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The malignant potential of small congenital nevocellular nevi
The malignant potential of small congenital nevocellular nevi An estimate of association based on a histologic study of 234 primary cutaneous melanomas Arthur R. Rhodes, M.D., Arthur J. Sober, M.D., Calvin L. Day, M.D., John W. Melski, M . D . , Terence J. Harrist, M.D., Martin C. Mihm, Jr., M . D . , and Thomas B. Fitzpatrick, M.D. Boston, MA In order to assess a relationship between small congenital nevocellular nevi and cutaneous melanoma, histologic features commonly associated with congenital nevi were sought in 234 melanomas. The detection of one or more histologic features of congenital nevi in 8.1% (19/234) of melanoma specimens was directly related to the number of slides and tissue sections with melanoma available for review, the predominance of superficial spreading melanoma (SSM) and the historic relationship to a preexisting pigmented nevus at the tumor site. The histologic association was inversely related to melanoma thickness and tumor location on the lower extremities. The observed frequency of histologic association was estimated to be approximately 4,000 to 13,000 times greater than expected on the basis of surface area by chance alone. These findings suggest that small congenital nevi may be precursors for at least some cases of cutaneous melanoma. The strength of histologic association is highly dependent on the specificity of methods used for detecting congenital nevi in melanoma specimens. (J AM ACAD DERMATOL6:230-241, 1982.)
From the Division of Dermatology, Department of Medicine, Children's Hospital Medical Center (Dr. Rhodes), the Department of Dermatology (Drs. Sober, Day, Mihm, and Fitzpatrick) and Pathology (Dr. Harfist), Massachusetts General Hospital, the Department of Computer Medicine, Beth Israel Hospital (Dr. Melski), and the Departments of Dermatology, Pathology, and Medioine, Harvard Medical School. Supported in part by grants from the Jackson Trust, The National Cancer Institute (CA 13651), and The National Center for Health Services Research (HS-00188 and H8-04050), United States Public Health Service. Presented at the meeting of ttle Society for Investigative Dermatology, San Francisco, CA, April 28, 198l. Reprint requests to: Dr. Arthur R, Rhodes, Division of Dermatology, Hunnewell-3, Children's Hospital Medical Center, 300 Longwood Ave,, Boston, MA 02115/617-735-6126f6127.
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Current melanoma management emphasizes the early diagnosis of thin tumors and the recognition of precursor lesions. Congenital nevocellular nevi (CN), collections of nevus cells in pigmented lesions of the skin in newborns, t-a are generally acknowledged to be precursors for melanoma when their size is extremely large (giant). 4 Giant CN, observed in fewer than one per thousand newborns, t-3 have an estimated lifetime melanoma risk of at least 6.3%. 4 It is worth knowing whether relative size is the only determinant of risk for CN, because small CN are at least ten times more common than giant CN. 2,a Presuma0 1 9 0 - 9 6 2 2 / 8 2 / 0 2 0 2 3 0 + 12501.20/0 © 1982 Am Acad Dermatol
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Table
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I. Histologic features o f congenital nevi versus acquired nevi* Location of nevus cells
.
Lower two-thirds reticular dermal collagen Sebaceous glands Arrectores pilorum Hair follicles Eccrine ducts Nerves Lymphatic vessels Blood vessels
Congenital nevi
Acquired nevi
Sensitivity
Specificity
(%)
(%)
59/60
2/60
98.3
96.7
22/60 48/60 12/60 22/60 37/60 13/60 9/60
0/60 2/60 3/60 2/60 0/60 2/60 0/60
36.7 80.0 20.0 36.7 61.7 21.7 I5.0
100.0 96.7 95.0 96.7 100.0 96.7 100.0
*Based on historicascertainmentof cases; adapted from Mark GL, et al: Hum Pathol 4:395-418, 1973. bly, the strength of a relationship between small CN and cutaneous melanoma could be estimated by comparing the observed rate o f histologic association with an expected rate based on chance alone. Therefore, a histologic survey o f primary cutaneous melanomas was conducted in order to determine the frequency of tumor-associated nevocellular nevi with microscopic features characteristic of CN. MATERIALS AND M E T H O D S Two hundred thirty-four patients with primary cutaneous melanoma (all histologic types) 5 were entered prospectively into a study group at the Harvard Melanoma Registry during the period Sept. 1, 1972, to May 30, 1977. A standardized patient interview was conducted within 30 days of melanoma excision. The series included 119 males and 115 females whose ages ranged from 12 to 90 years (mean, 47.9 years). One patient was black, and 233 were white. Patients were followed for evidence of recurrent disease at 3month intervals for the first 2 years after diagnosis, every 6 months for the next 3 years, and annually thereafter. The tumor specimens from these 234 patients were reviewed by four of the authors (A. R. R., C. L. D., T. J. H., and M. C. M.) for the presence of nevocellular nevi in association with melanoma. For cases to be called "positive" for tumor-associated nevi, unanimous agreement among the reviewers required the presence of obvious nests, sheets, cords, and/or single-file disposition of cytologically benign nevus cells in the dermis immediately adjacent to the melanoma ("in contiguity"). To distinguish congenital from noncongenital nevi, the reviewers relied on data
provided by Mark et al ~ for historically documented lesions (Table I). Melanoma-associated nevoeellular nevi were designated as having congenital features if nevus cells were found within the collagen of the lower two thirds of the reticular dermis and/or nevus cells were present within one or more appendages (follicles, sebaceous glands, arrectores pilorum, and eccrine ducts), inside perineural sheaths, within blood vessel walls, or associated with lymphatic vessels causing luminal distortion. Microscopic tumor thickness was determined by one pathologist (M. C. M.) according to the method of Breslow. ? All histologic data were entered on computer, and correlations were determined for selected characteristics in the 234 patients. RESULTS In 27.4% (64/234) o f m e l a n o m a specimens, a dermal nevocellular nevus was found in contiguity with the melanoma. Of the 64 nevus cases, 19 (8.1% o f 234) had tumor-associated nevocellular nevi with congenital features (NNCF) (Table II), and 45 (19.2% of 234) appeared identical to "acquired" (ordinary) nevocellular nevi (ON) (Table I). ~+Of the 19 NNCF, 8 had nevus cells extending into the collagen o f the midreticular dermis or deeper (Figs. 1 and 2) (Table II); o f these 8 tumor-associated N N C F , 7 had nevus cells in one or more appendageal, neural, or vascular structures with high specificity for historic congenital nevi (Tables I and II; Figs. 2 to 4). The eleven N N C F patients w h o had nevus cells no deeper than the collagen o f the u p p e r reticular dermis were designated N N C F on the basis o f appendageal, neural, or vascular involvement by
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Table II. Location of nevus cells in 17 melanoma-associated dermal nevi with congenital features Age
Sex
Anatomic site
1" 2
28 57
F M
Leg Forearm
3 4 5 6 7 8
30 80 45 50 73 29
F M F F M M
Cheek Scalp Arm Chest Forehead Back
9
40
M
Back
10 Il
41 71
M M
Back Back
12 13 14 15 16
21 33 37 41 26
F M M F F
Arm Chest Back Arm Back
17 18 19
34 28 61
F M M
Back Neck Back
Patient
Deepest site of penetration and involvement of other structures
Deep reticular dermal collagen Nerves, lymphatic vessels Arrectores pilomm Midreticular dermal collagen Hair follicles, nerves None Nerves Hair follicles, nerves Blood vessels Hair follicles, nerves, blood vessels Upper reticular dermal collagen Hair follicles, sebaceous glands Arrectores pilorum Hair follicles, sebaceous glands Blood vessels Hair follicles Eccrine ducts, nerves Nerves, lymphatic vessels Nerves, lymphatic and blood vessels Blood vessels Lymphatic and blood vessels Hair follicles, arrectores pilorum
Melanoma type (level/thickness)
SSM (II/0.8) SSM (II/0.3) SSM 0W1.0) AAM (IV/I.3) SSM (IV/2.0) SSM (III/0.75) UNC (IV/2.2) NM (IV/4.5)
SSM (lII/l.0) SSM (III/1.6) SSM (III/1.8) SSM SSM SSM SSM SSM
(II/1.15) (II/0.8) (III/2.0) (III/1.0) (II/0.6)
SSM (IV/1.4) SSM (II/0.5) SSM (II/0.45)
Superficial spreading melanoma (SSM), nodular melanoma (NM), unclassified radial growth phase melanoma (UNC). *Panniculus also involved by nevus cells,
nevus cells (Tables I and II; Fig. 5). None of the nineteen NNCF-associated melanomas had an obvious origin in the dermal component of a nevocellular nevus. None of the 234 melanomas was associated with a giant CN, i.e., a nevus so large that it could not be removed by simple excision and primary closure using adjacent tissues in a single surgical procedure) The gross size of an intact melanoma was represented by its greatest diameter according to exact measurements, which were available for 10/19 NNCF cases, 24/45 ON cases, and 77/170 cases without nevi. The greatest tumor diameter for the NNCF cases (mean + SD = 16 + 6 ram) tended to be smaller than for ON cases (20 _+ 12
mm) (p > 0.2)* and cases without nevi (21 + 14 ram) (p = 0.0587).* For the 9 NNCF cases without photographs, the largest skin ellipse (according to pathology reports) was -<45 ram. When compared to the 170 cases without nevi, the sixty-four nevus cases (NNCF + ON) occurred significantly more often on the torso (43/64 = 67.2% vs 59/170 = 34.7%) and in patients --<40 years of age (56.2% vs 29.4%) and were significantly less often associated with nodular melanoma (7.8% vs 18.8%), lentigo maligna melanoma (0 vs 5.9%), and microscopic tumor invasion to anatomic level V (3.1% vs 12.4%) *Student's two-sided t test with unequal variances.
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Fig. 1. Case 1. Invasive melanoma is present in the papillary dermis in association with a nevus, the cells of which are disposed singly and as nests, sheets, and cords permeating the collagen of the lower two thirds of the reticular dermis. (Hematoxylin-eosin stain; x96.)
(p < 0.05 for all c o m p ~ i s o n s , chi-square test). There were no significant differences in these features when the N N C F cases were compared to ON cases and cases without nevi. When compared to cases without nevi, NNCF
cases were significantly less likely to occur on the lower extremities and significantly m o r e likely to be associated with microscopic t u m o r thickness --<2.25 mm, histologic tumor type superficial spreading melanoma (SSM), and a greater number
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Fig. 2. Case 1. Nevus cells are present in the deep reticular dermis, extending focally into the panniculus (P). Nevus cells covered by endothelium protrude into the lumen of a lymphatic vessel (arrow). (Hematoxylin-eosin stain; x240.) of slides and tissue sections with melanoma available for review (Table III).* Except for number of slides with melanoma, there were no significant differences in these selected features when N N C F cases were compared with ON cases. The mean *Four or more tissue sections and two or more slides with tumor were available in 95.7% and 82.9% of the 234 cases, respectively.
age at diagnosis for NNCF cases (43.6 +- 17.2 yr) was similar to that of ON cases (41.8 + 16.3 yr) but less than that of cases without nevi (50.6 + 16.7 yr) (p = 0.087).* The mean tumor thickness for the NNCF cases (1.30 _+ 0.87 ram) tended to be less than that of ON cases (1.75 _+ 1.46 ram) *Student's two-sided t test with equal variances.
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3. Case 8. Nevus cell nests are present within a hair follicle. Within the collagen of the reticular dermis, invasive melanoma (M) and nevus cells (N) are identified. (Hematoxylin-eosin stain; ×240.) Fig.
(p > 0.1),* but significantly less than that of patients without nevi (2.25 _+ 2.08 mm) (p = 0,0005).* At the time of this writing, fewer NNCF patients tended to have documented metastases (Cases 4, 7, and 8) or be dead from melanoma *Student's two-sided t test with uneaual variances,
(Cases 4 and 8) (Table 1II). The m a l e : f e m a l e ratios for the N N C F cases (11:8), ON cases (24:21), and cases without nevi (84:86) were similar. In the standard questionnaire, interviewers made a final judgment based on history as to whether or not the melanoma arose from a mole. N N C F cases
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Fig. 4. Case 8. N e v u s cells are present in the wall of an arteriole (small arrows) and within the perineural sheath of a small nerve (large arrow). ( x 2 4 0 . ) Inset, Infiltration o f the nerve sheath b y nevus cells is apparent. ( x 1,000.) (Hematoxylin-eosin stain.)
Nevocellular nevi have been reported in histologic association with 4% to 41% of cutaneous melanomas, s-1~ To our knowledge, however, only
one previously published histologic study has attempted to determine the proportion of melanomaassociated nevi likely to represent congenital nevi. Kopf et al ~ reported four tumor-associated NNCF among 349 selected melanomas of the superficial spreading type (1.1%), none of which was associated with a giant CN.* Kopf et al concluded 1'~ that a 1.1% rate of association was no greater than expected when the 1% prevalence rate of small CN in newborns was considered. However, this conclusion does not take into account the small proportion of body surface area involved. Even a 1% histologic association of small CN and melanoma should be regarded as significant when compared with the expected association based on surface area by chance alone. The chance of finding melanoma in microscopic
*Fisher exact test, two-sided.
*Kopf AW: Personal communication.
tended to have a greater association with melanomas arising from moles than ON cases (57.9% vs 42.2%) (p = 0.2841),* but significantly greater than patients without nevi (57.9% vs 31.8%) (p = 0.0388).* Age of onset and/or duration of preexisting moles were data not specifically sought by the standard questionnaire. However, additional information noted by interviewers for NNCF patients included preexisting moles "since birth" in 3 (Cases 9, 12, and 17), "lifelong" in 1 (Case 11), -->10 years in 3 (Cases 7, 16, and 19), and >--3 years in 3 (Cases 2, 3, and 6). DISCUSSION
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Fig. 5. Case 11. Invasive melanoma (M), admixed with inflammatory cells, fills the papillary dermis. Nevus cells (N) are seen in the collagen of the upper reticular dermis and within a sebaceous gland. (× 96.) Inset, Nevus cells are seen within a sebaceous gland. (× 192.) (Hematoxylin-eosin stain.) contiguity with small CN in consecutive melanoma specimens of white adults depends on the simultaneous occurrence of two events: (1) finding small CN in white adults (identical to prevalence rate) and (2) finding small CN in microscopic contiguity with melanoma. The prevalence rate of small CN in adults may be assumed to be the same as in newborns, based on the relatively stable oc-
currence in newborns noted for the United States and Latin America during the past three decades, l-a'~c~ A stable prevalence rate permits the supposition that each age cohort has the same chance of having small CN. The most completely documented data available for a homogeneous racial group is that of Walton et al,t in which biopsy examination was done on twenty-one pigmented
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Table lII. Selected features in 234 patients with cutaneous melanoma correlated with the presence or absence of tumor-associated nevi* Features
Tumor thickness 42.25 mm Tumor location lower extremities Tumor histology SSM~+ Slides with melanoma ~>5 Tissue sections with reelanoma 314 Age 440 yr Metastatic disease present Death from melanoma
% N N C F cases (n = 19)
% ON cases (n = 45)
% cases w i t h o u t nevi
94.7
77.8
65.9"I"
5.3
6.7
31.8t
89.5 82.4 78.9
84.4 44.41" 68.9
62.4t 44. i t 52.9-I"
52.6 15.8 10.5
57.8 26.7 17.8
29.4 35.3 24.1
(n = 170)
*Tumor-associated nevi include nevocellular nevi with congenital features (NNCF) and ordinary nevi (ON). "[p < 0.05, Fisher exact test, two-sided; comparisons have been made between NNCF and ON cases, and between NNCF cases and cases without nevi. :[:Superficial spreading melanoma.
lesions observed within 72 hours of birth in 841 white neonates to determine the true prevalence rate of small CN. Only seven of these twenty-one pigmented lesions were reported as nevocellular nevi, all --<3 cm in greatest diameter, i.e., a prevalence rate of 0.83% (7/841) for small CN in white newborns. The probability of contiguity for melanoma and small CN in an adult with both lesions (Fig. 6) is estimated by: (1) assigning a size of 2.6 × 1.3 cm to a small CN in adults, derived from measurements of fifty-six small CN observed in newbores la (mean dimensions, 8 x 5 mm), and expanded eightfold to account for the average increase in body surface area from the newborn period to adulthood17'18; (2) assuming the average melanoma to be a circle with a 2.0 cm diameter19; and (3) representing the location of a melanoma by a point at its center, which is placed at random on the body surface with uniform probability for all points. The probability of contiguity for the average melanoma and small CN is 1/1,429, computed by dividing the area of an ellipse (11.9 cm") (Fig. 6) by the total body surface area for an average adult (17,000 cm2). Only 0.83% (7/841) of patients with melanoma are likely to have small CN; therefore, in consecutive melanoma specimens, fewer than 5.8 × 10-4% (1/1,429 x 7/
841 × 100%) are expected to be associated with small CN in microscopic contiguity. Histologic features may not absolutely or adequately define congenital nevi. The criteria for N N C F used in our studies were derived from the report by Mark et al, (~which is the only investigation to our knowledge that formally compares histologic findings of historically documented congenital and acquired nevocellular nevi. Unfortunately, the total number of cases studied was relatively small, if the ratio of small CN (1% of newbores) 1-s'1~ to all acquired nevocellular nevi (an average of twenty-four lesions per Caucasian adult) '-'° is taken into account. The predictive value of a single criterion used for diagnosis o f a disease is influenced not only by the sensitivity and specificity of the criterion, but also by the prevalence of the disease. ~1 Thus, a very low prevalence of small CN in relationship to all nevocellular nevi greatly reduces the predictive value of a single criterion if specificity is even slightly less than 100%. 21 For purposes of demonstrating a reliable "mini m u m " histologic association for small CN and melanoma (and reducing the chance of misclassifying acquired nevi as congenital), a combination of histologic features that impart a high probability of predicting tree CN may be applied to our
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nineteen NNCF cases. The requirement that nevus cells reside in the lower two thirds of the reticular dermal collagen (98.3% sensitivity, Table I)plus the presence of nevus cells in sebaceous glands, blood vessels, or nerves ( " 1 0 0 % " specificity, Table I) would reduce the number of NNCF cases from nineteen to six (Table II). It is proposed that these six cases very likely represent the minimum association of small CN and melanoma in our 234 cases (2.6%). It should be emphasized, however, that such a combination of requirements eliminates the NNCF cases having features with " 1 0 0 % " specificity for CN but without nevus cells in the deep reticular dermis (Tables I and II). Also eliminated are several patients for whom there was an available history of a pigmented lesion at the tumor site since birth (Cases 9, 12, and 17). The almost uniform occurrence of nevus cells in the deep reticular dermal collagen of historically documented CN in children and adults, according to Mark et aP (Table I), must be contrasted with direct observations in neonates. Only two of eleven nevocellular nevi, on which biopsy examination was done (2-mm punch) in the newborn period by Walton et al, had nevus cells in the deep reticular dermal collagen, while the rest had the appearance of acquired nevi. 1 On the other hand, all fifteen CN noted at birth, and later excised by Alper et al, 2 had the presence of nevus cells in the deep reticular dermis. Until the discrepancies in these studies are reconciled, nevus cells in the deep reticular dermal collagen may be a sufficient, but not necessary, criterion for CN. To ignore other features "highly specific" for historic CN (Table I) because nevus cells are not found in the deep reticular dermis is to introduce a classification bias that may falsely reduce the histologic association of small CN and melanoma. In our estimate of chance association of small CN and melanoma, it was assumed that (1) nevus size increases relative to total body surface area during growth (eightfold), 17 and (2) the prevalence rate of small CN in adults is identical to race-matched newborns. The lack of significant nevus expansion during normal body growth and/or the regression of small CN with age, as noted for acquired nevi, 2° would have the effect of
Malignant potential of small congenital nevi
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\
// \
i J
Fig. 6. Conditions for microscopic contiguity between a small congenital nevus (CN) (represented by a 2.6 x 1.3-cm ellipse) and a melanoma (M) (represented by a circle with a diameter of 2.0 cm) are met when .the center of the melanoma is within its radial distance of the CN (clotted line). The probability of contiguity for the two lesions is computed to be 1/1,429, the area within the elliptical dotted line (11,9 cm 2, dimensions 4.6x3.3 cm) divided by the total body surface area for an average adult (17.000 cm~), (See text.)
reducing the expected chance association between melanoma and small CN to a rate much smaller than 5.8 × 1 0 - 4 % . It was also assumed that there is only one small CN per individual. More than one lesion per person and/or a significant tendency for a nonrandom distribution for both melanomas and small CN (restricted to the same localized anatomic areas) would have the effect of increasing the chance association. In 5,699 newborns examined collectively by Walton et al I and Alper et al. ~ only one infant was found to have more than one small CN. In the studies by Castilla et al, a 9% of newborns with CN had more than one lesion3; however, the authors admit to an underreporting bias of 80%, a factor which might falsely inflate the proportion of patients with multiple CN. For 922 CN in newborns observed by Castilla et al a and 761 melanomas in adults studied by Sober et al,'-"-' there are notable deviations for both lesions
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relative to the distribution of body surface area in newborns and adults, t8 The biases created by these deviations, however, are not likely to account for the 4,000- to 13,000-fold difference noted between the observed histologic (2.6-8.1%) and expected chance (5.8 x 1 0 - 4 % ) associations for small CN and melanoma. Our NNCF patients had significantly thinner microscopic tumors and tended to have smaller gross diameters than patients without nevi, suggesting a less aggressive growth pattern for tumors associated with CN. Alternatively, distinguishing melanomas for having associated nevi (NNCF or ON) might bias selection for thinner microscopic tumors (i.e., less destruction) and/or earlier diagnosis. If gross tumor diameter were directly related to microscopic tumor thickness, and nevusassociated patients are more likely to have thinner microscopic tumors (Table III), then finding a smaller mean tumor diameter among the N N C F cases would not be surprising. Wick et a119 showed gross tumor diameter to vary directly with anatomic level of microscopic tumor invasion; a similar relationship to gross tumor size has been demonstrated for microscopic tumor thickness.* Significantly more of our sixty-four combined nevus cases (NNCF + ON) were associated with patient age -<40 years than 170 cases without nevi. This age difference also may be related to thinner microscopic tumors, since thinner tumors and more superficial levels of microscopic tumor invasion have been associated with younger patient age. 1:~''3 The lower extremities were significantly less likely to be the area of involvement in NNCF patients than in patients without nevi, with no difference between NNCF and ON patients (Table III). This association may be indirectly related to microscopic tumor thickness; Levine et al '~a reported finding thicker tumors in this anatomic location, and our own studies show a significant relationship between the presence of a nevus (NNCF or ON) and tumor thickness -----2.25 mm (Table III). Reduced numbers of nevi on the lower extremities relative to the anatomic distribution of body surface area in adults a,~x'2° and/or more aggressive
tumor growth related to body site are other factors that might contribute to this finding. Optimal tumor representation and a minimum o f nevus architecture disruption are required to detect congenital features in melanoma-associated nevi. These factors may represent selection biases, probably accounting for our N N C F cases being associated with a significantly greater number of slides with melanoma (and trends for a greater number of tissue sections, thinner microscopic tumors, and smaller gross tumor diameter) than ON cases. It is likely that additional cases of melanoma-associated nevi (and N N C F cases in particular) may have been identified had all tumors been excised at an early phase of dermal invasion and been uniformly prepared by close step-sectioning. Significantly more of our sixty-four combined nevus cases were observed with tumors classified as SSM than 170 cases without nevi (84.4% vs 62.4%) (p < 0.01, chi-square test). This association may be due at least in part to the relationship between acquired dysplastic nevi (DN) and SSM. DN usually have a dermal nevus component in addition to intraepidermal atypical melanocytic hyperplasia (AMH)...,4 AMH has been found adjacent to five primary SSMs in one study,24 supporting the notion that DN may be precursors for SSM. AMH also has been noted in historically documented CN, (~''-'5 in addition to 42.1% of our nineteen NNCF cases and 31.1% of our forty-five ON cases (compared to 15.9% of 170 cases without nevi).* These findings suggest the need to determine gross characteristics o f nevi (congenital or acquired) that predict the presence of A M H and allow for the recognition of " h i g h - r i s k " lesions. One easily recognized variety of high-risk lesions is the giant CN. However, giant CN represent only a minority of nevocellular nevi observed in newborns 1-~ and a rare association in most unselected cases of cutaneous melanoma. In ten published series for which information is available about preexisting pigmented lesions at the site of melanoma, s,'~'2~-'~3 a giant CN was specifically stated to be associated in only one of 1,130 cases, al In contrast, small CN were alleged to be
*Harvard MelanomaRegistry: Unpublished data.
*A. R. R., T. J. H., M. G. M.: Unpublished observations.
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preexisting lesions in 9% to 41% (mean, 20%) of cases. 8,~,2~-:~:~More importantly, there may not be a satisfactory way of classifying CN on the basis of size, a'~ histology, 1'2'~ or malignant potential. Accessibility to gross recognition (by physicians and parents), relatively common occurrence (1% of newborns), and circumstantial association with melanoma not easily attributed to chance (2.6%8.1% by histology and 9%-41% by history) combine to make small CN of practical importance in the epidemiology of cutaneous melanoma. Small CN may be precursors for at least some cases of cutaneous melanoma and ought to be considered for prophylactic excision. REFERENCES
1. Walton RG, Jacobs AH, Cox HJ: Pigmented lesions in newborn infants. Br J Dermatol 95:389-396, 1976. 2. Alper J, Holmes LB, Mihm MC: Birthmarks with serious medical significance: Nevocellular nevi, sebaceous nevi, and multiple caf6-au-lait spots. J Pediatr 95:696-700, 1979. 3. Castilla EE, Da Graca Durra M, Orioli-Parreiras IM: Epidemiology of congenital pigmented nevi; incidence rates and relative frequencies. Br J Dermatol 104:307315, 1981. 4. Rhodes AR, Wood WC, Sober AJ, Mihm MC: Nonepidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 67:782-790, 1981. 5. Mihm MC, Lopansri S: A review of the classification of malignant melanoma. J Dermatol 6:131-142, 1979. 6. Mark GJ, Mihm MC, Liteplo MG, Reed RJ, Clark WH: Congenital malanocytic nevi of the small and garment type. Hum Pathol 4:395-418, 1973. 7. Breslow A: Tumor thickness, level of invasion and node dissection in Stage I cutaneous melanoma. Ann Surg 182:572-575, 1975. 8. Ackerman LV: Malignant melanoma of the skin--a clinical and pathological analysis of 75 cases. Am J Clin Pathol 18:602-624, 1948. 9. Helwig EB: Malignant melanoma of the skin in man. Natl Canc Inst Monogr 10:287-295, 1963. 10. Clark WH, From L, Bernardino EA, Mihm MC: The histiogenesis and biologic behavior of primary human melanomas of the skin. Cancer Res 29:705-726, 1969. 11. Cochran A J: Histology and prognosis in malignant melanoma. J Pathol 97:459-468, 1969. 12. McGovern VJ: The classification of melanoma and its relationship with prognosis. Pathology 2:85-98, 1970. 13. Rippey JJ, Whiting DA: Moles and melanoma. Lancet 2:137, 1977. 14. Larsen TE: Tile classification of primary cutaneous malignant melanoma. Acta Pathol Microbiol Scand [A] 86:451-459. 1978.
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15. Kopf AW, Ban RS, Hennessey P: Congenital nevocytic nevi and malignant melanomas. J AM ACAD DERMATOL 1:123-130, 1979. 16. Pratt AG: Birthmarks in infants, Arch Dermatol 67: 302-306, 1953. 17. Diem K, editor: Documenta Geigy scientific tables, ed. 6. Ardsley, NY, 1962, Geigy Pharmaceuticals, pp. 613, 622,633. 18. Lund CC, Browder NC: The estimation of areas of bums. Surg Gynecol Obstet 79:352-358, 1944. 19. Wick MM, Sober AJ, Fitzpatrick TB, Mihm MC, Kopf AW, Clark WH, Blois M J: Clinical characteristics of early cutaneous melanoma. Cancer 45:2684-2686, 1980. 20. Nicholls EM: Development and elimination of pigmented moles, and the anatomical distribution of primary malignant melanoma. Cancer 32:191-t95, 1973. 21. Vecchio TJ: Predictive value of a single diagnostic test in unselected populations. N Engl J Med 274:1 i71-1173, 1966. 22. Sober AJ, Blois MS, Clark WH, Fitzpatrick TB, Kopf AW, Mihm MC Jr: Primary malignant melanoma of the skin--1130 cases from the Melanoma Clinical Cooperative Group, in Proceedings XV International Congress of Dermatology, Mexico, October, 1977. Amsterdam, 1979, Exeerpta Medica Foundation. 23. Levine J, Kopf AW, Rigel DS, Bart RS, Hennessey P, Friedman RJ, Mintzis MM: Correlation of thickness of superficial spreading melanomas and ages of patients. J Dermatol Surg Oncol 7:311-316, 1981. 24. Elder DE, Goldman LI, Goldman SC, Greene MH, Clark WH: Dysplastic nevus syndrome: A phenotypie association of sporadic cutaneous melanoma. Cancer 46:1787-1794, 1980. 25. Silvers DN, Helwig EB: Melanocytic nevi in neonates. 1 AM ACAD DERMATOL4: 166-175, 1981. 26. Williams IG, Martin LC: Naevocarcinoma of the skin and mucous membranes. Lancet 232:135-138, 1937. 27. Daland EM, Holmes JA: Malignant melanoma: A clinical study. N Engl J Med 220:651-660, 1939. 28. Driver JR, MacVicar DN: Cutaneous melanoma--a clinical study of sixty cases. JAMA 121:413-420, 1943, 29. Wright CJE: Prognosis in cutaneous and ocular malignant melanoma: A study of 222 cases. J Pathol Bacteriol 61:507-525, 1949. 30. Booher RJ, Pack GT: Malignant melanoma of the feet and hands. Surgery 42:1084-1121, 1957. 31. Bader JL, Li FP, Miller RW, Roegner R: Malignant melanoma in patients under 20 years of age: An epidemiologic study. Proc Am Assoc Cancer Res 20:316, 1979. (Abst.) 32. Rhodes AR, Sober AJ, Melski JW, Mihm MC, Fitzpatrick TB: Possible risk factors for cutaneous malignant melanoma. Clin Res 28:252, 1980. (Abst.) (Presented at the annual meeting of the Federation for Clinical Research, May 12, 1980.) 33. Pratt CB, Palmer MK, Thatcher N, Crowther D: Malignant melanoma in children and adolescents. Cancer 47:392-397, 1981.
From the Division of Dermatology, Department of Medicine, Children's Hospital Medical Center (Dr. Rhodes), the Department of Dermatology (Drs. Sober, Day, Mihm, and Fitzpatrick) and Pathology (Dr. Harfist), Massachusetts General Hospital, the Department of Computer Medicine, Beth Israel Hospital (Dr. Melski), and the Departments of Dermatology, Pathology, and Medioine, Harvard Medical School. Supported in part by grants from the Jackson Trust, The National Cancer Institute (CA 13651), and The National Center for Health Services Research (HS-00188 and H8-04050), United States Public Health Service. Presented at the meeting of ttle Society for Investigative Dermatology, San Francisco, CA, April 28, 198l. Reprint requests to: Dr. Arthur R, Rhodes, Division of Dermatology, Hunnewell-3, Children's Hospital Medical Center, 300 Longwood Ave,, Boston, MA 02115/617-735-6126f6127.
230
Current melanoma management emphasizes the early diagnosis of thin tumors and the recognition of precursor lesions. Congenital nevocellular nevi (CN), collections of nevus cells in pigmented lesions of the skin in newborns, t-a are generally acknowledged to be precursors for melanoma when their size is extremely large (giant). 4 Giant CN, observed in fewer than one per thousand newborns, t-3 have an estimated lifetime melanoma risk of at least 6.3%. 4 It is worth knowing whether relative size is the only determinant of risk for CN, because small CN are at least ten times more common than giant CN. 2,a Presuma0 1 9 0 - 9 6 2 2 / 8 2 / 0 2 0 2 3 0 + 12501.20/0 © 1982 Am Acad Dermatol
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Table
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I. Histologic features o f congenital nevi versus acquired nevi* Location of nevus cells
.
Lower two-thirds reticular dermal collagen Sebaceous glands Arrectores pilorum Hair follicles Eccrine ducts Nerves Lymphatic vessels Blood vessels
Congenital nevi
Acquired nevi
Sensitivity
Specificity
(%)
(%)
59/60
2/60
98.3
96.7
22/60 48/60 12/60 22/60 37/60 13/60 9/60
0/60 2/60 3/60 2/60 0/60 2/60 0/60
36.7 80.0 20.0 36.7 61.7 21.7 I5.0
100.0 96.7 95.0 96.7 100.0 96.7 100.0
*Based on historicascertainmentof cases; adapted from Mark GL, et al: Hum Pathol 4:395-418, 1973. bly, the strength of a relationship between small CN and cutaneous melanoma could be estimated by comparing the observed rate o f histologic association with an expected rate based on chance alone. Therefore, a histologic survey o f primary cutaneous melanomas was conducted in order to determine the frequency of tumor-associated nevocellular nevi with microscopic features characteristic of CN. MATERIALS AND M E T H O D S Two hundred thirty-four patients with primary cutaneous melanoma (all histologic types) 5 were entered prospectively into a study group at the Harvard Melanoma Registry during the period Sept. 1, 1972, to May 30, 1977. A standardized patient interview was conducted within 30 days of melanoma excision. The series included 119 males and 115 females whose ages ranged from 12 to 90 years (mean, 47.9 years). One patient was black, and 233 were white. Patients were followed for evidence of recurrent disease at 3month intervals for the first 2 years after diagnosis, every 6 months for the next 3 years, and annually thereafter. The tumor specimens from these 234 patients were reviewed by four of the authors (A. R. R., C. L. D., T. J. H., and M. C. M.) for the presence of nevocellular nevi in association with melanoma. For cases to be called "positive" for tumor-associated nevi, unanimous agreement among the reviewers required the presence of obvious nests, sheets, cords, and/or single-file disposition of cytologically benign nevus cells in the dermis immediately adjacent to the melanoma ("in contiguity"). To distinguish congenital from noncongenital nevi, the reviewers relied on data
provided by Mark et al ~ for historically documented lesions (Table I). Melanoma-associated nevoeellular nevi were designated as having congenital features if nevus cells were found within the collagen of the lower two thirds of the reticular dermis and/or nevus cells were present within one or more appendages (follicles, sebaceous glands, arrectores pilorum, and eccrine ducts), inside perineural sheaths, within blood vessel walls, or associated with lymphatic vessels causing luminal distortion. Microscopic tumor thickness was determined by one pathologist (M. C. M.) according to the method of Breslow. ? All histologic data were entered on computer, and correlations were determined for selected characteristics in the 234 patients. RESULTS In 27.4% (64/234) o f m e l a n o m a specimens, a dermal nevocellular nevus was found in contiguity with the melanoma. Of the 64 nevus cases, 19 (8.1% o f 234) had tumor-associated nevocellular nevi with congenital features (NNCF) (Table II), and 45 (19.2% of 234) appeared identical to "acquired" (ordinary) nevocellular nevi (ON) (Table I). ~+Of the 19 NNCF, 8 had nevus cells extending into the collagen o f the midreticular dermis or deeper (Figs. 1 and 2) (Table II); o f these 8 tumor-associated N N C F , 7 had nevus cells in one or more appendageal, neural, or vascular structures with high specificity for historic congenital nevi (Tables I and II; Figs. 2 to 4). The eleven N N C F patients w h o had nevus cells no deeper than the collagen o f the u p p e r reticular dermis were designated N N C F on the basis o f appendageal, neural, or vascular involvement by
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Table II. Location of nevus cells in 17 melanoma-associated dermal nevi with congenital features Age
Sex
Anatomic site
1" 2
28 57
F M
Leg Forearm
3 4 5 6 7 8
30 80 45 50 73 29
F M F F M M
Cheek Scalp Arm Chest Forehead Back
9
40
M
Back
10 Il
41 71
M M
Back Back
12 13 14 15 16
21 33 37 41 26
F M M F F
Arm Chest Back Arm Back
17 18 19
34 28 61
F M M
Back Neck Back
Patient
Deepest site of penetration and involvement of other structures
Deep reticular dermal collagen Nerves, lymphatic vessels Arrectores pilomm Midreticular dermal collagen Hair follicles, nerves None Nerves Hair follicles, nerves Blood vessels Hair follicles, nerves, blood vessels Upper reticular dermal collagen Hair follicles, sebaceous glands Arrectores pilorum Hair follicles, sebaceous glands Blood vessels Hair follicles Eccrine ducts, nerves Nerves, lymphatic vessels Nerves, lymphatic and blood vessels Blood vessels Lymphatic and blood vessels Hair follicles, arrectores pilorum
Melanoma type (level/thickness)
SSM (II/0.8) SSM (II/0.3) SSM 0W1.0) AAM (IV/I.3) SSM (IV/2.0) SSM (III/0.75) UNC (IV/2.2) NM (IV/4.5)
SSM (lII/l.0) SSM (III/1.6) SSM (III/1.8) SSM SSM SSM SSM SSM
(II/1.15) (II/0.8) (III/2.0) (III/1.0) (II/0.6)
SSM (IV/1.4) SSM (II/0.5) SSM (II/0.45)
Superficial spreading melanoma (SSM), nodular melanoma (NM), unclassified radial growth phase melanoma (UNC). *Panniculus also involved by nevus cells,
nevus cells (Tables I and II; Fig. 5). None of the nineteen NNCF-associated melanomas had an obvious origin in the dermal component of a nevocellular nevus. None of the 234 melanomas was associated with a giant CN, i.e., a nevus so large that it could not be removed by simple excision and primary closure using adjacent tissues in a single surgical procedure) The gross size of an intact melanoma was represented by its greatest diameter according to exact measurements, which were available for 10/19 NNCF cases, 24/45 ON cases, and 77/170 cases without nevi. The greatest tumor diameter for the NNCF cases (mean + SD = 16 + 6 ram) tended to be smaller than for ON cases (20 _+ 12
mm) (p > 0.2)* and cases without nevi (21 + 14 ram) (p = 0.0587).* For the 9 NNCF cases without photographs, the largest skin ellipse (according to pathology reports) was -<45 ram. When compared to the 170 cases without nevi, the sixty-four nevus cases (NNCF + ON) occurred significantly more often on the torso (43/64 = 67.2% vs 59/170 = 34.7%) and in patients --<40 years of age (56.2% vs 29.4%) and were significantly less often associated with nodular melanoma (7.8% vs 18.8%), lentigo maligna melanoma (0 vs 5.9%), and microscopic tumor invasion to anatomic level V (3.1% vs 12.4%) *Student's two-sided t test with unequal variances.
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Fig. 1. Case 1. Invasive melanoma is present in the papillary dermis in association with a nevus, the cells of which are disposed singly and as nests, sheets, and cords permeating the collagen of the lower two thirds of the reticular dermis. (Hematoxylin-eosin stain; x96.)
(p < 0.05 for all c o m p ~ i s o n s , chi-square test). There were no significant differences in these features when the N N C F cases were compared to ON cases and cases without nevi. When compared to cases without nevi, NNCF
cases were significantly less likely to occur on the lower extremities and significantly m o r e likely to be associated with microscopic t u m o r thickness --<2.25 mm, histologic tumor type superficial spreading melanoma (SSM), and a greater number
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Fig. 2. Case 1. Nevus cells are present in the deep reticular dermis, extending focally into the panniculus (P). Nevus cells covered by endothelium protrude into the lumen of a lymphatic vessel (arrow). (Hematoxylin-eosin stain; x240.) of slides and tissue sections with melanoma available for review (Table III).* Except for number of slides with melanoma, there were no significant differences in these selected features when N N C F cases were compared with ON cases. The mean *Four or more tissue sections and two or more slides with tumor were available in 95.7% and 82.9% of the 234 cases, respectively.
age at diagnosis for NNCF cases (43.6 +- 17.2 yr) was similar to that of ON cases (41.8 + 16.3 yr) but less than that of cases without nevi (50.6 + 16.7 yr) (p = 0.087).* The mean tumor thickness for the NNCF cases (1.30 _+ 0.87 ram) tended to be less than that of ON cases (1.75 _+ 1.46 ram) *Student's two-sided t test with equal variances.
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3. Case 8. Nevus cell nests are present within a hair follicle. Within the collagen of the reticular dermis, invasive melanoma (M) and nevus cells (N) are identified. (Hematoxylin-eosin stain; ×240.) Fig.
(p > 0.1),* but significantly less than that of patients without nevi (2.25 _+ 2.08 mm) (p = 0,0005).* At the time of this writing, fewer NNCF patients tended to have documented metastases (Cases 4, 7, and 8) or be dead from melanoma *Student's two-sided t test with uneaual variances,
(Cases 4 and 8) (Table 1II). The m a l e : f e m a l e ratios for the N N C F cases (11:8), ON cases (24:21), and cases without nevi (84:86) were similar. In the standard questionnaire, interviewers made a final judgment based on history as to whether or not the melanoma arose from a mole. N N C F cases
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Fig. 4. Case 8. N e v u s cells are present in the wall of an arteriole (small arrows) and within the perineural sheath of a small nerve (large arrow). ( x 2 4 0 . ) Inset, Infiltration o f the nerve sheath b y nevus cells is apparent. ( x 1,000.) (Hematoxylin-eosin stain.)
Nevocellular nevi have been reported in histologic association with 4% to 41% of cutaneous melanomas, s-1~ To our knowledge, however, only
one previously published histologic study has attempted to determine the proportion of melanomaassociated nevi likely to represent congenital nevi. Kopf et al ~ reported four tumor-associated NNCF among 349 selected melanomas of the superficial spreading type (1.1%), none of which was associated with a giant CN.* Kopf et al concluded 1'~ that a 1.1% rate of association was no greater than expected when the 1% prevalence rate of small CN in newborns was considered. However, this conclusion does not take into account the small proportion of body surface area involved. Even a 1% histologic association of small CN and melanoma should be regarded as significant when compared with the expected association based on surface area by chance alone. The chance of finding melanoma in microscopic
*Fisher exact test, two-sided.
*Kopf AW: Personal communication.
tended to have a greater association with melanomas arising from moles than ON cases (57.9% vs 42.2%) (p = 0.2841),* but significantly greater than patients without nevi (57.9% vs 31.8%) (p = 0.0388).* Age of onset and/or duration of preexisting moles were data not specifically sought by the standard questionnaire. However, additional information noted by interviewers for NNCF patients included preexisting moles "since birth" in 3 (Cases 9, 12, and 17), "lifelong" in 1 (Case 11), -->10 years in 3 (Cases 7, 16, and 19), and >--3 years in 3 (Cases 2, 3, and 6). DISCUSSION
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Fig. 5. Case 11. Invasive melanoma (M), admixed with inflammatory cells, fills the papillary dermis. Nevus cells (N) are seen in the collagen of the upper reticular dermis and within a sebaceous gland. (× 96.) Inset, Nevus cells are seen within a sebaceous gland. (× 192.) (Hematoxylin-eosin stain.) contiguity with small CN in consecutive melanoma specimens of white adults depends on the simultaneous occurrence of two events: (1) finding small CN in white adults (identical to prevalence rate) and (2) finding small CN in microscopic contiguity with melanoma. The prevalence rate of small CN in adults may be assumed to be the same as in newborns, based on the relatively stable oc-
currence in newborns noted for the United States and Latin America during the past three decades, l-a'~c~ A stable prevalence rate permits the supposition that each age cohort has the same chance of having small CN. The most completely documented data available for a homogeneous racial group is that of Walton et al,t in which biopsy examination was done on twenty-one pigmented
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Table lII. Selected features in 234 patients with cutaneous melanoma correlated with the presence or absence of tumor-associated nevi* Features
Tumor thickness 42.25 mm Tumor location lower extremities Tumor histology SSM~+ Slides with melanoma ~>5 Tissue sections with reelanoma 314 Age 440 yr Metastatic disease present Death from melanoma
% N N C F cases (n = 19)
% ON cases (n = 45)
% cases w i t h o u t nevi
94.7
77.8
65.9"I"
5.3
6.7
31.8t
89.5 82.4 78.9
84.4 44.41" 68.9
62.4t 44. i t 52.9-I"
52.6 15.8 10.5
57.8 26.7 17.8
29.4 35.3 24.1
(n = 170)
*Tumor-associated nevi include nevocellular nevi with congenital features (NNCF) and ordinary nevi (ON). "[p < 0.05, Fisher exact test, two-sided; comparisons have been made between NNCF and ON cases, and between NNCF cases and cases without nevi. :[:Superficial spreading melanoma.
lesions observed within 72 hours of birth in 841 white neonates to determine the true prevalence rate of small CN. Only seven of these twenty-one pigmented lesions were reported as nevocellular nevi, all --<3 cm in greatest diameter, i.e., a prevalence rate of 0.83% (7/841) for small CN in white newborns. The probability of contiguity for melanoma and small CN in an adult with both lesions (Fig. 6) is estimated by: (1) assigning a size of 2.6 × 1.3 cm to a small CN in adults, derived from measurements of fifty-six small CN observed in newbores la (mean dimensions, 8 x 5 mm), and expanded eightfold to account for the average increase in body surface area from the newborn period to adulthood17'18; (2) assuming the average melanoma to be a circle with a 2.0 cm diameter19; and (3) representing the location of a melanoma by a point at its center, which is placed at random on the body surface with uniform probability for all points. The probability of contiguity for the average melanoma and small CN is 1/1,429, computed by dividing the area of an ellipse (11.9 cm") (Fig. 6) by the total body surface area for an average adult (17,000 cm2). Only 0.83% (7/841) of patients with melanoma are likely to have small CN; therefore, in consecutive melanoma specimens, fewer than 5.8 × 10-4% (1/1,429 x 7/
841 × 100%) are expected to be associated with small CN in microscopic contiguity. Histologic features may not absolutely or adequately define congenital nevi. The criteria for N N C F used in our studies were derived from the report by Mark et al, (~which is the only investigation to our knowledge that formally compares histologic findings of historically documented congenital and acquired nevocellular nevi. Unfortunately, the total number of cases studied was relatively small, if the ratio of small CN (1% of newbores) 1-s'1~ to all acquired nevocellular nevi (an average of twenty-four lesions per Caucasian adult) '-'° is taken into account. The predictive value of a single criterion used for diagnosis o f a disease is influenced not only by the sensitivity and specificity of the criterion, but also by the prevalence of the disease. ~1 Thus, a very low prevalence of small CN in relationship to all nevocellular nevi greatly reduces the predictive value of a single criterion if specificity is even slightly less than 100%. 21 For purposes of demonstrating a reliable "mini m u m " histologic association for small CN and melanoma (and reducing the chance of misclassifying acquired nevi as congenital), a combination of histologic features that impart a high probability of predicting tree CN may be applied to our
Volume 6 Number 2 February, 1982
nineteen NNCF cases. The requirement that nevus cells reside in the lower two thirds of the reticular dermal collagen (98.3% sensitivity, Table I)plus the presence of nevus cells in sebaceous glands, blood vessels, or nerves ( " 1 0 0 % " specificity, Table I) would reduce the number of NNCF cases from nineteen to six (Table II). It is proposed that these six cases very likely represent the minimum association of small CN and melanoma in our 234 cases (2.6%). It should be emphasized, however, that such a combination of requirements eliminates the NNCF cases having features with " 1 0 0 % " specificity for CN but without nevus cells in the deep reticular dermis (Tables I and II). Also eliminated are several patients for whom there was an available history of a pigmented lesion at the tumor site since birth (Cases 9, 12, and 17). The almost uniform occurrence of nevus cells in the deep reticular dermal collagen of historically documented CN in children and adults, according to Mark et aP (Table I), must be contrasted with direct observations in neonates. Only two of eleven nevocellular nevi, on which biopsy examination was done (2-mm punch) in the newborn period by Walton et al, had nevus cells in the deep reticular dermal collagen, while the rest had the appearance of acquired nevi. 1 On the other hand, all fifteen CN noted at birth, and later excised by Alper et al, 2 had the presence of nevus cells in the deep reticular dermis. Until the discrepancies in these studies are reconciled, nevus cells in the deep reticular dermal collagen may be a sufficient, but not necessary, criterion for CN. To ignore other features "highly specific" for historic CN (Table I) because nevus cells are not found in the deep reticular dermis is to introduce a classification bias that may falsely reduce the histologic association of small CN and melanoma. In our estimate of chance association of small CN and melanoma, it was assumed that (1) nevus size increases relative to total body surface area during growth (eightfold), 17 and (2) the prevalence rate of small CN in adults is identical to race-matched newborns. The lack of significant nevus expansion during normal body growth and/or the regression of small CN with age, as noted for acquired nevi, 2° would have the effect of
Malignant potential of small congenital nevi
239
\
// \
i J
Fig. 6. Conditions for microscopic contiguity between a small congenital nevus (CN) (represented by a 2.6 x 1.3-cm ellipse) and a melanoma (M) (represented by a circle with a diameter of 2.0 cm) are met when .the center of the melanoma is within its radial distance of the CN (clotted line). The probability of contiguity for the two lesions is computed to be 1/1,429, the area within the elliptical dotted line (11,9 cm 2, dimensions 4.6x3.3 cm) divided by the total body surface area for an average adult (17.000 cm~), (See text.)
reducing the expected chance association between melanoma and small CN to a rate much smaller than 5.8 × 1 0 - 4 % . It was also assumed that there is only one small CN per individual. More than one lesion per person and/or a significant tendency for a nonrandom distribution for both melanomas and small CN (restricted to the same localized anatomic areas) would have the effect of increasing the chance association. In 5,699 newborns examined collectively by Walton et al I and Alper et al. ~ only one infant was found to have more than one small CN. In the studies by Castilla et al, a 9% of newborns with CN had more than one lesion3; however, the authors admit to an underreporting bias of 80%, a factor which might falsely inflate the proportion of patients with multiple CN. For 922 CN in newborns observed by Castilla et al a and 761 melanomas in adults studied by Sober et al,'-"-' there are notable deviations for both lesions
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relative to the distribution of body surface area in newborns and adults, t8 The biases created by these deviations, however, are not likely to account for the 4,000- to 13,000-fold difference noted between the observed histologic (2.6-8.1%) and expected chance (5.8 x 1 0 - 4 % ) associations for small CN and melanoma. Our NNCF patients had significantly thinner microscopic tumors and tended to have smaller gross diameters than patients without nevi, suggesting a less aggressive growth pattern for tumors associated with CN. Alternatively, distinguishing melanomas for having associated nevi (NNCF or ON) might bias selection for thinner microscopic tumors (i.e., less destruction) and/or earlier diagnosis. If gross tumor diameter were directly related to microscopic tumor thickness, and nevusassociated patients are more likely to have thinner microscopic tumors (Table III), then finding a smaller mean tumor diameter among the N N C F cases would not be surprising. Wick et a119 showed gross tumor diameter to vary directly with anatomic level of microscopic tumor invasion; a similar relationship to gross tumor size has been demonstrated for microscopic tumor thickness.* Significantly more of our sixty-four combined nevus cases (NNCF + ON) were associated with patient age -<40 years than 170 cases without nevi. This age difference also may be related to thinner microscopic tumors, since thinner tumors and more superficial levels of microscopic tumor invasion have been associated with younger patient age. 1:~''3 The lower extremities were significantly less likely to be the area of involvement in NNCF patients than in patients without nevi, with no difference between NNCF and ON patients (Table III). This association may be indirectly related to microscopic tumor thickness; Levine et al '~a reported finding thicker tumors in this anatomic location, and our own studies show a significant relationship between the presence of a nevus (NNCF or ON) and tumor thickness -----2.25 mm (Table III). Reduced numbers of nevi on the lower extremities relative to the anatomic distribution of body surface area in adults a,~x'2° and/or more aggressive
tumor growth related to body site are other factors that might contribute to this finding. Optimal tumor representation and a minimum o f nevus architecture disruption are required to detect congenital features in melanoma-associated nevi. These factors may represent selection biases, probably accounting for our N N C F cases being associated with a significantly greater number of slides with melanoma (and trends for a greater number of tissue sections, thinner microscopic tumors, and smaller gross tumor diameter) than ON cases. It is likely that additional cases of melanoma-associated nevi (and N N C F cases in particular) may have been identified had all tumors been excised at an early phase of dermal invasion and been uniformly prepared by close step-sectioning. Significantly more of our sixty-four combined nevus cases were observed with tumors classified as SSM than 170 cases without nevi (84.4% vs 62.4%) (p < 0.01, chi-square test). This association may be due at least in part to the relationship between acquired dysplastic nevi (DN) and SSM. DN usually have a dermal nevus component in addition to intraepidermal atypical melanocytic hyperplasia (AMH)...,4 AMH has been found adjacent to five primary SSMs in one study,24 supporting the notion that DN may be precursors for SSM. AMH also has been noted in historically documented CN, (~''-'5 in addition to 42.1% of our nineteen NNCF cases and 31.1% of our forty-five ON cases (compared to 15.9% of 170 cases without nevi).* These findings suggest the need to determine gross characteristics o f nevi (congenital or acquired) that predict the presence of A M H and allow for the recognition of " h i g h - r i s k " lesions. One easily recognized variety of high-risk lesions is the giant CN. However, giant CN represent only a minority of nevocellular nevi observed in newborns 1-~ and a rare association in most unselected cases of cutaneous melanoma. In ten published series for which information is available about preexisting pigmented lesions at the site of melanoma, s,'~'2~-'~3 a giant CN was specifically stated to be associated in only one of 1,130 cases, al In contrast, small CN were alleged to be
*Harvard MelanomaRegistry: Unpublished data.
*A. R. R., T. J. H., M. G. M.: Unpublished observations.
Volume 6 Number 2 February, 1982
preexisting lesions in 9% to 41% (mean, 20%) of cases. 8,~,2~-:~:~More importantly, there may not be a satisfactory way of classifying CN on the basis of size, a'~ histology, 1'2'~ or malignant potential. Accessibility to gross recognition (by physicians and parents), relatively common occurrence (1% of newborns), and circumstantial association with melanoma not easily attributed to chance (2.6%8.1% by histology and 9%-41% by history) combine to make small CN of practical importance in the epidemiology of cutaneous melanoma. Small CN may be precursors for at least some cases of cutaneous melanoma and ought to be considered for prophylactic excision. REFERENCES
1. Walton RG, Jacobs AH, Cox HJ: Pigmented lesions in newborn infants. Br J Dermatol 95:389-396, 1976. 2. Alper J, Holmes LB, Mihm MC: Birthmarks with serious medical significance: Nevocellular nevi, sebaceous nevi, and multiple caf6-au-lait spots. J Pediatr 95:696-700, 1979. 3. Castilla EE, Da Graca Durra M, Orioli-Parreiras IM: Epidemiology of congenital pigmented nevi; incidence rates and relative frequencies. Br J Dermatol 104:307315, 1981. 4. Rhodes AR, Wood WC, Sober AJ, Mihm MC: Nonepidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 67:782-790, 1981. 5. Mihm MC, Lopansri S: A review of the classification of malignant melanoma. J Dermatol 6:131-142, 1979. 6. Mark GJ, Mihm MC, Liteplo MG, Reed RJ, Clark WH: Congenital malanocytic nevi of the small and garment type. Hum Pathol 4:395-418, 1973. 7. Breslow A: Tumor thickness, level of invasion and node dissection in Stage I cutaneous melanoma. Ann Surg 182:572-575, 1975. 8. Ackerman LV: Malignant melanoma of the skin--a clinical and pathological analysis of 75 cases. Am J Clin Pathol 18:602-624, 1948. 9. Helwig EB: Malignant melanoma of the skin in man. Natl Canc Inst Monogr 10:287-295, 1963. 10. Clark WH, From L, Bernardino EA, Mihm MC: The histiogenesis and biologic behavior of primary human melanomas of the skin. Cancer Res 29:705-726, 1969. 11. Cochran A J: Histology and prognosis in malignant melanoma. J Pathol 97:459-468, 1969. 12. McGovern VJ: The classification of melanoma and its relationship with prognosis. Pathology 2:85-98, 1970. 13. Rippey JJ, Whiting DA: Moles and melanoma. Lancet 2:137, 1977. 14. Larsen TE: Tile classification of primary cutaneous malignant melanoma. Acta Pathol Microbiol Scand [A] 86:451-459. 1978.
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