EVIDENCE-BASED DERMATOLOGY: ORIGINAL CONTRIBUTION Cutaneous Associated With Nevi

Caroline Bevona, MD; William Goggins, ScD; Timothy Quinn, MD; Julie Fullerton, BA; Hensin Tsao, MD, PhD

Objective: To determine the frequency of and the his- Results: Twenty-six percent of the melanomas re- tologic and clinical factors associated with ex- viewed were histologically associated with nevi (dysplas- isting in histologic contiguity with a . tic nevi, 43.0%; and other nevi, 57.0%). Factors that were significantly associated with an increased likelihood of Design: Pathology reports from melanomas collected a melanoma being histologically contiguous with a ne- from January 1, 1993, to December 31, 1997, were ret- vus included younger age, superficial spreading sub- rospectively reviewed. type, truncal location, Breslow thickness, and Clark level. However, after multivariate analysis, only younger age Setting: Independent, community-based dermatopa- (odds ratio, 1.27; 95% confidence interval, 1.19-1.37), thology laboratory. superficial spreading subtype (odds ratio, 2.96; 95% con- fidence interval, 2.17-4.02), and truncal location (odds Patients: A total of 1606 patients with a histologic di- ratio, 3.26; 95% confidence interval, 2.55-4.19) re- agnosis of melanoma. mained significant.

Intervention: None. Conclusions: Most melanomas were not histologically contiguous with a nevus. Younger age, superficial spread- Main Outcome Measures: Differences in histologic ing subtype, and truncal location are independent sig- (subtype, Breslow thickness, and Clark level) and clini- nificant predicators of a melanoma being histologically cal (age, sex, and anatomic location) features between associated with a nevus. melanomas that are associated and unassociated with a nevus. Arch Dermatol. 2003;139:1620-1624

HE NOTION that a melano- ity of melanomas appear to arise de novo. cytic nevus can serve as a Furthermore, the actual risk of any given precursor lesion from nevus transforming into a melanoma has which melanoma may de- been estimated to be exceedingly low.19 velop is supported by clini- Although virtually any type of ne- calT and histologic evidence. Clinically, vus can be found in association with mela- From the Melanoma Center melanomas have been observed to arise in noma, much attention has been given to (Drs Bevona and Tsao and previously photographed nevi and, as such, the (DN) as a precursor Ms Fullerton), Department of may present as a focal color change in a and risk factor for melanoma. An esti- Dermatology (Drs Bevona and previously stable lesion.1 By patient his- mated 2% to 8% of the population have Tsao), and Wellman 1,20 Laboratories of Photomedicine tory, the percentage of melanomas be- DN. Such patients comprise a geneti- (Dr Tsao), Massachusetts lieved to have arisen from preexisting nevi cally and phenotypically heterogeneous General Hospital, Boston; ranges from 18% to 85%.2 Histologically, group, with the actual risk of melanoma Department of Mathematics, evidence of an associated nevus can be seen being dependent on factors such as the Hong Kong Baptist University, in melanomas that demonstrate portions number of DN the patient has and the pres- Hong Kong (Dr Goggins); and of nevi lateral to or below the tumor.3 In ence or absence of a family history of DN Pathology Services, Inc, an attempt to estimate the frequency with and melanoma.21-23 Although the pres- Cambridge, Mass (Dr Quinn). which melanomas are associated with nevi, ence of DN confers an elevated risk for de- Dr Bevona is now with the 3-18 Boston University Dermatology studies have examined series of mela- veloping melanoma, increased numbers of Clinical Research Center, nomas for histologic evidence of nevic common acquired nevi are also associ- 1,24 Brockton, Mass. The authors remnants. Although a percentage of mela- ated with an increased risk. have no relevant financial nomas is found in contiguity with nevi, Our study examines the frequency interest in this article. most studies demonstrate that the major- with which melanomas are histologically

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All pathology reports from invasive cutaneous melanomas di- 200 agnosed between January 1, 1993, and December 31, 1997, at Pathology Services, Inc, were obtained using a computer- 150 No. of Melanomas assisted natural language search. Pathology Services, Inc, is an 100 independent community-based dermatopathology laboratory that receives biopsy and excision specimens chiefly from local 50 dermatologists and plastic surgeons. Pathology Services, Inc, 0 also functions as a regional and national reference laboratory <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 ≥90 for pigmented lesions, which comprise less than 5% of the re- Age, y ported melanomas. Pathology Services, Inc, uses standard meth- ods in the evaluation of elliptical excision specimens whereby Figure 1. Distribution of melanomas by age group. each specimen is serially sectioned and entirely submitted for histologic examination. In specimens for which the primary der- associated 95% confidence intervals and P values were calcu- matopathologist generates a diagnosis of melanoma, the slides lated using multivariate logistic regression. The final multivar- are reviewed independently by a second staff dermatopatholo- iate model was determined using a backward stepwise proce- gist before the final diagnosis is released. During the study pe- dure. Variables with PϽ.20 were considered significant and were riod, if the first 2 observers did not reach concordance, then retained in the final model. Indicator variables were created for the medical director of the laboratory or the senior dermato- sex (with men as baseline), location, and subtype. Clark level pathologist in residence would be consulted for an additional of I through V was entered as an ordinal categorical variable, tiebreaking opinion. A test set of 346 randomly selected mela- and age and depth were entered as continuous variables. noma cases that were reviewed by pathologists at Pathology Ser- vices, Inc, revealed 5 disagreements (1.4%) over the diagno- sis. A standard protocol is followed at Pathology Services, Inc, RESULTS whereby the reviewing pathologist comments on melanoma sub- type, growth phase, mitotic count, regression, tumor infiltrat- The study population was composed of 841 men and 739 ing lymphocytes, Breslow thickness, Clark level, site, sex, and women, with a mean age of 60 years (range, 11-95 years). presence or absence of a precursor lesion. The mean tumor thickness was 0.87 mm (range, 0.05- Pathology reports from the study period were reviewed, 17.4 mm). The number of melanomas measuring 1.0 mm and melanomas representing a local recurrence or a cutane- or less, 1.01 to 4.0 mm, and greater than 4.0 mm in depth ous metastasis were omitted from analysis. Biopsies from speci- was 1221, 347, and 26, respectively. Most melanomas were mens that were not adequate to accurately assess the lesion (ie, classified as SSM (n=1013), followed by ma- Ͻ small shave biopsies) were also omitted ( 2.0% of reports ligna (n=257), unclassified (n=231), nodular (n=80), reviewed). In situ melanomas (n=392) were also omitted from desmoplastic (n=13), and acral lentiginous (n=12) mela- analysis because of the morphologic overlap between dysplas- nomas. The distribution of melanomas by age is shown tic nevi and melanoma in situ, which can sometimes make clas- sification difficult. After excluding the aforementioned cases, in Figure 1. Information on sex, Breslow thickness, ana- pathology reports from 1606 melanomas remained. When avail- tomic location, and age was not available for 26, 12, 5, able, information from the pathology report of a reexcised mela- and 2 patients, respectively. noma was combined with that of the initial biopsy. The pa- Overall, 26.2% of the melanomas in our series were thology reports were reviewed, and data were collected on sex, histologically associated with nevi (M-N). Of these, 43.0% age at diagnosis, histologic subtype, Breslow thickness, Clark were associated with DN and 57.0% with other nevi. The level, anatomic location, whether a nevus was associated with percentage of M-N was found to steadily decrease with the melanoma, and, if so, the nevus type. The histologic sub- increasing age and ranged from 63.6% in patients younger types were categorized as superficial spreading melanoma (SSM), than 20 years to 11.1% in those 90 and older (Figure 2). , melanoma, acral lentigi- Because we identified only 11 cases of melanoma in pa- nous melanoma, , or unclassified. Location was divided into head and neck, trunk, upper ex- tients younger than 20, estimates in this age group may tremities, and lower extremities. Melanomas that were ana- be somewhat unreliable. However, the overall trend of a tomically located on the shoulder were designated truncal. Ne- continuous drop in the percentage of M-N by age is re- vus type was classified as DN or other nevus. Histologic criteria tained. used to determine melanoma subtype, diagnose dysplastic nevi, When examined by subtype, a higher percentage of and distinguish nevus cells from small melanoma cells were as SSMs (35.4%) showed evidence of an associated nevus outlined by Elder and Murphy.25 Nevic remnants categorized compared with unclassified (19.0%), nodular (11.3%), as other included junctional, dermal, compound, intradermal, and lentigo maligna (3.5%) melanomas (Figure 3). No and congenital nevus or nevus with congenital features. Con- nevi were found in association with acral lentiginous or genital nevi or nevi with congenital features were not ana- desmoplastic melanomas. None of the lentigo maligna lyzed as a separate category, as no clinical history was avail- able to confirm whether these nevi were present at birth. melanomas were associated with DN, and most of the The collected data were analyzed using SAS version 8.0 nodular melanomas that were associated with nevi were statistical software (SAS Institute, Cary, NC). Odds ratios and with other nevi. A higher percentage of truncal melano- corresponding 95% confidence intervals and P values were cal- mas had associated nevi, compared with those on the head culated using logistic regression. Adjusted odds ratios and their and neck or the upper and lower extremities (Figure 4).

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 70 60 Dysplastic Nevi Trunk Other Nevi Upper Extremities 60 50 Lower Extremities 50 Head and Neck 40 40

Associated With Nevi 30 30

% of Melanomas 20 20

10 10 % of Melanomas

0 0 <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 ≥90 Men Women Age, y Sex

Figure 2. Percentage of melanomas associated with nevi by age group. Figure 5. Percentage of melanomas by anatomic location and sex.

40 50 Dysplastic Nevi Men 45 35 Other Nevi Women 40 30 35 25 30 20 25

15 20 15 10 10 5 5 % of Melanomas Associated With Nevi % of Melanomas Associated With Nevi 0 0 Superficial Spreading Unclassified Nodular Lentigo Maligna Trunk Upper Lower Head and Melanoma Melanoma Melanoma Melanoma Extremities Extremities Neck Histologic Subtype Anatomic Location

Figure 3. Percentage of melanomas associated with nevi by histologic Figure 6. Percentage of melanomas associated with nevi by anatomic subtype. location and sex. There was no statistically significant difference between men and women for each anatomic location (trunk, P=.23; upper extremities, P=.81; lower extremities, P=.79; and head and neck, P=.48).

45 Dysplastic Nevi 40 Other Nevi Odds Ratios for the Association of Clinical 35 and Pathologic Variables With Melanomas 30 in Histologic Contiguity With Nevi 25

20 Odds Ratio Variable (95% Confidence Interval) P Value 15

10 Unadjusted Age 1.40* (1.30-1.49) Ͻ.001 5

% of Melanomas Associated With Nevi Sex 0.83† (0.68-1.07) .17 0 SSM 2.49 (1.36-4.55) .003 Trunk Upper Lower Head and Ͻ Extremities Extremities Neck Truncal location 4.11 (3.24-5.21) .001 Breslow thickness 0.80‡ (0.70-0.92) .002 Anatomic Location Clark level 0.84§ (0.74-0.96) Ͻ.01 Adjusted Figure 4. Percentage of melanomas associated with nevi by anatomic Age 1.27* (1.19-1.37) Ͻ.001 location. SSM 2.96 (2.17-4.02) Ͻ.001 Truncal location 3.26 (2.55-4.19) Ͻ.001 Dysplastic nevi comprised a higher percentage of trun- cal M-N compared with those on the head and neck or Abbreviation: SSM, superficial spreading melanoma. *Odds ratio corresponds to a 10-year decrease in age. extremities. Although men had a higher percentage of †Men designated as baseline for odds ratio of sex. melanomas located on the trunk than did women ‡Odds ratio corresponds to a 1-mm increase in thickness. (Figure 5), there was no significant difference in the §Odds ratio corresponds to a 1-U increase in level. percentage of M-N on the trunk between men and women (P=.23) (Figure 6). low thickness were also significant predictors in univari- Among the variables univariately associated with an ate models, with lower level and thinner melanomas more increased likelihood of M-N were younger age, SSM sub- likely to be associated with a nevus. After adjusting for type, and truncal location (Table). Clark level and Bres- the possibility of confounding using a multivariate model,

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 only younger age, SSM, and truncal location were still diagnosed with incisional punch or shave biopsies; there- significant predictors of an increased likelihood of M-N. fore, complete examination of the lesion was not always Among these, location was the most strongly associ- possible even when the reexcision was analyzed. In cases ated. Melanomas on the trunk were more than 3 times for which the reexcised specimen was not available for as likely to be associated with a nevus compared with those review, it was possible that the reexcised melanoma might in other locations. have shown an associated nevus that was not detected on initial biopsy, thus underestimating the percentage COMMENT of M-N. Another limitation is the difficulty sometimes encountered when trying to differentiate nevus cells from Twenty-six percent of the melanomas in our series were melanoma. Two cases in which this distinction is par- histologically associated with nevi. This rate falls within ticularly problematic are nevoid melanomas, in which the range of results from similar studies,3-18 which have deep melanoma cells may show differentiation and be mis- found remnants of nevi in 9% to 58% of melanomas. There taken for an associated nevus, and melanomas arising from have been several clinical and pathologic variables that DN, because there is overlap between the histologic fea- differ between studies and may contribute to the broad tures of DN and melanoma.4,10 range of estimated M-N. These include the histologic sub- In conclusion, we performed one of the largest ret- type, Clark level, and Breslow thickness of the melano- rospective analyses to date and found that 26.2% of mela- mas included in the analysis, differences between pa- nomas in our series were histologically contiguous with tient populations, and variation among the histologic nevi. Our findings are in agreement with other similar criteria used to diagnose nevic remnants. The latter is par- studies and support the idea that most melanomas arise ticularly true in the case of dysplastic nevi, which is a de novo from previously normal skin. Patients should be topic that is surrounded by much controversy.11 educated to pay as much attention to suspicious new pig- In our series, SSMs were more frequently associ- mented lesions as they would to changing moles. We also ated with nevi compared with other melanoma sub- demonstrated that SSM, truncal location, and younger types. This finding confirms previous reports7,14,16,17 and age were more likely to be associated with M-N. Our find- supports the idea that different melanoma subtypes may ings support the idea that there is variation in the histo- evolve through different histogenic pathways.7 By strati- genesis of melanoma, with nevi tending to give rise to fying our series into 10-year age groups, we observed an SSM more often than to other subtypes. Although we inverse relationship between age and percentage of mela- found a decrease in the likelihood of M-N to occur with nomas associated with nevi. Our study is one of the larg- increasing age, clinicians should not assume that any given est analyses to date documenting this effect, although nevus on an older patient has a lower risk of malignant smaller series have noted similar trends.11,14,16,26 This age transformation. Increasing age should not alter the level effect is likely due to the smaller numbers of nevi noted of clinical suspicion or the decision to perform a biopsy in older individuals,27,28 which might result from a time- of a changing nevus that may otherwise be indicated. related involution of nevi and fewer nevic precursors avail- able from which melanomas may develop. Alterna- Accepted for publication June 11, 2003. tively, melanomas in older individuals may result from This work was supported in part by Clinical Research cumulative solar damage to epidermal melanocytes, while Training Grant CRTG-99-249-01 CCE from the American melanomas in younger patients may be more prone to arise Cancer Society, Atlanta, Ga (Dr Tsao) and by the Derma- from an altered precursor substrate, such as a nevus. tology Foundation, Evanston, Ill (Dr Tsao). Although younger age, male sex, truncal location, We thank Arthur J. Sober, MD, for his critical review SSM subtype, and thinner tumors were associated with of the manuscript and helpful suggestions. an increased likelihood of M-N, only subtype, truncal lo- Corresponding author: Hensin Tsao, MD, PhD, De- cation, and age remained significant predictors by mul- partment of Dermatology, Massachusetts General Hospi- tivariate analysis. Interestingly, truncal location ap- tal, 55 Fruit St, Bartlett 622, Boston, MA 02114. pears to be the leading predictor for M-N (odds ratio, 3.26). Two smaller studies have addressed the effect of REFERENCES confounding factors in their statistical analyses. Skender- Kalnenas et al14 found SSM, truncal location. and younger 1. Elder DE, Clark WH Jr, Elenitsas R, Guerry D IV, Halpern AC. The early and in- age to be associated more frequently with M-N. In addi- termediate precursor lesions of tumor progression in the melanocytic system: common acquired nevi and atypical (dysplastic) nevi. 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