Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(2):e2023122 1 Junctional Nevus and Early Melanoma on Sun-Damaged Skin of the Head/Neck: a Clinico-Pathologic Challenge Elvira Moscarella1, Pascale Guitera2-4, Richard A. Scolyer2,3,5,6, Lilian Rocha5, Luc Thomas7,8,9, Andrea Ronchi10, Camila Scharf1, Gabriella Brancaccio1, Giuseppe Argenziano1 1. Dermatology Unit, University of Campania L.Vanvitelli, Naples, Italy 2. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia 3. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia 4. Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia 5. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia 6. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia 7. Centre Hospitalier Lyon Sud, Lyons, France 8. Lyon 1 University, Lyons, France 9. Lyons cancer research center, Lyons, France 10. Pathology Unit, University of Campania L.Vanvitelli, Naples, Italy Key words: melanoma, junctional nevus, dermoscopy, partial biopsy, facial lesions Citation: Moscarella E, Guitera P, Scolyer RA, et al. Junctional Nevus and Early Melanoma on Sun-Damaged Skin of the Head/Neck: A Clinico-Pathologic Challenge. Dermatol Pract Concept. 2023;13(2):e2023122. DOI: https://doi.org/10.5826/dpc.1302a122 Accepted: November 18, 2022; Published: April 2023 Copyright: ©2023 Moscarella 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: This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1093017) (to RAS). RAS is supported by an NHMRC Practitioner Fellowship (APP1141295). Support from colleagues at the authors’ respective institutions is also gratefully acknowledged. Competing interests: RAS has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline.PG received Honoria form Metaoptima. Authorship: All authors have contributed significantly to this publication. Corresponding author: Elvira Moscarella, MD, Dermatology Unit, University of Campania L. Vanvitelli, Naples, Italy. Email: Elvira.moscarella@gmail.com Introduction: Melanoma on the head/neck area can show subtle clinical, dermoscopic and histologic features at early stages, being difficult to differentiate from junctional nevi. Objectives: This case series aims to raise awareness on the topic of misdiagnosis of early lentigo maligna as junctional nevi. Methods: From the databases of three pigmented lesion clinics in Italy, Australia, and France, we retrieved all cases of lesions of the head/neck area with an initial histopathologic diagnosis ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(2):e2023122 Introduction The clinical and histologic diagnosis of early melanoma on sun-damaged skin of the head/neck area may be challenging. Lentigo maligna (LM) is the commonest melanoma subtype occurring on the head and neck region. Clinically, LM usu- ally presents as a macule or patch of variable dimension and coloration, ill-defined borders and slowly grows over time [1-3]. Dermoscopically, atypical pseudo network with asym- metric perifollicular pigmentation, peppering and/or gray circles are found in classical cases. LM is typically characterized histologically by a lentig- inous and sometimes nested proliferation of atypical mela- nocytes arising in skin typified by sun damaged features of epidermal atrophy and solar elastosis. Cases of LM lacking the typical clinical and histologic hallmarks can be challenging to diagnose. From a clinical and dermoscopic point of view, the main differential diagnoses of LM include non-melanocytic be- nign lesions, such as solar lentigo, pigmented actinic kerato- ses and lichen planus-like keratoses (LPLK). Nevi are rarely included in the differential diagnosis of LM, since most nevi on the head/neck of adults and elderly are of the compound and dermal subtype. These nevi clinically present as dome shaped to nodular lesions, skin colored or only slightly pig- mented [4]. In recent years, it has become increasingly recognized that LM can include a prominent nested component mim- icking a junctional or dysplastic nevus. Zalaudek et al first reported one case of a lesion initially diagnosed as junctional nevus on the neck of an adult patient that recurred twice during a 4-year period, after apparent complete surgical excision with clear margins, and was ultimately diagnosed as LM [5]. Histopathologically, the diagnosis of LM can be challenging. In its early phases of development, LM may display subtle features, with only mild cellular atypia and a mixed junctional and lentiginous appearance of proliferating melanocytes with occasional nests [6,7]. In this report, we discuss the challenge of diagnosing facial atypical melano- cytic tumors with nested and lentiginous components. Objectives With the aim of raising awareness on this clinico-pathologic challenge, we present a series of 14 cases all of which were initially diagnosed as atypical/dysplastic junctional nevi but were ultimately considered to represent melanoma. These in- clude two main scenarios, namely the difficulty of diagnosing melanoma on a partial biopsy of suspicious lesions on the head/neck area, and the diagnosis of melanoma only after sev- eral recurrences of completely excised flat junctional lesions. Methods From the databases of three pigmented lesion clinics in Italy, Australia, and France, we retrieved all cases of lesions of the head/neck area with an initial histopathologic diagnosis of junctional nevus (JN) or dysplastic junctional nevus (DJN) which subsequently recurred and were ultimately diagnosed as melanoma. Moreover, we also retrieved those cases with an initial diagnosis of JN/DJN made on a partial biopsy that were diagnosed as melanoma after a complete surgical removal. Information about patient demographic, lesion location, type of biopsy, and first and subsequent histopathologic diagnoses were recorded. In most cases, the initial biopsies were taken outside, and then the patient was referred to one of our specialized centers only after the lesion recurred. Given the difficulty to retrieve the material from the initial biopsies, central histologic review was not performed. All cases had clinical and dermoscopic images taken be- fore the final excision that led to the diagnosis of melanoma. Dermoscopic evaluation was conducted by consensus by two experienced dermoscopists (GB, CS). Follow up information was recorded when available. Ethic committee approval was not required, this was analysis of datasets, where the data are properly anonymized. Results We collected 14 cases of pigmented lesions of the head and neck with an initial diagnosis of JN/DJN that were ultimately of junctional nevus (JN) or dysplastic junctional nevus (DJN) which subsequently recurred and were ultimately diagnosed as melanoma. Moreover, we also retrieved those cases with an initial diagnosis of JN/DJN made on a partial biopsy that were diagnosed as melanoma after complete surgical removal. Results: Here we report 14 cases in which the initial histologic diagnosis was junctional nevus or dysplastic junctional nevus. The lesions recurred over time with a final diagnosis of lentigo maligna. Conclusions: Clinicians should critically question a given histologic diagnosis of junctional or dys- plastic junctional nevus on the head/neck area if the clinical or dermoscopic features are discordant. Clinico-pathologic correlation is the best way to increase diagnostic accuracy and optimize manage- ment for the patient. Original Article | Dermatol Pract Concept. 2023;13(2):e2023122 3 considered melanoma. We can recognize two main scenar- ios. Eleven cases had an initial diagnosis of JN/DJN and the final diagnosis of melanoma was made only after several re- currences (cases 1 to 11 in Table 1). The majority of lesions re- curred ones after a complete surgical excision (N = 7; 63.6 %), in 3 (27.3%) cases there were 2 recurrences over time, in 1 case the lesion initially diagnosed as JN recurred 4 times after com- plete surgical excision, with a final diagnosis of LM 12 years after the first biopsy. Mean time from first biopsy to the latest recurrence for the 11 cases was 4.5 years (range 1-12 years). The second scenario comprises three other cases in which the diagnosis of DJN was made on partial biopsy; however, because of suspicious clinical and dermoscopic features the lesions were excised, and the final diagnosis on the whole specimen was LM (case 12, table 1) and early invasive mela- noma (cases 13-14, table 1). Clinical and demographic infor- mation of the cases are summarized in Table 1, as well as data on the type of biopsy and the total number of recurrences. All lesions were flat pigmented macules. Dermoscopically most lesions had ill-defined borders (84.6%). Structureless brown pigmentation was present in six lesions (42.9%), while a black pigmented blotch was seen in 2 (14.3%) le- sions. Gray globules were detected in six cases (42.9%). An atypical pseudo network was identified in five cases (35.7%), background erythema was seen in four lesions (28.6%), a regular pseudo-network was seen in three lesions (21.4%). In two lesions, moth-eaten borders were observed (14.3%). Gray circles were seen in one lesion (7.1%). None of them showed prevalent non-melanoma features [8]. Conclusions The diagnosis of early melanoma involving the head/neck can be very difficult for both clinicians and pathologists. (9) Our series highlights this challenge that encompasses two main scenarios, namely, (i) the diagnostic underestimation following a partial (incisional) biopsy, and (ii) the problem of histopathologically inconspicuous features of very early melanomas that were completely excised. Flat pigmented lesions of the head and neck are often large in diameter, or even if small in size, given their loca- tion, they are frequently biopsied with punch or partial shave biopsies to obtain a histologic diagnosis before per- forming larger excisions. In three cases in our series (cases 12-14, Table 1), the clinician decided to remove the lesion completely after an initial diagnosis of DJN was made on Table 1. Demographic information of patients and history of lesions, including number of recurrences and type of initial biopsy. Patient  Id Age at first excision Sex Lesion location Type of biopsy  (incisional=0; excisional=1) First histologic diagnosis Total number of recurrences Final histologic diagnosis Years from first biopsy 1 45 M Scalp 1 DJN 1 LM 3 2 71 M Right temple 1 DJN 1 LM 1 3 48 F Chin 1 DJN 1 LM 2 4 37  M Left cheek 1 JN 4 LM 12 5 60 F Right eyelid 1 DJN 1 LM 1 6 51 F Neck 1 JN 2 LM 3 7 53 F Right cheek 1 JN 1 LMM 0.5 mm Breslow 9 8 45 M Frontal 1 JN 1 LM 1 9 55 F Right temple 1 DJN 1 LM 3 10 62 F Right eyelid 0 DJN 2 LM 7 11 71 F Left cheek 0 DJN 2 LM 7 12 53 M Frontal 0 DJN - LM 1 13 89 F Right cheek 0 DJN - LMM 0.2 mm Breslow - 14 78 F Scalp 0 DJN - LMM 0.2 mm Breslow - DJN = dysplastic junctional nevus; JN = junctional nevus; LM = lentigo maligna; LMM = lentigo maligna melanoma. 4 Original Article | Dermatol Pract Concept. 2023;13(2):e2023122 view, junctional nevi are extremely rare in the adult/elderly population, the majority facial naevi in the adult are intra- dermal naevi of the Miescher type, clinically presenting as dome-shaped, hypopigmented or skin-colored nodules [10]. Clinicians should be aware of the possibility of diagnostic er- rors and should promote the best possible clinico-pathologic correlation for these cases. Of note, two of the partially bi- opsied lesions in our series were finally diagnosed as early invasive melanomas, which would have progressed, even if slowly, if left untreated. In the other group (case 1 to 11, Table 1), we have a series of lesions with an initial diagnosis of nevus that, de- spite displaying very subtle features histologically, behaved as melanoma, recurring and growing after apparently com- plete surgical excision (Figure 2). The time to reach a definite diagnosis ranged from 1 to 12 years after the initial biopsy, partial biopsy. The lesions displayed features of melanoma at clinical and dermoscopic examination. In these 3 cases, the final histologic evaluation revealed LM and early inva- sive melanomas of the LM subtype (LMM) (Figure 1). These cases underline the need for clinicians to always critically evaluate a histologic diagnosis performed on partial biopsies in the clinical and dermoscopic context of the lesion. The final decision on patient management is in the hands of the clinician, who should be aware of the possibility of a diag- nostic underestimation on a small biopsy sample of the given lesion either due to non-representative sampling or simply insufficient tissue to enable full evaluation of the lesion [5-9]. The histologic similarities between LM, LMM and DJN are well-known and can be difficult or impossible to distinguish on small biopsies and represent a recognized pitfall for pa- thologists [6,7]. Moreover, from an epidemiological point of Figure 1. (A) A flat pigmented macule on the frontal region of a 53-year-old man. On an initial punch biopsy, the lesion was di- agnosed as atypical junctional nevus. The lesion was left untreated for 1 year. The patient sought consultation because the lesion was enlarging in size. (B) In dermoscopy, pseudo-network and asymmetrically pigmented follicular openings are seen. Histologic diagnosis after a complete surgical removal revealed a lentigo maligna (case #12 from Table 1). Figure 2. (A) A flat pigmented lesion on the frontal area in a 45-year-old man. The pigmented lesion was recurring one year after acomplete surgical excision, a scar is visible, the initial diagnosis was JN. (B) On dermoscopy brown pseudo network and gray circles were visible at the time of the recurrence. The lesion was excised with a final diagnosis of lentigo maligna (case #8 from Table 1). Original Article | Dermatol Pract Concept. 2023;13(2):e2023122 5 2. Ferrara G, Ligrone L, Zalaudek I, Mordente I, Argenziano G. Lentigo maligna in a young adult. Dermatology. 2008; 17(1):66-68. DOI: 10.1159/000125549. PMID: 18401175. 3. Stolz W, Schiffner R, Burgdorf WH. Dermatoscopy for facial pigmented skin lesions. Clin Dermatol. 2002; 20(3):276-278. DOI: 10.1016/s0738-081x(02)00221-3. PMID: 12074867. 4. Witt C, Krengel S. Clinical and epidemiological aspects of sub- types of melanocytic nevi (Flat nevi, Miescher nevi, Unna nevi). Dermatol Online J. 2010;16(1):1. PMID: 20137743. 5. Zalaudek I, Cota C, Ferrara G, et al. Flat pigmented macules on sun-damaged skin of the head/neck: junctional nevus, atyp- ical lentiginous nevus, or melanoma in situ? Clin Dermatol. 2014;32(1):88-93. DOI: 10.1016/j.clindermatol.2013.05.029. PMID: 24314381. 6. Sina N, Saeed-Kamil Z, Ghazarian D. Pitfalls in the diagnosis of lentigo maligna and lentigo maligna melanoma, facts and an opinion. J Clin Pathol. 2021;74(1):7-9. DOI: 10.1136/ jclinpath -2020-207051. PMID: 33051287. 7. Farrahi F, Egbert BM, Swetter SM. Histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopath- ologic distinction. J Cutan Pathol. 2005;32(6):405-412. DOI: 10.1111/j.0303-6987.2005.00355.x. PMID: 15953373. 8. Lallas A, Lallas K, Tschandl P, et al. The dermoscopic in- verse approach significantly improves the accuracy of human readers for lentigo maligna diagnosis. J Am Acad Dermatol. 2021;84(2):381-389. DOI: 10.1016/j.jaad.2020.06.085. PMID: 32592885. 9. McCarthy SW,  Scolyer RA. Melanocytic lesions of the face: diagnostic pitfalls. Ann Acad Med Singap. 2004;33(4 Suppl):3-14. PMID: 15389301 10. Moscarella E, Kyrgidis A, Sperduti I, et al. Age-related prevalence and morphological appearance of facial skin tumours: a pro- spective, cross-sectional, observational, multicentre study with special emphasis on melanocytic tumours. J Eur Acad Derma- tol Venereol. 2015;29(7):1331-1338. DOI: 10.1111/jdv.12844. PMID: 25399612. 11. Kossard S. Atypical lentiginous junctional naevi of the elderly and melanoma. Australas J Dermatol. 2002;43(2):93-101. DOI: 10.1046/j.1440-0960.2002.t01-1-00568.x. PMID: 11982564. 12. Kossard S, Commens C, Symons M, Doyle J. Lentinginous dys- plastic naevi in the elderly: a potential precursor for malignant with a mean time of 4.5 years and a number of recurrences after complete excision ranging from 1 to 4. The scenario of completely excised junctional prolifera- tions recurring over time and finally diagnosed as LM can be interpreted into different ways, namely precursor lesions or early phases of a neoplastic process. Some authors elabo- rated the concept of atypical junctional nevi being possibly melanoma precursors, acquiring malignant potential over time [11,12]. However, in our estimation a lesion showing the tendency to multiple recurrences after complete excision is most probably a very early phase of a neoplastic prolifera- tion rather than a precursor lesion. From a clinical point of view, these very initial lesions will probably never affect the patients’ life expectancy. However, it is well known that melanoma prognosis depends mainly on Breslow thickness rather than the histologic subtype, and until now we do not have a reliable marker to predict which lesion will evolve to invasive melanoma [13-15]. One limitation of our study is that we did not review the histological slides from the initial biopsies. This was because they were mainly cases from other centers that were referred to us only after recurrence. However, the majority had only slight atypia also at the final histologic evaluation, as high- lighted by Figure 3. From a clinician perspective this case series aims to raise awareness on the topic of misdiagnosis of early LM. Clinicians should revise critically a given histologic diagnosis of JN, DJN on the head/neck area. The best possible clinico-pathologic correlation is the only way to increase diagnostic accuracy and assure the best possible management to the patient. References 1. Reed JA, Shea CR. 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