Dermatology: Practical and Conceptual Opinion | Dermatol Pract Concept. 2023;13(4):e2023246 1 Overdiagnosis of Melanoma: Is It a Real Problem? Cristian Navarrete-Dechent1,2, Aimilios Lallas3 1 Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile 2 Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile 3 First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece Citation: Navarrete-Dechent C, Lallas A. Overdiagnosis of Melanoma: Is it a Real Problem? Dermatol Pract Concept. 2023;13(4):e2023246. DOI: https://doi.org/10.5826/dpc.1304a246 Accepted: August 7, 2023; Published: October 2023 Copyright: ©2023 Navarrete-Dechent 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: Aimilios Lallas, First Department of Dermatology, School of Medicine, Aristotle University, Thessaloniki, Greece. Tel.: +302313308879 E-mail: alallas@auth.gr “The best physician is also a philosopher” Claudius Galen Is Melanoma Over-diagnosis a Reality? Overdiagnosis in cancer is the correct diagnosis of a can- cer that, if left untreated, would never cause symptoms or morbidity. Over-diagnosis is caused by both over-detection (i.e. screening) and overdefinition (ie expanding disease defi- nitions of diagnostic tests) [1]. The sine qua non requisite for establishing over-diagnosis of a cancer is a disproportionate increase in incidence without an accompanying increase in mortality (Figure 1). All these conditions are met in the case of melanoma and explain to some extent the tremendous increase in incidence [2,3]: Evidence suggests that many melanomas grow slowly and might remain intraepidermal for a long period [4]. One of the most frequent subtypes, lentigo maligna (LM), might re- main in the epidermis for several years or even decades, with only a small proportion (< 5%) evolving into invasive mel- anoma, making it an ideal paradigm of overdiagnosis [5,6]. Additionally, in last decades, early melanoma detection is considered a supreme task by healthcare systems world- wide and numerous efforts to increase screening and public awareness have been applied [7,8]. Furthermore, diagnostic tools evolved to allow earlier melanoma recognition. Der- matoscopy played a major role in changing practice, since the dermatoscope is a hand-held device available at any set- ting [9]. Finally, because of a diagnostic shift in the histo- pathologic diagnosis, tumors that were previously labelled as non-melanoma (i.e. ‘dysplastic’ nevi) are now classified as melanoma, usually in situ [3]. The latter is highlighted by the disproportionate incidence increase of melanoma in situ as compared to invasive melanoma [2]. Melanoma Over-diagnosis Exists. So What? Considering all the above, there is little doubt that over-diagnosis of melanoma exists. In addition to causing an epidemiological artifact, over-diagnosis induces a vicious cycle of increased awareness, more screening, more biopsies and more over-diagnosis with significant impact on health 2 Opinion | Dermatol Pract Concept. 2023;13(4):e2023246 Figure 1. Evolution of melanoma incidence (red line) and melanoma mortality (blue line). Mortality has remained stable as incidence dramatically increases, characteristic of over-diagnosis. If there is a relevant increase in melanoma incidence, one should expect an accompanying increase in melanoma mortality (a, red dashed line). Should screening programs be effective, one should expect a decrease in mortality (b, green dashed line). and insurance sources and possibly unneeded emotional stress [3]. Although these parameters should not be underes- timated, the most relevant question is whether over-diagnosis has a negative impact on patients’ health and if we should modify our clinical practice to address it. The vast majority of the so-called ‘over-diagnosed mela- nomas’ are intra-epidermal or minimally invasive lesions and their definitive treatment usually implies a wide local exci- sion with 5-10 mm margins, which usually translates into a small scar and almost zero morbidity [10]. Subsequently, these patients usually enter a prospective surveillance that al- lows an early detection of subsequent melanomas and other skin cancers that develop in a considerable proportion [11]. Overall, overdiagnosis does not cause any significant medi- cal harm to the individual patients, probably the opposite. Over-diagnosis or Over-treatment? Let’s go back to the “paradigm” of over-diagnosis, LM. LM typically arises on sensitive areas and any surgical treatment might cause aesthetic or functional concerns [12]. Addition- ally, LM tends to extend subclinically, which explains the in- creased recurrence rates when 5-mm margins are used [13]. For this reason, melanoma guidelines recommend wider margins or, ideally, staged excisions with margin control, that usually have significant requirements in time and costs [14]. All this for a tumor that has very low chance to invade the dermis even if left untreated [5]. To our understanding, the real problem results not from the ‘early diagnosis’ of LM, but from the exaggerated treatment for a tumor that is min- imally aggressive. Recent data suggest that conservative surgery followed by adjuvant imiquimod allows for excel- lent cure rates, akin margin-controlled excisions, offering an example of how the problem of “over-diagnosis”, which in fact is a problem of “over-treatment”, could be partially addressed [15]. Similar considerations could be made for non-melanoma skin cancers, which although usually not biologically aggressive, are often treated with sophisticated and costly surgery [16]. Can We Do Something Else to Address Over-diagnosis? Although not causing significant harm to the individual patients, the negative economic and emotional effects of over-diagnosis justify some efforts to address it, provided of course that these efforts will not put patient outcomes at risk. In the last decades, total body photography (TBP) and sequential digital dermatoscopy (SDD) are increasingly used [17]. In contrast to static examinations, these techniques provide information on the biologic dynamic of lesions, im- prove the sensitivity for melanoma diagnosis and reduce the number of excisions by revealing the biologic stability of lesions that might have been considered as suspicious at baseline [18]. A wider use of TBP and SDD might help to minimize over-diagnosis, but is limited by the significant re- quirement in time and expertise. Therefore, the use of these techniques is limited to individuals at very high risk, which restricts their impact [17]. The new generation of 2D TBP and the development of 3D TBP offer a fast documentation of the total skin surface at an unprecedented quality, and the addition of artificial intelligence (AI) has the potential Opinion | Dermatol Pract Concept. 2023;13(4):e2023246 3 to improve the diagnostic accuracy of clinicians. This new era might allow a wider application of TPB and maximize its impact [19]. Other solutions proposed to address over-diagnosis are to downgrade the histopathologic terminology and increase the threshold for biopsy/excision of suspicious lesions.3 Al- though re-labelling some in situ melanomas into terms like ‘atypical melanocytic proliferations’ would not solve the uncertainty on their biologic potential, it would indeed de- crease the recorded melanoma incidence without causing sig- nificant harm, since they would have been excised anyway [20]. In contrast, the recommendation to return to an era when clinical diameter was used as a criterion to excise a le- sion or not, is highly problematic in terms of medical ethics, since evidence suggests that melanomas < 6mm in diameter can already be invasive [3,21]. Although the aforementioned and other efforts may par- tially address over-diagnosis, a definitive solution is not fea- sible until the diagnostic gold standard procedure becomes more efficient [22]. Currently, the diagnostic gold standard for melanoma is histopathology, a purely morphological, subjective and static assessment that does not take into ac- count the biologic course [22,23]. Ideally, melanoma diag- nosis should involve a dynamic assessment of biology that would aim to spot those lesions with potential to invade the dermis, grow significantly and/or metastasize [23]. In the future, molecular or other tests, alone or combined with histopathology, possibly with the aid of AI, may improve baseline predictions on which melanomas will ultimately disseminate and threaten patients lives. Until then, histopa- thology remains our most effective method, but with signifi- cant limitations [22,23]. These limitations dictate that every melanoma is considered a potentially life-threatening tumor and explain the applied management at an individual basis. Diagnostic and therapeutic medical care is not applied at a population, but at an individual basis; it is well stated that “we treat humans, not numbers”. Therefore, the above discussion on epidemiology of melanoma and over-diagnosis has little value when it comes to medical decision-making for an individual patient. We believe that no clinician (and no patient) would ever take the risk not to excise a suspi- cious lesion just because of the epidemiologic problem of over-diagnosis, as long as available science and technology are insufficient to predict the biologic course of every sin- gle tumor. Conclusions In conclusion, over-diagnosis of melanoma is a fact explained mainly by our limited ability to predict the biologic course of melanoma. It has negative economic and emotional ef- fects that justify some efforts to address it. 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