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Table 1.  Demographic Characteristics and Clinical History of Patients and Characteristics of Biopsied Moderately Dysplastic Nevi
Demographic Characteristics and Clinical History of Patients and Characteristics of Biopsied Moderately Dysplastic Nevi
Table 2.  Univariate and Multivariate Logistic Regression Models for Development of CM at Any Future Site Separate From the Biopsy of Moderately Dysplastic Nevi
Univariate and Multivariate Logistic Regression Models for Development of CM at Any Future Site Separate From the Biopsy of Moderately Dysplastic Nevi
Table 3.  Summary of Recent Studies Examining Outcomes of Excisionally Biopsied Moderately Dysplastic Nevi With Positive Histologic Margins
Summary of Recent Studies Examining Outcomes of Excisionally Biopsied Moderately Dysplastic Nevi With Positive Histologic Margins
1.
Duffy  KL, Mann  DJ, Petronic-Rosic  V, Shea  CR.  Clinical decision making based on histopathologic grading and margin status of dysplastic nevi.  Arch Dermatol. 2012;148(2):259-260. doi:10.1001/archdermatol.2011.2045PubMedGoogle ScholarCrossref
2.
Tong  LX, Wu  PA, Kim  CC.  Degree of clinical concern and dysplasia affect biopsy technique and management of dysplastic nevi with positive biopsy margins: Results from a survey of New England dermatologists.  J Am Acad Dermatol. 2016;74(2):389-91.e1, 2. doi:10.1016/j.jaad.2015.09.055PubMedGoogle ScholarCrossref
3.
Nelson  KC, Grossman  D, Kim  CC,  et al.  Management strategies of academic pigmented lesion clinic directors in the United States.  J Am Acad Dermatol. 2018;79(2):367-369. doi:10.1016/j.jaad.2017.12.069PubMedGoogle ScholarCrossref
4.
Kim  CC, Swetter  SM, Curiel-Lewandrowski  C,  et al.  Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statement.  JAMA Dermatol. 2015;151(2):212-218. doi:10.1001/jamadermatol.2014.2694PubMedGoogle ScholarCrossref
5.
Fleming  NH, Egbert  BM, Kim  J, Swetter  SM.  Reexamining the threshold for reexcision of histologically transected dysplastic nevi.  JAMA Dermatol. 2016;152(12):1327-1334. doi:10.1001/jamadermatol.2016.2869PubMedGoogle ScholarCrossref
6.
Blum  A, Hofmann-Wellenhof  R, Marghoob  AA,  et al.  Recurrent melanocytic nevi and melanomas in dermoscopy: results of a multicenter study of the International Dermoscopy Society.  JAMA Dermatol. 2014;150(2):138-145. doi:10.1001/jamadermatol.2013.6908PubMedGoogle ScholarCrossref
7.
Gutman  DA, Khalilia  M, Lee  S,  et al.  The Digital Slide Archive: a software platform for management, integration, and analysis of histology for cancer research.  Cancer Res. 2017;77(21):e75-e78. doi:10.1158/0008-5472.CAN-17-0629PubMedGoogle ScholarCrossref
8.
Arumi-Uria  M, McNutt  NS, Finnerty  B.  Grading of atypia in nevi: correlation with melanoma risk.  Mod Pathol. 2003;16(8):764-771. doi:10.1097/01.MP.0000082394.91761.E5PubMedGoogle ScholarCrossref
9.
Nickleach  D, Liu  Y, Shrewsberry  A, Ogan  K, Kim  S, Wang  Z. SAS macros to conduct common biostatistical analyses and generate reports. Paper presented at: 26th Annual SouthEast SAS Users Group (SESUG) Conference; October 20-23, 2013; St Pete Beach, Florida. Paper PO-5.
10.
Kmetz  EC, Sanders  H, Fisher  G, Lang  PG, Maize  JC  Sr.  The role of observation in the management of atypical nevi.  South Med J. 2009;102(1):45-48. doi:10.1097/SMJ.0b013e3181904289PubMedGoogle ScholarCrossref
11.
Goodson  AG, Florell  SR, Boucher  KM, Grossman  D.  Low rates of clinical recurrence after biopsy of benign to moderately dysplastic melanocytic nevi.  J Am Acad Dermatol. 2010;62(4):591-596. doi:10.1016/j.jaad.2009.06.080PubMedGoogle ScholarCrossref
12.
Hocker  TL, Alikhan  A, Comfere  NI, Peters  MS.  Favorable long-term outcomes in patients with histologically dysplastic nevi that approach a specimen border.  J Am Acad Dermatol. 2013;68(4):545-551. doi:10.1016/j.jaad.2012.09.031PubMedGoogle ScholarCrossref
13.
Hiscox  B, Hardin  MR, Orengo  IF, Rosen  T, Mir  M, Diwan  AH.  Recurrence of moderately dysplastic nevi with positive histologic margins.  J Am Acad Dermatol. 2017;76(3):527-530. doi:10.1016/j.jaad.2016.09.009PubMedGoogle ScholarCrossref
14.
Gandini  S, Sera  F, Cattaruzza  MS,  et al.  Meta-analysis of risk factors for cutaneous melanoma: I, common and atypical naevi.  Eur J Cancer. 2005;41(1):28-44. doi:10.1016/j.ejca.2004.10.015PubMedGoogle ScholarCrossref
15.
Duncan  LM, Berwick  M, Bruijn  JA, Byers  HR, Mihm  MC, Barnhill  RL.  Histopathologic recognition and grading of dysplastic melanocytic nevi: an interobserver agreement study.  J Invest Dermatol. 1993;100(3):318S-321S. doi:10.1038/jid.1993.55PubMedGoogle ScholarCrossref
16.
Duray  PH, DerSimonian  R, Barnhill  R,  et al.  An analysis of interobserver recognition of the histopathologic features of dysplastic nevi from a mixed group of nevomelanocytic lesions.  J Am Acad Dermatol. 1992;27(5, pt 1):741-749. doi:10.1016/0190-9622(92)70248-EPubMedGoogle ScholarCrossref
17.
Nobre  AB, Piñeiro-Maceira  J, Luiz  RR.  Analysis of interobserver reproducibility in grading histological patterns of dysplastic nevi.  An Bras Dermatol. 2013;88(1):23-31. doi:10.1590/S0365-05962013000100002PubMedGoogle ScholarCrossref
18.
Piepkorn  MW, Barnhill  RL, Cannon-Albright  LA,  et al.  A multiobserver, population-based analysis of histologic dysplasia in melanocytic nevi.  J Am Acad Dermatol. 1994;30(5, pt 1):707-714. doi:10.1016/S0190-9622(08)81499-5PubMedGoogle ScholarCrossref
Original Investigation
December 2018

Risk of Subsequent Cutaneous Melanoma in Moderately Dysplastic Nevi Excisionally Biopsied but With Positive Histologic Margins

Author Affiliations
  • 1Pigmented Lesion Clinic and Cutaneous Oncology Program, Department of Dermatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 2Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
  • 3Division of Dermatology, Atlanta Veterans Administration Medical Center, Decatur, Georgia
  • 4Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Pigmented Lesion and Melanoma Program, Department of Dermatology, Stanford University Medical Center, Palo Alto, California
  • 6Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
  • 7Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 8Department of Dermatology, Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 9Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 10Pigmented Lesion Clinic and Multidisciplinary Cutaneous Oncology Program, Division of Dermatology, Department of Medicine, University of Arizona, Tucson
  • 11Pigmented Lesion Clinic, Department of Dermatology, University of Pennsylvania, Philadelphia
  • 12University of Massachusetts Medical School, Worcester
  • 13Morehouse School of Medicine, Atlanta, Georgia
  • 14University of Utah, Salt Lake City
JAMA Dermatol. 2018;154(12):1401-1408. doi:10.1001/jamadermatol.2018.3359
Key Points

Question  Can moderately dysplastic nevi that have been excisionally biopsied with no residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins) be closely observed instead of reexcised?

Findings  This multicenter cohort study of 467 moderately dysplastic nevi with positive histologic margins found no cases of cutaneous melanoma at the biopsy site after a mean follow-up time of 6.9 years. However, patients with 2 or more biopsied dysplastic nevi had an increased risk of developing a subsequent cutaneous melanoma at a separate site.

Meaning  Observation of moderately dysplastic nevi with positive histologic margins may be reasonable; however, screening for subsequent cutaneous melanoma at separate sites appears to be warranted for individuals with multiple histologic dysplastic nevi.

Abstract

Importance  Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins).

Objective  To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more.

Design, Setting, and Participants  A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The χ2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018.

Main Outcomes and Measures  Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins.

Results  A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23-5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up.

Conclusions and Relevance  This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site.

Introduction

Owing to a lack of guidelines and a paucity of outcomes data, there is significant variability in the management of histologic dysplastic nevi across the United States. One of the most controversial areas remains whether to observe or reexcise moderately dysplastic nevi excisionally biopsied without clinical residual pigment but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins). Results of surveys of general dermatologists in Chicago, Illinois, conducted in 2009,1 and in New England, conducted in 2014,2 showed that most of these practitioners (81% in Chicago and 61% in New England) prefer to reexcise moderately dysplastic nevi with positive margins. A recent survey of directors of pigmented lesion clinics in the United States revealed disagreement among expert professionals in the management of these lesions; 51.5% (17 of 33) favored observation and 48.5% (16 of 33) recommended reexcision with margins of at least 1 mm.3

In 2015, the Pigmented Lesion Subcommittee published a consensus statement with the following conclusions: (1) mildly and moderately dysplastic nevi with negative margins do not warrant reexcision, (2) mildly dysplastic nevi biopsied without clinical residual pigment but with positive histologic margins may be safely monitored rather than reexcised, and (3) observation may be a reasonable option for the management of moderately dysplastic nevi with positive histologic margins.4 However, the Pigmented Lesion Subcommittee recommended the acquisition of more data to make definitive recommendations for the clinical care of patients with moderately dysplastic nevi with positive histologic margins.

We report the results of a multicenter retrospective study conducted by members of the Pigmented Lesion Subcommittee on outcomes of moderately dysplastic nevi with positive histologic margins observed for at least 3 years, with confirmation of histologic grading of cases sent by each institution by a central dermatopathologist. Our goal was to address the knowledge gap identified in the Pigmented Lesion Subcommittee consensus statement to help guide future management of moderately dysplastic nevi with positive histologic margins. Incisional or partial biopsies revealing moderately dysplastic nevi were not included in our study because data have demonstrated the potential for histologic misdiagnosis owing to sampling error in these cases.5

Methods
Data Collection

Inclusion criteria for the study were patients who had undergone an excisional biopsy without clinical residual pigment of a nevus with resulting pathologic findings showing moderately dysplastic nevi with positive histologic margins (inclusive of mildly to moderately dysplastic nevi) managed by observation (standard visualization and dermoscopic examinations) for 3 years or more. Given that banal recurrent pigmentation generally occurs within 8 months of a biopsy, and CM has been reported to present as repigmentation more than 20 months after biopsy,6 we chose 3 years as our minimal follow-up interval to ensure that we would not miss cases of CM development owing to insufficient follow-up time. Exclusion criteria were fewer than 3 years of follow-up after the biopsy, incisional or partial biopsy, complete reexcision of the biopsy site, and patient younger than 18 years. Each site conducted a retrospective record review of clinical notes and pathology reports of patients who fit the inclusion and exclusion criteria from January 1, 1990, to August 31, 2014. Atlanta Veterans Affairs Medical Center (Georgia), Beth Israel Deaconess Medical Center (Boston, Massachusetts), Emory University (Atlanta, Georgia), Memorial Sloan Kettering Cancer Center (New York, New York), Palo Alto Veterans Affairs Medical Center (California), Stanford University (California), University of Arizona (Tucson), University of Pittsburgh (Pennsylvania), and University of Utah (Salt Lake City) participated in this study after approval from the institutional review board at each institution. Patient consent was waived by each institutional review board, as all data were deidentified.

The clinical data collected included age at initial biopsy, sex, family history of cutaneous melanoma (CM), personal history of CM, prior biopsied dysplastic nevi, date and location of biopsy, biopsy method (saucerization or shave, punch, or elliptical excision), degree of histologic atypia of dysplastic nevi (mild to moderate or moderate), location of positive margin (lateral, deep, or both lateral and deep), reexcision (yes or no), clinical recurrence of pigment, development of CM at biopsy site, Breslow thickness for any CMs prior to biopsy, development of CM at a separate site, death (yes or no), date of death, last clinical follow-up date, and follow-up source (electronic health record, pathology log, or other). Data on patient phenotype, history, and clinical exposures were also collected when available. Once the data were collected, the study teams shared the deidentified data with Emory University in accordance with each institution’s data use agreement, if required.

Central Dermatopathologic Review of Representative Cases

To confirm the histologic grading of moderately dysplastic nevi across all study sites, a central dermatopathologic review was conducted by a dermatopathologist at an independent site (E.Y.C.) who reviewed 5 deidentified slides or high-resolution digitized slide images of moderately dysplastic nevi included in the study from each site. Participating institutions used the same randomization protocol to select 5 cases of mildly to moderately dysplastic nevi or moderately dysplastic nevi for review. All digitized slide images were uploaded to the Digital Slide Archive viewing platform developed by the Gutman Laboratory at Emory University.7 All sites shared deidentified slides or digitized images in accordance with their institution’s data transfer agreement, if applicable. The grading of dysplastic nevi followed a 5-grade system of mild, mild to moderate, moderate, moderate to severe, and severe based on the degree of cytologic atypia and architectural disorder of the lesion based on criteria set forth by Arumi-Uria et al.8 Specifically, features including lateral circumscription, symmetry, rete ridge distortion, junctional extension, and nuclear size were considered in assigning grades. Any case upgraded to CM was also reviewed by additional dermatopathologists at Emory University and University of Pennsylvania.

Statistical Analysis

Statistical analysis was performed from October 1, 2017, to June 22, 2018, using SAS, version 9.4 (SAS Institute Inc), and SAS macros or software developed at Biostatistics and Bioinformatics at the Winship Cancer Institute.9 Descriptive statistics for each variable were reported. The univariate association of each covariate with the presence of subsequent CM at any site was assessed using the χ2 test or the Fisher exact test, where appropriate, for categorical covariates and analysis of variance for numerical covariates at an α = .05. Two multivariable logistic regression models were developed to elucidate factors significantly associated with the development of CM at the same site as the biopsy of moderately dysplastic nevi with positive histologic margins as well as CM at a separate site. Covariates of interest were age, sex, past medical history of CM, history of prior dysplastic nevi, and family history of CM. All P values were from 2-sided tests and results were deemed statistically significant at P < .05.

In our original consensus statement, we had performed a power calculation that determined that if no melanomas evolved during a prolonged period within a sample size of 2995 dysplastic nevi with positive histologic margins, one would have 95% confidence that the transformation rate was less than 1:1000.4 Given that the analysis in this study for CM at a separate site was secondary and exploratory, no power calculations were performed.

Results
Patient Characteristics

Nine study sites identified 438 patients with 467 moderately dysplastic nevi with positive histologic margins that met inclusion criteria (eTable 1 in the Supplement). Each site contributed at least 3 patients with 3 moderately dysplastic nevi with positive histologic margins. The highest enrolling site contributed 98 patients with 106 moderately dysplastic nevi with positive histologic margins. Table 1 summarizes patient demographics, clinical history, and biopsy characteristics. Of the study cohort, 245 patients (55.9%) were men and the cohort had a mean (SD) age of 46.7 (16.1) years (range, 18-85 years). Of patients with documented clinical data, 96.7% (292 of 302) were white, 33.2% (145 of 437) had a personal history of CM, 50.4% (192 of 381) had prior biopsied dysplastic nevi, and 23.8% (83 of 349) had a family history of CM.

Biopsy Characteristics

The mean (SD) follow-up time for the 467 biopsies was 6.9 (3.4) years (range, 3.0-21.3 years) (Table 1). Most (69.5% [324 of 466]) of the biopsies were located on the trunk. The mean (SD) reported nevus size was 5.7 (2.5) mm (range, 2-15 mm). Of the 466 biopsy techniques, 46.4% (216 of 466) were saucerizations or shave excisions, 45.3% (211 of 466) were punch excisions, and 7.7% (36 of 466) elliptical excisions. Pathology reports showed that 52.7% of dysplastic nevi (246 of 467) were interpreted as mild to moderate and 47.3% (221 of 467) were interpreted as moderate. Regarding histologically positive margins, 89.9% (346 of 385) were positive at the peripheral margins, 3.6% (14 of 385) at the deep margins, and 6.5% (25 of 385) at both peripheral and deep margins.

Development of CM at the Biopsy Site

After a mean (SD) follow-up time of 6.9 (3.4) years, no cases of CM occurred at the biopsy site of the 467 moderately dysplastic nevi with positive histologic margins. The rate of clinical recurrent pigmentation at the biopsy site was 1.2% (3 of 251).

Development of CM at a Separate Site

Of the 438 patients in our study with moderately dysplastic nevi with positive histologic margins, 100 (22.8%) developed a subsequent primary CM at a separate site from the original moderately dysplastic nevi with positive histologic margins during the follow-up period. Three of these patients (0.7%) developed metastatic CM, 2 of whom had invasive CM prior to biopsy of their moderately dysplastic nevi and 1 of whom developed invasive CM after the biopsy; however, data on Breslow depth or other features of those CMs were not included in the collected data. Of the 100 patients with a new primary CM, 93 were alive at follow-up, 5 were deceased, and 2 were listed as unknown.

Risk Factors for Subsequent CM at Separate Site

Factors associated with the risk for subsequent CM at a separate site by univariate analyses are summarized in Table 2. Patients who developed a subsequent CM were older than those who did not (mean [SD] age, 49.7 [15.8] years vs 45.9 [16.9] years; P = .04). In addition, patients who developed a subsequent CM were more likely to have a prior CM (71 of 145 [49.0%] vs 29 of 292 [9.9%]; P < .001) and a prior biopsied dysplastic nevus (64 of 191 [33.5%] vs 25 of 190 [13.2%]; P < .001). A patient’s sex and family history of CM were not statistically associated with risk for subsequent CM. Multivariate logistic regression revealed that prior CM (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001) and biopsy-proven dysplastic nevi prior to the moderately dysplastic nevi with positive histologic margins (OR, 2.55; 95% CI, 1.23-5.28; P = .01) were independently associated with subsequent CM at a separate site, even after adjusting for sex, family history of CM, and age (Table 2).

Central Dermatopathologic Review Across Study Sites

A total of 40 slides were reviewed because the cases from 2 sites were pooled owing to low numbers. The reviewing dermatopathologist agreed that 35 of 40 of the study cases represented lesions within the spectrum of mildly to moderately dysplastic nevi or moderately dysplastic nevi. Thus, we determined that the rate of capture of eligible samples was 87.5%. Of the remaining cases, 5% (2 of 40) were interpreted as mildly dysplastic nevi and 5% (2 of 40) were interpreted as moderately to severely dysplastic nevi. A single case was interpreted as melanoma in situ. Review of this case with the host institution revealed that the patient had not had a clinical recurrence at the biopsy site after 5 years of clinical follow-up.

Discussion

To our knowledge, this multicenter retrospective observational study of 467 moderately dysplastic nevi with positive histologic margins represents the largest of its kind to date. To investigate possible impairment of the study by the smaller number of cases than the proposed sample size, we performed a post hoc power calculation. Based on the 438 patients, the study was powered to produce a 1-sided 95% CI with a distance from the observed sample proportion (0%) to an upper limit of 0.5%. Thus, when we project the study findings to the entire population, we expect the rate of CM at the biopsy site to be less than 5 of 1000, with a 90% chance. Clinically, we feel comfortable to claim that, with an observed incidence rate of less than 0.5% and a mean of 6.9 years of follow-up, it is unlikely for a CM to develop at the site of a moderately dysplastic nevus with positive histologic margins, thus supporting the 2015 Pigmented Lesion Subcommittee consensus recommendation that observation is a reasonable management option for moderately dysplastic nevi with positive histologic margins.4

Several studies have investigated the outcomes of recurrence and biopsy site CMs in observed dysplastic nevi with positive margins.5,10-13 Only Hocker et al12 and Hiscox et al13 specified cases of moderately dysplastic nevi with positive histologic margins, reporting a total of 82 such cases without any resulting in CM. Adding the 467 cases from our study, no biopsy site CM developed in 549 unique cases of moderately dysplastic nevi with positive histologic margins (Table 3). Fleming et al5 described a single case of an excisionally biopsied mildly dysplastic nevi in which an atypical intraepidermal melanocytic proliferation, favoring melanoma in situ lentigo maligna type, developed 5 years later at the biopsy site. This finding underscores the need for continued monitoring of patients with biopsied dysplastic nevi. However, one should be reassured in this case that melanoma in situ, by definition, confers low risk of death.

Our recurrence rate for moderately dysplastic nevi with positive histologic margins was 1.2%, lower than Hiscox et al13 (4% of moderately dysplastic nevi), Goodson et al11 (3.6% of mildly to moderately dysplastic nevi), and Fleming et al5 (3.3% of mildly to severely dysplastic nevi). Our study excluded incisional biopsies with residual pigment, while these other studies did not, suggesting that lesions biopsied with a lower burden of residual melanocytic cells are less likely to recur than those with more residual cells, as seen in incisionally biopsied lesions. Biopsy technique may also be related to our lower recurrence rate. Goodson et al11 found that the shave biopsy technique was statistically associated with higher rates of recurrence. Our study had a lower percentage of shave biopsies in our cohort (46.4%) compared with that reported by Hiscox et al13 (100%).

As a secondary exploratory aim, our study also assessed histologic moderately dysplastic nevi as a factor associated with subsequent CM elsewhere on the body. Of our 438 patients, 22.8% developed CM at another location after biopsy of their moderately dysplastic nevi. Although prior CM was the factor most strongly associated with developing a CM at a separate site (odds ratio, 11.74), our findings suggest that the presence of 2 or more biopsied dysplastic nevi (1 of which is moderately dysplastic) conveyed twice the odds of developing a future CM at a separate site. This finding remained significant even after adjusting for history of CM. Prior studies have focused largely on clinically atypical nevi and risk of future melanoma,14 while in contrast, we explored the role of histologically confirmed dysplastic nevi. Our findings reinforce the need for regular skin examinations and patient education for those with a history of CM and/or 2 or more biopsied dysplastic nevi (at least 1 of which is moderately dysplastic).

We conducted a central dermatopathologic review of dysplastic nevi, which ensured high adequacy of capture (87.5%) because of prior evidence demonstrating poor concordance between pathologists grading dysplastic nevi (ranging from 16% to 75% and κ coefficients of 0.055-0.7115-18). We did not report another κ coefficient because agreement statistics are used when trying to compare raters who have the same range of possible rankings. Ratings by the institution were binary (yes or no eligible), and the possible rankings for the central review were 5 levels of dysplasia.

The decision to manage moderately dysplastic nevi with positive histologic margins with observation may also be affected by several clinical factors. First, the degree of clinical concern for the biopsied lesion (pretest probability) may play a role in management; if a clinician has a strong concern for CM, the clinician may elect to reexcise even moderately dysplastic nevi with positive histologic margins. Second, if the patient is unable to self-monitor or is unlikely to follow up, a clinician may favor reexcision. However, if the clinical concern for CM is low, if patient self-monitoring is possible, and if clinical follow-up is likely, then we recommend that moderately dysplastic nevi with positive histologic margins may be clinically observed. Importantly, as with any other nevus biopsy site, both patient and clinician should continue to observe the area for suspicious regrowth.

Limitations

We had several limitations to our study. Although we aimed to collect 2995 cases with 3 or more years of follow-up according to our 2015 Pigmented Lesion Subcommittee consensus statement,4 we believe that we fell short of this mark for several reasons: (1) the participating institutions had high rates of full-thickness excisional biopsy techniques (punch and elliptical) with negative histologic margins, (2) observation may have been a more recent management approach for dysplastic nevi with positive margins for some institutions, and (3) some institutions were unable to participate because their dermatopathologists do not report grades of atypia for dysplastic nevi. However, our post hoc power analysis demonstrated acceptable confidence (95%) with a reasonable malignant transformation rate (<0.5%). Another limitation of our study is its retrospective nature, which may have introduced latent biases and confounding by indication. The retrospective nature of our multi-institutional study also precluded concordance tests to assess fidelity of observations across study sites. In addition, any patient who may have developed a CM at a biopsy site within 3 years would not be accounted for because medical records were reviewed only if they had at least 3 years of clinical follow-up. Missing data across study sites in regard to phenotype and exposure factors (eg, UV radiation exposure, tanning bed use, immunosuppression, and phototherapy), prevented in-depth analysis of more variables relevant to the risk of CM (eTable 2 in the Supplement). Family history was not strongly correlated with the development of subsequent CM. This finding may be owing to limitations of patient-reported family history, missing data in 89 patients, and data collection that did not specify first-degree relatives only. Despite these limitations, the data from our study are still compelling, given that it is the largest cohort of moderately dysplastic nevi (n = 467) observed to date, with a substantial follow-up time (6.9 years) and a diverse geographic distribution of the 9 participating institutions.

Conclusions

Our data support observation as a reasonable management approach for moderately dysplastic nevi excisionally biopsied but with positive histologic margins. Our data also support a second recommendation, that patients with a history of CM and/or 2 or more biopsied dysplastic nevi (1 of which is moderately dysplastic) be monitored closely with routine self-examinations and clinical skin examinations, given the increased risk of developing a subsequent CM at a separate site compared with those without this history. In contrast to previous studies examining clinically atypical nevi as a potential variable associated with CM, our exploratory analysis of the development of CM at a separate site specifies the risk of CM with histologic dysplastic nevi, with specific level of dysplasia (at least 1 moderate) and number of dysplastic nevi (at least 2). These data underscore the fact that dysplastic nevi are not obligate precursors of CM but, instead, represent a surrogate risk factor for future CM development. Our recommendation for close observation of moderately dysplastic nevi with positive histologic margins may save patients the morbidity of reexcision, while our recommendation for surveillance for patients with 2 or more biopsied dysplastic nevi (of which 1 is moderately dysplastic) may facilitate early detection or prevention of future CM. Both recommendations have the potential to significantly reduce the health care cost and resource burden associated with reexcisions and CM diagnosis.

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Article Information

Accepted for Publication: August 10, 2018.

Corresponding Author: Caroline C. Kim, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Shapiro 2, Boston, MA 02215 (ckim3@bidmc.harvard.edu).

Published Online: October 10, 2018. doi:10.1001/jamadermatol.2018.3359

Author Contributions: Drs Kim and Berry had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kim and Berry are co–first authors and contributed equally.

Concept and design: Kim, Berry, Swetter, Grossman, Curiel-Lewandrowski, Ming, Ferris, Chen.

Acquisition, analysis, or interpretation of data: Kim, Berry, Marchetti, Swetter, Lim, Curiel-Lewandrowski, Chu, Ming, Zhu, Brahmbhatt, Balakrishnan, Davis, Wolner, Fleming, Ferris, Nguyen, Trofymenko, Liu, Chen.

Drafting of the manuscript: Kim, Berry, Grossman, Zhu, Brahmbhatt, Balakrishnan, Davis.

Critical revision of the manuscript for important intellectual content: Kim, Berry, Marchetti, Swetter, Lim, Curiel-Lewandrowski, Chu, Ming, Wolner, Fleming, Ferris, Nguyen, Trofymenko, Liu, Chen.

Statistical analysis: Berry, Brahmbhatt, Wolner, Liu.

Administrative, technical, or material support: Zhu, Davis, Ferris, Trofymenko, Chen.

Supervision: Kim, Grossman, Curiel-Lewandrowski, Chen.

Conflict of Interest Disclosures: Dr Kim reported serving as an investigator for Hoffmann-La Roche Inc. Dr Grossman reported serving as an investigator for Orlucent Inc. Dr Curiel-Lewandrowski reported serving as an Investigator for Amgen and consultant for Novartis. Dr Ferris reported serving as a consultant for DermTech International and an investigator for Castle Biosciences. Dr Chen reported serving as a consultant for Leo Pharma US, receiving grants from the National Eczema Association, and receiving royalties from the licensing of ItchyQoL (Procter & Gamble, Regeneron Pharmaceuticals Inc) and RosaQoL (Novartis, Intendis Inc). No other disclosures were reported.

Funding/Support: Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource and the Summer Scholars Program of the Winship Cancer Institute of Emory University and National Institutes of Health/National Cancer Institute under award number P30CA138292. Dr Marchetti’s work was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30CA008748.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Pigmented Lesion Subcommittee, Melanoma Prevention Working Group members for the duration of the study were Caroline C. Kim, MD (Pigmented Lesion Clinic and Cutaneous Oncology Program, Department of Dermatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts); Susan Swetter, MD (Pigmented Lesion and Melanoma Program, Department of Dermatology, Stanford University Medical Center, Palo Alto, California; Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California); Clara Curiel-Lewandrowski, MD (Pigmented Lesion Clinic and Multidisciplinary Cutaneous Oncology Program, Division of Dermatology, Department of Medicine, University of Arizona, Tucson); James M. Grichnik, MD, PhD (Melanoma Program, Department of Dermatology, Miller School of Medicine, University of Miami, Miami, Florida); Douglas Grossman, MD, PhD (Pigmented Lesion Clinic, Departments of Dermatology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City); Allan C. Halpern, MD (Pigmented Lesion Clinic, Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York); John Kirkwood, MD (Melanoma Program, University of Pittsburgh Cancer Institute, Department of Medicine, Dermatology and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania); Sancy Leachman, MD, PhD (Melanoma and Cutaneous Oncology Program, Department of Dermatology, Oregon Health and Science University, Portland); Ashfaq Marghoob, MD (Pigmented Lesion Clinic, Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York); Michael Ming, MD (Pigmented Lesion Clinic, Department of Dermatology, University of Pennsylvania, Philadelphia); Kelly Nelson, MD (Pigmented Lesion Clinic, Department of Dermatology, Duke University Medical Center, Durham, North Carolina); Suraj Venna, MD (Skin Oncology and Melanoma Center, Department of Medicine, MedStar Washington Cancer Institute and Georgetown University Medical Center, Washington, DC); Suephy C. Chen, MD, MS (Melanoma and Pigmented Lesion Clinic, Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia; Division of Dermatology, Atlanta Veterans Administration Medical Center, Decatur, Georgia); Elizabeth Berry, MD (Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia; Division of Dermatology, Atlanta Veterans Administration Medical Center, Decatur, Georgia); Michael Marchetti, MD (Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York); Emily Y. Chu, MD, PhD (Pigmented Lesion Clinic, Department of Dermatology, University of Pennsylvania, Philadelphia); Laura K. Ferris, MD, PhD (Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania); and Jennifer A. Stein, MD, PhD (Pigmented Lesion Section, New York University School of Medicine, New York).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Meeting Presentation: This article was presented at the International Investigative Dermatology Conference; May 19, 2018; Orlando, Florida.

Additional Contributions: Doug Parker, MD, DDS, Emory University and Rosalie Elenitsas, MD, University of Pennsylvania, reviewed the case of moderately dysplastic nevi upgraded to melanoma in situ. Dr David Gutman’s Bioinformatics Team assisted in digital slide archiving that allowed us to share deidentified slides with the University of Pennsylvania. Madeline Turner and Kendall Brothers, Emory University, participated in data collection as Winship Cancer Center Summer Scholars. None of these individuals were compensated for their contribution.

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