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Number of melanocytic nevi as a major risk factor for malignant melanoma
II
I
I
Number of melanocytic nevi as a major risk factor for malignant melanoma Elizabeth A. Holly, Ph.D., M.P.H.,*'**'**** John W. Kelly, M.D., F.A.C.D.,***'***** Steven N. Shpall, M.D.,*** and Shu-Hui Chiu, M.S.* Belmont, San Francisco, and Stanford, CA, and
Melbourne, Australia A study of 121 melanoma patients and 139 control subjects from the University of California, San Francisco clinics was conducted among whites to examine the relationship between number of melanocytic nevi and cutaneous melanoma. Nevi that measured 2 mm or more in diameter were counted over the body by a dermatologist and a dermatology fellow. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p < 0.001). Relative risks were 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for more than 100 nondysplastic melanocytic nevi. Relative risks were 3.8 (p = 0.001) for 1 to 5 dysplastic nevi and 6.3 (p = 0.003) for 6 or more of these lesions. Report of blistering sunburns or of a previous skin cancer and having red or blond hair at the age of 20 were also independently associated with an increased risk of cutaneous melanoma. If confirmed in larger studies, the results presented on number of nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma. (J AM ACAD DERMATOL1987;17:459-68.)
Early diagnosis and intervention is the only method known to alter dramatically the course of malignant melanoma. Increased awareness of the importance of early diagnosis has focused attention on the identification of persons at high risk for the development of melanoma. There has been some indication in the medical literature that common acquired melanocytic nevi may be an important risk factor for cutaneous melanoma. ~.~ Other From Northern California Cancer Center, Betmont,* the Departments of Epidemiology** and Dermatology,*** University of California, San Francisco, the Department of Family and Community Medicine, Stanford University, Stanford,**** and Alfred Hospital, Melbourne.***** Supported by National Cancer Institute Grant No. 5 P30 CA19408 to the Northern California Cancer Center. Accepted for publication May 6, 1987. Reprint requests to: Dr. Elizabeth A. Holly, Northern California Cancer Center, P.O. Box 2030, Belmont, CA 94002-5030.
studies have suggested that dysplastic nevi may be a risk factor for melanoma, 2 particularly in melanoma-prone families. 3 However, the degree of risk for nonfamilial melanoma that is contributed by nondysplastic melanocytic nevi and clinicalIy determined dysplastic nevi 4 remains uncertain. Three case-control studies have examined the number of melanocytic nevi occurring on the arms and found this to be the strongest single risk factor for melanomaY 7 These studies did not examine nevi at other sites nor were dysplastic nevi considered. Dysplastic melanocytic nevi are a subset of melanocytic nevi that show characteristic clinical and histologic features and may be considered as intermediates between common acquired nevi and melanomaJ '9 Greene and coworkers 4 demonstrated that dysplastic nevi served as a marker for melanoma risk in a group of melanoma-prone fam459
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T a b l e I . Characterizations u s e d to count lesions Lesion
Common acquired nevi Junctional
I
Size
I
Profile
I
>/2 m m
Flat, macular
Compound
~ 2 mm
Intradermal
t>2 mm
Slightly raised plaque, nodular, sessile, or pedunculated Slightly raised plaque, nodular, sessile, or pedunculated Flat, macular
Benign lentigo
<7 mm
Color
Border
Medium to dark brown or black Light, medium, dark brown, or black
Even and well defined Even and well defined
Skin-colored or mildly to markedly erythematous Light, medium dark brown, or black
Even and well defined Even and well defined or finely irregular
Freckle
< 3 mm
Flat, macular
Caf6 au lair spot
~>3 mm
Flat, macular
>t10 mm
Flat, macular
Nevus spilus
Blue nevus Congenital nevus
~<5 mm > 10 mm
Light to medium brown Light brown
Macular, plaquelike, or nodular Macular, plaquelike, or nodular
ilies. In these families the lifetime risk for develo p m e n t of m e l a n o m a , associated with presence o f dysplastic nevi, approached 1 0 0 % ? T h e r e is, however, little k n o w l e d g e about the degree of risk for melanoma associated with dysplastic nevi occurring outside the context o f familial melanoma, m T h e aim o f this study was to apply carefully a set o f clinical diagnostic criteria to assess the number o f nondysplastic m e l a n o c y t i c nevi and dysplastic nevi at all body sites in a group of patients with nonfamilial m e l a n o m a and in a group o f control subjects. The numbers o f nevi were then related to m e l a n o m a risk, while simultaneously controlling for the confounding influence of other k n o w n risk factors for m e l a n o m a . PATIENTS A N D M E T H O D S Subjects
Study cases consisted of 121 consecutive melanoma patients with nodular or superficial spreading melano-
Grouped brown speckles +- caf6 au lait background Blue to slate-gray Light brown to black
Even and sometimes poorly defined Well defined and irregular Poorly defined
Even with variable definition Well defined and even
mas, 61 men and 60 women, seen in the Melanoma Clinic at the University of Califomia, San Francisco. The control group of 139 patients, 68 men and 71 women, was also seen in clinics at the University of California Medical Center. Patients with lentigo maligna melanoma were excluded from the study because these melanomas rarely arise in association with a preexisting nevus and such associations may be coincidental. Patients with acral lentiginous melanoma were also excluded because the relationship of these melanomas to nondysplastic melanocytic nevi remains unclear. Patients first seen at the Medical Screening Clinic, who were to be referred to other clinics for various outpatient procedures, comprised 80% of the control subjects. Patients seen in the Orthopedic Clinic comprised the other 20% of the control group. The dermatology clinic was not used for control subject selection. All subjects were white, were seen between April 1984 and October 1985, and were between the ages of 20 and 74. Control subjects were chosen to be proportionally representative of the melanoma patients by sex and by age within 5-year age groups.
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Table II. Criteria for diagnosis o f dysplasia in melanocytic nevi
Distribution of pigmentation
Skin markings
Even or evenly and finely speckled Even or evenly and finely speckled
Unchanged or slightly accentuated Accentuated, diminished, or absent
Absent
Diminished or absent
Even
Even
Unchanged or, in the case of a senile lentigo, flattened by hyperkeratosis Unchanged
Even
Unchanged
Speckled
Unchanged
Even
Unchanged
Even
Mammillated, rugose, papular, or verrucous
At least three of the following six criteria must be present: Ill-defined border Irregular border Irregularly distributed pigmentation Diameter ~5.0 mm Background erythema Accentuated skin markings ("pebbled" or "cobblestoned")
ing three or more major clinical features was regarded as clinically dysplastic. Lesion counts
Clinical diagnostic criteria The clinical diagnosis of common acquired nevi will, in many instances, be difficult and the differential diagnosis must include lentigines, freckles, nevi spili, dysplastic nevi, congenital nevuslike nevi, caf6 au lait spots, blue nevi, seborrheic keratoses, dermatofibromas, pigmented solar keratoses, and pigmented basal cell carcinomas. In order to minimize error in our lesion counts, a series of clinical characterizations of'the lesions to be counted was established (Table I), and these were used by a dermatologist and a dermatology fellow to assess each lesion counted. As it was not possible to excise every nevus that was considered to be dysplastic for histologic confirmation of the diagnosis, the results of a previous study by one of the investigators were used for the clinical identification of dysplastic nevi. ~ From the examination of clinical photographs of 175 dysplastic nevi, confirmed on histology, six common distinguishing clinical features were found (Table II). Ninety-five percent of these dysplastic nevi showed at least three of the six major features.S For the purpose of this study, any nevus show-
Melanocytic nevi were counted over the entire body, except the scalp and genitals, by a dermatologist (J. W. K.) and a dermatology fellow (S. N. S.). Nevi that measured 2 mm or more in diameter were counted and recorded according to body location: head and neck, upper arms, forearms and back of hands, palms, chest, abdomen, upper part of back, lower part of back, buttocks, thighs, legs, top of feet, and soles of feet. A count also was made of other types of pigmented lesions: caf6 au lair spots, nevi spill, congenital melanocytic nevi, blue nevi, and melanomas. Freckles and lentigines were recorded as none, few, moderate, and many. Clinically determined dysplastic nevi for each body location were counted separately. To develop consistency of diagnoses and accuracy in lesion counts between the two observers, lesions were counted on a dozen patients by both observers before the study began. Each physician counted nevi on approximately the same proportion of melanoma patients as on control subjects. All pathology slides for the melanoma patients were reviewed by one derrnatopathologist (Richard W. Sagebiel) at the University of California, San Francisco. A separate report will include the distribution of melanocytic nevi, with details on histology, and other types of pigmented lesions by body location. Interviews Prior to the nevi count, subjects were queried in the clinic by one of the physicians or by a trained interviewer. The interview took approximately 30 minutes to complete and covered the following topics: ethnic origin, education, residential history, eye color, natural hair color at age 20, exposure to sunlight on the job,
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Table I I I . Relative risks (RR) and 95% confidence intervals (CI) for melanocytic nevi greater than 2 m m in diameter counted on m e l a n o m a patients and control subjects* Subjects, number, and percent Number of nevi
0- 10 11- 25 26- 50 51-100 101 +
139 con/foist
121 casest
7 18 28 34 34
(6) (15) (23) (28) (28)
28 51 30 22 8
(20) (37) (22) (16) (6)
Unadjusted
Adjusted
RR
95% CI
RR
95% CI
1.0 1.4 3.7 6.2 17.0
-0.52- 3,8 1.4 - 9.9 2.3 -16.6 5.5 -52.7
1.0 1.6 4.4 5.4 9.8
-0.50- 4.9 1.4 -13.9 1.6 -18.4 2.5 -38.6
*Tile logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair color, previous skin cancers, and age. tNumber of cases and controls are presented for the univariate analyses; missing values may make these numbers slightly lower for multivariate analyses.
Table IV, Relative risks (RR) and 9 5 % confidence intervals (CI) for clinically determined dysplastic nevi for m e l a n o m a patients and control subjects* Subjects, number, and percent Number of dysplastie nevi
Adjusted
Unadjusted
I
121 cases
[
139 controls
RR
115 (83) 19 (14) 5 (3)
1 4.6 1 I. 1
I
95% CI
RR
95% CI
-2.4- 8.7 4.0-30.4
1.0 3.8 6.3
-1.7- 8.3 1.9-21.5
F
0 1-5 6+
54 (45) 41 (34) 26 (21)
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair color, previous skin cancers, and age.
skin type, frequency and duration of sunbathing during different life stages, number of painful and blistering sunburns at different times of life, use of tanning salons, history of skin cancer, number of family members with large numbers of moles, and number of family members diagnosed as having melanoma or skin cancer. Questionnaires were edited and coded with most questions coded as they were asked o f the subjects.
Analysis The BMDP multiple logistic regression analysis program was used to control for potential confounding and to calculate odds ratios (hereafter called relative risks [RR]) and 95% confidence intervals (CI) ~ after preliminary univariate analyses were completed. Adjusted relative risks are presented in the text unless otherwise noted. The six variables used in the final logistic model were: total number of nondysplastic melanocytic nevi, number of dysplastic nevi, reported number of sunburns that caused blisters, hair color, history of a previous skin cancer other than melanoma, and age.
Because subjects with a history of melanoma in their families might be different from the rest of the group, six patients and four controls who reported this history in one other family member were removed from the data set and the logistic analyses were repeated. No subjects were from families who reported two or more relatives with melanoma. Since no significant differences were noted between these two analyses, the results presented here include all subjects in the study. No significant differences were noted between men and women for the variables used in the model; therefore, the data by sex were combined. All p values calculated were two-sided. RESULTS T h e response rate o f the m e l a n o m a patients and controls was greater than 95%. Melanoma patients had more nevi that were 2 m m or more in diameter than did the nonmelanoma patients. The mean and median values for both sexes combined were
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Table V. Relative risks (RR) and 95% confidence intervals (CI) for nondysplastic melanocytic nevi greater than 2 m m in diameter counted on melanoma patients and control subjects with and without dysplastic nevi Subjects with dysplastic nevi* Number and percent Number of nevi
67 cases
0- 25 26- 50 51-100 101 +
5 11 22 29
( 8) (16) (33) (43)
Unadjusted
I
Adjusted
24 controls
RR
95% CI
RR
95% CI
5 (21) 7 (29) 10 (42) 2 ( 8)
1.0 1.6 2.2 14.5
-0.33- 7.5 0.52- 9.4 2.2 -96.4
1.0 1.9 2.5 15.4
-0.33- 10.4 0.48- 12.8 2.0 -119.9
Subjects without dysplastic nevit Number and percent Number of nevi
Unadjusted
Adjusted I
54 cases
,
115 controls
RR
95% CI
RR
[
95% CI
l
0-25 26-50 51 +
20 (37) 17 (32) 17 (32)
74 (64) 23 (20) 18 (16)
1.0 2.7 3.5
-1.2-6.1 1.5-8.0
1.0 4.5 5.1
-1.8-11,0 2.0-12,6
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, hair color, and age. tThe logistic model included total number of nondysplastic melanocytlc nevi, hair color, previous skin cancer, and age.
nearly three times larger in the melanoma patients when compared to the control subjects. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p < 0.001). The minimum and maximum number of nondysplastic melanocytic nevi counted was 5 and 539 for melanoma patients and 0 and 304 for control subjects. The multiple logistic model was used to determine relative risks for number of nondysplastic melanocytic nevi (as a categorical variable) after controlling for the five other variables noted in the analysis section above. The relative risk was 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for having more than 100 nondysplastic melanocytic nevi (Table III). The p value for linear trend was p < 0.0001. Melanoma patients were more likely than control subjects to have clinically determined dysplastic nevi (p < 0.0001). These lesions were present in 67 of 121 melanoma patients (55%), while 24 of 139 control subjects (17%) had dysplastic nevi. When the six melanoma patients who reported relatives with melanoma were removed
from the study data set, 62 of the 115 patients or 54% had dysplastic nevi. The average number of clinically determined dysplastic nevi was 6.3 for melanoma patients and 0.7 for control subjects. The minimum and maximum number of dysplastic nevi counted was 0 and 153 for melanoma patients and 0 and 14 for control patients. After adjustment for the five other variables in the model, the relative risk associated with having 1 to 5 dysplastic nevi was 3.8 (p = 0.001) and 6.3 (p = 0.003) for six or more dysplastic nevi (Table IV). The p value for trend was p < 0.0001. To determine the effects of nondysplastic melanocytic nevi and clinically determined dysplastic nevi separately from each other, the study group was divided into persons with and those without dysplastic nevi, and the logistic model was rerun. Table V shows the relative risks and 95% confidence intervals for nondysplastic melanocytic nevi in persons with and without clinically determined dysplastic nevi on univariate and multivariate analysis. Among subjects with dysplastic nevi (Table V), relative risks for nondysplastic melanocytic nevi were 1.9 for 26 to 50 nevi (p = 0.48), 2.5 for 51 to 100 nevi (p = 0.28), and 15.4 (p = 0.009) for having more than 100 nondysplastic
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Table VI. Relative risks (RR) and 95% confidence intervals (CI) for blistering burns, hair color, and previous skin cancer for melanoma patients and control subjects* Subjects, number, and percent 121 cases
Unadjusted
Adjusted
139 controls
Characteristic
No.
%
No.
Sunburns with blisters Score valuer 0 1 2 3+ Red or blond hair Previous skin cancer
33 36 18 24 48 18
30 32 16 22 40 15
66 40 19 11 33 6
[
%
RR
95% CI
RR
95% CI
49 29 14 8 24 4
1.0 1.8 1.9 4.4 2.1 3.9
-0.97- 3.3 0.88- 4.1 1.9 -10.0 1.2 - 3.6 1.5 -10.3
1.0 1.4 1.7 3.8 2.2 3.8
0.67- 3.0 0.66- 4.4 1.4 -10.4 1.1 - 4.5 1.2 -12.4
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic rtevi, sunburns with blisters, hair color, previous skin cancers, and age. tThe score combined number of sunburns that caused blisters reported during elementary school, high school, and young adult years (see text).
melanocytic nevi. The p value for trend was p < 0.0001. Among persons without clinically determined dysplastic nevi (Table V), relative risks for nondysplastic melanocytic nevi were 4.5 for 26 to 50 nevi (p = 0.001) and 5.1 for 51 or more nevi (p < 0.001). The p value for trend was p < 0.001. The groups 51 to 100 and 100 or more nevi were combined for persons without dysplastic nevi because the number of subjects in the 1 0 0 + group was too small for meaningful analysis. To determine whether the subjects with dysplastic nevi were more likely to have more of these lesions if they had more nondysplastic melanocytic nevi, the means and medians for dysplastic nevi were calculated within each group of nondysplastic melanocytic nevi. The more nondysplastic melanocytic nevi present on the skin of melanoma patients, the more likely they were to have a larger number of dysplastic nevi. The mean number of dysplastic nevi was 2 in melanoma patients with 0 to 25 nondysplastic melanocytic nevi, 3 for 26 to 50 nevi, 5 for 51 to 100 nevi, and 21 for patients who had more than 100 nondysplastic melanocytic nevi. To control for potential residual confounding, because dysplastic nevi were more common in subjects w h o had more nondysplastic nevi, adjustment was made for the number Of dysplastic nevi in the logistic model. Using the logistic model that included the six previously named variables, melanoma patients re-
ported more sunburns that caused blisters than did the control subjects. A sunburn score was devised that combined recall of number of blistering burns in elementary school, high school, and young adult years. Subjects were asked to recall the number of blistering burns they sustained within a range (none, 1-10, 11-20, 21-30, >30) during each life stage. A score was assigned to each range selected so that "none" received a score of 0 and " > 3 0 " a score of 4. For each subject the scores for each life stage were summed to obtain a single value to indicate the number of blistering burns over the three life stages. The possible scores ranged from zero, which meant the subject did not recall any blistering burns in any of these three periods of his or her life, to 12, which meant recall of a large number of blistering burns in each of these periods. The highest score obtained by any subject using this method was 9. Relative risks associated with the sunburn score were 1.4 for a score of 1 (p = 0.30), 1.7 for a score of 2 (p = 0.27), and 3.8 (0 = 0.01) for a score of 3 or greater (Table VI). In the logistic model, melanoma patients and control subjects were different with regard to natural hair color at age 20, with a relative risk of 2.2 for having blond or red hair versus brown or black (p = 0.03) (Table VI). In the same model, a relationship also was noted between previous skin cancer and melanoma. Melanoma patients
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Table VII. Relative risks and 95% confidence intervals for hair and eye color* $ubjects~ number, and percent
Color of Hair
Eyes
Dark Dark Light Light
Dark Light Dark Light
Cases
19 54 2 46
(16) (45) ( 2) (38)
Unadjusted
Controls
RR
95% CI
37 (27) 59 (50) 1 ( 1) 32 (23)
1.0 1.5 3.9 2.8
0.79- 2.9 0.33-45.8 1.4 - 5.7
--
Adjusted RR
95% CI
1.0
1.9 6.4 3.4
0.76- 4.6 0.35-115.0 1.3 - 9.2
*Hair and eye color are mutually adjusted for each other; variables in the logistic model were total numbers of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair and eye color (mutually adjusted to be one variable), previous skin cancer, and age.
tended to report a previous nonmelanoma skin cancer more often than did control subjects with a relative risk o f 3.8 (p = 0.03). Eye color on univariate analysis tended to be lighter in melanoma patients than in controls with a relative risk of 1.8 (p = 0.06). Eye color was not used in the earlier multivariate model because it was correlated with hair color. However, because hair color and eye color each have been shown to be related to melanoma risk in other studies, 1'57 the two variables were mutually adjusted for each other with relative risks and confidence intervals calculated for the mutually adjusted variables while controlling for the other variables used in the earlier model. Natural hair color was categorized as light if red or blond at age 20, and eyes were considered dark if they were brown. Table VII gives mutually adjusted relative risks with a relative risk of 1.9 (p = 0.17) if the subjects had dark hair and light eyes, 6.4 (p = 0.21) if the subjects had light hair and dark eyes (based on only three subjects), and 3.4 (p = 0.02) if the subjects had light hair and light eyes. In the multiple logistic model that included all six variables, the order of importance of the variables using stepwise regression was: total number o f nondysplastic melanocytic nevi and dysplastic nevi as the most important variables (each contributed nearly identically to the log-likelihood), followed by reported number of sunburns that caused blisters, having red or blond hair, having reported a previous skin cancer, and age. The patients with cutaneous melanoma were similar to the patients in the control group with respect to: education; exposure to sunlight while at work; skin
type; the number of times they sunbathed each year; time in life when they sunbathed the most-that is, elementary school, high school, or adult years; their use of tanning salons; and tendency to freckle. DISCUSSION This study shows both nondysplastic melanocytic nevi and dysplastic nevi to be independent and strong risk factors for cutaneous melanoma when total number o f nevi at least 2 m m in diameter and clinically determined dysplastie nevi 8 were counted on the entire body surface excluding the scalp and genitals. The relative risk for melanoma rose with increasing numbers of nondysplastic melanocytic nevi. The same was true for the relationship between melanoma risk and numbers of dysplastic nevi. The magnitude of the relative risks associated with large numbers of nondysplastic melanocytic and dysplastic nevi was considerably greater than that associated with the more established melanoma risk factors studied. Tables III and V gave the estimated relative risks for various numbers of nondysplastic melanocytic nevi, either adjusting for number of dysplastic nevi using a logistic model (as in Tables III and V) or for subjects separated into those with and without dysplastic nevi (as in Table V). The relative risks increased with an increasing number of nondysplastic nevi regardless of whether the subjects had dysplastic nevi. However, among subjects with dysplastic nevi (Table V), the number of nondysplastic melanocytic nevi reached statistical significance only if more than 100 nondysplastic melanocytic nevi were present, indicating the impor-
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tance of dysplastic nevi in this group. Comparison of the two parts in Table V shows that the number of nondysplastic melanocytie nevi is an indicator of risk among persons with and without dysplastic nevi; however, significant relative risks were noted for persons with a smaller number of nevi among subjects who had no dysplastic nevi. These results support the findings of another study conducted about the same time in Scotland. ~2 The Scottish study also showed a progressive rise in melanoma risk with increasing numbers of melanocytic nevi greater than 2 mm in diameter. The presence of individual clinical features (large size, color variation, and irregular edge) associated with dysplastic nevi was also studied, each feature in isolation, and found to be associated with marked increases in relative risk. A study conducted in Sydney, Australia showed greater numbers of total melanocytic nevi and dysplastic nevi among melanoma patients than among controls. ~ Few studies comparing melanoma patients and nonpatients have reported actual counts of melanocytic nevi. A group from Queensland, Australia counted nevi on arms and noted moles were more common on the arms of melanoma patients than on the arms of the control s u b j e c t s : After adjustment for hair color and propensity to sunburn, the relative risk estimate was 30 for any nevi counted on the arms versus none. Family history of melanoma was not found to be an independent determinant of disease, a result similar to that found in the current study. A study in Western Australia reported the number of palpable benign pigmented nevi counted on the arms to be the strongest risk factor for melanoma in their study. Estimates of the relative risk were: 2 for persons with 1 to 4 nevi, 4 for persons with 5 to 9 nevi, and 11.3 for persons with 10 or more palpable nevi on their a r m s : Family history was also determined to be a risk factor for cutaneous malignant melanoma in the Western Australia study. A study conducted in England noted that the most strongly associated risk factor for melanoma was the number of raised nevi on the upper arms. 7 Compared to those with no nevi on their upper arms, subjects with 1 or 2 raised moles had an estimated relative risk of 1.8. Those with 3 or more
Journal of the American Academy of Dermatology nevi had a relative risk estimate of 17. Light hair color conveyed an elevated risk estimate while the risk for light eye color was elevated slightly but was not significant. Relative risk estimates for a whole body nevi count conducted by dermatologists were large in the Scottish study, z' ~a Odds ratios for melanoma were 3.0 for 10 to 24 nevi, 6.8 for 25 to 49, and 12.1 for 50 or more nevi. These elevated risk estimates were found in persons who had no clinically determined dysplastic nevi. A recent report from New York noted an odds ratio for melanoma of 1.9 for patients who estimated their average number of moles to be 26 to 100. t3 For those subjects who reported an estimate of 100 or more nevi, the odds ratio for melanoma was 3.7. No association was noted with melanoma risk and time spent exposed to the sun, nor was any significant risk conferred for reporting melanoma in a first-degree relative. A community survey of nevi counted over part of the body, in a population of adults in New Zealand, reported a comparison of nevi in their study with two earlier projects conducted in the early 1950s and early 1970s. 14 Data from the most recent community survey showed the number of nevi to be increasing over time as the incidence of melanoma has become more common. It should be emphasized that the differentiation of nondysplastic melanocytic nevi from other pigmented lesions, such as lentigines and seborrheic keratoses, can be difficult. It is important that the counting of nevi be done by experts and according to stated criteria if the results of studies are to be reliable and useful. The report of Cooke et a114 suggests that more than half of nevi are less than 2 mm in diameter. The nevi counted in the current and the Scottish study 12 were 2 mm or more in diameter, and the total numbers would have been greater had all nevi been counted. The counting of nevi of all sizes is tedious and not practical for the routine assessment of melanoma risk, but a count of all nevi may provide evidence of a stronger risk factor. It is likely that any study that attempts clinical diagnosis of dysplastic nevi will underestimate the risk for melanoma resulting from the presence of dysplasic nevi. It has been noted that criteria re-
Volume 17 Number 3 September 1987
liable for the diagnosis of dysplastic nevi in populations with the dysplastic nevus syndrome will have a very much lower positive predictive value when applied to the general population.15 Our diagnosis of dysplastic nevi among melanoma patients, many of whom had florid dysplastic nevus syndrome, will have been relatively accurate. However, though few dysplastic nevi were counted on the skin in control patients, dysplasia is likely to have been diagnosed by our clinical criteria in nevi that would not have shown histologic evidence of dysplasia, and therefore the effects of dysplastic nevi would have been underestimated. It is unlikely that observer bias could explain the relative risk estimates for the nondysplastic melanocytic nevi given the meticulous assessment of these lesions by body location and the strong risk gradient. However, although point estimates of relative risks for numbers of nevi and dysplastic nevi were large, confidence limits were wide, reflecting the small sample and the possibility of the data being compatible with a smaller risk than given by the point estimates. Melanoma patients were more likely than were control subjects to report first-degree relatives with large numbers of nevi and sunburns with blisters. For these variables, it was not possible to rule out increased awareness on the part of the melanoma patients as a reason for this observation. Although we were unable to rule out selective recall of the cases' history of blistering sunburns, it is noteworthy that cases and controls did not differ with respect to other questions related to frequency and duration of sun exposure. Further, characteristics of the host, such as light hair and eye color, which accompany the likelihood of having had sunburns severe enough to cause blisters, were also more common among the patients with melanoma when compared to the control subjects. The lack of a statistically significant association between family history of melanoma and cutaneous melanoma among patients in this study may be due to small sample size or perhaps incomplete information regarding family members' melanoma history. Since the autosomal dominant form of malignant melanoma is manifest in only a small proportion of all melanoma subjects, these factors together may have been adequate to mask any sta-
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tistical association of familial melanoma as a risk factor in this study population. Other factors that increase the risk of melanoma, such as light eye, hair, or skin color, tendency to bum rather than tan, having had a previous skin cancer, and having had sunburns that caused blisters, have been noted in previous studies? '5'7'1618 None of the previously noted risk factors have been of the same magnitude as that conferred by large numbers of nondysplastic melanocytic nevi and dysplastic nevi. The proportion of melanoma patients who had dysplastic nevi and no report of a family member with melanoma, 54%, was quite similar to the 50% reported among persons with sporadic melanoma in a large clinic on the east coast of the United States. ~9 If confirmed in larger studies, the results presented on number of nondysplastic and dysplastic nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma. 12 The technics of baseline photography of the skin surface and regular follow-up have been well described for management of the dysplastic nevus syndrome. 8.20The results of the present study provide evidence for the value of such management of patients with dysplastic nevi. Further, our findings with respect to total number of nondysplastic melanocytic nevi suggest that these clinical technics might be usefully applied to persons with large numbers of nondysplasic nevi as these individuals are also at increased risk for the development of melanoma. REFERENCES 1. Beral V, Evans S, Shaw H, Milton G. Cutaneous factors related to the risk of malignant melanoma. Br J Dermatol 1983;109:165-72. 2. Swerdlow AJ, English J, MacKie RM, O'Doherty CJ, Hunter JAA, Clark J. Benign naevi associated with high risk of melanoma. Lancet 1984;2:168. 3. Nordlund JJ, Kirkwood J, Forget BM, etal. Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 1985;45:1855-61. 4. Greene MH, Clark WH Jr, Tucker MA, Kraemer K, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-69. 5. Green A, MacLennan R, Siskind V. Common acquired naevi and the risk of malignant melanoma. Int J Cancer 1985 ;35:297-300.
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6. Holman CDJ, Armstrong BK. Pigmentary traits, ethnic origin, benign nevi, and family history as risk factors for cutaneous malignant melanoma. JNCI 1984;72:257-66. 7. Elwood JM, WilliamsonC, StapletonPJ. Malignantmelanoma in relation to moles, pigmentation, and exposure to fluorescent light and other lighting sources. Br J Cancer 1986;53:65-74. 8. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastie melanocytic nevi. J AM ACAD DERMATOL 1986;14:1044-52. 9. Elder DE, Greene MH, Guerry D, Kraemer KH, Clark WH Jr. The dysplastic nevus syndrome--our definition. Arn J Dermatopathol 1982;4:455-60. 10. Kraemer KH, Greene MH, Tarone R, Elder DE, Clark WH Jr, Guerry D. Dysplastic nevi and cutaneous melanoma risk. Lancet 1983;2:1076-7. 11. Breslow NE, Day NE. Statistical methods in cancer research. I. The analysis of case-control studies. Lyon: IARC, 1980. 12. Swerdiow AJ, English J, MacKie RM, et al. Benign melanocytic naevi as a risk factor for malignant melanoma. Br Med J 1986;292:1555-9. 13. Dubin N, Moseson M, Pasternack BS. Epidemiology of malignant melanoma: pigmentary traits, ultraviolet radiation, and the identification of high-risk populations. Recent Results. Cancer Res 1986;102:56-75.
14. Cooke K_R, Spears GFS, Skegg DCG. Frequency of moles in a defined population. J Epidemiol Community Health 1985;39:48-52. 15. Rousch GC, Barnhill RL, Duray PH, Titus LJ, Emstoff MS, Kirkwood JM. Diagnosis of the dysplastie nevus in different populations. J AM ACAD DERMATOL 1986;14: 419-25. 16. Elwood JM, Gallagher RP, Hill GB, Spinelli JJ, Pearson JCG, Threlfall W. Pigmentation and skin reaction to sun as risk factors for cutaneous melanoma: Western Canada melanoma study. Br Med J 1984;288:99-102. 17. Elwood JM, Gallagher RP, Davison J, Hill GB. Sunburn, suntan and the risk of cutaneous malignant melanoma: the Western Canada melanoma study. Br J Cancer 1985 ;51:543-9. 18. Lew RA, Sober AJ, Cook N, Marvell R, Fitzpatrick TB. Sun exposure habits in patients with cutaneous melanoma: a case-control study. J Dermatol Surg Oncol 1983;9:981-6. 19. Kraemer KH, Tucker M, Tarone R, Elder DE, Clark WH Jr. Risk of cutaneous melanoma in dysplastic nevus syndrome types A and B. N Engl J Med 1986;315:1615-6. 20. Greene MH, Clark WH Jr, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma: the familial dysplastic nevus syndrome. N Engl J Med 1985;312:91-7.
ABSTRACTS
Diltiazem-associated exfoliative dermatitis in a patient with psoriasis Lavrijsen APM, Van Dijke C, Vermeer B-L Acta Derm Venereol (Stock_h) 1986;66:536-8 A 73-year-old woman with psoriasis developed exfoliativedermatitis with fever, malaise, and liver enzyme elevations2 days after the introduction of the new calciumantagonist, diltlazem. The disorder rapidly resolved after discontinuationof the drug and treatment with prednisone. Three years previouslythe patient had developed a similar reaction after 12 days of treatment with chloroquine. Diltiazem and chioroquinehavestructuralsimilarities,suggestinga crossreaction between them.
The detectionrate was compared to the isolationrate of the tissue culture technic. In extragenital lesions the sensitivity of the ELISA technic and immunofluorescencewas 79%, in genital lesions, 46.2%, and in cervicallesions, 5,7% and 15.4%, respectively. In some cases immunolluorescence and ELISA were positive while culture was negative, and these results were confirmedwith other immunologic technics. Yehudl M. Felman, M.D.
Psoriasis in immune deficiency related to HTLV III: cellular immunity and immunohistological findings Steigleder GK, Rasokat H, Wemmer U. Z Hautkr 1986;61:1671-8 (German)
J. Graham Smith, Jr., M.D.
Detection of herpes simplex virus antigen with an enzyme immunoassay and direct immunofluorescence technique Henries B, Kruse W, Hofmann H, Petzoldt D, Hautarzt 1986;37:662-6 (German) Four hundred sixty-four clinical specimens from patients with exlxagenital and genital lesions as well as cervical lesions from asymptomatie women were examinedfor the presence of herpes simplex virus antigen by using a commercially available enzyme immunoassay kit (ELISA; Dakopalts, Copenhagen, Denmark) and a direct immnnofluorescence technic with monoclonal antibodies (Syva-Merck, Federal Republicof Germany).
Four patients suffering from immune deficiencyrelated to human T-lymphotrop~c viras type III (HTLV-III) developed psoriasis vulgaris. All patients showed lymphadenopathyand cutaneous hypergy or anergy. In three of them the count of peripheral helper ceils was critically decreased (400/1), and they showed oral candidiasis. One patient suffered from disseminatedKaposi's sarcoma and developed Pneumocystic carinii pneumonia. The psoriasis was extensive, exudative, and refractory. The bulk of dermal infiltratingmononuclear cells were T lymphocytes, mostly the T8-positive phenotype. The majority of these cells were not diminished. The authors here note the developmentof psoriasis in spite of severe disturbancesof cellular immunity and suggest that immunemechanismsmediated by T cells, after having gotten out of control, might play some role in the pathogenesis of the disease. Yehudt M. Felman, M.D.
I
I
Number of melanocytic nevi as a major risk factor for malignant melanoma Elizabeth A. Holly, Ph.D., M.P.H.,*'**'**** John W. Kelly, M.D., F.A.C.D.,***'***** Steven N. Shpall, M.D.,*** and Shu-Hui Chiu, M.S.* Belmont, San Francisco, and Stanford, CA, and
Melbourne, Australia A study of 121 melanoma patients and 139 control subjects from the University of California, San Francisco clinics was conducted among whites to examine the relationship between number of melanocytic nevi and cutaneous melanoma. Nevi that measured 2 mm or more in diameter were counted over the body by a dermatologist and a dermatology fellow. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p < 0.001). Relative risks were 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for more than 100 nondysplastic melanocytic nevi. Relative risks were 3.8 (p = 0.001) for 1 to 5 dysplastic nevi and 6.3 (p = 0.003) for 6 or more of these lesions. Report of blistering sunburns or of a previous skin cancer and having red or blond hair at the age of 20 were also independently associated with an increased risk of cutaneous melanoma. If confirmed in larger studies, the results presented on number of nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma. (J AM ACAD DERMATOL1987;17:459-68.)
Early diagnosis and intervention is the only method known to alter dramatically the course of malignant melanoma. Increased awareness of the importance of early diagnosis has focused attention on the identification of persons at high risk for the development of melanoma. There has been some indication in the medical literature that common acquired melanocytic nevi may be an important risk factor for cutaneous melanoma. ~.~ Other From Northern California Cancer Center, Betmont,* the Departments of Epidemiology** and Dermatology,*** University of California, San Francisco, the Department of Family and Community Medicine, Stanford University, Stanford,**** and Alfred Hospital, Melbourne.***** Supported by National Cancer Institute Grant No. 5 P30 CA19408 to the Northern California Cancer Center. Accepted for publication May 6, 1987. Reprint requests to: Dr. Elizabeth A. Holly, Northern California Cancer Center, P.O. Box 2030, Belmont, CA 94002-5030.
studies have suggested that dysplastic nevi may be a risk factor for melanoma, 2 particularly in melanoma-prone families. 3 However, the degree of risk for nonfamilial melanoma that is contributed by nondysplastic melanocytic nevi and clinicalIy determined dysplastic nevi 4 remains uncertain. Three case-control studies have examined the number of melanocytic nevi occurring on the arms and found this to be the strongest single risk factor for melanomaY 7 These studies did not examine nevi at other sites nor were dysplastic nevi considered. Dysplastic melanocytic nevi are a subset of melanocytic nevi that show characteristic clinical and histologic features and may be considered as intermediates between common acquired nevi and melanomaJ '9 Greene and coworkers 4 demonstrated that dysplastic nevi served as a marker for melanoma risk in a group of melanoma-prone fam459
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T a b l e I . Characterizations u s e d to count lesions Lesion
Common acquired nevi Junctional
I
Size
I
Profile
I
>/2 m m
Flat, macular
Compound
~ 2 mm
Intradermal
t>2 mm
Slightly raised plaque, nodular, sessile, or pedunculated Slightly raised plaque, nodular, sessile, or pedunculated Flat, macular
Benign lentigo
<7 mm
Color
Border
Medium to dark brown or black Light, medium, dark brown, or black
Even and well defined Even and well defined
Skin-colored or mildly to markedly erythematous Light, medium dark brown, or black
Even and well defined Even and well defined or finely irregular
Freckle
< 3 mm
Flat, macular
Caf6 au lair spot
~>3 mm
Flat, macular
>t10 mm
Flat, macular
Nevus spilus
Blue nevus Congenital nevus
~<5 mm > 10 mm
Light to medium brown Light brown
Macular, plaquelike, or nodular Macular, plaquelike, or nodular
ilies. In these families the lifetime risk for develo p m e n t of m e l a n o m a , associated with presence o f dysplastic nevi, approached 1 0 0 % ? T h e r e is, however, little k n o w l e d g e about the degree of risk for melanoma associated with dysplastic nevi occurring outside the context o f familial melanoma, m T h e aim o f this study was to apply carefully a set o f clinical diagnostic criteria to assess the number o f nondysplastic m e l a n o c y t i c nevi and dysplastic nevi at all body sites in a group of patients with nonfamilial m e l a n o m a and in a group o f control subjects. The numbers o f nevi were then related to m e l a n o m a risk, while simultaneously controlling for the confounding influence of other k n o w n risk factors for m e l a n o m a . PATIENTS A N D M E T H O D S Subjects
Study cases consisted of 121 consecutive melanoma patients with nodular or superficial spreading melano-
Grouped brown speckles +- caf6 au lait background Blue to slate-gray Light brown to black
Even and sometimes poorly defined Well defined and irregular Poorly defined
Even with variable definition Well defined and even
mas, 61 men and 60 women, seen in the Melanoma Clinic at the University of Califomia, San Francisco. The control group of 139 patients, 68 men and 71 women, was also seen in clinics at the University of California Medical Center. Patients with lentigo maligna melanoma were excluded from the study because these melanomas rarely arise in association with a preexisting nevus and such associations may be coincidental. Patients with acral lentiginous melanoma were also excluded because the relationship of these melanomas to nondysplastic melanocytic nevi remains unclear. Patients first seen at the Medical Screening Clinic, who were to be referred to other clinics for various outpatient procedures, comprised 80% of the control subjects. Patients seen in the Orthopedic Clinic comprised the other 20% of the control group. The dermatology clinic was not used for control subject selection. All subjects were white, were seen between April 1984 and October 1985, and were between the ages of 20 and 74. Control subjects were chosen to be proportionally representative of the melanoma patients by sex and by age within 5-year age groups.
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Table II. Criteria for diagnosis o f dysplasia in melanocytic nevi
Distribution of pigmentation
Skin markings
Even or evenly and finely speckled Even or evenly and finely speckled
Unchanged or slightly accentuated Accentuated, diminished, or absent
Absent
Diminished or absent
Even
Even
Unchanged or, in the case of a senile lentigo, flattened by hyperkeratosis Unchanged
Even
Unchanged
Speckled
Unchanged
Even
Unchanged
Even
Mammillated, rugose, papular, or verrucous
At least three of the following six criteria must be present: Ill-defined border Irregular border Irregularly distributed pigmentation Diameter ~5.0 mm Background erythema Accentuated skin markings ("pebbled" or "cobblestoned")
ing three or more major clinical features was regarded as clinically dysplastic. Lesion counts
Clinical diagnostic criteria The clinical diagnosis of common acquired nevi will, in many instances, be difficult and the differential diagnosis must include lentigines, freckles, nevi spili, dysplastic nevi, congenital nevuslike nevi, caf6 au lait spots, blue nevi, seborrheic keratoses, dermatofibromas, pigmented solar keratoses, and pigmented basal cell carcinomas. In order to minimize error in our lesion counts, a series of clinical characterizations of'the lesions to be counted was established (Table I), and these were used by a dermatologist and a dermatology fellow to assess each lesion counted. As it was not possible to excise every nevus that was considered to be dysplastic for histologic confirmation of the diagnosis, the results of a previous study by one of the investigators were used for the clinical identification of dysplastic nevi. ~ From the examination of clinical photographs of 175 dysplastic nevi, confirmed on histology, six common distinguishing clinical features were found (Table II). Ninety-five percent of these dysplastic nevi showed at least three of the six major features.S For the purpose of this study, any nevus show-
Melanocytic nevi were counted over the entire body, except the scalp and genitals, by a dermatologist (J. W. K.) and a dermatology fellow (S. N. S.). Nevi that measured 2 mm or more in diameter were counted and recorded according to body location: head and neck, upper arms, forearms and back of hands, palms, chest, abdomen, upper part of back, lower part of back, buttocks, thighs, legs, top of feet, and soles of feet. A count also was made of other types of pigmented lesions: caf6 au lair spots, nevi spill, congenital melanocytic nevi, blue nevi, and melanomas. Freckles and lentigines were recorded as none, few, moderate, and many. Clinically determined dysplastic nevi for each body location were counted separately. To develop consistency of diagnoses and accuracy in lesion counts between the two observers, lesions were counted on a dozen patients by both observers before the study began. Each physician counted nevi on approximately the same proportion of melanoma patients as on control subjects. All pathology slides for the melanoma patients were reviewed by one derrnatopathologist (Richard W. Sagebiel) at the University of California, San Francisco. A separate report will include the distribution of melanocytic nevi, with details on histology, and other types of pigmented lesions by body location. Interviews Prior to the nevi count, subjects were queried in the clinic by one of the physicians or by a trained interviewer. The interview took approximately 30 minutes to complete and covered the following topics: ethnic origin, education, residential history, eye color, natural hair color at age 20, exposure to sunlight on the job,
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Table I I I . Relative risks (RR) and 95% confidence intervals (CI) for melanocytic nevi greater than 2 m m in diameter counted on m e l a n o m a patients and control subjects* Subjects, number, and percent Number of nevi
0- 10 11- 25 26- 50 51-100 101 +
139 con/foist
121 casest
7 18 28 34 34
(6) (15) (23) (28) (28)
28 51 30 22 8
(20) (37) (22) (16) (6)
Unadjusted
Adjusted
RR
95% CI
RR
95% CI
1.0 1.4 3.7 6.2 17.0
-0.52- 3,8 1.4 - 9.9 2.3 -16.6 5.5 -52.7
1.0 1.6 4.4 5.4 9.8
-0.50- 4.9 1.4 -13.9 1.6 -18.4 2.5 -38.6
*Tile logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair color, previous skin cancers, and age. tNumber of cases and controls are presented for the univariate analyses; missing values may make these numbers slightly lower for multivariate analyses.
Table IV, Relative risks (RR) and 9 5 % confidence intervals (CI) for clinically determined dysplastic nevi for m e l a n o m a patients and control subjects* Subjects, number, and percent Number of dysplastie nevi
Adjusted
Unadjusted
I
121 cases
[
139 controls
RR
115 (83) 19 (14) 5 (3)
1 4.6 1 I. 1
I
95% CI
RR
95% CI
-2.4- 8.7 4.0-30.4
1.0 3.8 6.3
-1.7- 8.3 1.9-21.5
F
0 1-5 6+
54 (45) 41 (34) 26 (21)
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair color, previous skin cancers, and age.
skin type, frequency and duration of sunbathing during different life stages, number of painful and blistering sunburns at different times of life, use of tanning salons, history of skin cancer, number of family members with large numbers of moles, and number of family members diagnosed as having melanoma or skin cancer. Questionnaires were edited and coded with most questions coded as they were asked o f the subjects.
Analysis The BMDP multiple logistic regression analysis program was used to control for potential confounding and to calculate odds ratios (hereafter called relative risks [RR]) and 95% confidence intervals (CI) ~ after preliminary univariate analyses were completed. Adjusted relative risks are presented in the text unless otherwise noted. The six variables used in the final logistic model were: total number of nondysplastic melanocytic nevi, number of dysplastic nevi, reported number of sunburns that caused blisters, hair color, history of a previous skin cancer other than melanoma, and age.
Because subjects with a history of melanoma in their families might be different from the rest of the group, six patients and four controls who reported this history in one other family member were removed from the data set and the logistic analyses were repeated. No subjects were from families who reported two or more relatives with melanoma. Since no significant differences were noted between these two analyses, the results presented here include all subjects in the study. No significant differences were noted between men and women for the variables used in the model; therefore, the data by sex were combined. All p values calculated were two-sided. RESULTS T h e response rate o f the m e l a n o m a patients and controls was greater than 95%. Melanoma patients had more nevi that were 2 m m or more in diameter than did the nonmelanoma patients. The mean and median values for both sexes combined were
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Table V. Relative risks (RR) and 95% confidence intervals (CI) for nondysplastic melanocytic nevi greater than 2 m m in diameter counted on melanoma patients and control subjects with and without dysplastic nevi Subjects with dysplastic nevi* Number and percent Number of nevi
67 cases
0- 25 26- 50 51-100 101 +
5 11 22 29
( 8) (16) (33) (43)
Unadjusted
I
Adjusted
24 controls
RR
95% CI
RR
95% CI
5 (21) 7 (29) 10 (42) 2 ( 8)
1.0 1.6 2.2 14.5
-0.33- 7.5 0.52- 9.4 2.2 -96.4
1.0 1.9 2.5 15.4
-0.33- 10.4 0.48- 12.8 2.0 -119.9
Subjects without dysplastic nevit Number and percent Number of nevi
Unadjusted
Adjusted I
54 cases
,
115 controls
RR
95% CI
RR
[
95% CI
l
0-25 26-50 51 +
20 (37) 17 (32) 17 (32)
74 (64) 23 (20) 18 (16)
1.0 2.7 3.5
-1.2-6.1 1.5-8.0
1.0 4.5 5.1
-1.8-11,0 2.0-12,6
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic nevi, hair color, and age. tThe logistic model included total number of nondysplastic melanocytlc nevi, hair color, previous skin cancer, and age.
nearly three times larger in the melanoma patients when compared to the control subjects. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p < 0.001). The minimum and maximum number of nondysplastic melanocytic nevi counted was 5 and 539 for melanoma patients and 0 and 304 for control subjects. The multiple logistic model was used to determine relative risks for number of nondysplastic melanocytic nevi (as a categorical variable) after controlling for the five other variables noted in the analysis section above. The relative risk was 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for having more than 100 nondysplastic melanocytic nevi (Table III). The p value for linear trend was p < 0.0001. Melanoma patients were more likely than control subjects to have clinically determined dysplastic nevi (p < 0.0001). These lesions were present in 67 of 121 melanoma patients (55%), while 24 of 139 control subjects (17%) had dysplastic nevi. When the six melanoma patients who reported relatives with melanoma were removed
from the study data set, 62 of the 115 patients or 54% had dysplastic nevi. The average number of clinically determined dysplastic nevi was 6.3 for melanoma patients and 0.7 for control subjects. The minimum and maximum number of dysplastic nevi counted was 0 and 153 for melanoma patients and 0 and 14 for control patients. After adjustment for the five other variables in the model, the relative risk associated with having 1 to 5 dysplastic nevi was 3.8 (p = 0.001) and 6.3 (p = 0.003) for six or more dysplastic nevi (Table IV). The p value for trend was p < 0.0001. To determine the effects of nondysplastic melanocytic nevi and clinically determined dysplastic nevi separately from each other, the study group was divided into persons with and those without dysplastic nevi, and the logistic model was rerun. Table V shows the relative risks and 95% confidence intervals for nondysplastic melanocytic nevi in persons with and without clinically determined dysplastic nevi on univariate and multivariate analysis. Among subjects with dysplastic nevi (Table V), relative risks for nondysplastic melanocytic nevi were 1.9 for 26 to 50 nevi (p = 0.48), 2.5 for 51 to 100 nevi (p = 0.28), and 15.4 (p = 0.009) for having more than 100 nondysplastic
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Table VI. Relative risks (RR) and 95% confidence intervals (CI) for blistering burns, hair color, and previous skin cancer for melanoma patients and control subjects* Subjects, number, and percent 121 cases
Unadjusted
Adjusted
139 controls
Characteristic
No.
%
No.
Sunburns with blisters Score valuer 0 1 2 3+ Red or blond hair Previous skin cancer
33 36 18 24 48 18
30 32 16 22 40 15
66 40 19 11 33 6
[
%
RR
95% CI
RR
95% CI
49 29 14 8 24 4
1.0 1.8 1.9 4.4 2.1 3.9
-0.97- 3.3 0.88- 4.1 1.9 -10.0 1.2 - 3.6 1.5 -10.3
1.0 1.4 1.7 3.8 2.2 3.8
0.67- 3.0 0.66- 4.4 1.4 -10.4 1.1 - 4.5 1.2 -12.4
*The logistic model included total number of nondysplastic melanocytic nevi, dysplastic rtevi, sunburns with blisters, hair color, previous skin cancers, and age. tThe score combined number of sunburns that caused blisters reported during elementary school, high school, and young adult years (see text).
melanocytic nevi. The p value for trend was p < 0.0001. Among persons without clinically determined dysplastic nevi (Table V), relative risks for nondysplastic melanocytic nevi were 4.5 for 26 to 50 nevi (p = 0.001) and 5.1 for 51 or more nevi (p < 0.001). The p value for trend was p < 0.001. The groups 51 to 100 and 100 or more nevi were combined for persons without dysplastic nevi because the number of subjects in the 1 0 0 + group was too small for meaningful analysis. To determine whether the subjects with dysplastic nevi were more likely to have more of these lesions if they had more nondysplastic melanocytic nevi, the means and medians for dysplastic nevi were calculated within each group of nondysplastic melanocytic nevi. The more nondysplastic melanocytic nevi present on the skin of melanoma patients, the more likely they were to have a larger number of dysplastic nevi. The mean number of dysplastic nevi was 2 in melanoma patients with 0 to 25 nondysplastic melanocytic nevi, 3 for 26 to 50 nevi, 5 for 51 to 100 nevi, and 21 for patients who had more than 100 nondysplastic melanocytic nevi. To control for potential residual confounding, because dysplastic nevi were more common in subjects w h o had more nondysplastic nevi, adjustment was made for the number Of dysplastic nevi in the logistic model. Using the logistic model that included the six previously named variables, melanoma patients re-
ported more sunburns that caused blisters than did the control subjects. A sunburn score was devised that combined recall of number of blistering burns in elementary school, high school, and young adult years. Subjects were asked to recall the number of blistering burns they sustained within a range (none, 1-10, 11-20, 21-30, >30) during each life stage. A score was assigned to each range selected so that "none" received a score of 0 and " > 3 0 " a score of 4. For each subject the scores for each life stage were summed to obtain a single value to indicate the number of blistering burns over the three life stages. The possible scores ranged from zero, which meant the subject did not recall any blistering burns in any of these three periods of his or her life, to 12, which meant recall of a large number of blistering burns in each of these periods. The highest score obtained by any subject using this method was 9. Relative risks associated with the sunburn score were 1.4 for a score of 1 (p = 0.30), 1.7 for a score of 2 (p = 0.27), and 3.8 (0 = 0.01) for a score of 3 or greater (Table VI). In the logistic model, melanoma patients and control subjects were different with regard to natural hair color at age 20, with a relative risk of 2.2 for having blond or red hair versus brown or black (p = 0.03) (Table VI). In the same model, a relationship also was noted between previous skin cancer and melanoma. Melanoma patients
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Table VII. Relative risks and 95% confidence intervals for hair and eye color* $ubjects~ number, and percent
Color of Hair
Eyes
Dark Dark Light Light
Dark Light Dark Light
Cases
19 54 2 46
(16) (45) ( 2) (38)
Unadjusted
Controls
RR
95% CI
37 (27) 59 (50) 1 ( 1) 32 (23)
1.0 1.5 3.9 2.8
0.79- 2.9 0.33-45.8 1.4 - 5.7
--
Adjusted RR
95% CI
1.0
1.9 6.4 3.4
0.76- 4.6 0.35-115.0 1.3 - 9.2
*Hair and eye color are mutually adjusted for each other; variables in the logistic model were total numbers of nondysplastic melanocytic nevi, dysplastic nevi, sunburns with blisters, hair and eye color (mutually adjusted to be one variable), previous skin cancer, and age.
tended to report a previous nonmelanoma skin cancer more often than did control subjects with a relative risk o f 3.8 (p = 0.03). Eye color on univariate analysis tended to be lighter in melanoma patients than in controls with a relative risk of 1.8 (p = 0.06). Eye color was not used in the earlier multivariate model because it was correlated with hair color. However, because hair color and eye color each have been shown to be related to melanoma risk in other studies, 1'57 the two variables were mutually adjusted for each other with relative risks and confidence intervals calculated for the mutually adjusted variables while controlling for the other variables used in the earlier model. Natural hair color was categorized as light if red or blond at age 20, and eyes were considered dark if they were brown. Table VII gives mutually adjusted relative risks with a relative risk of 1.9 (p = 0.17) if the subjects had dark hair and light eyes, 6.4 (p = 0.21) if the subjects had light hair and dark eyes (based on only three subjects), and 3.4 (p = 0.02) if the subjects had light hair and light eyes. In the multiple logistic model that included all six variables, the order of importance of the variables using stepwise regression was: total number o f nondysplastic melanocytic nevi and dysplastic nevi as the most important variables (each contributed nearly identically to the log-likelihood), followed by reported number of sunburns that caused blisters, having red or blond hair, having reported a previous skin cancer, and age. The patients with cutaneous melanoma were similar to the patients in the control group with respect to: education; exposure to sunlight while at work; skin
type; the number of times they sunbathed each year; time in life when they sunbathed the most-that is, elementary school, high school, or adult years; their use of tanning salons; and tendency to freckle. DISCUSSION This study shows both nondysplastic melanocytic nevi and dysplastic nevi to be independent and strong risk factors for cutaneous melanoma when total number o f nevi at least 2 m m in diameter and clinically determined dysplastie nevi 8 were counted on the entire body surface excluding the scalp and genitals. The relative risk for melanoma rose with increasing numbers of nondysplastic melanocytic nevi. The same was true for the relationship between melanoma risk and numbers of dysplastic nevi. The magnitude of the relative risks associated with large numbers of nondysplastic melanocytic and dysplastic nevi was considerably greater than that associated with the more established melanoma risk factors studied. Tables III and V gave the estimated relative risks for various numbers of nondysplastic melanocytic nevi, either adjusting for number of dysplastic nevi using a logistic model (as in Tables III and V) or for subjects separated into those with and without dysplastic nevi (as in Table V). The relative risks increased with an increasing number of nondysplastic nevi regardless of whether the subjects had dysplastic nevi. However, among subjects with dysplastic nevi (Table V), the number of nondysplastic melanocytic nevi reached statistical significance only if more than 100 nondysplastic melanocytic nevi were present, indicating the impor-
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tance of dysplastic nevi in this group. Comparison of the two parts in Table V shows that the number of nondysplastic melanocytie nevi is an indicator of risk among persons with and without dysplastic nevi; however, significant relative risks were noted for persons with a smaller number of nevi among subjects who had no dysplastic nevi. These results support the findings of another study conducted about the same time in Scotland. ~2 The Scottish study also showed a progressive rise in melanoma risk with increasing numbers of melanocytic nevi greater than 2 mm in diameter. The presence of individual clinical features (large size, color variation, and irregular edge) associated with dysplastic nevi was also studied, each feature in isolation, and found to be associated with marked increases in relative risk. A study conducted in Sydney, Australia showed greater numbers of total melanocytic nevi and dysplastic nevi among melanoma patients than among controls. ~ Few studies comparing melanoma patients and nonpatients have reported actual counts of melanocytic nevi. A group from Queensland, Australia counted nevi on arms and noted moles were more common on the arms of melanoma patients than on the arms of the control s u b j e c t s : After adjustment for hair color and propensity to sunburn, the relative risk estimate was 30 for any nevi counted on the arms versus none. Family history of melanoma was not found to be an independent determinant of disease, a result similar to that found in the current study. A study in Western Australia reported the number of palpable benign pigmented nevi counted on the arms to be the strongest risk factor for melanoma in their study. Estimates of the relative risk were: 2 for persons with 1 to 4 nevi, 4 for persons with 5 to 9 nevi, and 11.3 for persons with 10 or more palpable nevi on their a r m s : Family history was also determined to be a risk factor for cutaneous malignant melanoma in the Western Australia study. A study conducted in England noted that the most strongly associated risk factor for melanoma was the number of raised nevi on the upper arms. 7 Compared to those with no nevi on their upper arms, subjects with 1 or 2 raised moles had an estimated relative risk of 1.8. Those with 3 or more
Journal of the American Academy of Dermatology nevi had a relative risk estimate of 17. Light hair color conveyed an elevated risk estimate while the risk for light eye color was elevated slightly but was not significant. Relative risk estimates for a whole body nevi count conducted by dermatologists were large in the Scottish study, z' ~a Odds ratios for melanoma were 3.0 for 10 to 24 nevi, 6.8 for 25 to 49, and 12.1 for 50 or more nevi. These elevated risk estimates were found in persons who had no clinically determined dysplastic nevi. A recent report from New York noted an odds ratio for melanoma of 1.9 for patients who estimated their average number of moles to be 26 to 100. t3 For those subjects who reported an estimate of 100 or more nevi, the odds ratio for melanoma was 3.7. No association was noted with melanoma risk and time spent exposed to the sun, nor was any significant risk conferred for reporting melanoma in a first-degree relative. A community survey of nevi counted over part of the body, in a population of adults in New Zealand, reported a comparison of nevi in their study with two earlier projects conducted in the early 1950s and early 1970s. 14 Data from the most recent community survey showed the number of nevi to be increasing over time as the incidence of melanoma has become more common. It should be emphasized that the differentiation of nondysplastic melanocytic nevi from other pigmented lesions, such as lentigines and seborrheic keratoses, can be difficult. It is important that the counting of nevi be done by experts and according to stated criteria if the results of studies are to be reliable and useful. The report of Cooke et a114 suggests that more than half of nevi are less than 2 mm in diameter. The nevi counted in the current and the Scottish study 12 were 2 mm or more in diameter, and the total numbers would have been greater had all nevi been counted. The counting of nevi of all sizes is tedious and not practical for the routine assessment of melanoma risk, but a count of all nevi may provide evidence of a stronger risk factor. It is likely that any study that attempts clinical diagnosis of dysplastic nevi will underestimate the risk for melanoma resulting from the presence of dysplasic nevi. It has been noted that criteria re-
Volume 17 Number 3 September 1987
liable for the diagnosis of dysplastic nevi in populations with the dysplastic nevus syndrome will have a very much lower positive predictive value when applied to the general population.15 Our diagnosis of dysplastic nevi among melanoma patients, many of whom had florid dysplastic nevus syndrome, will have been relatively accurate. However, though few dysplastic nevi were counted on the skin in control patients, dysplasia is likely to have been diagnosed by our clinical criteria in nevi that would not have shown histologic evidence of dysplasia, and therefore the effects of dysplastic nevi would have been underestimated. It is unlikely that observer bias could explain the relative risk estimates for the nondysplastic melanocytic nevi given the meticulous assessment of these lesions by body location and the strong risk gradient. However, although point estimates of relative risks for numbers of nevi and dysplastic nevi were large, confidence limits were wide, reflecting the small sample and the possibility of the data being compatible with a smaller risk than given by the point estimates. Melanoma patients were more likely than were control subjects to report first-degree relatives with large numbers of nevi and sunburns with blisters. For these variables, it was not possible to rule out increased awareness on the part of the melanoma patients as a reason for this observation. Although we were unable to rule out selective recall of the cases' history of blistering sunburns, it is noteworthy that cases and controls did not differ with respect to other questions related to frequency and duration of sun exposure. Further, characteristics of the host, such as light hair and eye color, which accompany the likelihood of having had sunburns severe enough to cause blisters, were also more common among the patients with melanoma when compared to the control subjects. The lack of a statistically significant association between family history of melanoma and cutaneous melanoma among patients in this study may be due to small sample size or perhaps incomplete information regarding family members' melanoma history. Since the autosomal dominant form of malignant melanoma is manifest in only a small proportion of all melanoma subjects, these factors together may have been adequate to mask any sta-
Number of nevi as risk factor
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tistical association of familial melanoma as a risk factor in this study population. Other factors that increase the risk of melanoma, such as light eye, hair, or skin color, tendency to bum rather than tan, having had a previous skin cancer, and having had sunburns that caused blisters, have been noted in previous studies? '5'7'1618 None of the previously noted risk factors have been of the same magnitude as that conferred by large numbers of nondysplastic melanocytic nevi and dysplastic nevi. The proportion of melanoma patients who had dysplastic nevi and no report of a family member with melanoma, 54%, was quite similar to the 50% reported among persons with sporadic melanoma in a large clinic on the east coast of the United States. ~9 If confirmed in larger studies, the results presented on number of nondysplastic and dysplastic nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma. 12 The technics of baseline photography of the skin surface and regular follow-up have been well described for management of the dysplastic nevus syndrome. 8.20The results of the present study provide evidence for the value of such management of patients with dysplastic nevi. Further, our findings with respect to total number of nondysplastic melanocytic nevi suggest that these clinical technics might be usefully applied to persons with large numbers of nondysplasic nevi as these individuals are also at increased risk for the development of melanoma. REFERENCES 1. Beral V, Evans S, Shaw H, Milton G. Cutaneous factors related to the risk of malignant melanoma. Br J Dermatol 1983;109:165-72. 2. Swerdlow AJ, English J, MacKie RM, O'Doherty CJ, Hunter JAA, Clark J. Benign naevi associated with high risk of melanoma. Lancet 1984;2:168. 3. Nordlund JJ, Kirkwood J, Forget BM, etal. Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 1985;45:1855-61. 4. Greene MH, Clark WH Jr, Tucker MA, Kraemer K, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-69. 5. Green A, MacLennan R, Siskind V. Common acquired naevi and the risk of malignant melanoma. Int J Cancer 1985 ;35:297-300.
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6. Holman CDJ, Armstrong BK. Pigmentary traits, ethnic origin, benign nevi, and family history as risk factors for cutaneous malignant melanoma. JNCI 1984;72:257-66. 7. Elwood JM, WilliamsonC, StapletonPJ. Malignantmelanoma in relation to moles, pigmentation, and exposure to fluorescent light and other lighting sources. Br J Cancer 1986;53:65-74. 8. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastie melanocytic nevi. J AM ACAD DERMATOL 1986;14:1044-52. 9. Elder DE, Greene MH, Guerry D, Kraemer KH, Clark WH Jr. The dysplastic nevus syndrome--our definition. Arn J Dermatopathol 1982;4:455-60. 10. Kraemer KH, Greene MH, Tarone R, Elder DE, Clark WH Jr, Guerry D. Dysplastic nevi and cutaneous melanoma risk. Lancet 1983;2:1076-7. 11. Breslow NE, Day NE. Statistical methods in cancer research. I. The analysis of case-control studies. Lyon: IARC, 1980. 12. Swerdiow AJ, English J, MacKie RM, et al. Benign melanocytic naevi as a risk factor for malignant melanoma. Br Med J 1986;292:1555-9. 13. Dubin N, Moseson M, Pasternack BS. Epidemiology of malignant melanoma: pigmentary traits, ultraviolet radiation, and the identification of high-risk populations. Recent Results. Cancer Res 1986;102:56-75.
14. Cooke K_R, Spears GFS, Skegg DCG. Frequency of moles in a defined population. J Epidemiol Community Health 1985;39:48-52. 15. Rousch GC, Barnhill RL, Duray PH, Titus LJ, Emstoff MS, Kirkwood JM. Diagnosis of the dysplastie nevus in different populations. J AM ACAD DERMATOL 1986;14: 419-25. 16. Elwood JM, Gallagher RP, Hill GB, Spinelli JJ, Pearson JCG, Threlfall W. Pigmentation and skin reaction to sun as risk factors for cutaneous melanoma: Western Canada melanoma study. Br Med J 1984;288:99-102. 17. Elwood JM, Gallagher RP, Davison J, Hill GB. Sunburn, suntan and the risk of cutaneous malignant melanoma: the Western Canada melanoma study. Br J Cancer 1985 ;51:543-9. 18. Lew RA, Sober AJ, Cook N, Marvell R, Fitzpatrick TB. Sun exposure habits in patients with cutaneous melanoma: a case-control study. J Dermatol Surg Oncol 1983;9:981-6. 19. Kraemer KH, Tucker M, Tarone R, Elder DE, Clark WH Jr. Risk of cutaneous melanoma in dysplastic nevus syndrome types A and B. N Engl J Med 1986;315:1615-6. 20. Greene MH, Clark WH Jr, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma: the familial dysplastic nevus syndrome. N Engl J Med 1985;312:91-7.
ABSTRACTS
Diltiazem-associated exfoliative dermatitis in a patient with psoriasis Lavrijsen APM, Van Dijke C, Vermeer B-L Acta Derm Venereol (Stock_h) 1986;66:536-8 A 73-year-old woman with psoriasis developed exfoliativedermatitis with fever, malaise, and liver enzyme elevations2 days after the introduction of the new calciumantagonist, diltlazem. The disorder rapidly resolved after discontinuationof the drug and treatment with prednisone. Three years previouslythe patient had developed a similar reaction after 12 days of treatment with chloroquine. Diltiazem and chioroquinehavestructuralsimilarities,suggestinga crossreaction between them.
The detectionrate was compared to the isolationrate of the tissue culture technic. In extragenital lesions the sensitivity of the ELISA technic and immunofluorescencewas 79%, in genital lesions, 46.2%, and in cervicallesions, 5,7% and 15.4%, respectively. In some cases immunolluorescence and ELISA were positive while culture was negative, and these results were confirmedwith other immunologic technics. Yehudl M. Felman, M.D.
Psoriasis in immune deficiency related to HTLV III: cellular immunity and immunohistological findings Steigleder GK, Rasokat H, Wemmer U. Z Hautkr 1986;61:1671-8 (German)
J. Graham Smith, Jr., M.D.
Detection of herpes simplex virus antigen with an enzyme immunoassay and direct immunofluorescence technique Henries B, Kruse W, Hofmann H, Petzoldt D, Hautarzt 1986;37:662-6 (German) Four hundred sixty-four clinical specimens from patients with exlxagenital and genital lesions as well as cervical lesions from asymptomatie women were examinedfor the presence of herpes simplex virus antigen by using a commercially available enzyme immunoassay kit (ELISA; Dakopalts, Copenhagen, Denmark) and a direct immnnofluorescence technic with monoclonal antibodies (Syva-Merck, Federal Republicof Germany).
Four patients suffering from immune deficiencyrelated to human T-lymphotrop~c viras type III (HTLV-III) developed psoriasis vulgaris. All patients showed lymphadenopathyand cutaneous hypergy or anergy. In three of them the count of peripheral helper ceils was critically decreased (400/1), and they showed oral candidiasis. One patient suffered from disseminatedKaposi's sarcoma and developed Pneumocystic carinii pneumonia. The psoriasis was extensive, exudative, and refractory. The bulk of dermal infiltratingmononuclear cells were T lymphocytes, mostly the T8-positive phenotype. The majority of these cells were not diminished. The authors here note the developmentof psoriasis in spite of severe disturbancesof cellular immunity and suggest that immunemechanismsmediated by T cells, after having gotten out of control, might play some role in the pathogenesis of the disease. Yehudt M. Felman, M.D.