Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2025;15(4):6994 1 Rethinking Melanocytic Tumors: A Critical Appraisal of the WHO Classification and the Myth of Nevus-to-Melanoma Progression Giuseppe Argenziano1, Giulia Briatico1, Eugenia Veronica Di Brizzi1, Camila Scharf1, Gabriella Brancaccio1, Elvira Moscarella1, Maria Maddalena Nicoletti1, Pasquale Verolino1, Aimilios Lallas2, Harald Kittler3 1 Dermatology Unit, University of Campania, Naples, Italy 2 First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece 3 Department of Dermatology, Medical University of Vienna, Vienna Key words: Melanocytic tumors, Dysplastic nevus, WHO classification, Nevus-to-melanoma progression, Dermoscopy, Diagnostic gray zone Citation: Argenziano G, Briatico G, Di Brizzi EV, et al. Rethinking Melanocytic Tumors: A Critical Appraisal of the WHO Classification and the Myth of Nevus-to-Melanoma Progression. Dermatol Pract Concept. 2025;15(4):6994. DOI: https://doi.org/10.5826/ dpc.1504a6994 Accepted: October 7, 2025; Published: October 2025 Copyright: ©2024 Argenziano 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: Giulia Briatico, MD PhD, Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: giuliabriatico@gmail.com Introduction: The recent WHO classification of melanocytic tumors introduces a refined molecular and histopathological framework suggesting distinct pathways and precursor lesions for all melanoma subtypes. While conceptually appealing, its clinical applicability is increasingly questioned. Objectives: This review critically examines the transformation theory from benign nevi to melanoma, highlighting inconsistencies between the proposed models and real-life practice. Methods: Through illustrative cases and key epidemiological evidence, we evaluated the validity of current models proposing intermediate lesions in melanoma development. Results: We argue that most melanomas arise de novo and that the so-called intermediate lesions, such as dysplastic nevi and atypical Spitz tumors, may mimic melanoma but are not true biological precursors. Conclusions: We propose a simplified, clinically oriented reclassification of melanocytic lesions based on morphologic ambiguity and actual behavior, aiming to guide therapeutic decisions and reduce di- agnostic overinterpretation. ABSTRACT 2 Review | Dermatol Pract Concept. 2025;15(4):6994 Introduction The classification and management of melanocytic tumors re- main among the most debated areas in dermatology. Advances in molecular diagnostics and the recognition of a diagnostic gray zone [1] have blurred the boundaries between nevi, atyp- ical lesions, and melanoma. This gray zone comprises lesions that resist clear categorization, resulting in considerable vari- ability in diagnosis, terminology, and management. The latest World Health Organization (WHO) classifi- cation [2] seeks to impose order by introducing molecularly defined pathways and attributing biological significance to many lesions traditionally regarded as intermediate. Accord- ing to this model, virtually all melanomas arise from pre- cursor lesions that evolve from benign to intermediate, then finally, to malignant, following specific molecular trajecto- ries (Table 1). While theoretically elegant, this concept has raised con- cerns among clinicians who rarely observe these progression models in everyday practice. This review critically examines the WHO model, particularly its concept of biologically intermediate melanocytic tumors. We argue that the trans- formation theory, in which nevi evolve into melanocyto- mas and ultimately into melanoma, is overemphasized and sometimes misleading. Instead, we advocate for a pragmatic, observation-based classification focused on morphologic ambiguity and risk of recurrence or invasion. The Diagnostic Gray Zone: Clinical and Pathological Perspectives Most melanocytic lesions encountered in dermatology can be safely diagnosed as clearly benign or clearly malignant. Yet a small but important subset falls into a diagnostic gray zone, displaying architectural disorder, cytologic atypia, or unusual dermoscopic patterns without fulfilling the criteria for melanoma [1]. For dermatologists, this gray zone consists of lesions that raise suspicion but lack definitive malignant features. For pathologists, the dilemma is greater; they are expected to provide definitive diagnoses, yet many such lesions can only be described with umbrella terms such as dysplastic nevus, atypical Spitz tumor, or melanocytoma that convey uncer- tainty more than precision. These ambiguous lesions are often graded biologi- cally (low or high grade) to imply malignant potential. However, such assessments rely on variably interpreted histopathological criteria and lack robust prospective validation. The result may be over- or underdiagnosis, over- or un- dertreatment [3], and patient anxiety. A biopsy showing architectural disorder and cytologic atypia may be labeled high-grade dysplastic nevus, prompting re-excision despite no clinical evidence of aggressiveness. Conversely, a melanoma with blunt morphologic features might be under-classified and undertreated. These paradoxes highlight the limits of current diagnostic frameworks and the need for a case based clinical approach. The WHO Classification: A New Paradigm or Theoretical Overreach? The 2018 WHO Classification of Skin Tumours marked a conceptual shift. Moving beyond the traditional clinical and histopathological categories of superficial spreading, nodu- lar, lentigo maligna, and acral lentiginous melanoma, it pro- poses nine molecularly-defined pathways, each linked to a specific melanoma subtype and its putative precursor. Table 1. WHO Melanoma Pathways: The 9 Progression Routes. Pathway No. WHO Designation Cumulative Sun Damage (CSD) Proposed Precursor 1 Low-CSD melanoma including superficial spreading melanoma Low Common and dysplastic nevus 2 High-CSD Lentigo Maligna Melanoma High (chronic) Intraepidermal melanocytic proliferation 3 Desmoplastic Melanoma High (chronic) Intraepidermal melanocytic proliferation 4 Spitz Melanoma None Spitz nevus 5 Acral Melanoma None Acral nevus* 6 Mucosal Melanoma None Mucosal melanosis* 7 Melanoma in Congenital Nevus Variable Congenital nevus 8 Melanoma in Blue Nevus None Blue nevus 9 Uveal Melanoma None Uveal melanocytic proliferation *Note: In some pathways (e.g., mucosal, acral), the precursor lesion is hypothetical or histologically undefined. Review | Dermatol Pract Concept. 2025;15(4):6994 3 According to this model, most melanomas emerge through stepwise transformation from a benign nevus to an intermediate lesion and ultimately to melanoma. Each path- way is presented as a predictable, lineage-specific progres- sion, similar to the multistep evolution of certain epithelial cancers. While intellectually appealing and valuable for research, the clinical utility of this stratified model is doubtful. The assumption that every melanoma derives from a known pre- cursor contradicts decades of clinical observation [4]. Sev- eral proposed sequences remain biologically speculative and lack corroboration in daily practice. For example, the Spitz pathway posits a linear evolution from Spitz nevus to Spitz melanocytoma to melanoma, a se- quence rarely, if ever, documented [5]. Likewise, the idea that all superficial spreading melanomas arise from a common acquired nevus progressing through dysplastic stages to mel- anoma in situ and then invasive disease is seldom reflected in clinical case series or histopathological slides [6]. The most striking logical flaw involves congenital nevi. The WHO classification suggests that transformation pro- ceeds through proliferative nodules to an in situ melanoma. Yet by definition, an in situ melanoma confined to the epi- dermis cannot logically arise as the next step after an already invasive dermal proliferative nodule. Thus, while the WHO framework enriches molecular tax- onomy, applying it rigidly in clinical dermatology risks overint- erpreting histopathological atypia as biological aggressiveness, leading to unnecessary surgeries and psychological burden. Class I and II Melanocytic Tumors: What Do They Really Mean Clinically? A central feature of the new WHO classification is the divi- sion of melanocytic tumors into four broad classes accord- ing to biological behavior and presumed risk of progression. While Classes III and IV refer to clearly malignant melanomas (thin and thick invasive lesions, respectively), Classes I and II encompass the so-called precursor melanocytic tumors. Class I lesions are described as low-grade melanocytic tumors with an estimated risk of malignant transformation of about 1 in 10,000 [7]. The WHO advises no treatment beyond conservative excision. This group includes: • Common acquired nevi (no atypia) • Congenital nevi (no atypia) • Dysplastic nevi (low grade) • Common blue nevi For clinicians this categorization seems acceptable. These lesions have indolent behavior and are rarely problematic. Yet calling them precursor lesions creates confusion, because they appear entirely banal clinically and dermoscopically. Class II lesions, in contrast, are labeled as high-grade mela- nocytic tumors, with a low but not negligible risk of progres- sion (approximately 1 in 100) [7]. The WHO recommends complete excision and often re-excision. This group includes: • Dysplastic nevi (high grade) • Spitz nevi • Cellular blue nevi • Deep penetrating nevi (plexiform) • Lentigo maligna • Melanoma in situ This classification leads to striking therapeutic incon- sistencies. Conventional Spitz nevi and melanoma in situ, which are biologically and clinically distinct, are placed in the same category. Likewise, the inclusion of cellular blue nevi, lesions that very rarely progress to melanoma, along- side lentigo maligna is not supported by clinical experience. A particularly problematic example is the high-grade dysplastic nevus. Despite its ominous label and histopatho- logical atypia, it is very common, especially in young individ- uals, and usually benign. Many dermatologists therefore find themselves re-excising lesions that are biologically indolent simply because of a category assignment rather than any real clinical risk. By contrast, dysplastic nevi are very rare in the elderly, a diagnosis in this age group likely representing an under-classification of a featureless melanoma. These con- tradictions expose the gap between histopathological theory and patient care. The WHO framework assigns a theoreti- cal progression risk based on morphology, whereas clinical decision-making must also consider age, body site, dermo- scopic pattern, patient history, and lesion dynamics. Without this context, strict application of the WHO classification sys- tem risks unnecessary treatment and loss of personalized care. The Spitz Conundrum Among the most debated elements of the WHO classification is the idea that Spitz tumors represent a biological contin- uum culminating in melanoma. The proposed Spitz pathway describes a linear evolution from Spitz nevus to Spitz mela- nocytoma (previously termed atypical Spitz tumor), then to melanocytic tumor of uncertain malignant potential or spit- zoid tumor of uncertain malignant potential, and finally to Spitz melanoma. This sequence finds little support in clinical reality. Der- matologists and dermatopathologists seldom observe a con- ventional Spitz nevus evolving into melanoma. In fact, Spitz nevi, especially in children and adolescents, usually regress or stabilize and often develop a more conventional appear- ance over time [8]. Even when they grow asymmetrically or exhibit worrisome features, excision typically confirms a be- nign Spitz nevus without evidence of progression. 4 Review | Dermatol Pract Concept. 2025;15(4):6994 Moreover, the diagnosis of Spitz melanoma is exception- ally rare and often based solely on histopathological features without documented clinical evolution from a precursor. This raises the possibility that some lesions classified as Spitz melanoma are actually melanomas with spitzoid morphol- ogy rather than descendants of a benign Spitz lineage. Confusion is amplified by the bidirectional overlap of morphology: some melanomas can mimic Spitz nevi and vice versa. As a practical safeguard, any spitzoid-looking lesion that appears after puberty is usually excised [9]. The overall picture is not one of linear progression but of morphological overlap between two distinct entities. Con- flating overlap with true progression risks diagnostic infla- tion and unnecessary re-excisions, increasing both patient anxiety and healthcare costs. The Spitz example illustrates the danger of applying rigid theoretical models to lesions whose behavior is better understood through clinical obser- vation and dermoscopic follow-up. Three Clinical Cases that Challenge the Progression Theory While the transformation model from benign nevus to mela- noma is conceptually appealing, clinical evidence often tells a different story. The following cases highlight how real-world dermatology practice contradicts the notion of stepwise ne- vus to melanoma transformation. Case 1: The Supposed Precursor that Became a 7.5 mm Melanoma A 45-year-old male presented with a pigmented lesion on the face that was excised and diagnosed as a junctional me- lanocytic proliferation consistent with a dysplastic nevus, a WHO Class I low-grade lesion (Figure 1). Two and a half years later, a nodular lesion appeared in the same location and proved to be a 7.5 mm thick melanoma with 12 mitoses per square millimeter (Figure 2). Either the first lesion transformed in record time, or it was already a melanoma misdiagnosed as a nevus. Given the short interval and aggressive behavior, misclassification is the more likely explanation. Case 2: A High-Grade Dysplastic Nevus that was Clearly Benign A 27-year-old female had two pigmented lesions excised. One was called a low-grade dysplastic nevus, and the other one was diagnosed as a high-grade dysplastic nevus. This lat- ter lesion, located on the leg, showed no clinical or dermo- scopic sign of malignancy (Figure 3). The WHO guidelines called for re-excision, yet clinical judgment favored simple observation. Figure 1. A pigmented lesion on the cheek of a middle-aged male. Dermoscopically, no prevalent benign criterion is seen. Furthermore, a black blotch could be suggestive of an invasive melanoma, a di- agnosis that was not supported by the histopathologists, who con- cluded it was a dysplastic nevus. Figure 2. Same patient as Figure 1. A relapse of the previous lesion was observed and diagnosed histopathologically as a melanoma, 7.5 mm Breslow thickness. Figure 3. The patient’s young age and the regular pigment network suggest the diagnosis of a benign nevus. However, histopathologi- cally, this lesion was diagnosed as high-grade dysplastic nevus. Case 3: A High-Grade Dysplastic Nevus that was a Melanoma A 58-year-old female presented with a solitary pigmented lesion on the leg (Figure 4). Histopathology labeled it a com- pound nevus with severe dysplasia. However, the asymme- try and dermoscopic pattern strongly suggested melanoma in situ. Together, these cases show that so-called intermediate diagnoses can obscure the true nature of a lesion, either by exaggerating or underestimating risk, and they demonstrate Review | Dermatol Pract Concept. 2025;15(4):6994 5 the need to integrate clinical and dermoscopic information with histopathology. Three Facts That Undermine the Precursor Theory Fact 1: Over 70% of Melanomas Arise De Novo Multiple studies have shown that more than 70% of melano- mas are not associated histopathologically with a pre-existing nevus [10]. In other words, in the majority of cases, no ne- vus remnant is found within or adjacent to the melanoma. Proponents of the progression theory argue that the origi- nal nevus may have been obliterated early in the malignant process, thus becoming undetectable. However, this expla- nation is neither parsimonious nor consistent with clinical experience. It implies that nevus remnants should vanish while the lesion is still very small, given that even in a series of very small melanoma, excised when they were less than 5 mm, nevus remnants are usually not found (Figures 5 and 6). The absence of nevus remnants in the vast majority of melanomas weakens the concept of obligatory precursor le- sions and instead supports the idea that most melanomas arise de novo, from a single melanocyte of the normal skin acquiring tumorigenic mutations. Fact 2: The Progression Sequence Is Never Seen in Full If the stepwise model were valid, we would expect to see his- topathological specimens showing coexisting zones of com- mon nevus, dysplastic nevus, and melanoma within the same lesion. In practice, such histopathological continuity is ex- tremely rare-to-nonexistent. Moreover, among the minority (about 30%) of melanomas that do appear associated with a nevus, more than half arise from banal dermal nevi, not dysplastic ones [11] (Figure 7). This observation challenges the logic of the progression model, which would require dysplastic nevi as obligatory intermediates. Rather than true Figure 4. Solitary lesion on the leg of a middle-aged female. Dermo- scopically, atypical network, atypical globules, and prominent skin markings are visible, suggesting the diagnosis of melanoma in situ. Again, the histopathological diagnosis was high-grade dysplastic nevus. Figure 5. This is a melanoma in situ with a diameter of about 2 mm. Figure 6. Dermoscopic image of the lesion shown in Figure 5 show- ing clear-cut melanoma-specific features such as irregular streaks at the periphery and regression structures in the center. This is a mela- noma in situ with no clinical, dermoscopic, or histopathological sign of an associated nevus. progression, these may represent collision tumors, i.e., the coexistence of an evolving melanoma adjacent to or super- imposed on a pre-existing nevus, without biological lineage continuity. Fact 3: The Statistical Probability Is Exceedingly Low Large-scale epidemiological studies have estimated that the risk of malignant transformation of a single nevus is approx- imately 1 in 200,000 [7]. This extremely low figure is incom- patible with the idea that nevi are common steppingstones toward melanoma. Even in high-risk patients with hundreds of nevi, most melanomas still arise de novo (Figures 8 and 9). This further invalidates the rationale for treating dysplastic or atypical nevi as biologically dangerous entities requiring special at- tention. Certainly, individuals with many nevi need long-term monitoring with total body photography and sequential dig- ital dermoscopy imaging [12], but the main aim of sequential surveillance is to facilitate the detection of a melanoma de- veloping among the numerous clinically similar nevi rather than monitoring nevi that may progress to melanoma, which is much less likely to happen. 6 Review | Dermatol Pract Concept. 2025;15(4):6994 assigning to every melanoma a defined precursor lesion is not supported by clinical experience or epidemiologi- cal data. In light of these discrepancies, we propose a simplified and pragmatic classification of melanocytic tumors that bet- ter reflects the reality of clinical dermatology. Rather than relying on assumed biological progression or histopatho- logical terminology with variable interpretation, we suggest categorizing lesions based on the degree of morphological ambiguity and actual clinical behavior. This framework would consist of three primary categories: 1. Clearly Benign Melanocytic Nevi • Diagnostically straightforward in most cases • Rarely if ever recur or evolve 2. Clearly Malignant Melanomas • In situ or invasive melanomas with well-established clinical, dermoscopic, and histopathological criteria • Require prompt excision and staging 3. Ambiguous Melanocytic Tumors (The “Gray Zone”) • Lesions that defy easy classification, either clinically, dermoscopically, or histopathologically • Management should be individualized based on clin- ical scenario, dermoscopic features, histopathological criteria, and multidisciplinary discussion • Re-excision should be decided case-by-case, not man- dated by label alone Such a framework would better align with daily practice, minimize over- and underdiagnosis and over- and under- treatment, and still integrate pathology and molecular in- sights where they add genuine value. Figure 7. Six dermoscopic images of nevus-associated melanomas. The nevus component is represented by a classical dermal nevus. Figure 8. Clinical image of a patient with multiple nevi. Taken together, these three facts provide compelling evi- dence that the nevus-to-melanoma transformation model is an exception, not the rule. As such, it should not drive rou- tine clinical decision-making, particularly in the absence of a good clinical-histopathological correlation. A Proposal for a More Useful Classification The current WHO classification, while theoretically sophis- ticated and grounded in molecular pathology, attempts to impose a linear logic on the process of melanoma genesis. However, clinical observations suggest that, like most com- plex biological phenomena, melanoma genesis is nonlinear, chaotic, and unpredictable. As discussed, the insistence on Review | Dermatol Pract Concept. 2025;15(4):6994 7 clinical, dermoscopic, and histopathological evidence, used in harmony, not in isolation. References 1. Kittler H. Biologic Gray Zone of Melanocytic Tumors, Fiction or Reality?  Dermatol Pract Concept. 2024;14(2):e2024148. DOI:10.5826/dpc.1402a148 2. Ho J, Collie CJ. What's new in dermatopathology 2023: WHO 5th edition updates. J Pathol Transl Med. 2023;57(6):337-340. DOI:10.4132/jptm.2023.09.22 3. Annessi G, Annessi E. Considerations on The Biologic Gray Zone of Melanocytic Tumors.  Dermatol Pract Concept. 2024;14(2):e2024154. DOI:10.5826/dpc.1402a154 4. 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:10.5826/dpc.1402a153 5. Urso C, De Giorgi V, Massi D. Conceptual Evolution and Cur- rent Approach to Spitz Tumors.  Dermatopathology (Basel). 2022;9(2):136-142. Published 2022 Apr 26. DOI:10.3390 /dermatopathology9020017 6. Saida T. Histogenesis of cutaneous malignant melanoma: The vast majority do not develop from melanocytic nevus but arise de novo as melanoma in  situ.  J Dermatol. 2019;46(2):80-94. DOI:10.1111/1346-8138.14737 7. Elder DE, Bastian BC, Cree IA, Massi D, Scolyer RA. The 2018 World Health Organization Classification of Cutaneous, Muco- sal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Conclusions and Practical Recommendations The management of melanocytic tumors, particularly those falling into the so-called “intermediate” or “gray zone,” re- mains one of the most challenging aspects of dermatology practice. While the latest WHO classification offers a refined framework rooted in molecular pathology, its clinical trans- position is far from straightforward. This review highlights how many of the assumptions un- derlying the nevus-to-melanoma transformation model are not corroborated by real-world evidence. Most melanomas arise de novo, not from pre-existing nevi, many so-called “high-grade dysplastic nevi” are biologically indolent, and some melanomas with bland histopathological features are misclassified as borderline lesions, delaying appropriate management. Instead of rigidly adhering to histopathological labels or theoretical pathways, clinicians must embrace a case-by- case approach that prioritizes clinical scenario, dermoscopic morphology, lesion dynamics, and patient history. Only through this integrative method can we avoid both over- and undertreatment. The ultimate goal should not be to fit every lesion into a predefined category but to provide patients with the most appropriate precision care based on the best available Figure 9. Dermoscopic images of some of the lesions of the patient in Figure 8. Many of these lesions are dermo- scopically atypical. However, only the lesion indicated by the arrow was diagnosed histopathologically as a de novo melanoma in situ. 8 Review | Dermatol Pract Concept. 2025;15(4):6994 Prevalence and practical implications.  J Am Acad Dermatol. 2017;77(5):938-945.e4. DOI:10.1016/j.jaad.2017.06.149 11. Zalaudek I, Conforti C, Guarneri F, et al. Clinical and dermoscopic characteristics of congenital and noncongenital nevus-associated melanomas.  J Am Acad Dermatol. 2020;83(4):1080-1087. DOI:10.1016/j.jaad.2020.04.120 12. Russo T, Piccolo V, Moscarella E, et al. Indications for Digital Monitoring of Patients With Multiple Nevi: Recommenda- tions from the International Dermoscopy Society.  Dermatol Pract Concept. 2022;12(4):e2022182. Published 2022 Oct 1. DOI:10.5826/dpc.1204a182 Defined by Their Evolutionary Pathway. Arch Pathol Lab Med. 2020;144(4):500-522. DOI:10.5858/arpa.2019-0561-RA 8. Argenziano G, Agozzino M, Bonifazi E, et al. Natural evo- lution of Spitz nevi.  Dermatology. 2011;222(3):256-260. DOI:10.1159/000326109 9. Lallas A, Apalla Z, Ioannides D, et al. Update on dermoscopy of Spitz/Reed naevi and management guidelines by the Inter- national Dermoscopy Society.  Br J Dermatol. 2017;177(3): 645-655. DOI:10.1111/bjd.15339 10. Pampena R, Kyrgidis A, Lallas A, Moscarella E, Argenziano G, Longo C. A meta-analysis of nevus-associated melanoma: