I II Illll Ill I I I I I II

Relationship in dysplastic

of nevocytic nevi to nevus syndrome

sun exposure

Alfred W. Kopf, M.D., Alison C. Lindsay, M.D., Gary S. Rogers, M.D., Robert J. Friedman, M.D., DarrellS. Rigel, M.D., and Marcia Levenstein, D.Sc. New York, NY

In eighty consecutive patients who have the dysplastic nevus syndrome, the concentration of nevocytic nevi on the relatively sun-protected lateral thoracic area was compared to the concentration on the relatively sun-exposed areas of the anterior and posterior thorax. Nevocytic nevi in an area 7 × 20 cm were counted in each location. There was a total of 177 nevi on the lateral thorax (average, 2.2 nevi/person), 361 on the anterior thorax (average, 4.5 nevi/person), and 506 on the posterior thorax (average, 6.3 nevi/person). Men showed no significant difference in the number of nevi on the anterior and posterior thoracic areas, but women had fewer nevi on the anterior than on the posterior thoracic sites. These findings are consonant with the hypothesis that sunlight induces nevocytic nevi in patients who have the dysplastic nevus syndrome. (J AM ACAD DERMATOL 12:656-662, 1985.)

We previously reported that common acquired nevocytic nevi are more prevalent on the lateral (sun-exposed) surfaces of the arms than on the medial (sun-protected) aspects. ~ This suggested the possibility that sunlight may play a role in the induction of nevocytic nevi of the common ac- quired variety. The intent of the present study was to compare the concentration of nevocytic nevi in relatively sun-exposed and sun-protected thoracic areas in individuals who have the dysplastic nevus syndrome, in order to determine whether a similar phenomenon could be demonstrated in this genet- ically determined disorder. It was found that the concentration of nevocytic nevi on the lateral tho- rax (relatively sun-protected site) was significantly

From the NYU Melanoma Cooperative Group, New York University Medical Center and the Ontology Section, Skin and Cancer Unit, Department of Dermatology, New York University School of Med- icine.

Accepted for publication Nov. 28, 1984.

Reprint requests to: Dr. Alfred W. Kopf, Skin and Cancer Unit, 562 First Ave,, New York, NY 10016.

less than the concentration of nevocytic nevi on the anterior and posterior thoracic areas (relatively sun-exposed sites).

MATERIALS AND METHODS

This study concerned eighty patients who had the dysplastic nevus syndrome. These patients were con- secutively seen in the practice of one of the authors (A. W. K.). In each, histologic confirmation of dys- plastic nevus was obtained on one or more cutaneous lesions.* In this series, 31.3% of the patients had prior or concurrent malignant melanomas at the time of ex- amination. Furthermore, 22.5% had family histories of malignant melanoma in one or more first-degree relatives.

Each of the patients had a series of twenty-four pho- tographs taken in order to document their nevocytic nevi on the major body areas. These photographs were re-

*Friedman RJ: The histologic diagnosis of dysplastic nevi: A ease analysis of 183 step-sectioned lesions. Symposium on Precursor Lesions to Malignant Melanoma. Presented at the 43rd Annual Meeting of the American Academy of Dermatology, Washington, DC, December, 1984.

656

Volume 12 Number 4 April, 1985 Sun exposure in dysplastic nevus syndrome 657

177 NEVI

80 PATIENTS

AVERAGE 2,2 NEVI

/ Fig. 1. Nevocytic nevi in representative rectangle on lateral thorax.

viewed for the concentration of nevocytic nevi on three anatomic sites: anterior, lateral (subaxillary), and pos- terior thorax. This was accomplished by projecting the photographic image on a rear view screen so that the resultant picture was one-half reaMife size. A rectangle 3.5 x 10 cm was held against the screen and the nev- ocytic nevi failing within the rectangle were counted. The rectangle, therefore, was outlining an area corre- sponding to 7 × 20 cm in real life.

The cephalad end of the lateral thoracic rectangle began at the inferior limit of the axillary vault at a point where the axillary hairs ended (Fig. I). The anterior thoracic rectangle was placed such that the cephalad end of the rectangle was aligned with the origin of the anterior axillary fold. The rectangle was then positioned so that its lateral side coincided with the most medial silhouette of the thorax (Fig. 2). The cephalad end of the posterior thoracic rectangle was aligned with the beginning of the posterior axiUary fold and then posi- tioned so that its lateral side coincided with the most medial silhouette of the thorax (Fig. 3).

J

j 0

6

Fig. 2. Nevocytic nevi in representative rectangle on anterior thorax.

In each of the rectangular areas, all pigmented lesions with the clinical appearance of nevocytic nevi 4 mm or larger (i.e., 2 mm or larger on the screen) were counted.* Light tan lesions were eliminated but tan, dark tan, brown, dark brown, and black lesions were included. Seborrheic keratoses (tan lesions with dull verrucoid surfaces) were omitted, as were other types of pigmented lesions such as ephelides and caf6 au lait spots.

There were thirty-two men and forty-eight women included in the study. The men ranged in age from 22 to 63 years with a mean of 41.4 years; the women ranged from 20 to 65 years with a mean of 32.2 years. This age difference is not statistically significant (p = 0.10). Seven additional patients were excluded from the study because it was not possible to count their nevocytic nevi accurately, due either to excess hair (three men) or to a profusion of seborrheic keratoses (three women, one man),

The total number of nevocytic nevi in each of the

*At times nevocytic nevi will be referred to as "nevi" or "moles" in this paper.

658 Kopf et al Journal o f the

A m e r i c a n A c a d e m y of

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506 NEVI / 80 PATIENTS /

AVERAGE 6,3 NEVI

Fig. 3. Nevocytic nevi in representative rectangle on posterior thorax.

rectangles was counted. For each patient, six obser- vations were made (i.e., three observations on the right side and three on the left). For each anatomic location, the numbers of nevi on the right and left sides were combined to give a total figure for each site, for each patient. Then a total for all eighty patients was calcu- lated for the anterior, lateral, and posterior thoracic sites. The data were analyzed for differences in the concentration of nevocytic nevi by location, sex, and age. Statistical analysis was performed by analysis of variance and Student's t test?

RESULTS

A total of 1,044 nevocytic nevi was counted in the eighty patients. There were 177 nevi (16.9% of the total) on the lateral thoracic area, an average of 2.2 nevi/patient. The comparable figure for the anterior thoracic area was 361 nevi (34.6% of the total) for an average of 4.5 nevi/patient. On the

Table I. Frequency distribution of nevocytic nevi in three thoracic locations in patients with the dysplastic nevus syndrome (both sexes combined)

Thoracic Number of area patients

Number of nevi

Average number of nevi

Lateral 80 177 2.2" Anterior 80 361 4.5 b Posterior 80 506 6.3 c Total 80 1,044 13.0

p values: a vs b, p < 0,001; b vs e, p = 0,04; a vs c, p < 0,001.

posterior thoracic location, there were 506 nevi (48.5% of the total) for an average of 6.3 nevi/ patient. Table I summarizes these data and indi- cates that there was a statistically significant dif- ference comparing each of these sites. Overall, there were fewest nevocytic nevi on the lateral thorax, more on the anterior thorax, and the great- est number on the posterior thorax.

Table II summarizes the results regarding sex differences. The average number of nevocytic nevi for men, totaled for all three locations, is 18.0. The comparable figure for women is 9.7 and this is significantly less than that for men (p < 0.001). In comparing the number of nevocytic nevi in men and women, according to location, men showed an average of 2.5 nevi for the lateral thorax, com- pared with 2.0 nevi for women. This difference is not significant (p = 0.36). On the anterior thorax, however, men had an average of 7.1 nevi and women had significantly fewer, with an average of 2.8 nevi (p < 0.001). Similarly, for the pos- terior thorax, the average of 8.4 for men was sig- nificantly greater than that of 4.9 for women (p < 0.01).

Examining the preceding data for the distribu- tion in men, according to location, we found that the concentration of nevi on the lateral thorax was significantly less than that on both the anterior and posterior thorax (p < 0.001 for both). However, in men the concentration of nevi in anterior and posterior thoracic regions was not significantly dif- ferent (p = 0.48). Similar analyses were per- formed for women. In contrast to the men studied,

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Apr i l , 1985 Sun exposure in dysplastic nevus syndrome 659

Table II. Frequency distribution of nevocytic nevi according to sex and thoracic location

Men (N = 32)

Thoracic Total number area of nevi

Lateral 80 Anterior 228 Posterior 270 All above 578

Women (N = 48)

Average number Total number Average number of nevi of nevi of nevi

2.Y 97 2.0 a 7. I b 133 2,8 ~ 8.4 c 236 4.9 r

18.0 g 466 9.7"

p values: a vs d, p = 0.36; b vs e, p < 0.001; c vs f, p < 0.01; a vs b, p < 0.001; a vs c, p < 0.001; b vs c, p = 0.48; d vs e, p = 0.06; d vs f, p < 0.001; e vs f, p < 0.001; g vs h, p < 0.001.

Table III. Age-related differences in average number of nevi per patient

Mean age Average number Age group Number of patients (yr) of nevi per patient

<40 yr 17 men; 30 women 30.9 11.00 __+ 7.05 ~ ~>40 yr 15 men; 18 women 50.3 15.97 _+_ 15.08 b

p value: a versus b, p = 0.06.

women had significantly fewer nevi in the anterior and lateral thoracic regions when compared with the posterior thoracic region (p < 0.001 for both). In addition, there was a trend (but not statistically significant) for fewer nevi on the lateral than on the anterior thorax (p = 0.06).

The third variable examined was age. We com- pared all patients who were <40 years old with those who were >t40 years old. Table III sum- marizes the data. There was a trend, but not sta- tistically significant difference (p = 0.06) for the average number of nevi per patient to be less for those in the <402year, old group (11.00 __- 7.05 nevi) compared with those in the --->40-year-old group (15,97 +-- 15.08 nevi). This was also true for men (p = 0.06) but no such trend was seen in women (p = 0.99), as indicated in Table IV. We then analyzed Nicholls' data 3 for age-related differences, separating the patients into the pre- ceding age groups (i.e., men, women; <40 years, >~40 years). Table V records the average number of nevi per patient on the "chest" and "upper back" areas, selected to be the most comparable from his group to our "anterior" and "posterior thoracic" regions. Table V also shows our findings for these age groups and locations. In our study, there are no Significant differences between the

Table IV. Age-related differences in number of nevocytic nevi per patient in men and women

sex] M M F F

groups Number of I Average number Age patients of nevi per p~tient

<40 17 13.29 -+ 9.22 a 340 15 23.47 --- 19.52 b <40 30 9.70 --- 5.2P I>40 18 9172 --. 4.81 d

p values: a vs b, p = 0.06; c vs d, p = 0.99.

age groups except for the anterior thoracic region in menl in whic h the older group has significantly more nevi (p = 0.04).

Since there was not sufficient information in our study population to distinguish between the fa- milial and the sporadic types of the dysplastic ne- vus syndrome, it was not possible to determine if there is a phenotypic difference between these types in regard to the inducing effects of sun ex- posure.

DISCUSSION

The present study indicates that in patients who have dysplastic nevi, relatively sun-protected areas have fewer nevocytic nevi than do sun-exposed

660 Kopf et al Journal of the

American Academy of

Dermatology

Table V. Age-related differences in average number of nevi per patient (Nicholls '3 study)

Average number Average number of nevi pel: patient of nevi per patient

Sex Location <40 yr >~40 yr'

Nicholls'3 study

Men

Women

Present study

Men

Women

% Fewer nevi in older age group

Chest 2.12 0.69 67.4 Upper back 3.30 1.78 46.1 Chest 0.83 0.60 27.7 Upper back 1.69 1.07 36.7

Anterior thorax 4.94" 9,60 b 0.0 (chest)

Posterior thorax 6.24 ¢ 10.93" 0.0 (upper back)

Anterior thorax 3.10 ~ 2.22 r 28.4 (chest)

Posterior thorax 4.63 ~ 5.39" 0.0 (upper back)

p values: a vs b, p = 0.04; c vs d, p = 0.08; e vs f, p = 0.12; g vs h, p = 0,45,

areas. This is demonstrated by the difference in the total number of nevi on sun-protected (lateral thoraciC) versus sun-exposed (anterior and poste- rior thoracic) areas of the trunk. The implications are that sunlight may play a significant role in the induction of nevocytic nevi in individuals who have the dysplastic nevus syndrome.

During periods of intense sun exposure (e.g., sunbathing), the anatomic areas exposed in men are different from those exposed in women. Men will often have the chest and back fully exposed whereas women will have these areas partly or completely sun-protected, We postulate that this variation in sun exposure of the different thoracic sites may account for the fewer nevocytic nevi in women. However, other factors, such as hor- mones, may also influence dysplastic nevi. 4

Many of the nevi counted had clinical features of dysplastic nevi. However, since the lesions were not removed and histologically examined, we do not know what proportion were of the common acquired variety and what proportion were dys- plastic nevi.

In our study, no significan t difference was found in the two age groups (<40 years versus >~40 years) analyzed. In fact, in the men there is a trend toward an increased number of nevi in the group I>40 years of age. This contrasts with the work of

Nicholls who reported that nevi increase in number until a peak is reached at the age of 15 in men and at the age of 20 to 29 in w o m e n ) The number of moles then substantially decreases with increasing age. Stegmaier 5 has described mechanisms for this regression. ~ In analyzing Nicholls' data, men and women exhibited a trend toward fewer nevi in those subjects >140 years of age compared with those <40 years of age (there are as many as 67% fewer moles in the chest location of men in the older group), Dysplastic nevi, however, un- like common acquired nevi, continue to appear throughout l i fe? Perhaps, then, we did not find a decrease with age because many of the lesions we counted were dysplastic nevi. It is also interesting to note that in the relatively small, rectangular areas studied, we found many more nevi than Nicholls counted for the entire chest or upper por- tion of the back. This is also consistent with the fact that patients with the dysp!astic nevus syn- drome have far more nevi than found on the av- erage individual in the general population. 4 In ad- dition, our data frequently show large standard deviations, consistent with the great variability in the expression of this syndrome.

Our study suggests that sun exposure causes the development of moles, both of the common ac- quired variety and of the dysplastic type. Perhaps

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Sun exposure in dysplastic nevus syndrome 661

patients with the genotypes for the dysplastic nevus syndrome, like those with the genotypes for xe- roderma pigmentosum, manifest phenotypic ex- pression in areas that are more heavily sun-ex- posed. 6 Dysplastic nevi are, however, also seen on sun-protected areas, such as the buttocks and scalp in both sexes and on the breasts in women. There- fore, sun is unlikely to be the sole etiologic factor in the pathogenesis of dysplastic nevi.

Both Clark et al 7 and Holman et al 8 have sug- gested that malignant melanoma in patients who have the dysplastic nevus syndrome may result from a stepwise process in which the first event is the development of common acquired nevi. Then, in those genetically susceptible individuals, a hor- izontal outgrowth ("shoulder") of atypical me- lanocytes occurs. FinallY, within such lesions, ma- lignant melanoma may have its origin. Our study would support the hypothesis that solar radiation may bring about the appearance of nevocytic nevi in individuals susceptible to the development of dysplastic nevi.

In the classic "two-step" theory of carcinogen- esis it is possible that sunlight may act as both initiator and promoter in the transformation of ge- netically susceptible melanocytes to dysplastic ne- vus to malignant melanoma. Others have already suggested this or similar theories [Greene4; Hol- man et aP]. Furthermore, Holman* has found that children who have had painful sunburns prior to the age of 10 have more nevocytic nevi than those who have not had such intense exposure to sunlight in childhood. Again, the implication is that sun- light might induce nevocytic nevi.

This study also served to clarify the question whether the distribution of nevocytic nevi could be simply a manifestation of flow pattern and con- centration of melanocytes during embryonic de- velopment rather than a consequence of exposure to sunlight. We considered the former possibility in our previous study on common acquired nevo- cytic nevi on the armst; i.e., could the higher con- centration of nevocytic nevi on the lateral aspects of the arms compared to the medial aspects be

*Holman CD: Risk factors in the causation of human malignant melanoma of the skin, Thesis presented for Ph.D. at the University of Western Australia, 1982, Sect. 6.3.2.

explained by the unequal distribution of melano- cytes during their embryonic migration? This mi- gration is known to occur in a cephalocaudal, dor- soventral direction from the neural crest . 9 The find- ing in the present study that the concentration of nevocytic nevi in the lateral thoracic area is less than the anterior thoracic area would argue against the distribution of nevi being caused by such mi- gration.

The lateral thoracic wall below the axillary vault was chosen as a control site because it does not receive as much sun exposure as the anterior or posterior thorax. However, the lower prevalence of nevocytic nevi in the subaxillary area might also be due to other physical factors such as tempera- ture, humidity, and pressure. What role other fac- tors may play in the distribution of the pigmented lesions noted in this study is conjectural. For ex- ample, there may be a difference in the anatomic distribution of dysplastic and/or common acquired nevocytic nevi in the familial versus the sporadic types of the syndrome, a point we could not ad- dress for lack of information in our patients. None- theless, the most likely explanation for the vari- ation and distribution of these pigmented lesions is the relative degree of insolation received by the various anatomic areas on the thorax.

In summary, the concentration of nevocytic nevi in individuals who have the dysplastic nevus syn- drome is significantly greater in the sun-exposed thoracic areas than in the sun-protected thoracic areas. This observation has practical importance for the prevention of precursors of melanoma in such genetically susceptible individuals. Thus, based on this observation, it is recommended that individuals who are prone to develop the dysplastic nevus syndrome avoid unnecessary exposure to sunlight or wear protective clothing and 15-rated sunscreens whenever unable to avoid such exposure.

REFERENCES

1. Kopf AW, Lazar M, Bart RS, et al: Prevaienee of nevocytic nevi on lateral and medial aspects of arms, J Dermatol Surg Oncol 4:153-158, 1978.

2. Colton TC: Statistics in medicine. Boston, 1974, Little, Brown & Co.

3. Nicholls EM: Development and elimination of pigmented moles, and the anatomical distribution of primary malig- nant melanoma. Cancer 32:191-195, 1973.

Kopf et al Journal of the

American Academy of Dermatology

4. Greene MH: Dysplastic nevus syndrome. Hosp Pract 19:91-108, 1984.

5. Stegmaier OC: Natural regression of the melanocytic ne- vus. J Invest Dermatol 32:413-421, •959.

6. Kraemer KH: Xeroderma pigmentosum, in Demis DJ, Dobson RL, McGuire J, editors: Clinical dermatology. Hagerstown, MD, 1980, Harper & Row, Publishers Inc., unit 19-7.

7. Clark WH, Elder DE, Guerry D IV, et al: A study of tumor progression. The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol. (In press.)

8. Holman CD, Armstrong BK., Heenan PJ: A theory of the etiology and pathogenesis of human cutaneous malignant melanoma. JNCI 71:651-656, 1983.

9. Rawles ME: Origin of the mammalian pigment cell and its role in the pigmentation of hair, in Gordon M, editor: Pigment cell growth. Proceedings of the Third Conference on the Biology of Normal and Atypical Pigment Cell Growth. New York, 1953, Academic Press Inc., pp. 1-16.

1 Illl II

Occlusive wound dressings to prevent bacterial invasion and wound infection Patricia M. Mertz, B.A., David A. Marshall, B.S., and William H. Eaglstein, M.D. Pittsburgh, PA

This study was designed to examine the possibility that some occlusive dressings are barriers to wound penetration by pathogenic bacteria. Two common skin pathogens, the nonmotile, Staphylococcus aureus, and the motile, Pseudomonas aeruginosa, were used to challenge dressings placed on partial-thickness wounds in swine. S. aureus was recovered from 100% of air-exposed wounds (log, 5.5 ± 1.1) and from 50% of Op-Site-treated and Vigilon-treated wounds (log, 6.1 __- 1.1). S. aureus was not isolated from DuoDERM-covered wounds, P. aeruginosa was recovered from 100% of air-exposed wounds (log, 5.1 4- 0.5) and 100% of Op-Site-covered and Vigil0n-covered wounds (log, 5.8 + 1.8). P. aeruginosa was not recovered from DuoDERM-covered wounds. These studies lend support to the idea that dressings may protect/vounds from invasion by pathogenic bacteria and demonstrate the need to evaluate their bacterial barrier properties in situ. (J AM ACAD DF.RMATOL 12:662-668, 1985.)

In the past 5 years, several new types of wound dressings have become commercially available.

From the Department of Dermatology, University of Pittsburgh School of Medicine.

Supported by grants from the Pittsburgh Skin and Cancer Foundation and the Dermatology Education and Research Foundation.

Accepted for Publication Nov. 30, 1984. Reprint requests to: Patricia M. Mertz, University of Pittsburgh

School of Medicine, Department of Dermatology, RC-513 Seaife Hall, Pittsburgh, PA 15261/412-624-1398.

These dressings are known collectively as occlu- sive dressings. Although some of these occlusive dressings transmit moisture vapor, they are all de- signed to keep the wounds moist. Some of the advantages of healing beneath occlusive dressings have been known for at least 20 years, but because it was feared their use would promote wound infection, occlusive dressings and moist wound healing have only recently been used frequently. Among the reasons for fearing that occlusive

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