Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2023;13(1):e2023010 1 Melanocytic Lesions with Peripheral Globules: Proposal of an Integrated Management Algorithm Simone Cappilli1,2, Simone Ribero3, Luigi Cornacchia1,2, Silvia Catapano1,2, Laura Del Regno1, Laura Quattrini1,2, Alessandra D’Amore1,2, Francesco Federico4, Paolo Broganelli3, Ketty Peris1,2, Alessandro Di Stefani1,2 1 UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy 2 Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy 3 Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy 4 Patologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy Key words: melanoma, reflectance confocal microscopy, diagnostic imaging, dermoscopy Citation: Cappilli S, Ribero S, Cornacchia L, et al. Melanocytic Lesions With Peripheral Globules: Proposal Of An Integrated Management Algorithm. Dermatol Pract Concept. 2023;13(1):e2023010. DOI: https://doi.org/10.5826/dpc.1301a10 Accepted: May 18, 2022; Published: January 2023 Copyright: ©2023 Cappilli 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: Simone Cappilli, MD, Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy. Largo A. Gemelli 8, 00168, Rome, Italy. Tel.: +39 06-30154227 Fax: +39 06-30154919 Email: simo.cappilli@ gmail.com Introduction: A peripheral rim of globules represents a marker of the horizontal growth phase in nevi and is a common feature in children and adolescents. The observation of melanocytic lesions with peripheral globules (MLPGs) in adulthood deserves more attention, since melanoma may exhibit this feature, albeit rarely. Risk-stratified management recommendations considering a global clinical approach are still missing. Objectives: To analyze current knowledge on MLPGs and propose an integrated management algorithm stratified for age groups. Methods: We conducted a narrative review of current published data on MLPGs, analyzing clinical dermoscopic and confocal distinguishing features of melanoma from benign nevi. Results: The risk of finding a melanoma when removing an MLPG increases with age, especially in people >55 years old, and is significantly higher in the extremities, head/neck and in case of a single asymmetrical lesion, ≥6 mm in diameter. Dermoscopic features associated with melanoma diagnosis include atypical peripheral globules, asymmetrical distribution, multiple rims as well as the reap- pearance of globules after prior loss. In addition, wide blue-grey regression areas, atypical networks, ABSTRACT 2 Review | Dermatol Pract Concept. 2023;13(1):e2023010 Introduction A dermoscopic subset of melanocytic lesions is character- ized by the presence of round to oval globules regularly distributed at the edge of the lesion, representing a marker of the horizontal enlargement with a mean growth rate of 0.25mm2/month [1,2]. A decreased density or a complete disappearance of peripheral globules has been associated with a stabilization of nevi, with an estimated median time of growth cessation of 58.6 months (4-5 years) [1,3]. Enlarge- ment of nevi is commonly observed in children and adoles- cents with a linear age-related prevalence reduction [3,4]. The common approach towards melanocytic lesions with peripheral globules (MLPGs) in patients younger than 35 years is conservative, not requiring interventions, as regards their benign clinical behavior [2,3]. The occur- rence of MLPGs in adulthood and the elderly is infre- quent and requires a cautious approach, since change over time represents a suspicious feature [3]. Further- more, peripheral globules may also be detected, albeit rarely, in melanoma [3,5]. In 2007, the International Dermoscopic Society recommended that MLPGs exhib- iting asymmetry of structures within the lesion should be closely monitored or excised, regardless of age [6]. Afterwards, it has been suggested to monitor MLPGs in the absence of other dermoscopic melanoma-specific criteria beyond the age of 30, considering instead surgical excision or close follow-up for those over 50 [3]. Reflectance confocal microscopy (RCM) allowed the accurate definition of globules as junctional clusters of me- lanocytes protruding into dermal papillae, or widening the interpapillary space, at the edge of the lesions with a perfect correspondence to histology [7]. Consecutive confocal evalu- ations of MLPGs in adults supported the dynamic evolution of this process, through an eccentric elongation of junctional clusters with narrowing of their shape, associated with a cen- trifugal extension [7]. Recent studies have been focused on the clinical ap- proach to MLPGs, providing further insights into MLPGs, however heterogeneous management strategies have been proposed and common practical indications are still missing [5, 8-12]. Objectives The main aim of this manuscript is to critically review the cur- rent published data on MLPGs and to provide an integrated clinical, dermoscopic and confocal management algorithm stratified for age groups, resulting in a more appropriate and individualized management strategy. Methods Search Strategy To identify eligible studies, a comprehensive search was con- ducted using PubMed electronic database with the following terms: “dermoscopy (MeSH)”, “dermatoscopy (MeSH)”, “confocal microscopy (MeSH), “melanocytic lesions (MeSH)”, “melanoma (MeSH)” and any one of the terms “peripheral clods (MeSH)”, “peripheral globules (MeSH)” published in English. The main search and the screening of titles and abstracts were completed independently by two re- viewers (SC and LC). The manual search was concluded by the perusal of the reference sections of all relevant articles. All studies identified as relevant were analyzed and included. Case reports aiming to describe singular observations or written in non-native English language were excluded. Results Search Results We completed a literature review by searching the electronic database PubMed until 1 December 2021, for all relevant records. A total of 125 articles were retrieved in the data syn- thesis: 120 were excluded due to being duplicated (among MeSH terms), not written in English, and not relevant (not related to melanocytic lesions). Finally, a total number of 5 studies were included and analyzed, and their main features are summarized in Table 1. Age and Clinical Data The impact of patient age on clinical decision-making for MLPGs is well acknowledged but different thresholds and suggestions have been proposed [5,8-11]. Williams et al eccentric blotches, tan structureless peripheral areas and vascularization are atypical dermoscopic fea- tures. Confocal worrisome findings are represented by pagetoid cells within the epidermis, architectur- al disarrangement and atypical cells of the dermo-epidermal junction with irregular peripheral nests. Conclusion: We proposed a multi-step age-stratified management algorithm integrating clinical, dermoscopic and confocal findings that may increase the early recognition of melanoma and avoid surgical excision of benign nevi. Review | Dermatol Pract Concept. 2023;13(1):e2023010 3 observed all confirmed cases of melanoma (4/99, 4.0% of MLPGs) in adulthood, specifically in individuals aged 30, 35, 40 and 55, without difference in the proportion of ma- lignancy, when dichotomizing by age 50 (5.3% vs 3.9%, p=1.0) [11]. Conversely, Ribero et al observed 9.8% of MLPGs (45/457) being melanomas (age ranged from 35 to 85 years) with a dramatic increase of frequency in patients >55 years old (10/69, 15%) [5]. Two other studies found a positive trend between histologically proven dysplastic nevi and melanoma with patients’ ages, even though without statistical significance [9,10]. In particular, Reiter et al. re- ported a diagnosis of melanoma for 39.2% (115/293) of to- tal MLPGs with an average age of 50 years old (range 20-85 years old), and more than half of cases (68%) being younger than 60 years old [9]. A lower percentage of melanoma (1.9%, 3/154 MLPGs) was observed by Pampín- Francoin et  al with 49.5 years old estimated as the median age of malignancy in high-risk patients, defined as patients under digital dermoscopic surveillance for atypical mole syndrome and/or personal or familial history of melanoma [10]. In a similar selected population of high-risk adults, Carbone et al reported a higher rate of malignancy with 19 melanomas in 135 MLPGs (14%) with a mean age of 49.8 years old and 10% of cases occurring even in patients under 30 years old [8] (Table 1). Concerning the anatomic site of MLPGs, the most com- mon location was the torso and especially the back [5,8-10], while the risk of finding a melanoma when removing an MLPG resulted significantly higher in the extremities and head/neck [5,9]. A gender prevalence of MPLGs was largely not reported except for two studies with controversial results [5, 8-11]. In addition, Pampìn-Francoin et al. reported an av- erage size of MLPGs of 4.1 mm with a significant association with the diagnosis of melanoma in lesions ≥6mm in diameter, as well as in MLPGs showing asymmetry in two axes [10]. Moreover, the authors highlighted that multiple MLPGs in a single patient were statistically less likely to be diagnosed as melanoma [10] (Table 2). Dermoscopy The morphology and distribution of peripheral globules along with the presence of additional atypical features in MLPGs was recently investigated, with the objective to identify spe- cific structures indicating a diagnosis of melanoma [8-11]. Dermoscopic findings that support a diagnosis of mela- noma included atypical globules (irregular in shape, size or color) and/or their asymmetrical distribution. Completely circumferential atypical globules are reported to have the highest risk of being melanoma, followed by focal circum- ferential atypical globules and focal circumferential typical globules [9]. Globules distributed in more than a single rim (tiered) and departing within the edge of a lesion were found to be more frequently observed in melanoma rather than nevi, as were peripheral globules covering less than 25% of the entire circumference (especially in case of <1-history) [9,10]. In addition, the reappearance of peripheral globules after their previous disappearance has been also related to a diagnosis of melanoma, and this finding is in contrast with the expected evolution of MLPGs [2,10]. Other relevant diagnostic clues suggesting melanoma were the presence of blue-grey regression areas (especially when involving a large part of an MLPG, >50%) and atypical Table 1. Included studies on melanocytic lesions with peripheral globules. Study Study design Participant’s age No. of cases Williams et al. 2020 Retrospective study >20 yo 95 nevi 4 MM Ribero et al. 2020 Retrospective study 35-85 yo (median age 49) 412 nevi 45 MM - 19 in situ - 26 invasive Reiter et al. 2021 Cross-sectional, retrospective study 2- 85 yo (median age of MM=50 yo, median age of nevi=34 yo ) 178 nevi 115 MM Pampín-Franco et al. 2021 Prospective study, high risk patients 19-73 yo (median age 42 yo) 151 nevi 3 MM - 3 invasive Carbone et al. 2021 Prospective study, high-risk patients 16-79 yo (median age 41 yo) 116 nevi 19 MM - 5 in situ - 14 invasive MM= malignant melanoma, yo= years old 4 Review | Dermatol Pract Concept. 2023;13(1):e2023010 papillary dermis were seen either in benign nevi or in mel- anomas [10]. Proposal of an Integrated Management Algorithm Herein we propose a flowchart algorithm for individualized management of MLPGs considering clinical, dermoscopic and confocal criteria, with the aim to identify melanomas at an early stage and to reduce as much as possible the unnec- essary surgical excision of benign nevi (Figure 1). The pro- posed algorithm is outlined to provide risk stratification and includes the following steps: MLPGs in Patients <35 Years Old: regular dermoscopic monitoring is recommended for lesions showing an orga- nized rim of globules with a reticular, globular, or mixed central pattern. A decreased density of peripheral globules resulting in total disappearance, in an overall period of 4-5 years, is expected. This clinical evolution allows the inter- ruption of follow-up surveillance at the end of the process. We suggest performing RCM in MLPGs when at least two atypical dermoscopic structures are detected, as we still con- sider the very low percentage of melanoma exhibiting this pattern in patients younger than 35 years old. In the absence of cyto-architectural atypia a dermoscopic follow-up can be extended whereas in presence of confocal melanoma-specific criteria, surgical excision is recommended (Figure 2). MLPGs showing ≥2 new-onset atypical dermoscopic structures during dermoscopic surveillance should be further investigated by means of RCM and follow the same recommendations. MLPGs in Patients 35-55 Years Old: In this age group, MLPGs should be managed with more caution, with a careful assessment of dermoscopic features: if any atypical networks [10]. Eccentric blotches, tan structureless periph- eral areas and vascularization were also considered worri- some features [10,11]. In presence of a regular distribution of peripheral globules, at least two melanoma- specific crite- ria were considered indicative of malignancy by Reiter et al, while for Williams et al a single melanoma specific-structure was sufficient, although such circumstance was observed in more than half of nevi and in all melanoma cases (Table 2) [9,11]. Remarkably, the risk of an MLPG being a melanoma remains not negligible even for lesions that exhibit only peripheral regular globules without additional worrisome dermoscopic criteria [5]. Confocal Microscopy In-vivo confocal evaluation of MLPGs, with a detailed anal- ysis of global architecture and cytological aspects, was per- formed in two studies [8,10]. Classical melanoma-specific findings were detected in 100% of malignant MLPGs [8,10]. In detail, the presence of intraepidermal pagetoid cells (roundish or dendritic in shape) was strongly related to the diagnosis of melanoma [10]. Moreover, architectural disarray of the dermo-epidermal junction (DEJ), unspecific pattern or non-edged dermal papillae, and atypical junction thickening represented confocal findings more frequently observed in malignant lesions. Atypical cells at the DEJ, es- pecially when multiple, along with the presence of irregu- lar and sparse peripheral nests with an evident cleft, were also reported as being associated with histologically proven melanomas (Table 2) [8,10]. No lesions showed true cere- briform nets. Inflammatory cells and melanophages at the Table 2. Clinical, dermoscopic and confocal criteria associated with the diagnosis of melanoma showing peripheral globules. Clinical Data Dermoscopy RCM Extremities and head/neck Single lesion rather than multiple MLPG ≥6 mm diameter Asymmetry in two axes Regular PG with at least 2 melanoma-specific structures OR ≥2 of the following findings PG in less than 25% of the circumference with 1 year history Reappearance of PG PG irregular in size, shape, or color Atypical and/or asymmetric distribution of PG Blue-grey regression structures involving >50% of the lesion Vascularization Off-center blotches Peripheral tan structureless areas Epidermis Pagetoid cells (roundish or dendritic) DEJ Unspecific pattern Non-edged dermal papillae Architectural disarrangement Atypical thickenings Atypical cells Peripheral dense irregular (sparse) nests rcm= reflectance confocal microscopy, mlpg= melanocytic lesions with peripheral globules, pg= peripheral globules, dej= dermal-epidermal junction Review | Dermatol Pract Concept. 2023;13(1):e2023010 5 <35 YO DERMOSCOPY ATYPICAL STRUCTURES ≥2 EXCISION YES DERMOSCOPY ONSET OF NEW CRITERIA RCM MELANOMA SPECIFIC CRITERIA NO <2 DERMOSCOPY ONSET OF NEW CRITERIA 35–55 yo >55 yo YES YES RCM MELANOMA SPECIFIC CRITERIA DERMOSCOPY ATYPICAL STRUCTURES REQULAR FOLLOW-UP UNTIL STABILIZATION EXCISION EXCISION NO NO REQULAR FOLLOW-UP UNTIL STABILIZATION Figure 1. Our proposed algorithm for the clinical management of melanocytic lesions with peripheral globules, including dermoscopic and confocal findings in different age groups. Figure 2. Invasive melanoma (Breslow 0.9 mm) on the upper back of a 33-years old man: dermoscopy (a), RCM (b,c) and histology (d). Irregular blotches, shiny white streaks and blue-whitish veils are ob- served at dermoscopy beyond a regular distribution of peripheral globules (a). A confocal section of the dermal-epidermal junction displays dendritic cells and sparse nests (blue squares) (b, low magnification; c, high magnification) corresponding to the epidermal spreading of melanocytes and discohesive nests seen on histology (d) [Haematoxylin and eosin stain, original magnification x200]. 6 Review | Dermatol Pract Concept. 2023;13(1):e2023010 warning signal and the chance of an MLPG being a mela- noma exhibiting only organized peripheral globules without other worrisome dermoscopic features represents a concrete risk after 55 years old [5]. Limitations A limitation of this work is the inclusion of different stud- ies with heterogeneous methodological cohorts and inter- ventions, with no age-group standardisation. In addition, it should be considered that non-proven histologic MLPGs were not considered in the studies, and this may have con- tributed to a realistic underestimation of benign nevi exhib- iting peripheral globules. This scenario may be due to the most common approach of favoring a surveillance program of MLPGs over time, under 35 years old in daily practice. Lastly, data synthesising dermoscopic and confocal criteria were retrieved from a small number of studies, and larger prospective datasets are needed to validate the utility of the proposed algorithm. The suggested management indications should be interpreted with caution and individualized for ev- ery single patient. dermoscopic structure is detected, surgical excision is rec- ommended. In addition, we suggest performing RCM evalu- ation also in the absence of melanoma-specific dermoscopic criteria (Figure 3). Confocal cyto-architectural irregular fea- tures require surgical excision of the lesion, while a regular follow-up is suggested in case of reassuring findings. During the follow-up period, surgery is recommended where new atypical dermoscopic criteria are observed. The decision to perform RCM in the range of 35-55 years old, even in presence of reassuring dermoscopic crite- ria, is due to the still not negligible risk of a regular MLPG being a melanoma. Indeed, 50 years old was assessed as the median age of patients with a proven histological diagnosis of melanoma in different studies [9,10] and confocal eval- uation has been demonstrated to disclose irregular/atypi- cal findings with a 100% sensitivity for the diagnosis of MM [8,10]. MLPGs in Patients >55 Years Old: in this age group, the suggested management is surgical excision in all cases. While growth markers of melanocytic lesions are expected in young adults, the observation of MLPGs in the elderly represents a Figure 3. Nevus on the right leg of a 46-year-old woman: dermoscopy (a), RCM (b,c) and histology (d). Peripheral globules are symmetrically organized at the edge of the lesion (a), corresponding to dense melanocytic nests (blue squares) located at the dermal-epidermal junction and papillary dermis upon confocal view at low (b) and high (c) magnification. A ringed pattern composed of edged dermal papillae is observed in the central area (b). Junctional melanocytic nests are observed at histopathology (d) [Hae- matoxylin and eosin stain, original magnification x200]. Review | Dermatol Pract Concept. 2023;13(1):e2023010 7 6. Bowling J, Argenziano G, Azenha A. et al. Dermoscopy key points: recommendations from the international dermoscopy so- ciety. Dermatology. 2007;214(1):3-5. DOI: 10.1159/000096904. PMID: 17191039 7. Pellacani G, Scope A, Ferrari B. et al. New insights into nevo- genesis: in vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy. J Am Acad Dermatol. 2009 ;61(6):1001-13. DOI: 10.1016/j.jaad.2009.04.018. PMID: 19833408 8. Carbone A, Persechino F, Paolino G et al. Enlarging mela- nocytic lesions with peripheral globular pattern: a dermos- copy and confocal microscopy study. Ital J Dermatol Venerol. 2021;156(4):467-472. DOI: 10.23736/S2784-8671.19.06471-X. PMID: 31760729 9. Reiter O, Chousakos E, Kurtansky N. et al. Association be- tween the dermoscopic morphology of peripheral globules and melanocytic lesion diagnosis. J Eur Acad Dermatol Venereol. 2021;35(4):892-899. DOI: 10.1111/jdv.17035. PMID: 33205467 10. Pampín-Franco A, Gamo-Villegas R, Floristán-Muruzábal U, Pinedo-Moraleda FJ, Pérez-Fernández E, López-Estebaranz JL. Melanocytic lesions with peripheral globules: results of an ob- servational prospective study in 154 high-risk melanoma patients under digital dermoscopy follow-up evaluated with reflectance confocal microscopy. J Eur Acad Dermatol Venereol. 2021;35(5): 1133-1142. DOI: 10.1111/jdv.17105. PMID: 33428272 11. Williams NM, Navarrete-Dechent C, Marchetti MA De Bedout V, Jaimes N. Diagnostic Utility of Circumferential Peripheral Globules Under Dermoscopy in Adults. J Am Acad Dermatol. 2021;85(5):1300-1302. DOI: 10.1016/j.jaad.2020.08.107. PMID: 32891776 12. Lazaridou E, Fotiadou C, Apalla Z. Melanocytic lesions with peripheral globules: still a pitfall in the differential diagnosis of melanoma. J Eur Acad Dermatol Venereol. 2021;35(5):1040. DOI: 10.1111/jdv.17239. PMID: 33885195 Conclusions MLPGs are frequently seen in daily practice and represent a clinical challenge requiring the most appropriate manage- ment for individual patients. Herein we propose a multi-step and age-based management algorithm based on current pub- lished data integrating clinical, dermoscopic and confocal findings, in order to increase the early recognition of mela- noma and avoid surgical excision of benign lesions. References 1. Kittler H, Seltenheim M, Dawid M, Pehamberger H, Wolff K, Binder M. 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