Dermatology: Practical and Conceptual Commentary | Dermatol Pract Concept. 2024;14(2):e2024153 1 The Gray Zone of Melanocytic Tumors - A Clinical Point of View Camila Scharf1, Giulia Briatico1, Gabriella Brancaccio1, Elvira Moscarella1, Andrea Ronchi2, Giuseppe Argenziano1 1 Dermatology Unit, University of Campania L. Vanvitelli, Naples, Italy 2 Pathology Unit, University of Campania L. Vanvitelli, Naples, Italy Citation: Scharf C, Briatico G, Brancaccio G, Moscarella E, Ronchi A, Argenziano G. The Gray Zone of Melanocytic Tumors - A Clinical Point of View. Dermatol Pract Concept. 2024;14(2):e2024153. DOI: https://doi.org/10.5826/dpc.1402a153 Accepted: April 22, 2024; Published: April 2024 Copyright: ©2024 Scharf et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Camila Scharf, MD, University of Campania L. Vanvitelli, Nuovo Policlinico (edificio 9C) - Via Sergio Pansini, 5 - 80131 - Naples, Italy. Phone number: +39.081.5666828 E-mail: kmischarf@gmail.com As discussed by Kittler and Ferrara, melanocytic lesions, particularly those exhibiting challenging histopathologic features, pose a significant diagnostic and therapeutic di- lemma for clinicians. While Kittler navigates the nuanced territory of diagnosing melanocytic proliferations, critically examining the notion of the gray zone, debating its reality versus its conceptual fiction, the author also assumes that a melanocytic lesion cannot simultaneously be benign and ma- lignant, highlighting the dichotomy between biological and diagnostic uncertainties. The World Health Organization’s latest classification of melanocytic tumors attempts to navigate these complexities by delineating distinct pathways of progression from benign to malignant lesions. [1] Yet, the classification acknowledges the persistent ambiguity in defining clear precursor lesions for some pathways, highlighting the ongoing debate between bio- logical versus diagnostic gray zones, as implicated by Ferrara. From the 1970’, when first described, dysplastic nevus (DN) has always been a source of confusion. The key is whether, and to what level, DN represents a premalignant lesion that will progress to melanoma. [2] This assumption has been propagated over the years, considering that grading nevus cytologic atypia as mild, moderate, or severe by the pathologists could imply this continuous progression of DN towards melanoma, as it happens in actinic keratosis. [3] It is true that numerous studies have documented the re- lationship between DN and familial melanoma, and in fact, they were originally described in melanoma-prone families, with the implication that such lesions had a higher risk of transformation to melanoma than the patients’ regular nevi. However, in patients with familial melanoma and those with a high number of DN, still melanoma is most frequently devel- oping de novo and not in association to a pre-existing DN. [4] The basic concept included in the last WHO classifica- tion is that all melanomas develop from a benign precur- sor. The latter progresses first to a biologically intermediate lesion (DN, melanocytoma, atypical Spitz tumor, etc.) that finally transforms into a melanoma. The point is that clin- ically this concept if very difficult to belive, mainly for the following evidence: 1. More than 70% of melanomas are not found histo- pathologically in association to a pre-existing nevus. [5] How can it be possible that no nevus remnants are 2 Commentary | Dermatol Pract Concept. 2024;14(2):e2024153 found in such a high number of melanomas if it were true that all of them should be the result of a nevus transformation? 2. Of the minority of melanomas (less than 30%) found in association to a pre-existing nevus, more than half are as- sociated to a common dermal nevus and not to a DN. [6] How can it be possible that the biologically intermediate lesion is so frequently missing if the stepwise transforma- tion were true? 3. The probability of a single nevus to transform into mel- anoma is exceedingly low, being calculated in the order of 1 out 200.000 nevi and even in patients with mul- tiple nevi still melanoma develops most frequently de novo. [7] Although we believe the presence of multiple nevi in an individual is associated with increased melanoma risk, nevi are not melanoma precursors, and DN, melanocytomas and atypical Spitz tumors are not nevi evolving into mela- noma but benign lesions with challenging histopathological features. References 1. Ho J, Collie CJ. What’s new in dermatopathology 2023: WHO 5th edition updates. J Pathol Transl Med. 2023 Nov;57(6):337-340. 2. Clark WH Jr, Ackerman AB. An exchange of views regard- ing the dysplastic nevus controversy. Semin Dermatol. 1989 Dec;8(4):229-50. PMID: 2701712. 3. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era: part I. Histori- cal, histologic, and clinical aspects. J Am Acad Dermatol. 2012 Jul;67(1):1.e1-16; quiz 17-8. doi: 10.1016/j.jaad.2012.02.047. PMID: 22703915; PMCID: PMC3625372. 4. Clark WH, Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions ‘The B-K mole syndrome’  Arch Dermatol. 1978 5. Cymerman RM, Shao Y, Wang K, et al. De novo vs nevus- associated melanomas: differences in association with prognostic indicators and survival. J Natl Cancer Inst. 2016;108(10):djw121 6. 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;77(5):938–945.e4. 7. Lin WM, Luo S, Muzikansky A, et al. Outcome of patients with de novo versus nevus-associated melanoma.  J Am Acad Dermatol. 2015;72(1):54–58.