Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2022;12(02):e2022094 1 Prevalence and clinical-pathological features of nevus-associated versus de novo melanoma: a retrospective cross-sectional study of 2806 cases Michela Lai1,2, Simonetta Piana3, Giovanni Pellacani4, Caterina Longo1,2, Riccardo Pampena1,2 1 Centro Oncologico ad Alta Tecnologia Diagnostica, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy 2 Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy 3 Pathology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy 4 Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy Key words: melanoma, nevus-associated melanoma, de novo melanoma Citation: Lai M, Piana S, Pellacani G, Longo C, Pampena R. Prevalence and clinical-pathological features of nevus-associated versus de novo melanoma: a retrospective cross-sectional study of 2806 cases. Dermatol Pract Concept. 2022;12(02):e2022094. DOI: https://doi.org/10.5826/dpc.1202a94 Accepted: October 19, 2021; Published: April 2022 Copyright: ©2022 El-Azhary 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: Caterina Longo, MD, PhD, Department of Dermatology, University of Modena and Reggio Emilia, Italy, Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Centro Oncologico ad Alta Tecnologia Diagnostica-Dermatologia, Viale Risorgimento, 80, 42123, Reggio Emilia, Italy. E-mail: longo.caterina@gmail.com  Introduction: Nevus-associated melanoma (NAM) accounts for almost one third of all cutaneous melanomas; it is often associated with younger age, trunk location and lower Breslow’s thickness compared to de novo melanoma (DNM). Objectives: To define the prevalence of NAM in a tertiary referral Center in Italy and to analyze its distribution according to demographics, clinical and histopathological variables Methods: Data were retrospectively retrieved from the archive of the Pathology Unit from June 2011 to August 2020. NAMs were compared with DNMs according to demographic, clinical and histo- pathological variables. Results: A total of 2806 consecutive cases of melanoma were excised in 2537 patients. Of these, 431 (15.4%) were NAM. NAM patients were significantly younger than DNM patients (55.1±14.1 vs. 62.0±15.0 years, p<0.001); they were predominantly located on the trunk (64.0% vs. 47.9% of DNMs). Melanoma located on the head and neck, trunk and upper limbs respectively had 2.3 (95%CI:1.2-4.5, p:0.014), 3.2 (95%CI:2.1-5.1, p<0.001) and 3.5 (95%CI:2.0-6.1, p<0.001) more odds to be NAM than those on the lower limbs. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2022;12(02):e2022094 Introduction Nevus-associated melanoma (NAM) accounts for almost one third of all cutaneous melanomas [1]. A growing body of literature demonstrated that NAM is associated with younger age, trunk location and lower Breslow’s thickness compared to de novo melanoma (DNM) [2-9]. Objectives In this retrospective cross-sectional study, we reviewed our 10-year real-life experience at a tertial referral center for skin cancers with the aim to analyze the prevalence of NAM and its distribution according to demographics, clinical and his- topathological variables. Methods From the archive of the Pathology Unit, we retrieved 2806 consecutive cases of skin melanoma excised in 2537 patients from June 2011 to August 2020: 431 (15.4%) melanomas were NAM. NAMs were compared with DNMs according to demographic, clinical and histopathological variables us- ing the Student’s T and chi square tests; statistical signifi- cance was set at p<0.05 and age was categorized according to quartiles. Statistical analysis was performed using the IBM SPSS 27.0 package (Statistical Package for Social Sci- ences, IBM SPSS Inc., Chicago, Ill.). The study was approved by Local Ethical Committee (protocol number: 1249/CE). Results Our study revealed that NAM patients were significantly younger than DNM patients (55.1 ± 14.1[standard deviation, SD] versus 62.0 ± 15.0 SD years, P < 0.001), with 67.7% NAMs having ≤61 years and 52.5% of DNMs being older than 61 years. Moreover, the NAM ratio decreased with increas- ing age. Interestingly, when considering body site distribution, a significant higher proportion of NAMs were on the trunk (64.0% vs. 47.9% of DNMs, NAM ratio: 19.5%) whereas DNMs were predominantly located on the lower limbs (23.9% vs. 14.7% of NAM, NAM ratio: 8.1%) (Figure 1). No significant differences were found according to sex and Breslow’s thickness, while ulceration was significantly more observed among DNMs (Table 1). Conclusions: Our results confirm the association of NAM with younger age and trunk location. We also demonstrated that body site differences of NAM distribution are enhanced before the sixth decade of life. Figure 1. Ratio of nevus-associated versus de-novo melanoma ac- cording to body site and age-groups. DNM = de novo melanoma; NAM = nevus-associated melanoma. Original Article | Dermatol Pract Concept. 2022;12(02):e2022094 3 Table 1. Demographic, clinical and histopathological features of nevus-associated vs. de-novo melanoma (NAM vs. DNM). Variables Nevus-association NAM ratio Total p valueNAM DNM Age at excision (y) ≤50 176 (40.8%) 576 (24.3%) 23.4% 752 (26.8%) <0.001 51 - 61 116 (26.9%) 551 (23.2%) 17.4% 667 (23.8%) 62 - 73 88 (20.4%) 651 (27.4%) 11.9% 739 (26.3%) ≥74 51 (11.8%) 597 (25.1%) 7.9% 648 (23.1%) Sex M 237 (55.0%) 1269 (53.4%) 15.7% 1506 (53.7%) 0.551 F 194 (45.0%) 1106 (46.6%) 14.9% 1300 (46.3%) Location HN 39 (9.0%) 350 (14.7%) 10.0% 389 (13.9%) <0.001 trunk 276 (64.0%) 1138 (47.9%) 19.5% 1414 (50.4%) upper limbs 66 (15.3%) 320 (13.5%) 17.1% 386 (13.8%) lower limbs 50 (11.6%) 567 (23.9%) 8.1% 617 (22.0%) Stage in situ 203 (47.1%) 1183 (49.8%) 14.6% 1386 (49.4%) 0.3 invasive 228 (52.9%) 1192 (50.2%) 16.1% 1420 (50.6%) Breslow (mm) ≤1 181 (79.4%) 881 (73.9%) 17.0% 1062 (74.8%) 0.107 >1 & ≤2 27 (11.8%) 134 (11.2%) 16.8% 161 (11.3%) >2 & ≤4 11 (4.8%) 87 (7.3%) 11.2% 98 (6.9%) >4 9 (3.9%) 90 (7.6%) 9.1% 99 (7.0%) Ulceration superficial 11 (4.8%) 106 (8.9%) 9.4% 117 (8.2%) 0.041 Total 431 2375 15.4% 2806 NAM, nevus-associated melanoma; DNM, de-novo melanoma; y, years; M, male; F, female, HN, head and neck; mm, millimeters. To identify major independent factors associated with NAM status we constructed a multivariable logistic regres- sion model with backward variables selection including sex, location, ulceration, Breslow and age categories. We demon- strated that melanoma located on the head and neck, trunk and upper limbs, respectively had 2.3 (95% confidence inter- val [CI]1.2 -4.5, P = 0.014), 3.2 (95% CI 2.1-5.1, P <0.001) and 3.5 (95% CI 2.0-6.1, P < 0.001) more odds to be NAM than those on the lower limbs. Also, melanomas in patients aged ≤61 years were more likely to be NAM than those in patients ≥74 years (≤50 years: OR: 3.3; 95% CI 2.0-5.3, p<0.001; 51-61 years: OR: 2.7; 95%CI:1.6-4.5, p<0.001). Furthermore, we reported the prevalence of NAM and DNM according to the body site in two age groups: ≤61 years and ≥74 years (NAM ratio: 20.6% and 7.9%, re- spectively). We found significant differences between NAM and DNM only in the ≤61 years group, with higher prevalence of NAM on the trunk (69.2%, NAM ratio 26.1%) and DNM on the lower limbs (29.1%, NAM ratio: 9.4%) (Figure 1). Conclusions In conclusion, although we found a lower NAM preva- lence than expected from literature data, our results confirm the association of NAM with younger age and trunk location [1]. We also demonstrated that body site differences of NAM distribution are enhanced before the sixth decade of life. Together with previous studies, our findings further sup- port the existence of 2 divergent pathways of melanoma development [8,10]. References 1. 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 Derma- tol. 2017;77(5). DOI: 10.1016/j.jaad.2017.06.149. PMID: 28864306 2. Pandeya N, Kvaskoff M, Olsen CM, et al. Factors Related to Nevus-Associated Cutaneous Melanoma: A Case-Case Study. J Invest Dermatol. 2018;138(8). DOI: 10.1016/j.jid.2017.12.036. PMID: 29524457 3. Longo C, Rito C, Beretti F, et al. De novo melanoma and mel- anoma arising from pre-existing nevus: In vivo morphologic differences as evaluated by confocal microscopy. J Am Acad Dermatol. 2011;65(3). DOI: 10.1016/j.jaad.2010.10.035. PMID: 21715047 4. Haenssle HA, Mograby N, Ngassa A, et al. Association of Pa- tient Risk Factors and Frequency of Nevus-Associated Cutane- ous Melanomas. JAMA Dermatol. 2016;152(3). DOI: 10.1001/ jamadermatol.2015.3775. PMID: 26536613 5. Pampena R, Pellacani G, Longo C. Nevus-Associated Mela- noma: Patient Phenotype and Potential Biological Implications. 4 Original Article | Dermatol Pract Concept. 2022;12(02):e2022094 J Invest Dermatol. 2018;138(8). DOI: 10.1016/j.jid.2018.01.025. PMID: 30032788 6. Cymerman RM, Shao Y, Wang K, et al. De Novo vs Nevus-Asso- ciated Melanomas: Differences in Associations With Prognostic Indicators and Survival. J Natl Cancer Inst. 2016;108(10). DOI: 10.1093/jnci/djw121. PMID: 27235387 7. Massi D, Carli P, Franchi A, Santucci M. Naevus-associated melanomas. Melanoma Res. 1999;9(1). DOI: 10.1097/00008390- 199902000-00011. PMID: 10338338 8. Pampena R, Lai M, Piana S, Lallas A, Pellacani G, Longo C. Nevus-associated melanoma: Facts and controversies. G Ital Dermatol Venereol. 2020;155(1). DOI: 10.23736/S0392- 0488.19.06534-9. PMID: 32100974 9. Kaddu S, Smolle J, Zenahlik P, Hofmann-Wellenhof R, Kerl H. Melanoma with benign melanocytic naevus components: reap- praisal of clinicopathological features and prognosis. Melanoma Res. 2002;12(3). DOI: 10.1097/00008390-200206000-00011. PMID: 12140384 10. Whiteman DC, Pavan WJ, Bastian BC. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Pigment Cell Melanoma Res. 2011;24(5). DOI: 10.1111/j.1755-148X.2011.00880.x. PMID: 21707960