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R E V I E W A R TI C L E D O I 1 0 . 1 1 1 1 / j . 1 3 6 5 - 2 1 3 3 . 2 0 0 6 . 0 7 2 1 8 . x

Melanoma risk in congenital melanocytic naevi:

a systematic reviewS. Krengel, A. Hauschild* and T. Schafer

Department of Dermatology, Medical University Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany

*Department of Dermatology, University of Kiel, Kiel, Germany

Institute of Social Medicine, University of Lubeck, Lubeck, Germany

Correspondence

Sven Krengel.

E-mail: sven.krengel@uk-sh.de

Accepted for publication

22 December 2005

Key words

congenital naevus, epidemiology, malignantmelanoma, risk

Conflicts of interest

None declared.

Summary

Background The risk of malignant melanoma in congenital melanocytic naevi(CMN) is a matter of controversial and ongoing debate.ObjectivesThe purpose of this systematic review is to provide a careful and detailedsummary of the published data, including several recently published studies.MethodsArticles on CMN (n 1424) were retrieved from Medline, 1966October2005. Case reports and studies lacking relevant clinical information were exclu-ded. Only systematic collections of cases were taken into consideration. Series

with fewer than 20 patients or studies with a mean follow-up of

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specific shapes or patterns, probably reflecting genetic mosai-cism.2 The size of CMN varies from diameters of 40 cm in largest diameteror is expected to reach this size in adulthood.

The incidence of CMN in newborn infants has been repor-ted by numerous studies as being between 02%8 and 21%.9

Several studies observed a slightly higher incidence of CMN inwomen (male/female ratio between 1 : 117 and1 : 146,7,10,11). The incidence of CMN in South Americannewborns was 15 : 100 000 for naevi 4 cm and5 : 100 000 for naevi 10 cm.12 The incidence of GN has not

been specified in any study. Up to the early 1960s, about 90cases of this phenotype had been described, reporting a con-siderable degree of malignant transformation.13 Pers, in 1963,published the first retrospective follow-up study of 110patients with giant CMN, including 11 cases of GN.14 In hisseries, Pers found three cases of melanoma during 23 years offollow-up.

Since then, numerous prospective and retrospective studieshave been performed. Nowadays, CMN are commonly men-tioned in dermatological textbooks as a risk factor for malig-nant melanoma. Nevertheless, there is an ongoing debateabout the magnitude of this risk and as to whether it appliesto all CMN or only to larger CMN. The attempt to establish ahistopathological definition of congenital naevi irrespectiveof clinical information has led to additional confusion(reviewed by Krengel1).

In several articles, the published data have been summarizedin the form of short tabular presentations, without taking intoaccount the special features of each study.3,15,16 Watt et al.17

confined their systematic review to CMN >2% total body sur-face. Consistently, the authors did not consider several studiesthat include CMN of smaller sizes.1820 Moreover, three newstudies with data from more than 1500 patients have beenpublished only recently.7,10,11 In this article we present thefirst systematic review of all studies providing data on the

melanoma risk in CMN. The results of this analysis shouldprovide a reliable basis for the counselling of patients withCMN.

Materials and methods

We searched for the combination of the terms congenital,naevus and [melanoma OR malignant OR malignancyOR risk] in Medline (1966October 2005), without restric-tion for language. The titles and abstracts (if available) werestudied and all articles containing original clinical data, with

the exception of case reports, were retrieved as full texts.Additionally, we checked the bibliographic data of the full-textpublications and of other review articles about CMN for fur-ther studies. The decision was made whether an article repre-sented a selection of individual cases or a systematic casecollection in the sense of a retrospective or prospective study.Only the systematic collections of cases were taken into con-sideration for further analysis. Several studies, mainly focusing

on histological findings or aspects of treatment, representedsmaller case series or series with a relatively short follow-up.To avoid the increased potential of selection bias in thesestudies, we decided that studies with fewer than 20 patientsor with a mean follow-up of 20 cm in diameter.

Swerdlowet al.(1995).25 The authors retrospectively identi-fied 265 cases of CMN through diagnostic indexes held

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between 1950 and 1984 at one dermatological and one paedi-atric hospital in London. The patients were traced at theNational Health Service Central Register. The study includedall CMN irrespective of their size, 10% of which were>20 cm in diameter.

Dawson et al. (1996).20 This prospective study included 133children with CMN presenting between 1987 and 1993. Onehalf came from a dermatological clinic in London, the otherhalf from dermatologists, paediatricians and plastic surgeonsthroughout the U.K. who had been personally informed orinvited in journals. The parents filled in one initial and subse-quent annual questionnaires. All sizes of CMN were accepted;the mean size was 67% of the body surface (median 23%).

Sahin et al. (1998).27 This retrospective study analysed 230CMN from a dermatology practice in New York that presentedbetween 1955 and 1996. The patients were followed by clin-ical examination or by telephone. The naevi measuredbetween 15 and 20 cm in their largest diameter (medium-

sized CMN).Egan et al. (1998).28 Between 1973 and 1996, the authors

prospectively included 46 patients from two dermatology clin-ics in Philadelphia and New York. The patients were followedby medical records or by telephone. The size of the naevi was5% of the body surface or 20 cm diameter. One of 46patients (22%) had symptomatic neurocutaneous melanosis(NCM).

Foster et al. (2001).29 The study retrospectively reviews 46patients with CMN who presented at the paediatric dermatol-ogy service at the University of California at San Francisco

between 1990 and 1997. All patients had LCMN or multipleCMN. All naevi involved the head and neck or overlaid thedorsal spine. The authors found a high incidence of asympto-matic, magnetic resonance (MR)-positive NCM (11% of 42patients who underwent MR imaging).

Berg and Lindelof (2003).8 In this population-based study,the authors retrospectively analysed the Swedish Medical BirthRegister and the Swedish Cancer Register between 1973 and1993. They identified 3922 cases registered as CMN (02% ofall newborns). A quality test in 150 patients showed that thisdiagnosis was correct in about 85%. The cases from 1973 to1986 were classified as large (n 146) and small CMN; how-ever, this distinction was at the discretion of the reportingphysicians and lacked a clear-cut definition.

Ka et al.(2005).10 The authors evaluated an internet registryof LCMN (Nevus Outreach Inc.) which contains informationfrom a detailed questionnaire. The registry opened in 1998and, up to 2002, yielded 379 cases from 26 countries.

Twenty-six patients (69%) had a diagnosis of NCM, 22(58%) symptomatic and four (11%) asymptomatic.

Hale et al. (2005).11 This study represents an update on thelargest clinic-based collection of LCMN, the New York Univer-sity Registry (NYU-LCMN Registry). Since 1979, 205 caseshave been collected. One hundred and seventy of the 205patients were followed prospectively. Six additional patientshad already been diagnosed with melanoma at the time theyentered into the registry and were excluded from analysis.Seventeen of 205 patients (83%) had NCM, nine (44%)symptomatic and eight (39%) asymptomatic.

-

-

-

Articles not related to congenitalmelanocytic naevi: 202

Articles related to congenitalmelanocytic naevi: 1222

-Review articles: 254-Single case reports: 480-Basic science/ aetiopathogenesis/

histology/dermoscopy: 273

-Therapeutic strategies: 178

Studies chosen for analysis: 14

Studies, case series, or other articlesproviding data on multiple cases ofCMN (including articles found bymanual cross-referencing): 40

Total findings: 1424 articles

- Studies with fewer than 20 patients orwith a median follow-up of less than3 years (mainly studies focusing onaspects of treatment)

- Studies lacking sufficient informationconcerning the mode of acquisitionand/or the follow-up of the cases

-Studies (partly) based on patientswho were diagnosed with melanomaprior to enrolment

-Articles (mostly) presenting data fromother studies-Articles with data that were later

(These studies were regarded as

epidemiologically less significant)

presented by the same group

Fig 1. Algorithm of study selection criteria.

CMN, congenital melanocytic naevi. Search

terms: congenital AND naevus AND

[melanoma OR malignant OR malignancy

OR risk], Medline (1966October 2005).

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Table 2 Age at diagnosis and additionalcharacteristics of melanomas in patients withcongenital melanocytic naevi (CMN)

Authors

Age at diagnosis of melanoma

Non-fatal cases (n 23) Fatal cases (n 23)

Greeley et al.(1965)21 1 year,a 38 years 1 year, 10 years, 10 years,b

30 yearsb

Lorentzen et al.(1977)18 28 years,c 38 years, 40 yearsArons and Hurwitz (1983)19

Quaba and Wallace (1986)

22

7 years, 10 yearsRuiz-Maldonado et al.(1992)2414 yearsd 8 months, 2 yearsSwerdlowet al. (1995)25 18 years, 20 yearsDawsonet al. (1996)20 0 years, 0 yearse

Sahin et al. (1998)27 26 years,f 42 years, 57 yearsEgan et al. (1998)28 2 years 3 yearsFosteret al. (2001)29

Berg and Lindelof (2003)8 7 yearsg 1 yearh

Ka et al. (2005)10

Hale et al.(2005)11 1 year, 1 year, 1 year,i

3 yearsBett (2005)7 at birth, 3 months, 6 months,

7 months,j 9 months, 1 year,3 years, 7 years, 8 years,k

20 years, 26 years,l 34 years,39 years

4 years, 24 years, 39 years,58 years

Mean age 141 years 158 yearsMedian age 7 years 10 years

Studies were considered only where both the mean follow-up time and the mean age atentry were specified. For all cases combined, the mean age was 15 5 years (median 7).aHistologically diagnosed as juvenile melanoma. bLeptomeningeal melanosis at post mor-tem examination. cCMN were treated with X-rays in very large doses 8 years prior todiagnosis of melanoma. dHistologically diagnosed as minimal deviation melanoma. eBothcongenital melanomas were considered as a self-healing type of melanoma or a pseudo-melanoma. fPatient developed further cutaneous melanomas at 33 and 36 years. gLater his-tologically re-evaluated as a benign proliferative nodule. hConsidered by the authors ascongenital melanoma. iLeukaemic melanoma. jLymph node dissection, lost to follow-up.kHepatic metastases at age 24 years,

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risk of developing malignant melanoma, i.e. the ratio betweenobserved and expected cases in a similar age group. In onlyseven of the 14 studies were both the mean follow-up timeand the mean age at entry specified.18,20,22,24,2729 In thesestudies, comprising CMN of all sizes, 15 of 725 patientsdeveloped melanoma (21%). The mean age at entry was7 years; the mean follow-up time was 89 years. The inci-dence of melanoma in the general population between the ageof 10 and 14 years is 05 per 100 000 per year.31 Comparingthese data, we calculated that patients with CMN carry anapproximately 465-fold increased risk of developing melan-oma during childhood and adolescence. It is not possible tocalculate an exact standardized morbidity ratio (SMR) withoutindividual-based information on age and outcome. Thereforethe figure only represents an estimate. Swerdlow et al.25 calcu-lated the SMR for melanoma development as 103 for all CMN1 cm vs. 1224 for LCMN, suggesting highly size-dependentrisk magnitudes. In studies focusing on LCMN, the SMR hasbeen calculated as being between 101 and 324.6,11,26,28 Intheir review, Watt et al.17 considered four studies with a totalof five melanomas in 120 patients with LCMN and calculatedthe SMR as 2599 (95% confidence interval 8446064).

Kopf et al., in 1979, proposed to divide CMN depending ontheir largest diameter in adulthood into small (

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GN (Table 4). This difference indicates a better prognosis ofmelanomas in patients with non-garment LCMN than with GN.

Certain clinical features of CMN have been considered toinfluence the individual melanoma risk. Bett7 reported that all15 patients with GN and melanoma had a naevus involvingthe posterior axis. In their review of 289 cases, DeDavid etal.30 found that all patients with LCMN in whom melanomadeveloped had naevi in axial locations. Although most GN and

a significant proportion of LCMN involve this location, thispoint is of interest as the involvement of the posterior axis isalso a prerequisite for NCM.5 Possibly, pathophysiologicalevents reflected by this morphological pattern lead to a higherrisk of leptomeningeal involvement and malignant degener-ation. It has been recommended to perform MR imaging orat least a careful neurological and developmental assessmentwith a close follow-up in all infants with CMN >2 cm indiameter on the head or over the spine.33 Likewise, the pres-ence of more than 20 satellite naevi has been reported to rep-resent a risk factor for NCM.34 DeDavid et al.30 found no caseof melanoma originating from a satellite naevus. Recently,

Bett7

reported the first case of cutaneous melanoma in a satel-lite naevus.

In conclusion, the rarity of (large) CMN and the heterogen-eity of the studies only allow a preliminary assessment of therisk of melanoma. Regarding the range of follow-up timesbetween 34 and 237 years in the selected studies, conclu-sions on the lifetime risk of melanoma should be drawn withcaution. As a main result of our review, we would like toemphasize that nearly three in four melanomas appeared inGN. We agree with Ruiz-Maldonado,35 who recommended toclassify CMN according to their largest diameter as follows(patients with giant naevi and with more than 50 small ormedium-size satellite naevi should be classified one groupabove their corresponding size classification): small, 20 cm; G1,2130 cm; G2, 3140 cm; G3, >40 cm.

Minimum information required for epidemiological studieson the risk of melanoma in CMN includes: (i) diameter, per-centage of body surface, and localization of the CMN; (ii) per-centage of naevus area removed by excision or subject todermabrasion or other superficial treatments; (iii) mean andmedian age at entry into the study; (iv) mean and median fol-low-up time; (v) clinical and histopathological details on eachmelanoma case; (vi) relative risk of melanoma; and (vii) per-centage of patients with symptomatic and asymptomatic NCM.

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