther (2004)15 4.3, 2.3–8.0 NS 2.7, 1.3–5.9 2.5, 1.2–5.3 3.6, 1.9–6.8
(1+ vs. 0 sunburn)
Corona (2001)16 1.3, 0.7–2.4 3.2, 1.1–9.4 1.7, 0.9 – 3.1 1.0, 0.6 –1.6
(skin type)
Lock-Andersen (1999)17 1.9, 0.2–20.8 1.2, 0.7–2.2 0.8, 0.3 –2.3 2.1, 1.0 –4.2
(skin type)
Lear (1997)14 1.61, 1.03–2.55 1.71, 1.23–2.36 1.66, 1.07–2.57
(skin type)
Gallagher I (1995)18 2.1, 0.7–2.2 4.0, 1.4–11.3 1.40, 0.80 –2.40 1.8, 1.2–2.5 4.5, 1.7–12.3

Xu and Koo
(age 5–15 y) (2+ vs. 0,
painful burns)
© 2006 The International Society of Dermatology

Xu and Koo
Table 2 Continued

Pigmentary Sun exposure

factors indices
(adjusted RR, (adjusted RR, Skin
95% CI) 95% CI) Type*
Reference and Hair color Skin color Eye color Freckles (I vs IV) or
bibliography (red vs. (fair vs. (blue vs. (high vs. Actinic Solar Other painful
number brown/black) dark) brown/black) low/none) keratoses lentigines Nevi burns

Squamous cell carcinoma

Grodstein (1995)19 2.0, 1.1–3.7 1.6, 0.9 –2.9 2.4, 1.5–4.0
(6+ vs. 0,
painful burns)
English (1998)20 1.4, 0.51– 4.0 1.2, 0.47–2.80 1.5, 0.81– 2.7 14.0, 3.8–52.0 47, 20–110 (40+ vs. 0) 1.2, 0.41–2.9 1.5, 0.69 –3.3 2.6, 1.2–7.1
(10+ vs. 0) (severe burn)
3.5, 1.5–2.8
(unable to tan)
Zanetti (1996)22 12.5, 4.13–37.86 1.83, 1.11–3.03 2.04, 1.18–3.53

Predictive value of phenotypic variables for skin cancer Review

(skin type)
Gallagher II (1995)21 4.1, 1.1–15.5 1.6, 0.7–3.8 1.6, 1.0 –2.4 0.95, 0.32–2.84 10.5, 2.9–38.0
International Journal of Dermatology 2006, 45, 1275 –1283

(2+ per year

severe burns
1.6, 0.8 –3.5
(skin type)
Kricker (1991)23 2.42, 0.97–6.05 1.00, 0.49 –2.05 12.44, 3.86 –40.07 34.32, 14.02–84.01 1.54, 0.45–5.30
(40+ vs. 0) (skin type)

*Data on painful burns and the number of such burns.

Numbers in italics are statistically NS.

1279
1280 Review Predictive value of phenotypic variables for skin cancer
of common nevi, presence of atypical nevi, and freckling
serve as consistent, independent markers of risk for
melanoma.
Basal cell carcinoma
Basal cell carcinoma (BCC) is the most common skin cancer
among white people and causes significant morbidity. Studies
attempting to quantify the relative influence of pigmentary
factors have given heterogeneous results, although weak
trends are apparent. On the other hand, sun exposure indices
appear to be more consistent predictors of increased risk. The
most recent prospective study assessing risk factors involved
44,591 American-Caucasian male healthcare professionals,
40–75 years of age, who were followed for 8 years.12 There
were 3273 cases of self-reported BCCs, the majority of which
were confirmed by medical records. Factors that predicted an
elevated risk include red hair (red versus black, RR = 1.46,
95% CI = 1.15–1.86), a tendency to painfully burn (painfully
burn versus tan, RR = 2.13, 95% CI = 1.93–2.38), and greater
than ten lifetime sunburns (RR = 1.69, 95% CI = 1.32–2.18).
Painful burns were more significant than simply the tendency
to burn or tan. Eye color was no longer significant after
adjustment for other variables. Pigmentary variables only
became more significant when combined, showing that the
individual with red/blond hair, hazel/green/blue eyes and
tendency to sunburn had the highest relative risk (RR = 3.08,
95% CI = 2.51–3.79).
The other major prospective study was carried out in a
cohort of 73,366 USA female nurses, 34–59 years of age, who
were followed for 4 years.13 Hair color again emerged as a
positive risk factor in a dose-response manner. Red hair
(RR = 2.45, 95% CI = 1.89–3.19) had the most elevated age-
adjusted RR followed by blond (RR = 1.37, 95% CI = 1.09–
1.71) and light brown hair (RR = 1.27, 95% CI = 1.08–1.49).
Relative risks were obtained by comparing against dark
brown hair. Other significant risk factors were related to
intensity of sun exposure and personal susceptibility. Ten-
dency to sunburn as a child or adolescent and lifetime number
of severe and painful sunburns on the face or arms were
independent markers of increased risk in a dose-dependent
manner. Tendency to tan was associated with decreased risk,
but this risk was not significant after controlling for other
constitutional factors.
A number of case–control studies have examined the role
of pigmentary variables with inconsistent results. In the
largest case–control study involving 827 patients in the UK, eye
color (age and gender-adjusted RR = 1.71, 95% CI = 1.23–
2.36), skin type I (RR = 2.36, 95% CI = 1.07–2.57) and hair
color (RR = 1.61, 95% CI = 1.03–2.55) were all shown to be
statistically significant risk factors.14 In contrast, the most
recent study in Germany involving 213 cases showed that
among the pigmentary factors, only hair color retained
an elevated risk (red/fair versus brown/black, RR = 4.3,
International Journal of Dermatology 2006, 45, 1275 –1283
Xu and Koo
95% CI = 2.3–8.0).15 Other significant factors include sun
exposure indices such as actinic keratoses (RR = 2.7,
95% CI = 1.3–5.9) and solar lentigines (RR = 2.5,
95% CI = 1.2–5.3). A second recent case–control study of
165 cases in a Mediterranean population of Italy further
showed that neither pigmentary traits nor skin type was
statistically significant, whereas the presence of actinic
keratoses (RR = 3.2, 95% CI = 1.1–9.4) again emerged as a
more prominent risk factor.16 Similarly, in a Danish case–
control study involving 145 cases, hair, eye, and skin color
were not statistically significant and skin type II only showed
marginally increased risk.17 Finally, a Canadian case–control
study among white people showed that freckling (absent versus
present, RR = 1.8, 95% CI = 1.2–2.5) was an independent
risk factor for BCC.18 Therefore, although the data for pig-
mentary factors remain unclear, studies more consistently
show that sun exposure indices such as freckling, actinic
keratoses and solar lentigines lead to increased risk. In addition,
very few studies have examined if the number of nevi
increases the risk of BCC. The prospective study by van Dam
et al.12 is one of the few that examined the effect of moles, and
found that six or more common moles on the forearms had
little statistical significance (RR = 1.20, 95% CI = 1.00–1.45).
Therefore, markers of reaction to sun exposure appear to be
more consistent predictors of risk than individual pigmenta-
tion characteristics, which underscores the importance of
UV-light exposure in pathogenesis.
Squamous cell carcinoma
Squamous cell carcinoma (SCC) is the second most common
skin cancer in white people. However, there are surprisingly
few studies investigating phenotypic risk factors for SCC. In
1995, a prospective study of 107,900 white North American
female nurses aged 30–55 years had 197 histologically
confirmed cases of SCC over an 8-year follow up.19 Of the
pigmentary factors, only hair color was examined, and it
was found to have a statistically significant RR (red versus
dark brown, RR = 2.0, 95% CI = 1.1–3.7). Other variables
focused on measures of sun exposure, and it was found that
the number of severe sunburns was a strong risk factor
(RR = 2.4, 95% CI = 1.5–4.0), outweighing the importance
of tendency to burn or tan. Finally, the number of moles
on the arm was found to be insignificant (RR = 1.6,
95% CI = 0.9–2.9).
The majority of other studies are case–control studies
showing that like BCC, sun exposure indices such as freckling
and actinic keratoses are very predictive of increased risk
whereas individual pigmentary characteristics have a weaker
association. The only sun-exposure index not found to be
statistically significant was the presence of solar lentigines. In
the most recent Australian case–control study of 145 patients
between the ages of 40–64 years, they found that increased
risk was more strongly linked with sun exposure indices
© 2006 The International Society of Dermatology
Xu and Koo
rather than the pigmentary traits of hair, eye and skin color.20
In fact, multivariate adjusted RR were statistically in-
significant for hair color (red versus black, RR = 1.4,
95% CI = 0.51–4.0), eye color (light-blue versus brown,
RR = 1.2, 95% CI = 0.47–2.8), and skin color as measured
by skin reflectance (51% vs. 84%+, RR = 1.5, 95% CI = 0.81–
2.7). On the other hand, freckling as an adult (heavy versus
none, RR = 14, 95% CI = 3.8–52) and solar keratoses
(40+ vs. 0, RR = 47, 95% CI = 20–110) were very strongly
associated with increased risk. In addition, individuals who
severely burned on exposure to sunlight (RR = 2.6,
95% CI = 1.2–7.1) and those who were unable to tan
(RR = 3.5, 95% CI = 1.5–2.8) had high RRs.
With regard to pigmentary factors, although the trend is
weaker, hair color appears to be more predictive than eye or
skin color. A Canadian case–control study in a white male
population with 180 cases of SCC showed a statistically sig-
nificant RR for red hair only (red versus black, RR = 4.1,
95% CI = 1.1–15.5) and not for blond or brown hair.21 In
addition, this study showed that the number of severe
sunburns earlier in life was much more significant (RR = 10.5,
95% CI = 2.9–38.0) than skin type (I vs. IV, RR = 1.6,
95% CI = 0.8–3.5). The multicenter “Helios” case–control
study conducted in southern-Europe with 228 cases of SCC
in adults between 20–70 years again showed that light hair
color, especially red (red versus black, RR = 12.50,
95% CI = 4.13–37.86) and blond hair (blond versus black,
RR = 4.88, 95% CI = 2.24–10.63), were strong risk factors.
A weaker association was found for eye color but was still
statistically significant for blue/hazel/gray eye color (RR = 1.83,
95% CI = 1.11–3.03) and light brown/green eye color
(RR = 1.75, 95% CI = 1.12–2.71). Parallel RR were assessed
for BCC and although they were significant, the RR associa-
tions were not as strong. Thus, pigmentary factors were
shown to be more predictive of risk for SCC than BCC in this
study.22 Also, the study assembled combinations of different
risk factors to assess if these factors are additive and which
factor contributes more to risk. It was found, as expected,
that individuals with red hair and blue eyes who always
burned were at highest risk (RR = 53.98, 95% CI = 10.72–
271.86). However, when examining the various combina-
tions of data, all individuals with red hair had higher RRs
than individuals with blond or dark hair regardless of
other variables (eye color, tendency to burn or tan). Even the
individual with red hair and blue eyes who always tanned
(RR = 24.93, 95% CI = 4.98–124.72) had a higher RR than
someone with blond hair and blue eyes who always burned
(RR = 16.79, 95% CI = 3.75–75.25), suggesting that hair
color indeed seems to outweigh other pigmentary factors in
determining risk. Therefore, associations do exist between
SCC and pigmentary traits such as hair color, but sun
exposure indices and sunburn history are more consistent in
predicting risk.
© 2006 The International Society of Dermatology
Predictive value of phenotypic variables for skin cancer Review 1281
Aside from the “Helios” study, a case–control study in
Australia has also compared risk factors for BCC and SCC,
showing that for the sun exposure indices of adult freckling
(RR = 3.96, 95% CI = 1.66–9.44 for SCC and RR = 3.11,
95% CI = 1.63–5.93 for BCC) and solar keratoses (40+ vs. 0,
RR = 34.32, 95% CI = 14.02–84.01 for SCC, RR = 10.44,
95% CI = 5.81–18.78 for BCC), SCC had much more
elevated RR ratios than BCC.23
Discussion
Although the Fitzpatrick skin typing system is commonly
used to assess an individual’s risk for skin cancer, the latest
data show that skin type is not the best measure of risk.
For melanoma, BCC, and SCC there are more predictive
phenotypic variables specific to each type of cancer. Despite
the heterogeneity of data on these phenotypic risk factors in
white people, general trends can be identified based upon the
factors that consistently give the highest RR (Fig. 1).
For melanoma, our results show that light hair color,
freckling, a large number of common nevi (> 100), and the
presence of atypical nevi consistently predict increased risk.
These findings agree with studies suggesting multiple patho-
genetic mechanisms for melanoma. Sturm et al. described
two phenotypes that are at higher risk for melanoma: light-
skinned individuals with red hair who are prone to freckling
but with few melanocytic nevi, and those with a darker com-
plexion but with more nevi. These two phenotypes parallel
two postulated mechanisms in melanoma formation: one
along the UV-sensitivity pathway and the other along the
nevus pathway.24
For BCC, sun exposure indices such as actinic keratoses,
solar lentigines, and freckling consistently predict elevated
risk whereas the predictive value of pigmentary factors is not
clear. Only light hair color has been an inconsistent risk
predictor in prospective trials.12,13 In addition, the tendency
Figure 1 Predictive phenotypic risk factors
International Journal of Dermatology 2006, 45, 1275 –1283
1282 Review Predictive value of phenotypic variables for skin cancer
for severe burns and the number of such burns appear more
important than simply the tendency to burn or tan. This
observation supports the hypothesis that in BCC, intermit-
tent, intense exposure leading to sunburn is more significant
than cumulative lifetime exposure with minimal sunburn.18
Squamous cell carcinoma is more strongly associated with
both pigmentary factors and sun exposure indices than BCC.
Light hair color is the main pigmentary trait that remained a
consistent predictor of risk. Most importantly, the sun expo-
sure indices of freckling and actinic keratoses strongly predict
increased risk, again confirming the critical role of chronic
UV damage in a susceptible individual. Studies have shown
that a cumulative lifetime dose of sun exposure, especially higher
doses later in life leading to sunburn, plays an important role
in the pathogenesis of SCC.21,25
This is the first comprehensive review highlighting the most
important phenotypic risk factors of the three common types
of skin cancer. These results provide dermatologists with
better guidance in more precisely identifying and screening
high-risk individuals and determining if they are appropriate
candidates for treatments such as phototherapy. Data on
these phenotypic variables also provide further insight into
the pathogenetic mechanisms of these cancers. Individuals
with light phenotypic features have an increased risk of skin
cancer because of their sensitivity to ultraviolet light. How-
ever, UV-sensitivity is only one pathway to skin carcinogenesis.
For example, Sturm et al. discussed multiple pathways for
melanoma development.24,26 Aside from the UV-sensitivity
and nevus pathways, genes that determine phenotypic variation
may control cell-signaling pathways that contribute directly
to carcinogenesis. Characteristics such as red hair are strongly
determined by the polymorphic human melanocortin-1
receptor (MC1R) gene, and these same receptor variations
may cause changes in cAMP activation in cell-signaling
pathways that potentially influence the risk of melanoma
formation. Recent evidence of MC1R dimerization in vivo
provides mechanistic insight into the function of this receptor
and further attests to the highly complex nature of the MC1R
system in determining phenotype.27 Therefore, red hair may
have consistently served as an independent risk factor because
it predicts both environmental and genetic influences on
carcinogenesis. Whether the same genes that determine phe-
notypic characteristics also influence carcinogenesis at the
biochemical level is an area with much potential for further
research.
Limitations
Our results were obtained from a combination of different
study designs, but more weight was given to meta-analyses
and prospective trials because these are larger studies with
less potential for bias. Although meta-analyses may be limited
by poor control of bias within each individual study, the
results were mostly consistent with major prospective trials
International Journal of Dermatology 2006, 45, 1275 –1283
Xu and Koo
and case–control studies. Therefore, this data-set is likely to
be representative of the overall trend in risk factors.
Prospective studies are also preferred owing to elimination
of recall bias which may be problematic with case–control
studies. Unfortunately, only a few prospective trials have
been conducted to assess risk factors for skin cancer, with the
majority of studies being case–control in design. Despite
flaws with case–control studies such as recall bias and appro-
priate selection of controls, many phenotypic factors rely
more on visual assessment than recollection of remote events
in the past, with the exception of sunburn history. Thus, there
is a decreased likelihood of recall bias. In a recent study by
Rosso et al. the reproducibility of responses given by indi-
viduals about skin characteristics and sun exposure history
on two different occasions was assessed.28
The authors re-interviewed participants in the “Helios” trial
and found that hair and eye color showed high reproducibility,
lifetime sun exposure and sunburns during childhood showed
substantial reproducibility, and the number of lifetime
sunburns showed poor reproducibility. They found no
significant differences in responses between cases and
controls. Therefore, this study indicates that there is overall
good reproducibility even with regard to sun exposure
history.
Another concern with evaluating and comparing data
across studies is that there is variability between the ways that
traits are measured and differences in prevalence of risk
factors in various populations. For example, while in some
studies, skin type is determined visually, in others it is meas-
ured more objectively by spectrophotometer. Furthermore,
even among the white populations world-wide, there are
differences in prevalence rates of skin cancer and phenotypic
characteristics within each group. For example, multiple
studies have shown that individuals of southern-European
origin are much less likely to develop BCC or SCC. How-
ever, the “Helios” study assessed risk factors in a southern-
European population, and major risk factors still retained
their significance. Finally, there is also variability in the way
that data are presented in the different studies. In some studies,
red hair may be compared with dark brown hair, whereas in
others it is compared with black hair. Despite all the above
considerations, major trends exist even across different study
designs with varying populations, thus giving support to our
conclusions.
Conclusion
Despite the traditional and widespread use of the Fitzpatrick
skin typing system to identify individuals prone to skin can-
cer, the latest available data suggest that we should go beyond
skin typing for more precise risk assessment using the most
predictive phenotypic risk factors specific to each type of skin
cancer.
© 2006 The International Society of Dermatology
Xu and Koo
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