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Re-excising severely atypical nevi: A signature issue?

DII small banner By Warren R. Heymann, MD
Feb. 10, 2017

Clark nevus
Clark (dysplastic) nevus with atypical features. A, Low magnification demonstrates a broad compound melanocytic neoplasm with architectural asymmetry. B and C, Higher power reveals elongated rete ridges, subepidermal fibroplasia, parakeratosis, and marked variability in size and shape of melanocytes and their nuclei within the epidermis.
Credit: JAAD
Every day, in every dermatologist’s office, there is a discussion with patients about whether to re-excise their biopsied atypical nevus (AN, aka dysplastic nevus, Clark nevus, nevus with architectural disorder) that extended to the margin. The most recent literature suggests that cases of mild and moderate AN, with microscopically positive margins and no concerning clinical residual lesion, may be observed rather than re-excised (1). My read of the literature supports that conclusion (2). Is there data to support the same approach for severely atypical nevi?

The decision to re-excise a severely atypical nevus is based on the concern that the residual lesion could become (or is) melanoma. Engeln et al performed a retrospective single institutional study of 451 adult patients (mean age 41.3 years) with severely dysplastic nevi (SDN) having clinical follow-up of at least 5 years. Of these 451 patients, a re-excision was performed on 36.6% (I was surprised by the low number — the authors comment in the discussion that many of these lesions were from years ago, when concern for re-excision may have been less). They identified 2 cases of melanoma upon re-excision of a SDN, representing 0.4% of all patients in the study, and 1.2% of patients who underwent re-excision of the original biopsy site. There were no cases of melanoma recurring at the same site in any patients who did not undergo re-excision. They did not identify any cases of subsequent metastatic melanoma in patients without a history of invasive melanoma. Seven patients with metastatic melanoma occurring after the diagnosis of SDN were identified, however all of these patients had a prior diagnosis of invasive melanoma; it is almost certain that the metastases developed from the prior melanoma and not the SDN. The authors concluded that re-excision of all SDN may not be necessary.
The inherent problem, of course, is appropriately differentiating moderate versus severe atypia. Disagreement between dermatopathologists’ interpretation of AN is legion, leaving the clinician in a quandary. Fortunately, research toward a defining molecular signature is on the horizon. For example, Melamed et al sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42). Exome sequencing revealed that dysplastic nevi harbored a substantially lower mutational load than melanomas (21 protein-changing mutations versus >100). Known ‘driver’ mutations in genes for melanoma including CDKN2A,TP53, NF1, RAC1, and PTEN were not found among any melanocytic nevi sequenced. Additionally, melanocytic nevi including dysplastic nevi showed a significantly lower frequency and a different ultraviolet-associated mutational signature. While melanocytic nevi and dysplastic nevi harbor stable genomes with relatively few alterations, progression into melanomas requires additional mutational processes affecting key tumor suppressors. This study identified molecular parameters that could be useful for diagnosis (4).
I am confident that in my professional lifetime, such molecular analysis will be de rigueur in determining which nevi  require re-excisions. Currently we have to deal with the vagaries of subjective routine histopathologic interpretation. When choosing which lesion to biopsy, clinicians often consider the “ugly duckling” sign — the nevus appearing different from typical “signature” nevi (5).  It is my impression that atypical nevi also have a “signature” histologic appearance in a given patient.  I am not suggesting that multiple nevi be biopsied to determine the characteristic pattern in a given patient — if, however, there are several lesions that have been biopsied, and they all have the same pattern (including severely AN), perhaps it becomes a little easier to decide to follow the patient rather than perform re-excisions (with the understanding that such a patient may be a melanoma risk).

As a clinician, I am comfortable observing incompletely excised moderately AN; as a dermatopathologist, I inform the clinician that such lesions extends to the margin without recommending a re-excision [see the post “Does your dermatopathologist recommend treatment suggestions for melanocytic  lesions? My two cents (and sense)” January 5, 2017]. Perhaps I will establish the same approach with severely atypical nevi, however, I’m not there yet. When I diagnose a severely atypical nevus histologically, I’m on the verge of diagnosing melanoma. I will frequently get a second opinion and currently recommend a re-excision of the lesion if it extends to the margin. I look forward to prospective studies that give me the confidence to change my approach.

1. Fleming NH, et al. Reexamining the threshold for reexcision of histologically transected dysplastic nevi. JAMA Dermatology 2016; 152: 1327-34
2. Heymann WR. Should moderately atypical dysplastic nevi be re-excised? Follow the Yellow Brick Road! Skinmed 2015; 13: 475-6.
3. Engeln K, et al. Dysplastic nevi with severe atypia: Long-term outcomes in patients with and without re-excision. J Am Acad Dermatol 2017; 76: 244-9.
4. Melamed RD, et al. Genomic characterization of dysplastic neviunveils implications for diagnosis of melanoma. J Invest Dermatol 2016 Nov 24 [Epub ahead of print].
5. Suh KY, Bolognia JL. Signature nevi. J Am Acad Dermatol 2009; 60: 508-14.

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