It’s a common clinical scenario: A patient presents with a presumed dysplastic nevus for which the dermatologist performs an excisional biopsy to confirm the diagnosis and rule out melanoma. All of the pigmented lesion is removed. The pathology report confirms a moderately dysplastic nevus but shows that there are positive margins.

Some dermatologists would choose not to re-excise such a lesion in the majority of cases, opting to closely monitor the patient instead. But many dermatologists would argue that re-excision is generally indicated, citing concerns that a subsequent melanoma may develop at the positive margin. There are, to date, no consensus statements that offer clarification on the best approach to such cases. In fact, while the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group in 2015 concluded that mildly dysplastic nevi biopsied with positive margins could be safely monitored, their consensus statement on management indicated that observation may be reasonable in the case of moderately dysplastic nevi with positive margins. Furthermore, they called for additional study to support definitive recommendations.

It is against this backdrop that the PLS undertook a study to assess outcomes when moderately dysplastic nevi with positive margins were monitored rather than re-excised. Their findings indicate that monitoring is not only appropriate but perhaps preferable for long-term patient management.1

The Study

The current study was a multicenter retrospective cohort study conducted at nine centers in the US. Subjects were adults 18 years or older with moderately dysplastic nevi with positive histologic margins who had follow-up data available for three years or more post-excision. Researchers assessed univariate association for risk of subsequent cutaneous melanoma, in addition to multivariable logistic regression models.

Analysis was completed for a total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men). At a mean follow up of 6.9 years, no melanomas had developed at any of the biopsy sites.

Nearly one-quarter (22.8 percent) of subjects developed a cutaneous melanoma at a separate site during the follow-up period. Consistent with previous research, analysis showed that in this cohort, history of cutaneous melanoma was significantly associated with the risk of development of subsequent melanoma at a separate site. Additionally, prior biopsied dysplastic nevi were associated with risk for development of melanoma.

In efforts to confirm the histologic grading of moderately dysplastic nevi across study sites, a dermatopathologist at an independent site reviewed a random sample of five de-identified slides or images from each study site of subjects included in the analysis. While there was agreement for 35 of 40 cases, the reviewer upgraded the degree of atypia in three cases; one of the cases was actually upgraded to a melanoma in situ (however, no subsequent melanoma was detected at this site).

Melanoma Update: Data Show Durable Response for Nivolumab and Ipilimumab

Four-year data from the Phase 3 CheckMate-067 clinical trial—the longest follow-up to date—continue to demonstrate durable, long-term survival benefits with the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), versus Yervoy alone, in patients with advanced melanoma. Bristol-Myers Squibb recently reported the data, which showed (for a minimum follow-up of 48 months) four-year overall survival rates were 53 percent for the Opdivo plus Yervoy combination, 46 percent for Opdivo alone, and 30 percent for Yervoy alone. Additionally, the percentage of patients experiencing a complete response has continued to increase, with complete response rates of 21 percent for Opdivo plus Yervoy, 18 percent for Opdivo alone, and five percent for Yervoy alone.

In addition, results of an analysis of patients who were alive at the time of the four-year analysis showed that a higher proportion of patients were treatment-free (i.e., off study treatment and free of systemic subsequent therapy) in the combination group (71 percent) compared with the monotherapy groups (50 percent for Opdivo, 39 percent for Yervoy). The safety profile for Opdivo plus Yervoy in CheckMate-067 at four years was consistent with prior findings.

Data from CheckMate-067 were featured in an oral presentation (#LBA44) at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich with simultaneous publication in Lancet Oncology.

Practical Dermatology® Staff via DermWire.com

Implications

Excisions are routine in the dermatology office, but we must not overlook the cost of the procedure, as well as the variable risk for scarring, pigmentary change, and even infection every time that we excise a lesion. When the need for histologic evidence or other potential benefits of surgery outweigh the risks, excision is certainly indicated. When it comes to re-excision of moderately dysplastic nevi with positive margins, the risk/benefit analysis has been somewhat challenging. Although many clinicians have been concerned about the theoretical risk for nevus-associated melanoma developing at the margins, there has been no clear evidence of such risk. The most recent data from the PLS support the decision to monitor the patient rather than re-excise.

The option to monitor rather than re-excise may be particularly appropriate for patients with lesions in cosmetically sensitive areas and for those who are reluctant to undergo additional cutting. The fact that there were no subsequent melanomas at any of the 467 excision sites analyzed—including at least one site that appears to have been a melanoma in situ—should give comfort to clinicians who worry from both a patient care and a medico-legal risk perspective about the consequences of not re-excising a moderately dysplastic nevus with positive margins.

The results of this analysis also remind us that dysplastic nevi represent a risk factor for developing melanoma. Note that a recent systematic review and meta-analysis concluded that 29 percent of melanomas likely arose from a pre-existing nevus, while 71 percent arose de novo. Put another way, any given melanoma was 64 percent less likely to be nevus-associated than de novo.2

Because of their increased risk of developing melanomas, patients with dysplastic nevi should be undergoing regular full body skin exams both to assess any change in existing nevi as well as any signs of de novo melanoma. Clinicians can use the need to monitor the positive-margin excision site as additional motivation for patients to attend these regular exams.

It is also noteworthy that in the PLS analysis, the mean age of subjects was 46.7 years. Given that melanoma rates appear to be rising in younger patients, it is encouraging to see that patients had been presenting for assessment of suspicious lesions at a relatively young age. Keeping this younger population engaged in their care and on a routine monitoring schedule hopefully will allow for earlier diagnosis and treatment of any subsequent melanoma that may develop.

Finally: Know your pathologist! Understand what they are saying to you. How s/he communicates findings and her/his use of terminology is extremely important in deciding what to do. Something described as severely atypical may require a re-excision when a dermatopathologist describes this finding, being very careful not to use the word “melanoma” with its connotations, both medically and psychologically.

Make sure your pathologist is a board certified dermatopathologist. There is no question these lesions are hard to “read.” Working with pathologists that are experienced is of utmost importance and something we should demand, regardless of insurance parameters placed upon us as a profession.

Jonathan Wolfe, MD is an Associate Professor of Dermatology at the University of Pennsylvania.

1. Kim CC, Berry EG, et al; Pigmented Lesion Subcommittee, Melanoma Prevention Working Group. Risk of Subsequent Cutaneous Melanoma in Moderately Dysplastic Nevi Excisionally Biopsied but With Positive Histologic Margins. JAMA Dermatol. 2018 Oct 10.

2. Pampena R, Kyrgidis A, Lallas A, Moscarella E, Argenziano G, Longo C. A meta-analysis of nevus-associated melanoma: Prevalence and practical implications. J Am Acad Dermatol. 2017 Nov;77(5):938-945.