Issuu

ISSN-e 1984-8773

Volume 18 ● Number 3 ● July - September 2026

CASE REPORT

MELANOMA PITFALLS: WHEN DANGER LIES IN FAMILIARITY - A CASE SERIES OF FIVE MELANOMAS MIMICKING COMMON DERMATOSES SCIENTIFIC SUPPORT

REVIEW ARTICLE ■ Botulinum Toxin for Submandibular Gland Treatment: A Scoping Review of Aesthetic and Functional Outcomes ■

Melasma beyond the skin: psychosocial impact on quality of life - a narrative review

CASE REPORT ■ Onychocytic matricoma of the hallux: rare nail neoplasm in an unusual location

www.surgicalcosmetic.org.br

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Surgical Treatment of Rhinophyma: A Case Series

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Intralesional cryosurgery in the treatment of refractory keloids

Online ISSN: 1984-8773

Official publication of the Brazilian Society of Dermatology

www.surgicalcosmetic.org.br

Published Quarterly CHIEF EDITOR Hamilton Ometto Stolf State University of Campinas (Unicamp), Campinas (SP), Brazil.

CO-EDITORS Bogdana Victoria Kadunc Municipal Civil Servant Hospital, São Paulo (SP), Brazil. Célia Luiza Petersen Vitello Kalil Federal University of the Southern Border, Passo Fundo (RS), Brazil. Vitor Costa Fabris Center for Studies in Aesthetic Dermatology, Criciúma (SC), Brazil.

Surg Cosmet Dermatol. | Rio de Janeiro | v. 18 | n. 3 | julho-setembro. 2026 | p. 157-241. 157-245.

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Sociedade Brasileira de Dermatologia Afiliada à Associação Médica Brasileira

www.sbd.org.br

Surgical & Cosmetic Dermatology SURGICAL & COSMETIC DERMATOLOGY Publicação Oficial da Sociedade Brasileira de Dermatologia Official Publication of Brazilian Society of Dermatology Publicação Trimestral (Quarterly Edition) ISSN-e 1984-8773 l July - September - 2026 l Volume 18 l Number 3

Executive Board | 2025-2026

Areas editors

President: Carlos Baptista Barcaui | RJ

Cosmetic Dermatology Doris Hexsel Brazilian Center for Studies in Dermatology, Porto Alegre (RS), Brazil.

Editors Editor-in-chief: Hamilton Ometto Stolf State University of Campinas (Unicamp), Campinas (SP), Brazil. São Paulo State University, São Paulo (SP), Brazil. Coeditors: Bogdana Victoria Kadunc Municipal Civil Servant Hospital, São Paulo (SP), Brazil.

Reconstructive Dermatologic Surgery Lauro Lourival Lopes Filho Federal University of Piauí,Teresina (PI), Brazil.

Carolina Malavassi Murari University of Santo Amaro, São Paulo (SP), Brazil.

Healing and wounds Gisele Viana de Oliveira Minas Gerais State Civil Servants’ Pension Institute, Belo Horizonte (MG), Brazil.

Laser and Technology Celia Kalil Santa Casa de Misericordia Hospital in Porto Alegre, Porto Alegre (RS), Brazil.

Luciana Patrícia Fernandes Abbade Botucatu Medical School of the São Paulo State University – Unesp, São Paulo (SP), Brazil.

Luciana Cirillo Maluf Azevedo ABC Medical School, Santo André (SP), Brazil. Nail surgery Nilton Di Chiacchio Municipal Civil Servant Hospital, São Paulo (SP), Brazil. Tricologia Carolina Fechine School of Medicine of the University of São Paulo, São Paulo (SP), Brazil. Luciana Pontes Ruston Clinic, São Paulo (SP), Brazil. Micrographic Surgery Felipe Cerci Mackenzie Evangelical University Hospital, Curitiba (PR), Brazil.

Célia Luiza Petersen Vitello Kalil Federal University of the Southern Border, Passo Fundo (RS), Brazil. Vitor Costa Fabris UNIARP School of Medicine, Caçador (SC), Brazil. Center for Studies in Aesthetic Dermatology, Caçador (SC), Brazil.

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Cosmetic Dermatologic Surgery Carlos Gustavo Wambier Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States of America. Diagnostic Imaging Paula Tavares Colpas Pontifical Catholic University of Campinas, Campinas (SP), Brazil.

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National editorial board Alcidarta dos Reis Gadelha School of Medicine of the Amazonas State University, Manaus (AM), Brazil. Ana Paula Gomes Meski Clinical Hospital of the School of Medicine of the University of São Paulo, São Paulo (SP), Brazil.

Surgical & Cosmetic Dermatology Luciana Cirillo Maluf Azevedo ABC Medical School, Santo André (SP), Brazil. Luciana Patrícia Fernandes Abbade Botucatu Medical School of the São Paulo State University – Unesp, São Paulo (SP), Brazil.

Ana Cláudia Cavalcante Espósito Federal University of São Paulo, Department of Dermatology and Radiotherapy, Botucatu (SP), Brazil.

Luciana Takata Pontes Ruston Clinic, São Paulo (SP), Brazil. Luis Antonio Torezan University of São Paulo – USP, São Paulo (SP), Brazil.

André Luiz Simião Pontifical Catholic University of Campinas, Campinas (SP), Brazil.

Luiz Fernando F. Kopke Federal University of Santa Catarina – UFSC, Florianópolis (SC), Brazil.

Carlos Baptista Barcaui Rio de Janeiro State University, Pedro Ernesto University Hospital, Rio de Janeiro (RJ), Brazil.

Maria Fernanda Gavazzoni Santa Casa de Misericordia Hospital in Rio de Janeiro, Rio de Janeiro (RJ), Brazil.

Carlos Gustavo Wambier Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States of America.

Monica Manela Azulay Federal University of Rio de Janeiro, Rio de Janeiro (RJ), Brazil.

Carolina Oliveira Costa Fechine School of Medicine of the University of São Paulo, São Paulo (SP), Brazil.

Nilton Di Chiacchio Municipal Civil Servant Hospital, São Paulo (SP), Brazil.

Carolina Malavassi Murari University of Santo Amaro, São Paulo (SP), Brazil.

Paula Tavares Colpas Pontifical Catholic University of Campinas, Campinas (SP), Brazil.

Emerson Vasconcelos de Andrade Lima Santa Casa de Misericordia Hospital in Recife, Recife (PE), Brazil.

Samira Yarak Federal University of São Paulo, São Paulo (SP), Brazil.

Érica de Oliveira Monteiro Federal University of São Paulo – UNIFESP, São Paulo (SP), Brazil. Érico Pampado Di Santis University of Taubaté – UNITAU,Taubaté (SP), Brazil.

International Board of Reviewers

Fabiane Mulinari Brenner Clinical Hospital, Federal University of Paraná, Department of Dermatology, Curitiba (PR), Brazil.

Jerry Brewer University of South Carolina, Colúmbia (SC), Estados Unidos da América.

Felipe Bochnia Cerci Mackenzie Evangelical University Hospital, Curitiba (PR), Brazil. Flávia Alvim Sant’anna Addor MEDCIN Group, Clinical Research, Osasco (SP), Brazil. Francisco M. Paschoal ABC Medical School, São Paulo (SP), Brazil. Gisele Viana de Oliveira Minas Gerais State Civil Servants’ Pension Institute, Belo Horizonte (MG), Brazil. Izelda Carvalho Costa University of Brasilia - UnB, Brasília (DF), Brazil. José Roberto Pereira Pegas Padre Bento Hospital Complex in Guarulhos, Guarulhos (SP), Brazil. Lauro Lourival Lopes Filho Federal University of Piauí,Teresina (PI), Brazil. Luciana Archetti Conrado Integra Dermatologia Clinic, São Paulo (SP), Brazil.

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A/C SURGICAL & COSMETIC DERMATOLOGY Av. Rio Branco, 39 18º andar Cep: 20.090-003 Rio de Janeiro-RJ, Brazil. Phone: 55 (21) 2253-6747 E-mail: surgical@sbd.org.br website: www.surgicalcosmetic.org.br Surgical & Cosmetic Dermatology is an official publication of the Brazilian Society of Dermatology (SBD) in partnership with the Brazilian Society of Dermatological Surgery. The technical and scientific content presented in this publication is co-owned by the Brazilian Society of Dermatology.

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SURGICAL & COSMETIC DERMATOLOGY / INSTRUCTIONS TO AUTHORS GUIDE FOR AUTHORS Surgical & Cosmetic Dermatology is an interdisciplinary open-access journal dedicated to publishing research on all aspects of Dermatologic Surgery. It also welcomes articles in Cutaneous Oncology, Cosmetic Surgery and Dermatology, Laser, and other Therapy Technologies. Please see Editorial Policies to: General information Language Open access Authorship Peer-review policy Copyright and licensing Ethical guidelines and research integrity PREPRINT We accept the submission of articles deposited in preprints repositories. Authors can share their preprint anywhere at any time. If a preprint is accepted for publication, we encourage authors to link it to their formal publication through their Digital Object Identifier (DOI). Authors can update their preprints on bioRxiv (https:// www.biorxiv.org/), medRxiv (https://www.medrxiv.org/) or others with their accepted manuscript. DISCLAIMER Statements and opinions expressed in the articles and communications published on Surgical & Cosmetic Dermatology are those of the author(s) and not necessarily those of the Editor(s), Publisher, or Society. SUBMISSION GUIDELINES Proper preparation of the manuscript makes the review and publication processes more efficient. Thus, we recommend some precautions that can significantly facilitate the preparation of papers. Articles must be unpublished and written in the author’s original language (Portuguese or English): the editorial team will provide the necessary versions. The font must be Times New Roman or Arial, 12 points. The study's title must be concise, informed in Portuguese and English, containing up to 150 characters without spaces, accompanied by a short title. Abstracts in Portuguese and English must follow the appropriate format for the type of article. 4. Authors must inform full name, abbreviations, and their institutional affiliations, followed by city, state, and country. Links to institutions must be listed in hierarchical order (e.g., first the

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Department, second the University). The inclusion of minicurriculums is not allowed.When an author is affiliated with more than one institution, each must be identified separately.When two or more authors are affiliated with the same institution, it should be identified only once. Authors belonging to Private Clinics must cite them as an institution. It is mandatory to mention the ORCID number used to identify researchers for the first and last authors. The author must assume at least one responsibility in the elaboration of the study and must inform the contribution of each one in the submission. One of the authors must be designated as the corresponding author, providing an email address. Authors must also mention the place where the work was conducted. Authors must clearly state any conflicts of interest and financial support. The keywords must be cited in Portuguese and English, totaling 3 to 10 per language, and they must be included in all types of articles. We recommend that the keywords are obtained from DeCS (Health Science Descriptors) or MeSH (Medical Subject Headings), which can be accessed on the internet. The limit number of words for texts must follow the type of article and calculated excluding references and abstracts in Portuguese and English. Extensive and repetitive introductory information should be avoided, giving preference to the most recent, not yet published. Avoid repeating the same information in the abstract, introduction, and discussion. Weights and measurements must be expressed in the decimal metric system and temperatures in degrees centigrade. Drugs must be mentioned by their generic names, followed by the dose and dosage used, avoiding commercial terms or brands. Descriptions of any equipment, instruments, tests, and reagents must contain the name of the manufacturer and the place of manufacture. According to the ICMJE, only those who actively participated in the study can be designated as authors, thus assuming public responsibility for its content. Authorship credits must be based solely on substantial contributions to: discussion and planning of the topic and protocol, analysis or interpretation of data; writing of the article or its review; responsibility for final approval for publication. Other minor contributions such as literature suggestions, data collection and analysis, funding obtaining, technical assistance in conducting routines, patients referral, routine test interpretation, and head of service or department that are not involved in the study do not constitute criteria for authorship. They can be recognized separately in the “Acknowledgments” session, according to the authors’ decision.

ARTICLE TYPES A Surgical & Cosmetic Dermatology publishes the following article types: REVIEW ARTICLES Review articles deepen specific themes in the areas of interest of S&CD, algorithms, compilations, statistics, consensus, and guidelines.These papers have a free format; however, they must contain an unstructured abstract of up to 100 words and conclusions or final considerations. Limit: text up to 6000 words, 10 illustrations, and 60 references. Systematic review articles or meta-analyses must follow relevant guidelines (http://cochrane.org.br). ORIGINAL ARTICLE Original articles report original investigative research in Dermatological Surgery, Cutaneous Oncology, Imaging Diagnosis, Dermatology Technology, and Cosmetic Dermatology. Examples: experimental studies, clinical studies, comparisons and descriptions of techniques, or evaluation methods.The text should contain up to 4000 words, 10 illustrations, and 35 references and follow the IMRDC format (Introduction and objective, Methods, Results, Discussion, Conclusion). Abstract: The abstract must contain up to 250 words and be structured, comprising: Introduction, Objective, Methods, Results, and Conclusions. It is not allowed to state that results or other data will be presented or discussed. Introduction: State the reasons that motivated the study, describing the current state of knowledge on the subject. Use the last paragraph to specify the central question or objective of the research and the primary hypothesis tested, if any. Methods: Explain how the study was conducted: Study type: describe its design specifying the temporal direction (retrospective or prospective), the type of randomization, if any (pairing, drawing, sequencing, etc.), if the study was blind, comparative, placebo-controlled, etc. Location: indicate where the study was conducted (private or public institution), mentioning the research’s approval by the Research Ethics Committee, the selection procedures, the inclusion and exclusion criteria, and the initial number of patients. Procedures: describe the main characteristics of the interventions performed, detailing the technique and considering that the investigation study should be reproducible. Methodology: Description of the methods used to evaluate the results. Statistical analysis: Inclusion of descriptive and/or comparative statistical analysis describing the sample planning (representative of the universe to be studied), analysis and statistical tests, and presenting the adopted significance levels.We encourage using unusual statistical analyses, but a more detailed description should be made in this case.

Results: Report the main results that point estimates and measures of dispersion should accompany (e.g., mean and standard error) or interval estimates (e.g., confidence intervals), as well as the descriptive levels of the tests statistics used (e.g., “p-value”). Findings must also be interpreted from a clinical point of view. Discussion: Emphasize the new and essential results found by the study, which will be part of the conclusion. Also, report observations from other relevant studies, mentioning the limitations of the findings and implications for future research. Conclusions: Clearly and concisely answer the proposed objectives of the study. The same emphasis must be given to studies with positive or negative results. DIAGNOSTIC IMAGING Diagnostic Imaging addresses topics or clinical cases where imaging exams (dermoscopy, confocal microscopy, ultrasound, and other methods) are essential for diagnosis or treatment. It must contain unstructured abstract of up to 100 words, text up to 1200 words, 6 illustrations, and 5 references. HOW I DO IT? How do I do it? describes new techniques or details of procedures. It must contain unstructured abstract of up to 100 words, an introduction with a literature review, methods, results, discussion, and conclusion. Limit: 1200 words, 8 illustrations, and 30 references. CASE REPORT Case report is the description of cases or series of relevant cases in the areas of interest of S&CD, depicting treatments, complications, etc. It must contain unstructured abstract of up to 100 words, an introduction with a literature review, methods, results, discussion, and conclusion, whenever pertinent. Limit: text up to 1200 words, 8 illustrations and 30 references. LETTERS TO THE EDITOR Letters to the editor are objective, brief, and constructive comments on previously published studies or research. The text should be up to 600 words, with a maximum of 5 references. ETHICS COMMITTEE The authorization certificate by an Ethics Committee is only required for the Original Articles of prospective research. REFERENCES Bibliographic references must be listed on the last pages of the article and numbered according to the citation in the text (in sequential numerical order), following the Vancouver style, as indicated by the International Committee of Medical Journal Editors (ICMJE). References cited in table and figure legends must

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Surg Cosmet Dermatol. 2026;v.18: n.3 july - september. keep the sequence with the citations in the text. If a document has six or more authors, provide the name of the first six authors followed by "et al". Below are examples of the most common types of references taken from ICMJE: Journal articles: Hallal AH, Amortegui JD, Jeroukhimov IM, Casillas J, Schulman CI, Manning RJ, et al. Magnetic resonance cholangiopancreatography accurately detects common bile duct stones in resolving gallstone pancreatitis. J Am Coll Surg. 2005;200(6):869-75. Book chapter: Reppert SM. Circadian rhythms: basic aspects and pediatric implications. In: Styne DM, Brook CGD, editors. Current concepts in pediatric endocrinology. New York: Elsevier; 1987. p .91-125. Website and online content: With author: Fugh-Berman A. Pharmed OUT [Internet]. Washington: Georgetown University, Department of Physiology and Biophysics; c2006 [cited 2007 Mar 23]. Available from: http:// www.pharmedout.org/. When the author is an organization: International Union of Biochemistry and Molecular Biology. Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology etc. [Internet]. London: University of London, Queen Mary, Department of Chemistry; [updated 2006 Jul 24; cited 2007 Feb 22]. Available from: http://www.chem.qmul.ac.uk/iubmb/. Previous presentation at events: Bruhat M, Silva Carvalho JL, Campo R, Fradique A, Dequesne J, Setubal A, editors. Proceedings of the 10th Congress of the European Society for Gynaecological Endoscopy; 2001 Nov 22-24; Lisbon, Portugal. Bologna (Italy): Monduzzi Editore, International Proceedings Division; c2001. 474 p. FIGURES Figures, charts, and tables must be cited in sequential numerical order in the text in Arabic numerals (example: Figure 3, Chart 7), and the Editor is responsible for suppressing the redundant ones. Figure and charts legends and table titles and footnotes must accurately describe their content in short sentences, but sufficient for understanding, even if the article is not fully read. They must be uploaded in the system in the step corresponding to illustrations, avoiding using the field for the text, so the words within the figures are not counted. Figures must have a minimum resolution of 300 DPI, minimum width of 1,200 pixels with proportional height, and JPG or TIF formats. The photographs must be in focus, allowing the visualization of the details. Arrows or lines can be used to highlight areas of interest.The legends of histological images must specify staining and magnification. If a figure has been previously published, its source should be cited and included in the references.

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The copyright holder's permission for its reproduction must be sent to the journal. The use of pictures that identify patients’ faces requires a written authorization (see the document Consent of Publishing Patient Photographs on the journal’s website). Regarding videos, it is necessary to insert subtitles containing information such as the title of the manuscript, authorship, institution, and other relevant comments. When using patient images, their identity must be preserved; otherwise, written permission for disclosure must be attached. Charts must be prepared in Microsoft Excel. Tables do not need to be described in the text because their objective is to supplement it and not augment it. The units used to express the results (m, g, g/100, mL, etc.) should appear at the top of each column. Patients must be identified by numbers or letters, and never by names, initials, or hospital registration numbers. COVER LETTER The cover letter must include the following information: An explanation of why your manuscript is suitable for publishing in Surgical & Cosmetic Dermatology. Confirmation that the manuscript's content is original and has not been published nor is being considered for publication elsewhere. If the manuscript is being submitted for a particular special issue, its specific name must be mentioned in the cover letter. If the article reports the results of a health intervention in human participants, Surgical & Cosmetic Dermatology strongly recommends its record in an appropriate registry. The registration number and date must be indicated in this letter. AUTHORS’ DECLARATIONS The following final statements must be included in the final version of the manuscript. These declarations are expected to be submitted along with the cover letter since Surgical & Cosmetic Dermatology adopts a double-blind peer review. ‘Acknowledgments’ – list of people who contributed to the article (and does not meet the criteria for authorship), including contributors who provided professional writing services or materials. ‘Availability of data and materials’ – availability statements contain information on where data supporting the results reported in the article can be found, such as hyperlinks to publicly archived datasets. Example sentences are: ‘All data generated or analyzed during this study are included in this article’; ‘The datasets generated and/or analyzed during the current study are available in the [NAME] repository’, ‘The datasets generated during and/ or analyzed during the current study are available from the corresponding author on reasonable request’ or ‘Not applicable’ if no new data were created or analyzed in the study. ‘Financial support’ - all sources of funding of the study

should be disclosed; it is necessary to indicate grants that authors have received in support of the research. ‘Conflict of interest’ – all financial and non-financial competing interests must be declared in this section. If the authors do not have any competing interests, it is necessary to state ‘The authors declare that they have no conflict of interest’. ‘Authors’ contributions’ – Each author is expected to have made substantial contributions to the manuscript, which should be specified in this section. Please use initials to refer to each authors’ contribution. For example: ‘AB, CD, and EF conceived this research and designed experiments. GH participated in the design and interpretation of the data. IJ performed experiments and analysis. KL and MN wrote the paper and participated in the revisions of it. All authors read and approved the final manuscript’. The maximum acceptable limit of authors is 5 (five); there will only be an exception for more complex works (ex. Original Article, Review) upon justification and approval by the editors. ‘Ethics approval/Ethics approval and consent to participate’: manuscripts reporting studies involving human participants or human data must include a statement on ethics approval and consent and include the name of the ethics committee that approved the study and the committee’s reference number. Studies involving animals must include a statement on ethics approval. If the manuscript does not report on or involve the use of any animal or human data, it is necessary to state ‘Not applicable’. ‘Consent for publication’if the manuscript contains any individual's personal data in any form, consent for publication must be obtained from that person, or in the case of children, their parent or legal guardian. All presentations of case reports must have consent for publication.

SUBMISSION Manuscripts should be submitted through our online submission system (https://www.gnpapers.com.br/scd/default. asp?lang=en). The submitting author is responsible for the manuscript during the submission and peer-review process. They must ensure that all eligible co-authors have been included in the author list and have all read and approved the submitted manuscript. The following files are required to submit a manuscript: The main manuscript file, which must not include the names of authors or co-authors (an anonymous file since the journal uses double-blind peer review). References and smaller tables should be included in this file. A title page, which must contain the names of all authors and co-authors, their affiliations, emails, and all authors’ declarations. A cover letter. Figure files. Any additional files as supplemental material to the manuscript. All documents such as Copyright, Conflict of Interest, and Consent for Publishing Photographs are available on the journal’s website and in the online submission system. These documents must be signed by all participating authors and attached to the system when submitting the manuscript. Consent for Publishing Patient Photographs is only necessary when the patient’s face is fully identified. The editors will only request the Paper Participation document if necessary.

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Table of contents Official publication of the Brazilian Society of Dermatology July - September - 2027 l Volume 18 l Number 3 Online ISSN: 1984-8773

REVIEW ARTICLE Botulinum toxin for submandibular gland treatment: A scoping review of aesthetic and functional outcomes Doris Hexsel, Clarissa Reinehr, Patricia Caspary, Gabriela Mosena,Vitor Costa Fabris

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Melasma beyond the skin: psychosocial impact on quality of life - a narrative review Samyra Fernanda Santos Silva, Bruna Vitória da Silva, Fernanda Pires Máximo, Raquel de Oliveira Brito, Victória Oliveira Viana, Gabriela Roncada Haddad

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ORIGINAL ARTICLE Efficacy of a depigmenting serum containing tranexamic acid + niacinamide + 4-butylresorcinol and hydroxy acids complex compared to hydroquinone in the treatment of melasma: a randomized, double-blind, comparative clinical trial Sergio Schalka, Denise Steiner, Marta Furmanczyk, Anthony Brown, Monica Foyaca, Jaime Piquero Casals

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Clinical aesthetic effects of oral collagen oligopeptides on wrinkle appearance in women aged 45-60 years: a randomized, double-blind, placebo-controlled trial Vivian Zague, Ana Lúcia Tabarini Alves Pinheiro, Juliana Rodrigues Pinto,Viviane Cristina Albarici, Gustavo Facchini, Samara Eberlin

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Effectiveness of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy: a 5-year experience Márcia C. N.Yoshioka (in memoriam), Samira Yarak, Adriana Maria Porro, Jane Tomimori

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The effectiveness of a whitening and anti-aging double-layer serum and cream containing gamma-aminobutyric acid (GABA) 3%, dimethylaminoethanol (DMAE) 2%, cysteamine 2.5%, and bakuchiol 1% Widya Widita, Andi Hardianty, Anis Irawan Anwar, Andi Alfian Zainuddin, Wong Lip Wih, Cynthia Sandra Kuncoro, Annisa Alviariza, Adhisti Prihastuti, Andi Dhidit Dwiputra

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Table of contents

HOW DO I DO IT? Extending the reach of the East-West flap: a modified technique for larger paramedian nasal tip defects Valery Lynn Turner, Pablo Vargas Mora, Rubén González Cuevas

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Waterdrop excision technique for repairing a split earlobe after ear stretching Giulia Zanata Rossi,Vitória Castelo Branco Rocha Ibiapina do Monte, Lorena Queiroz Furtado de Mendonça, Anna Carolina Miola

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CASE REPORT Intralesional cryosurgery in the treatment of refractory keloids Barbara Brunca, Giulia Maria dos Santos Goedert, Ana Paula Weber, Sofia Leite Mitidieri, André Luiz Simião

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Dermal nerve sheath myxoma of the toe and its management – A case report Jiten Kumar Mishra, Abhijith Valsalan, Shamendra Anand Sahu, Jalaz Joezer Rahmi

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Melanoma pitfalls: When danger lies in familiarity – a series of 5 cases of clinical mimicry of common dermatoses Márcio Fellipe Menezes Viana, Renata Ferreira Magalhães, Andréa Fernandes Eloy da Costa França, Lucas de Teive Argollo, Thais Helena Buffo, Hamilton Ometto Stolf

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Onychocytic matricoma of the hallux: a rare nail neoplasm at an unusual site Heloisa Calegari Borges, Isabelle Sousa Medeiros Torres Ferreira, Flauberto de Sousa Marinho

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Surgical treatment of rhinophyma: a case series Geovanna Mourão Ishikawa, Airton Kenji Motizuki, Natalia Megumi Morikawa, João Augusto Gomes de Souza Monteiro de Brito, Renata Mie Oyama Okajima

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Botulinum toxin for submandibular gland treatment: A scoping review of aesthetic and functional outcomes Toxina botulínica para o tratamento das glândulas submandibulares: Revisão de escopo da literatura com foco em desfechos estéticos e funcionais

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180577

ABSTRACT Enlarged or ptotic submandibular glands (SmG) can negatively impact the mandibular angle and facial contour. Although botulinum toxin type A (BoNT-A) is well established as a treatment for parotid hypertrophy, its use for the treatment of SmG enlargement remains underexplored. A literature search was conducted in the PubMed, Cochrane, and LILACS databases, covering studies from November 1977 to November 2024. Seven studies met inclusion criteria, encompassing animal models, cadaveric studies, clinical trials, and case reports. Studies reporting SmG size found volumetric reduction following BoNT-A administration. Current evidence suggests BoNT-A injections into the SmG effectively reduce gland volume and may enhance facial contour. Keywords: Submandibular Gland; Botulinum Toxins, Type A; Neck; Aging; Esthetics

RESUMO As glândulas submandibulares (GSM) aumentadas ou ptóticas podem impactar negativamente o ângulo mandibular e o contorno facial. A toxina botulínica tipo A (BoNT-A) já está bem estabelecida como tratamento para hipertrofia das glândulas parótidas, mas o seu uso para o tratamento das GSM ainda é pouco explorado. Foi realizada uma busca nos bancos de dados PubMed, Cochrane e LILACS, abrangendo o período de novembro de 1977 a novembro de 2024. Sete estudos atenderam aos critérios de inclusão, incluindo modelos animais, estudos cadavéricos, ensaios clínicos e relatos de caso. Os estudos que avaliaram o tamanho das GSM demonstraram redução volumétrica após a aplicação de BoNT-A. As evidências atuais sugerem que a aplicação de BoNT-A nas GSM é eficaz para reduzir o tamanho glandular e pode melhorar o contorno facial. Palavras-chave: Glândula Submandibular;Toxinas Botulínicas Tipo A; Pescoço; Envelhecimento; Estética

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Review Article Authors: Doris Hexsel¹,² Clarissa Reinehr¹,² Patricia Caspary¹,² Gabriela Mosena¹,² Vitor Costa Fabris¹,³ ¹ Hexsel Dermatologic Clinic, Research Department, Porto Alegre (RS), Brazil ² Hexsel Dermatologic Clinic, Private Practice, Porto Alegre (RS), Brazil ³ Aesthetic Dermatology Research Center, Research Department, Criciúma (SC), Brazil

Correspondence: Vitor Costa Fabris E-mail: vitorfabris@gmail.com

Funding: None Conflict of interest: Doris Hexsel, MD: The author has acted as a speaker and consultant for Galderma. The author is also a consultant for Allergan. The other authors have no other conflict of interest to disclose.

Submitted on: 05/06/2026 Final decision: 07/09/2026 How to cite this article: Hexsel D, Reinehr C, Caspary P, Mosena G, Fabris V. Botulinum toxin for submandibular gland treatment: A scoping review of aesthetic and functional outcomes. Surg Cosmet Dermatol. 2026;18(3):e20260577.

Hexsel D, Reinehr C, Caspary P, Mosena G, Fabris V.

INTRODUCTION The neck plays a crucial role in overall facial aesthetics, particularly among patients seeking rejuvenation procedures. Structural deformities in the cervical region can compromise the visual harmony of the neck by disrupting its natural contour. The submandibular glands (SmG), as prominent anatomical components of this area, significantly influence the cervicomental angle.When these glands are enlarged or ptotic, they may detract from cervical aesthetics by distorting this angle and contributing to a poorly defined neck contour.1,3 Since its initial aesthetic application for the treatment of facial rhytides, botulinum toxin type A (BoNT-A) has demonstrated therapeutic efficacy in a variety of conditions, including rosacea and chronic parotid sialadenitis.4,5 Given the existing evidence supporting its use in the management of parotid gland hypertrophy,1 it is reasonable to hypothesize that botulinum toxin may also be effective in addressing enlargement of other salivary glands, such as the SmG. This scoping review aims to explore the potential role of BoNT-A in the treatment of SmG hypertrophy. Outcomes of interest included gland function, gland size, improvement in cervical aesthetics, and impact on salivary production.

The treatment was generally considered to be safe, and the adverse events described in the studies were attributed to errors in the injection technique (erroneous sites of injection adjacent to the masseter muscle, mylohyoid muscles, and subcutaneous fat tissue). Submandibular Gland Evaluation In the case report by G.Y. Bae et al., the authors conducted a preliminary evaluation prior to BoNT-A injections into the SmG to exclude alternative causes of gland enlargement, such as alcohol use, eating disorders, and tumoral lesions.6 In the studies included in the review, different imaging modalities were employed to localize and measure the SmG: Bae et al. and Lee et al. used computed tomography (CT), while Jung et al. used ultrasonography (US).6,7 In the study by Jung et al., US was used not only to measure the gland but also to guide BoNT-A injection placement.7 Treatment indications In the clinical studies included in this review (n = 3), the indications for SmG treatment with BoNT-A were as follows: (1) aesthetic concerns in patients with visibly prominent SmG, and (2) evaluation of the effect of BoNT-A injections on SmG volume reduction in patients with cerebral palsy.6-8

METHODS A literature search was conducted on November 11, 2024, using the PubMed, Cochrane Library, and LILACS databases to identify studies evaluating botulinum toxin treatment for the submandibular glands. The search encompassed articles published from November 1977 to November 2024. The search strategy employed the terms:“botulinum toxin”AND “submandibular gland.” Inclusion criteria comprised original studies in English that addressed clinical, anatomical, histological, or ultrasonographic aspects of the salivary glands before and after BoNT-A injections, conducted in human or animal models and focused on the treatment of hypertrophic or ptotic salivary glands. Exclusion criteria included studies involving salivary gland tumors and those exclusively addressing sialorrhea without reference to glandular hypertrophy. Extracted variables included the study model (human or animal), study design, intervention details, treatment and control groups, study protocol, type of BoNT-A used, reported outcomes, and adverse events.

Submandibular gland assessment In the study by So J et al. (2017), the SmG were localized using anatomical landmarks without US guidance. The authors established a reference line from the mandibular angle to the gnathion and administered injections at a point located 20%– 35% along this line from the mandibular angle, 1.5 cm below the inferior mandibular border, at a depth of 2 cm.9 The clinical study by Jung et al. (2019) combined anatomical landmarks with US guidance. The investigators divided the distance from the gnathion to the mandibular angle into thirds and performed US assessment in the lateral twothirds of this line to evaluate the mediolateral diameter of the gland and guide the injections.7 Injection technique All 3 human studies included in this review used US guidance for BoNT-A injections into the SmG.6-8 Jung et al. performed US-guided injections in the SmG of 20 patients. Each gland received 20 units of onabotulinum toxin type A (Botox® - BTX), diluted in 0.2 mL of saline, distributed across 5 injection points spaced 5 mm apart, using a 30-gauge, 0.5-inch needle, resulting in a total dose of 40 units per patient.7 Lee et al. treated 8 patients with cerebral palsy, also under US guidance. BTX was injected at a dose of 1 unit/ kg per gland, with a maximum of 100 units per patient. Five patients required sedation, while the remaining 3 underwent the procedure without anesthesia. The injection technique, whether

RESULTS Figure 1 presents the search results following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. Tables 1 and 2 summarize the 7 studies included in this review, consisting of 4 preclinical studies conducted in cadavers and animal models, 1 human case report, and 2 clinical trials. The clinical studies did not include a control group. All studies that evaluated SmG size before and after the treatment, both preclinical and clinical, reported a reduction in SmG size following treatment with BoNT-A.

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Figure 1: PRISMA flow diagram

via single or multiple injection points, was not specified in the study protocol.8 In the case report by Bae et al., US-guided injections of 20 units of BoNT-A were administered into each SmG.The toxin was diluted at 4 units per 0.1 mL saline (100 units in 2.5 mL saline).The brand of BoNT-A and the injection technique (eg, number and

distribution of injection points) were not reported. Treatment was repeated at 2 and 4 months following the initial injection.6 Potential adverse effects The main potential adverse effects of BoNT-A injection into the SmG include weakness of adjacent muscles, which

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Table 1: Summary of preclinical studies Study

Ellies et al. (1999)

Ellies et al. (2005)

Coskun et al. (2007)

So et al. (2017)

Study type

Animal model

Cadaveric anatomical study

Sample size

19 rats

40 rats

15 rats

6 fresh cadavers: 2 SmG from each cadaver

Study protocol

BoNT-A was injected into the SmG, and immunohistochemical analysis was subsequently performed on the excised tissues

Immunohistochemical analysis of neuronal nitric oxide synthase was performed in the SmG both in untreated controls and following intraglandular BoNT-A injection

BoNT-A was injected into the SmG, and morphological changes were assessed using US on days 14 and 28 postinjection

Dye was injected into the SmG either with or without US guidance. Subsequently, the cadavers were dissected by 2 blinded physicians to assess the precision of the injections

Intervention group

BoNT-A injected into right SmG (2.5 U); Left gland was injected 0.1 mL saline

BoNT-A injected into right SmG (2.5 U). Right glands of 5 animals were examined using US on day 14, and 5 on day 28 of the treatment

High-resolution 45-MHz transducer US-guided dye injection in the SmG

Control group

5 untreated animals

8 untreated animals

5 untreated animals

Non US-guided dye injection in SmG

Results

Decrease in acetylcholinesterase expression was observed in the SmG treated with BoNT-A

Significant decrease in neuronal nitric oxide synthase activity in SmG treated with BoNT-A compared to controls

SmG shrinkage was observed 2 and 4 weeks post-injection (p<0.01). No significant histopathological changes were noted, except lymphocytic infiltration

Accuracy rates for blind versus US-guided injection into the SmG: 50% and 91,67% (P=0.025), respectively

Not mentioned

Erroneous sites of injection: adjacent masseter muscle, mylohyoid muscles and subcutaneous fat tissue

Adverse events

Not mentioned

BoNT-A: botulinum toxin type A; SmG: Submandibular glands; US: ultrasound

may result in dysphagia and dysarthria, as well as intravascular or neurovascular injury due to improper injection technique.7 The most commonly reported erroneous injection sites are the mylohyoid muscles and subcutaneous fat tissue. To minimize the risk of BoNT-A diffusion into surrounding structures, Jung et al. recommend using high-concentration, low-volume injections, which may reduce the likelihood of adverse events such as dysphagia and dysarthria.7

guided injections, using a high-resolution 45-MHz transducer. Accuracy improved from 50% with the landmark-based method to 91.67% with US guidance.9 The authors concluded that the use of US enhances injection precision and may also reduce the risk of adverse events, such as weakness of adjacent muscles and intravascular or neurovascular puncture during the procedure.The most common sites of erroneous injection identified were the mylohyoid muscles and subcutaneous fat tissue.9

Ultrasound-guided injections of botulinum toxin BoNT-A injections into the SmG can be performed with or without US guidance. In a cadaveric study by Song JI et al., the accuracy of US-guided injections was compared to injections based solely on anatomical landmarks. The results demonstrated that US guidance significantly improved injection accuracy (p = 0.0025).9 The study involved fresh cadavers and compared 2 techniques: non-guided injections, based on a reference line from the mandibular angle to the gnathion, with injection points placed 20%–35% along this line from the mandibular angle, 1.5 cm below the inferior mandibular border, at a depth of 2 cm; and US-

Clinical effects of botulinum toxin injections in the submandibular glands BoNT-A injection into the SmG can result in several clinical effects. From an aesthetic standpoint, the most relevant outcome is reduction in gland size, which contributes to a smoother and more defined jawline. Studies employing CT imaging before and after BoNT-A injection have demonstrated a significant decrease in SmG volume.6-8 In the study by Lee Z et al., the SmG of 8 patients with cerebral palsy were injected with BoNT-A at a dose of 1 unit/ kg per gland, followed by CT imaging to assess morphological

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Table 2: Summary of clinical studies Study

Lee et al. (2011)

Bae et al. (2013)

Jung et al. (2019)

Study type

Clinical trial

Case Report

Clinical trial

Sample size

8 participants

1 participant

20 participants

Study protocol

BoNT-A was injected into the SmG CT was used to compare the size of the BoNT-A injection in the SmG; clinical under US guidance, with follow-up salivary glands before and 3 weeks after follow up US evaluations conducted monthly for BoNT-A injection 6 months

Intervention group

US-guided BoNT-A injections were administered into the SmG at a dose of 1 unit per gland per kilogram of body weight, with a maximum total dose of 100 units

US-guided BoNT-A injections were administered into the submandibular glands at a dose of 20 units per side. A second injection was performed 2 months later, with the same dose (20 units per gland), followed by a third injection at the same interval and dosage

US-guided BoNT-A injections were administered into the SmG at a dose of 20 units per side, distributed across 5 injection points

Control group

No control group

Results

Significant reduction in salivary gland Clinical assessment revealed Volume reduction peaked at size was observed 3 weeks after BoNT-A improvement in facial contour following approximately 2 months post-injection injection (p < 0.05), accompanied by treatment and persisted for about 6 months clinical improvement in drooling

Adverse events

Not mentioned

BoNT-A: botulinum toxin type A; CT: computed tomography; SmG: Submandibular glands; US: ultrasound

changes 3 weeks post-injection.The results revealed a statistically significant reduction in SmG size (p < 0.05).8 Specifically, the mean area of the right SmG decreased from 3.19 cm² to 2.76 cm², and that of the left SmG from 2.98 cm² to 2.76 cm² after 3 weeks.8 This finding supports the authors’ clinical observation of gland size asymmetry in nearly all cases. In the study by Jung et al., 20 patients received 20 units of BoNT-A per SmG, administered at 5 injection points under ultrasound guidance. A reduction in the mediolateral diameter of the SmG was observed, with the maximum effect occurring 2 months post-injection and persisting for approximately 6 months.7 The authors hypothesized that the observed glandular shrinkage may result from functional denervation, although the precise underlying mechanism remains unclear.7

treated with BoNT-A (2.5 units of Botox® diluted in 0.1 mL saline) compared with untreated and sham-injected glands.11 This suggests that nitric oxide pathways play a critical role in the neural regulation of salivary gland function. These findings are consistent with earlier work by Ellies et al. (1999), who reported a decrease in acetylcholinesterase concentration in the SmG of BoNT-treated rats, further supporting the hypothesis of functional denervation as a mechanism for glandular atrophy.11,12 DISCUSSION Studies suggest that SmG size does not significantly increase with age; however, age-related ptosis occurs gradually, making the glands more prominent over time.13 Additional, yet unidentified, factors may contribute to SmG descent or hypertrophy with aging. Submandibular gland ptosis correlates positively with age, is common in older adults, and accurate clinical assessment requires anatomical or imaging guidance due to overlying tissue laxity.13 Diagnosing SmG ptosis can be challenging because the laxity of overlying soft tissues may obscure clinical visualization.3 Therefore, the use of anatomical landmarks or imaging modalities (eg, US or CT) is recommended to ensure accurate gland localization and safe BoNT-A injection. To aid in clinical evaluation, Lee et al. proposed a grading system for SmG ptosis based on the distance from the inferior border of the mandible to the lowest point of the gland: Grade I, < 20 mm; Grade II, 20–25 mm; Grade III, 25–30 mm; Grade IV:

Histological and Immunohistochemical Changes Following Botulinum Toxin Injection in the Submandibular Gland Most studies investigating histological changes in the SmG following BoNT injection have been conducted in rat models. Coskun et al. evaluated morphological alterations in the rat SmG at 14 and 28 days after BoNT-A injection and reported a significant reduction in anteroposterior diameter and glandular circumference at both time points (p < 0.05), with maximal shrinkage observed on day 28. The only notable histopathological finding was lymphocytic infiltration.10 In another study, Ellies et al. demonstrated a significant reduction in neuronal nitric oxide synthase levels in SmG

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> 30 mm.14 This grading system may be useful for pretreatment assessment before administering BoNT-A injections. In a cross-sectional study, Lee et al. analyzed 100 CT scans (50 men and 50 women), from patients aged 18 to 91 years, to assess SmG ptosis. A linear correlation was found between age and gland descent (p < 0.001), with an average descent rate of 0.17 mm per year. Notably, 92.6% of patients aged 65 years or older exhibited Grade III or IV ptosis, with no significant difference between men and women.14 Lee et al. also defined a "safe zone" for SmG injection (Figure 2a), recommending BoNT-A administration between 20%–35% of the distance from the mandibular angle to the gnathion, 1.5 cm below the mandibular border, using a 2 cm deep injection (2-cm needle).14 Hu et al. described a technique involving palpation of the gland followed by injection using a 0.5-inch needle (Figure 2b). The gland is targeted along a vertical line intersecting the lateral canthus, while maintaining a 2-cm distance from the mandibular border to minimize the risk of intravascular injection. BoNT-A is delivered via a single injection point.15 Hu et al. recommended a dose ranging from 15 to 30 units of BoNT-A per gland.15 Reported injection depths vary from 0.5 to 2.0 cm across different studies.14-16 The grading system proposed by Lee et al. provides a practical framework for assessing submandibular gland ptosis and may guide pretreatment planning for BoNT-A injections.14 Defined injection zones, depths, and doses for BoNT-A, as described by Lee et al. and Hu et al., allow for safe and effective treatment of the submandibular gland while minimizing the risk of complications.14,15 Glandular atrophy, particularly after repeated botulinum toxin injections, is a potential concern associated with this treatment. None of the studies included in this review evaluated the effects of repeated treatment sessions. Nevertheless, a reduction in gland size was observed after a single injection, suggesting a decrease in gland volume, but true glandular atrophy cannot be confirmed based on the available evidence.17,18 Although no cases of xerostomia were reported in the included studies,6-8 reduced salivary function remains a plausible concern, particularly with repeated treatments.17 Experimental and clinical evidence from studies involving other major salivary glands, particularly the parotid gland, suggests that botulinum toxin-induced reductions in gland volume and secretory function are generally transient and reversible after the pharmacological effect subsides.17,18 Therefore, if clinically significant glandular hypofunction or xerostomia occurs, discontinuation of treatment would likely allow recovery of gland size and salivary function over the following months.17,18 The primary limitation of this scoping review is the limited number of clinical and preclinical studies currently available on this topic. Nonetheless, this review represents an important step toward guiding the standardization of the technique and fostering greater consistency and dialogue among future studies in this field.

Figure 2: A - Injection site demarcation as proposed by Lee et al.14 The green line represents the distance from the mandibular angle to the gnathion. The white square indicates the target area, located 1.5 cm inferior to the mandibular border and positioned at 20%–35% of the distance along the green line, measured from the mandibular angle. B - Injection site demarcation as described by Hu et al.15 The target region lies along a vertical line drawn through the lateral canthus, approximately 2 cm inferior to the mandibular border. The gland is palpated prior to injection to confirm anatomical positioning

CONCLUSIONS The studies included in this scoping review suggest that BoNT-A injections can effectively reduce the size of the SmG, resulting in improved visibility of the jawline and enhanced cervicofacial contour. However, a thorough diagnostic evaluation is essential to identify the underlying cause of cervical contour irregularities. Excluding alternative etiologies of submandibular fullness, such as tumoral, infectious, or systemic conditions, is critical to ensure that BoNT-A treatment is both appropriate and safe. l

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Minelli L, Yang HM, van der Lei B, Mendelson B. The surgical anatomy of the jowl and the mandibular ligament reassessed. Aesthetic Plast Surg. 2023;47:170-80.

Auersvald A, Auersvald LA. Management of the submandibular gland in neck lifts: indications, techniques, pearls, and pitfalls. Clin Plast Surg. 2018;45:507-25.

10. Coskun BU, Savk H, Cicek ED. Histopathological and radiological investigations of the influence of botulinum toxin on the submandibular gland of the rat. Eur Arch Otorhinolaryngol 2007;264:783-7.

Ramirez OM. Multidimensional evaluation and surgical approaches to neck rejuvenation. Clin Plast Surg. 2014; 41:99-107.

Alsaati AA, Alsaadoun D, Kinkar LI. The efficacy and safety of Botulinum Toxin A for the treatment of rosacea: a systematic review. Cureus. 2023;15:e51304.

11. Ellies M, Schütz S, Quondamatteo F, Laskawi R. The effect of local injection of botulinum toxin A on the immunoreactivity of nNOS in the rat submandibular gland: an immunohistochemical study. Int J Pediatr Otorhinolaryngol 2006;70:59-63.

Strohl MP, Chang CF, Ryan WR, Chang JL. Botulinum toxin for chronic parotid sialadenitis: a case series and systematic review. Laryngoscope Investig Otolaryngol. 2021;6:404-13.

JI, Song DH, Park JH. Accuracy of ultrasound-guided and nonSo ultrasound-guided botulinum toxin injection into cadaver salivary glands. Ann Rehabil Med. 2017;41:51-7.

12. Ellies M, Laskawi R, Getz W. Immunohistochemical and morphometric investigations of the influence of botulinum toxin on the submandibular gland of the rat. Eur Arch Otorhinolaryngol. 1999; 256:148-52. 13. Rohrich RJ, Rios JL, Smith PD, Gutowski KA. Neck rejuvenation revisited. Plast Reconstr Surg. 2006;118:1251–63.

Bae GY, Yune YM, Seo K, Hwang SI. Botulinum toxin injection for salivary gland enlargement evaluated using computed tomographic volumetry [published correction appears in Dermatol Surg]. Dermatol Surg. 2013;39:1404-7.

14. Lee JH, Lee BN, Kwon SO. Anatomical localization of submandibular gland for botulinum toxin injection. Surg Radiol Anat 2010;32:945-9. 15. Hu H, Kim SB, Wan J. Anatomical guidelines and technical tips for neck aesthetics with botulinum toxin. Arch Plast Surg. 2024;51:447-58.

Jung GS, Cho IK, Sung HM. Submandibular gland reduction using Botulinum Toxin Type A for a smooth jawline. Plast Reconstr Surg Glob Open. 2019;7:e2192.

16. Lee MK, Sepahdari A, Cohen M. Radiologic measurement of submandibular gland ptosis. Facial Plast Surg 2013; 29:316-20.

L ee ZI, Cho DH, Choi WD. Effect of botulinum toxin type a on morphology of salivary glands in patients with cerebral palsy. Ann Rehabil Med 2011;35:636-40.

17. Lakraj AA, Moghimi N, Jabbari B. Sialorrhea: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins (Basel). 2013;5(5):1010-31. 18. Jost WH, Friedman A, Michel O, Oehlwein C, Slawek J, Bogucki A, et al. SIAXI: Placebo-controlled, randomized, double-blind study of incobotulinumtoxinA for sialorrhea. Neurology. 2019;92(17):e1982-91.

AUTHOR’S CONTRIBUTION: Doris Hexsel 0000-0002-0615-9026 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Effective participation in the conduct of the study, Critical revision of the manuscript Clarissa Reinehr 0000-0003-1811-4519 Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript Patricia Caspary 0009-0000-9205-3051 Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript Gabriela Mosena 0000-0002-4907-2713 Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript Vitor Costa Fabris 0000-0002-3540-2769 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Effective participation in the conduct of the study, Critical review of the literature, Critical revision of the manuscript

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Melasma beyond the skin: psychosocial impact on quality of life—a narrative review Melasma além da pele: impacto psicossocial na qualidade de vida – uma revisão narrativa

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180600 ABSTRACT Melasma is a chronic facial dermatosis that strongly aﬀects mental health and self-esteem, especially among women, causing anxiety, depression, and frustration due to its visibility and recurrence. This narrative review analyzed publications from the last five years (PubMed, SciELO, LILACS, VHL) regarding the condition’s psychosocial impact.The results indicate a prevalence of depressive symptoms of up to 43.4%. Therapeutic success is found to depend on an integrated and humanized approach, combining effective treatments (such as oral tranexamic acid and the triple topical formula) with psychological support, aiming not only for lesion clearance but also for the restoration of patients’ quality of life. Keywords: Melanosis; Mental Health; Psychosocial Impact; Dermatology

RESUMO O melasma é uma dermatose facial crônica que com forte impacto na saúde mental e a autoestima, especialmente entre as mulheres, causando ansiedade, depressão e frustração devido à sua visibilidade e recorrência. Esta revisão narrativa analisou publicações dos últimos cinco anos (PubMed, SciELO, LILACS, BVS) sobre o impacto psicossocial da condição. Os resultados apontam prevalência de até 43,4% de sintomas depressivos. Observa-se que o sucesso terapêutico depende de uma abordagem integrada e humanizada, combinando tratamentos eficazes (como ácido tranexâmico e fórmula tripla) ao suporte psicológico, visando, além do clareamento das lesões, a restauração da qualidade de vida dos pacientes. Palavras-chave: Melanose; Saúde Mental; Impacto Psicossocial; Dermatologia

Review Article Authors: Samyra Fernanda Santos Silva1 Bruna Vitória da Silva2 Fernanda Pires Máximo3 Raquel de Oliveira Brito4 Victória Oliveira Viana5 Gabriela Roncada Haddad6 ¹ Universidade Nove de Julho (UNINOVE), School of Medicine, São Paulo (SP), Brazil 2 Universidade de Mogi das Cruzes, School of Medicine, Mogi das Cruzes (SP), Brazil 3Universidade de Taubaté (UNITAU), School of Medicine, Taubaté (SP), Brazil 3 Universidade de Taubaté (UNITAU), School of Medicine, Taubaté (SP), Brazil 4 UNIATENAS, School of Medicine, Paracatu (MG), Brazil 5 Centro Universitário das Américas (FAM), School of Medicine, São Paulo (SP), Brazil 6 Universidade Estadual Paulista Julio de Mesquita Filho (UNESP), School of Medicine, Botucatu (SP), Brazil

Correspondence: Gabriela Roncada Haddad E-mail: gabriela.haddad@yahoo.com gabriela.haddad@unesp.br

Funding source: None Conflict of interest: None Clinical trial? No Submitted on: June 27, 2026 Final decision: August 17, 2026

How to cite this article: Silva SFS, Silva BV, Máximo FP, Brito RO, Viana VO, Haddad GR. Melasma beyond the skin: psychosocial impact on quality of life—a narrative review. Surg Cosmet Dermatol. 2026;18(3):e20260600.

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Silva SFS, Silva BV, Máximo FP, Brito RO, Viana VO, Haddad GR.

RESULTS The studies analyzed show that melasma predominantly affects adult women, particularly those with darker skin phototypes, a history of prolonged sun exposure, oral contraceptive use, or hormonal changes. From a psychosocial perspective, a strong negative impact on self-esteem was identified, with frequent reports of shame, insecurity, feelings of inferiority, and social withdrawal. In addition, patients reported frustration over ineffective treatments and feelings of hopelessness given the recurrent nature of the condition. Prevalence rates of depression of up to 43.4% were identified among patients with melasma, particularly in Asian and Latin American populations.3 Emotional symptoms were assessed using validated instruments such as the PHQ-9 (Patient Health Questionnaire), HADS (Hospital Anxiety and Depression Scale), and SDS (Zung Self-Rating Depression Scale), which found a significant association between melasma and symptoms of anxiety and depression. It was also observed that the psychosocial impact does not necessarily correlate with the extent of the lesions, as measured by the MASI score, but rather with the patient’s subjective perception of their appearance. Furthermore, interventions combining effective clinical treatment, such as oral tranexamic acid and the topical triple combination, with psychological support have demonstrated significant improvements in self-esteem and quality of life.1,4

INTRODUCTION Melasma is a chronic, recurrent dermatosis of multifactorial etiology, characterized by hyperpigmented, usually symmetrical patches affecting photoexposed areas, particularly the face. It is more prevalent in women of childbearing age, especially those with Fitzpatrick skin phototypes III to V.The main triggering factors include sun exposure, hormonal changes, genetic predisposition, oral contraceptive use, and certain photosensitizing medications.1 Although it is a benign dermatological condition, melasma can have important emotional, social, and psychological consequences. Studies indicate that the visibility of facial lesions can impair self-esteem, promote social isolation, and is associated with anxiety and depression symptoms.2,3 A recent meta-analysis found a prevalence of depression of up to 43.4% among patients with melasma, particularly in Asian and Latin American populations.3 The recurrent nature of the disease, combined with frustration over ineffective treatments, contributes to the emotional distress of patients.2 In this context, it is essential for health care professionals to adopt an interdisciplinary approach that takes both clinical and psychosocial aspects into consideration, promoting care that is more empathetic, integrative, and patient-centered.1,4 OBJECTIVE To analyze the psychosocial impact of melasma on patients’ lives, with an emphasis on emotional and social aspects related to self-esteem and mental health, and to identify therapeutic strategies that promote improvements in quality of life through an integrated and humanized approach.

DISCUSSION The impact of melasma extends beyond skin changes, profoundly affecting patients’ emotional and social well-being. Hyperpigmented lesions located on the face—a central aspect of identity and interpersonal communication—can become a constant source of embarrassment and perceived aesthetic judgment. This context may contribute to low self-esteem, anxiety, and depression, as evidenced by studies in which patients reported fear of social exposure, self-deprecation, and withdrawal from social interactions.2 These findings are supported by studies finding a high prevalence of depressive symptoms among patients with melasma, particularly in populations in which aesthetic standards value lighter skin.3 The association between melasma and emotional distress highlights the need for health care professionals not only to treat the skin condition but also to recognize and address the subjective suffering associated with it. In this regard, integrating dermatological therapies and psychological support represents a promising strategy. The use of oral tranexamic acid and the classical topical combination has demonstrated clinical efficacy and a positive impact on self-esteem.1 These findings stress the importance of psychodermatology in the management of melasma.

METHODS This study is a narrative review of the literature. PubMed, SciELO, LILACS, and VHL databases were searched. The search strategy used the English descriptors “melasma,” “psychosocial impact,” “quality of life,” and “mental health,” combined using the Boolean operators AND and OR, as follows: (“melasma” AND “psychosocial impact”) AND (“quality of life” OR “mental health”). The review included studies published within the past 5 years, with full text available in Portuguese, English, or Spanish, addressing the psychosocial impacts of melasma and therapeutic strategies involving integrative approaches. The eligibility criteria included systematic reviews, literature reviews, clinical trials, observational studies (cross-sectional and longitudinal), qualitative or quantitative studies, and clinical guidelines. Case reports, brief or extended abstracts, articles without access to the full text, and publications outside the established time frame were excluded.

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CONCLUSION Although melasma is a benign dermatological condition, it has a strong impact on the self-esteem, social lives, and mental health of patients, particularly among women. The literature shows that the facial manifestation of the disease can impair quality of life, promoting the development of anxiety, depression, and social isolation. Therefore, it is essential for health care professionals

to adopt an interdisciplinary approach, integrating dermatological treatment with psychological support and empathetic care. Promoting person-centered care that acknowledges the patient’s subjective suffering is essential to ensure not only clinical improvement but also emotional well-being. In conclusion, therapeutic success should not be measured solely by lesion clearance, but also by the restoration of quality of life and social functioning. l

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Jiang J, Wang Y, Huang X. The eﬀect of melasma on self-esteem: a pilot study. Int J Womens Dermatol. 2018;4(1):38-42.

Chen W. Prevalence of depression in melasma: a systematic review and meta-analysis. Front Psychiatry. 2024;14:1276906.

S harma AN. The burden of melasma: race, ethnicity, and comorbidities. J Drugs Dermatol. 2024;23(8):691-3.

AUTHOR’S CONTRIBUTION: Samyra Fernanda Santos Silva - ORCID 0009-0006-7981-5668 Author’s contribution: Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Bruna Vitória da Silva - ORCID 0000-0002-3056-8559 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical review of the literature, Critical revision of the manuscript. Fernanda Pires Máxim - ORCID 0009-0009-5697-6743 Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature. Raquel de Oliveira Brito - ORCID 0000-0002-8806-357X Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical review of the literature, Critical revision of the manuscript. Victória Oliveira Viana - ORCID 0009-0003-1583-6687 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical review of the literature, Critical revision of the manuscript. Gabriela Roncada Haddad - ORCID 0000-0002-7516-9586 Approval of the final version of the manuscript, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical revision of the manuscript.

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Eﬃcacy of a depigmenting serum containing tranexamic acid + niacinamide + 4-butylresorcinol and hydroxy acids complex compared to hydroquinone in the treatment of melasma: a randomized, double-blind, comparative clinical trial Eficácia de um sérum despigmentante contendo ácido tranexâmico + niacinamida + 4-butilresorcinol e complexo de hidroxiácidos em comparação com hidroquinona no tratamento do melasma: ensaio clínico comparativo, randomizado e duplo-cego DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180564 ABSTRACT Background: Melasma is a common hyperpigmentary disorder. Hydroquinone is widely used to treat melasma, but its use may be limited by adverse effects.Topical tranexamic acid (TXA), alone or combined with other agents, is a potential alternative. Objectives: To evaluate the noninferiority of a new quadruple combination (QC) containing 3% TXA, niacinamide, 4-butylresorcinol and a hydroxyacid complex compared with 4% hydroquinone (HQ4) in the treatment of melasma. Methods: Eighty participants with melasma were included and randomly assigned to 2 groups: QC and HQ4. The study duration was 120 days. Efficacy criteria include mMASI, colorimetry (ITA and L*) and MELASQOL. Results: There was a significant improvement in mMASI, ITA, L* and MELASQOL in both groups (p<0.05) with no statistical difference (p>0.05) between them, indicating the noninferiority of QC serum compared with HQ4. Notably, the new serum showed greater improvements in mMASI, ITA and L* at D30 compared with HQ4, suggesting a greater initial response to treatment. Conclusion: The new QC serum demonstrated non-inferiority to HQ4 after 12 weeks of treatment. In addition, its benefits were maintained for 4 weeks after treatment discontinuation. QC serum may represent a safe and effective alternative to HQ4 in the treatment of facial melasma. Keywords: Hyperpigmentation; Melanosis; Tranexamic Acid; Niacinamide

RESUMO Introdução: O melasma é uma dermatose hiperpigmentária frequente. A hidroquinona é amplamente utilizada no tratamento do melasma, mas seu uso é limitado por seus efeitos adversos. O ácido tranexâmico tópico (TXA), isolado ou em combinação com outros agentes, é uma alternativa. Objetivos: Avaliar a não inferioridade de uma nova combinação quádrupla (QC), contendo 3% de TXA, niacinamida, 4-butilresorcinol e complexo de hidroxiácidos, em comparação com 4% de hidroquinona (HQ4) no tratamento do melasma. Métodos: Foram incluídos e randomizados 80 participantes com melasma em dois grupos: QC e HQ4. O estudo teve duração de 120 dias. Os critérios de eficácia incluíram mMASI, colorimetria (ITA e L*) e MELASQOL. Resultados: Observou-se melhora significativa dos escores de mMASI, ITA, L* e MELASQOL em ambos os grupos (p<0,05), sem diferença estatística (p>0,05) entre eles, indicando a não inferioridade do sérum QC em relação ao HQ4. Notavelmente, o novo sérum apresentou resultados superiores para mMASI, ITA e L* no D30 em comparação com HQ4, sugerindo uma maior resposta inicial ao tratamento. Conclusão: O novo sérum QC demonstrou ser não inferior ao HQ4 após 12 semanas de tratamento. Além disso, seus benefícios foram mantidos 4 semanas após a interrupção do tratamento. O sérum QC representa uma alternativa segura e eficaz ao HQ4 no tratamento do melasma facial. Palavras-chave: Hiperpigmentação; Melanose; Ácido Tranexâmico; Niacinamida

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Original Article Authors: Sergio Schalka1 Denise Steiner2 Marta Furmanczyk3 Anthony Brown3 Monica Foyaca3 Jaime Piquero Casals4

1 Medcin Pesquisa Clínica, Osasco, São Paulo (SP), Brazil 2 Universidade de Mogi das Cruzes, Dermatology, Mogi das Cruzes, São Paulo (SP), Brazil 3 ISDIN, Innovation and Development, Barcelona, Catalonia, Spain 4 Dermacentric Health & Aesthetics, Barcelona, Catalonia, Spain

Correspondence: Sergio Schalka E-mail: sergio.schalka@medcin.com.br Funding: All studies and publication costs were wholly funded by ISDIN, the manufacturer of the product under study. Conflict of interest: All studies and publication costs were wholly funded by ISDIN, the manufacturer of the product under study. Clinical trial? ISRCTN16361887 Research Ethics Committee approval CAAE Number: 70186923.2.0000.5514 Submitted on: 03/16/2026 Final decision: 06/25/2026

How to cite this article: Schalka S, Steiner D, Furmanczyk M, Brown A, Foyaca M, Casals JP. Eﬃcacy of a depigmenting serum containing tranexamic acid + niacinamide + 4-butylresorcinol and hydroxy acids complex compared to hydroquinone in the treatment of melasma: a randomized, double-blind, comparative clinical trial. Surg Cosmet Dermatol. 2026;18(3):e20260564.

Schalka S, Steiner D, Furmanczyk M, Brown A, Foyaca M, Casals JP.

INTRODUCTION Melasma is a chronic acquired hyperpigmentation disorder of the skin, clinically characterized by brownish macules, particularly on the face.1 While it can affect both genders and various ethnicities, it is more prevalent in women of childbearing age, especially those with intermediate Fitzpatrick skin types (III to V).2 Although not fully understood, the etiology of melasma involves intrinsic factors such as familial predisposition and hormonal profile, as well as environmental factors, especially exposure to solar radiation (ultraviolet and visible light).2,3,4 Due to its chronicity and tendency to relapse, the treatment of melasma remains challenging for dermatologists. Topical hydroquinone (HQ) is considered the gold standard but may cause both transient (such as irritant contact dermatitis) or permanent (such as ochronosis) adverse effects.1,2 For these reasons, its use is recommended at a maximum concentration of 4% and for a limited period, usually up to 90 days.1 This discourages doctors and patients from using it and highlights the need for safer alternatives. Recently, new therapeutic options with fewer side-effects and comparable efficacy to HQ have been proposed for melasma. Tranexamic acid (TXA) is emerging as an attractive alternative. TXA has been used for many years as an antifibrinolytic agent to treat heavy menstrual bleeding.4,5 Recent studies have shown promising results with topical TXA as an alternative treatment for melasma due to its ability to inhibit plasminogen activator (PA) and interfere with the plasminogen/plasmin pathway, thereby decreasing melanogenic factors such as prostaglandins, leukotrienes, fibroblast growth factor (FGF) and alpha-melanocyte stimulating hormone (α-MSH).5,6 In addition, one study found that TXA decreases the number of CD31+ blood vessels and downregulates endothelin-1, a melanogenic factor that induces pigmentation. A study in guinea pigs also found inhibition of tyrosinase activity.7 Based on the available literature, topical TXA at concentrations ranging from 2% to 5% has demonstrated eﬃcacy similar to that of HQ-containing agents, with fewer adverse events.4,7 TXA 2% in emulsion and lotion formulations for the treatment of melasma demonstrated a statistically significant improvement in MASI score at week 4 and 8.7 A double-blind, split-face trial evaluated the efficacy of liposomal TXA 5% vs. HQ 4% cream.7 A statistically significant reduction in MASI score was observed at week 12. Although a greater reduction in MASI score was seen with liposomal TXA 5%, no statistical difference between the 2 treatments was reported.7 Other effective depigmenting agents that are widely used include niacinamide and 4-n-butylresorcinol (4nBR). Niacinamide is the active form of niacin (vitamin B3) and a precursor of coenzymes such as nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH). In vitro studies have shown that niacinamide significantly de-

creases the transfer of melanosomes to keratinocytes.8 It also has an anti-inﬂammatory effect on the skin and is considered safe for use in pregnant and breastfeeding patients.1 In melasma, treatment with 4% niacinamide for 8 weeks resulted in a 62% reduction in MASI score.9 4nBR has been shown to inhibit the activity of both tyrosinase and tyrosinase-related protein-1, which catalyzes the oxidation of the melanogenic intermediate 5,6-dihydroxyindole-2carboxylic acid. Clinical trials have shown the efficacy of 4nBR at concentrations of 0.1% and 0.3%.10,11 A double-blind, randomized, split-face comparative trial compared the efficacy of twice-daily application of 0.3% 4nBR serum with vehicle in 28 women with Fitzpatrick skin types III-IV and melasma.12 At 12 weeks, 4nBR achieved significantly lower pigmentation scores than the vehicle. Another double-blind, randomized, split-face study involving 23 Korean women with melasma found a significant decrease in the melanin index following application of liposome-encapsulated 0.1% 4nBR compared with vehicle at 8 weeks.13 Hydroxy acids are also reported to be beneficial in the treatment of pigmentary lesions. Hydroxy acids are a class of organic carboxylic acids with one or more hydroxyl groups attached to the alpha or beta position of the carboxyl group. They can be categorized into alpha-hydroxy acids (AHAs), beta-hydroxy acids (BHAs), and polyhydroxy acids (PHAs).14 The main activity of hydroxy acids lies in their keratolytic and keratoplastic properties, which reduce the thickness of the stratum corneum while promoting increased cell turnover, thereby enhancing the efficacy of depigmenting agents. Furthermore, AHAs have been shown to improve skin architecture by increasing epidermal hyaluronic acid and thickening the dermis through enhanced glycosaminoglycan and collagen synthesis. Studies have demonstrated that AHAs stimulate collagen production and epidermal renewal without inducing proinﬂammatory cytokine production, supporting their safety profile in sensitive skin conditions like melasma.14,15,16 These effects contribute to the dispersion of melanin, reversal of cell atypia, and overall improvement of hyperpigmented lesions.15 Combining ingredients that target different steps of the melanogenesis pathway is a modern and efficient approach to the treatment of melasma.17 Taking this into account, a new cosmetic gel serum (QC) containing multiple effective ingredients was developed.18 This formulation contains TXA, 4nBR, niacinamide, and a combination of hydroxy acids (gluconolactone, phytic acid, mandelic acid, and salicylic acid) with exfoliating properties that promote the removal of pigmented keratinocytes from the upper layer to lighten the skin.18 The efficacy of this formulation has been previously demonstrated.18 In vitro, it reduced melanin production by 67.0% on D21 (p < 0.001), compared with controls. Clinical efficacy and tolerability following twice-daily applications for 3 months were demonstrated in 35 subjects with slight to moderate fa-

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cial hyperpigmentation by instrumental and clinical evaluation. These results supported the efficacy and tolerability of this new formulation. The aim of this study was to assess the noninferiority of this new formulation (QC) in the treatment of melasma compared with the gold-standard treatment, hydroquinone 4% (HQ4). MATERIAL AND METHODS A single-center, randomized, double-blind clinical trial was conducted in Brazil between July and December 2023. The study was conducted in accordance with the Good Clinical Practices guidelines and received ethical approval in accordance with federal regulations issued by the Research Ethics Committee, Universidade São Francisco (USF), under CAAE number 70186923.2.0000.5514 and opinion number 6,155,206 on June 30, 2023.The volunteers signed a consent form agreeing to participate in the study and authorizing the use of the data for publication. A total of 80 participants were included in the study. Their ages ranged from 35 to 64 years, with a mean age of 50 years. Inclusion criteria comprised women aged between 35 and 65 years with moderate to severe melasma for at least 1 year, who received no treatment for at least 3 months. Pregnant and lactating women were excluded from the study. Exclusion criteria included loss to follow-up, protocol deviation, or treatment compliance below 80%. Eligible participants were randomly assigned to 2 groups: Group I – Investigational treatment - quadruple combination (QC): facial serum with TXA 3%, NIC 4.5%, 4nBR 0.3%, and a hydroxy acid complex composed of gluconolactone 5%, phytic acid 4%, and mandelic acid 1.5%, plus SPF 50+ sunscreen. Group II – Comparative treatment – Hydroquinone 4% (HQ4) plus SPF50 + sunscreen Participants were instructed to apply either the QC serum (group I) or HQ4 (group II) to the facial lesions, twice daily (morning and night) and to apply the sunscreen on the morning (immediately after the depigmenting treatment) and every 2 hours after. The products were used for 90 consecutive days. Clinical evaluations, colorimetric measurements, and participant-reported quality-of-life assessments were performed at visits D0 (initial), D30 (intermediate), D90 (final product-use visit), and D120 (1-month post-treatment). Dermatological evaluations were performed by a board-certified dermatologist and included a safety assessment and the determination of the modified Melasma Area and Severity Score (mMASI), as previously described and validated.19 Colorimetry was assessed by determining the L* parameter (luminosity) and ITA (Individual Typology Angle) in the skin affected by melasma at each visit, using the CR-400 Chroma Meter (Konica Minolta).

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Colorimetry can quantify the intensity of erythema and skin pigmentation. The colorimeter makes it possible to quickly and non-invasively measure skin color, based on the L*a*b* coordinate system, established by Commission Internationale de I’Éclairage (CIE). It is determined using a polychromatic xenon arc lamp, which provides illumination to the skin, and 6 high-sensitivity silicone photocells, 3 of which monitor the light produced by the lamp, while the others measure the light reflected by the sample. A pulse of visible light is emitted from the source onto the surface of the skin, and the reﬂected light is analyzed by a single optical system connected to a microprocessor, which calculates the result.20 The L*a*b* system is the most widely used tool to quantify the color of the skin’s surface. The L* measurement runs on a scale that ranges from black to white, with values ranging from 0 to 100, respectively. The a* coordinate represents color values ranging from green (negative values) to red (positive values), and the b* coordinate represents color values ranging from blue (negative) to yellow (positive). The L* coordinate (luminosity) correlates with the melanin index.20 ITA (Individual Typology Angle), determined by the equation (ITA° = [ Arc Tangent ((L* - 50) / b*)] 180 / 3.14159) and expressed in Radians, represents the skin tone and correlates well with skin pigmentation.20 At each visit, the participants were instructed to fill out the Melasma Quality of Life Scale (MELASQOL), a validated quality-of-life questionnaire.21 The primary outcome was to assess the noninferiority of serum QC compared to HQ4 for the treatment of facial melasma, considering the change in mMASI as the endpoint after 90 days (D90) of use and 30 days after treatment discontinuation (D120). Secondary endpoints were the change in colorimetric parameters (ITA and L*) and quality of life as measured by the MELASQOL questionnaire. The Shapiro-Wilk normality test was used to determine the normality of the data. If the hypothesis of normality was not rejected, Student’s t-test for paired data was used to compare experimental times and Student’s t-test for independent samples was used to compare treatments. When normality is rejected, the Wilcoxon test for paired data was used to compare experimental times. Results were considered statistically significant at the 5% significance level (P ≤ 0.05). RESULTS Of the 80 participants previously randomized, 58 completed the study: 30 participants in group I and 28 participants in group II. Twenty-one participants withdrew and were excluded due to loss to follow-up. One participant withdrew from the study at visit D30 for personal reasons unrelated to the study,

Schalka S, Steiner D, Furmanczyk M, Brown A, Foyaca M, Casals JP.

and one participant was excluded from the study because her treatment compliance was below 80%, which was one of the exclusion criteria. The higher-than-expected attrition rate was mainly related to the long follow-up period and strict visit schedule, which can often limit adherence in cosmetic studies, rather than to treatment-related adverse events. The study ﬂowchart, according to CONSORT 2010, is presented in Figure 1. Regarding safety, non-serious adverse events were obser-ved in volunteers treated with both serum QC and HQ4. The events were considered mild, consisting primarily of burning and stinging, compatible with irritant dermatitis, and resolved despite continued treatment. Regarding efficacy, the results of the predefined outcomes are presented below:

A – Clinical Evaluation (mMASI) The results and the change (reduction) in mMASI from D0 to D30 D90, and D120 are presented in table 2. The 2 groups showed a statistically significant reduction in mMASI at all visits compared to the initial visit. These results demonstrate the efficacy of both treatments in reducing the cli-nical signs of melasma during the 90-day treatment period and the 30-day post-treatment period. Notably, at D30, the serum QC group showed a greater relative reduction in mMASI (-10.43%) compared with HQ4 (-2.65%). Although the difference was not statistically significant, there was a trend toward a faster initial response with the serum. Further investigation is needed to confirm this potential benefit.

CONSORT 2010 Flow Diagram

Enrollment

Assessed for eligibility (n=102)

Excluded (n=22) ♦ Not meeting inclusion criteria (n=20) ♦ Declined to participate (n=2) ♦ Other reasons (n=0)

Randomized (n=80)

Allocation Group I (investigational group) Allocated to intervention (n=40) ♦ Received allocated intervention (n=40) ♦ Did not receive allocated intervention (n=0)

Group II (comparator group) Allocated to intervention (n=40) ♦ Received allocated intervention (n=40) ♦ Did not receive allocated intervention (n=0)

Follow-Up Lost to follow-up (n=10)

Lost to follow-up (n=11)

Discontinued intervention (n=0)

Discontinued intervention (low compliance) (n=1)

Analysis Analyzed Per Protocol (n=30) ♦ Excluded from analysis (n=0)

Analyzed Per Protocol (n=28) ♦ Excluded from analysis (n=0)

Figure 1: CONSORT ﬂow diagram 414 180 176

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The Mann-Whitney test was applied to compare changes over time between the 2 groups. Compared to D0, no statistically significant difference between serum QC and HQ4 was observed at any visit (p > 0.05), indicating noninferiority of serum QC compared with HQ4% for the assessment of mMASI. Although the study was not originally powered or designed to establish a formal noninferiority margin, the absence of statistically significant differences across all endpoints suggests the comparable efficacy of both treatments. B - Individual Typology Angle (ITA) The results and the change (increase) in ITA from D0 to D30, D90, and D120 are presented in table 3. The results presented in table 3 showed that both treatments were effective in increasing the ITA and thereby reducing the intensity of melasma pigmentation. Both treatments showed statistically significant changes when comparing D30, D90 and D120 with the initial visit. Notably, the effect of the serum in increasing ITA was stronger at D30 (27.36%) than that of HQ4%

(20.25%), suggesting a faster initial response in line with that observed for mMASI. Surprisingly, after treatment discontinuation, there was a continuous increase in ITA, particularly for the serum QC group (ΔITA D120 vs D90: 0.9 for serum QC vs -0.8 for HQ4%), demonstrating a residual effect even after discontinuation. Analysis of ΔITA between the lesion and perilesional healthy skin (data not shown) found progressive improvements in pigmentation uniformity for both treatments, with the serum QC group achieving a cumulative reduction of 56.25% at D120 compared to 50.00% for HQ4. Although the difference between groups was not statistically significant, the sustained reduction observed in the serum group suggests consistent and lasting efficacy in improving skin tone uniformity. There was no statistically significant difference (Mann-Whitney test; p<0.05) in the variation of ITA between both groups, suggesting equivalent efficacy of the treatments in reducing the intensity of pigmentation in melasma lesions.

Table 1: Clinical and demographic data of participants (n = 58) Group I (Serum QC) Group II (HQ4%) 35-39 1 (3.33%) 2 (7.14%) 40-49 12 (40.00%) 10 (35.71%) Age 50-59 12 (40.00%) 14 (50.00%) 60+ 5 (16.67%) 2 (7.14%) 0 (0.00%) 0 (0.00%) I 0 (0.00%) 0 (0.00%) II 12 (40.00%) 8 (26.67%) III Phototype 15 (50.00%) 18 (60.00%) IV 1 (3.33%) 4 (13.33%) V 0 (0.00%) 0 (0.00%) VI mMASI, median (quartiles) at D0 8.15 (6.4 - 10.8) 7.55 (3.95 - 11.15) L*, median (quartiles) at D0 51.8 (48.1; 54.3) 51.1 (47.7; 55.4) ITA, median (quartiles) at D0 2.96 (-3.04; 4.04) 2.37 (-3.49; 3.96) MELASQOL, median (quartiles) at D0 48.3 (13.1) 46.5 (16.6) Parameters

Table 2. Intra-group comparison of D30, D90, and D120 with D0 for groups I (Serum QC) and II (HQ4). n=58. Data presented as median and quartiles Group I (Serum QC) Group II (HQ4) mMASI % reduction compared to D0 mMASI % reduction compared to D0 D0 8.15 (6.4 - 10.8) 7.55 (3.95 - 11.15) D30 7.30 (5.2 - 10.5) -10.43%* 7.35 (3.5 - 10.2) -2.65%* D90 5.95 (4 - 9.6) -26.99%* 4.90 (2.8 - 6.85) -35.10%* D120 4.95 (3.4 - 8.3) -39.26%* 3.45 (2.2 - 5.55) -54.30%* * (p<0.05) Wilcoxon test Comparison between Dx and D0

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Schalka S, Steiner D, Furmanczyk M, Brown A, Foyaca M, Casals JP.

Table 3: Intra-group comparison of D30, D90, and D120 with D0 for groups I and II. n=58. Data presented as median and quartiles Group I (Serum QC) Group II (HQ4%) Median ITAo (radians) % increase compared with % increase compared with D0 D0 ITAo (radians) D0 2.96 (-3.04; 4.04) 2.37 (-3.49; 3.96) D30 3.77 (-2.86; 4.23) 27.36%* 2.85 (-1.63; 4.37) 20.25%* D90 3.56 (-0.24; 4.3) 20.27%* 3.92 (0.82; 4.27) 65.40%* D120 3.98 (2.15; 4.45) 34.46%* 3.85 (-0.39; 4.20) 62.45%* * (p<0.05) Wilcoxon test Comparison between Dx and D0

DISCUSSION The results show noninferiority in clinical, colorimetric and quality-of-life outcomes in volunteers treated with the new depigmenting combination (QC), containing 3% tranexamic acid, 4.5% niacinamide, 0.3% 4-butylresorcinol, and a hydroxy acid complex containing 5% gluconolactone, 4% phytic acid, and 1.5% mandelic acid, compared with the gold-standard treatment, 4% hydroquinone. First, mMASI was evaluated as the primary endpoint, showing a significant reduction (p < 0.05) of 10.43% after 30 days of treatment with the new combination, which continued to improve over 90 days (26.99%) and even after 30 days of treatment discontinuation (39.26%). Notably, the effect of serum QC was stronger than that of HQ4 at this point in time. The residual effect of serum QC after discontinuation is noteworthy, suggesting continued activity of the depigmenting agents in the epidermis. Compared with HQ4, there was no statistically significant difference in mMASI, indicating comparable efficacy between the investigational product and HQ4%. As the study was not powered for a formal noninferiority design, this statement should be interpreted as comparable efficacy rather than strict statistical noninferiority. In the colorimetric evaluations, the results followed the same trend, with a significant improvement observed after 30 days of treatment and positive evolution at subsequent visits, with residual activity after discontinuation.

C – Luminosity (L*) The results and the change (increase) in L* parameter (luminosity) from D0 to D30, D90, and D120 are presented in table 4. There was a significant increase in the luminosity of the melasma lesions during and after treatments in both groups. As observed with ITA, the increase in the L* parameter persists even after treatment discontinuation. There was no statistically significant difference (Mann-Whitney test; p<0.05) in the variation in L* between the 2 groups, highlighting the comparable efficacy of both regimens in lightning melasma lesions. D – MELASQOL The results of the questionnaires completed by the volunteers to assess quality of life of patients with melasma (MELASQOL) are shown in Table 5. The results demonstrated a statistically significant reduction in the MELASQOL scores in both groups at all visits. These results reflect participant self-perception of improvement in quality of life related to melasma. There was no statistically significant difference (Mann-Whitney test; p<0.05) in variation in MELASQOL between the 2 groups, suggesting that both treatments were well perceived by participants in terms of reducing the impact of melasma on quality of life.

Table 4: Intra-group comparison of D30, D90, and D120 with D0 for groups I and II. n=58. Data presented as median and quartiles Group I (Serum QC) Group II (HQ4) L* % increase compared with D0 L* % increase compared with D0 D0 51.8 (48.1; 54.3) 51.1 (47.7; 55.4) D30 54.0 (48.6; 55.4) 4.25%* 51.7 (49.4; 56.1) 1.17%* D90 53.0 (49.9; 56.9) 2.32%* 54.9 (50.3; 58.1) 7.44%* D120 53.9 (50.8; 59.2) 4.05%* 54.1 (49.8; 56.5) 5.87%* * (p<0.05) Wilcoxon test Comparison between Dx and D0

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Table 5: Intra-group comparison of D30, D90, and D120 with D0 for groups I and II. n=58. Data presented as median and quartiles Group I (Serum QC) Group II (HQ4) MELASQOL % reduction compared with D0 MELASQOL % reduction compared with D0 D0 48.3 (13.1) 46.5 (16.6) D30 38.7 (16.8) -19.88%* 34.9 (17.1) -24.95%* D90 32.7 (17) -32.30%* 31.5 (18)-32.26%* D120 35.1 (17.9) -27.33%* 32.8 (19.3) -29.46%* * (p<0.05) Wilcoxon test Comparison between Dx and D0

The lack of statistically significant differences between groups supports the comparable efficacy of serum QC and HQ4. In addition, serum QC demonstrated sustained improvement, with significant residual effects in mMASI, ITA, and L* after treatment discontinuation, highlighting its potential as a long-term, well-tolerated alternative. The MELASQOL assessment was consistent with the previous findings, with significant improvement from the initial visit through 90 days. The 2 groups evolved in a similar fashion, and no statistically significant difference was observed between them. Mild symptoms of burning and stinging, compatible with irritant dermatitis, were reported with both serum QC and HQ4. These clinical manifestations have been widely reported in patients treated with hydroquinone.With respect to the investigational product, the symptoms may be related to the presence of the hydroxy acid complex, whose keratolytic action may affect the integrity of the skin barrier and produce the symptoms described. Previous publications comparing products containing niacinamide and other depigmenting ingredients have found similar results, with a reduction in mMASI of around 30% at 16 weeks,1 an improvement achieved at 12 weeks of treatment in the present study. Considering these studies, the results of the present study showed a faster activity of the QC. Compared with the previous study conducted with the same product, some differences in the results were observed. mMASI showed a greater reduction in the previous study after 90 days of treatment (63%) compared with the results found in the present study (27%). This difference may be related to the differences in populations evaluated (Brazilians vs. Portuguese

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participants) and possibly to the time of year when the studies were conducted. As is well documented, melasma tends to worsen after sun exposure, even with sunscreen use. The other parameters cannot be directly compared between the studies. From a clinical point of view, the possibility of using a topical treatment with the efficacy comparable to that of 4% hydroquinone but with a faster onset of action is highly attractive for dermatologists and their patients alike. This study has some limitations. It was conducted at a single center with a relatively small sample size, which may limit the generalizability of the results. The attrition rate was higher than ideal, mainly related to the long follow-up period and visit schedule rather than treatment-related events. In addition, no prespecified noninferiority margin was defined, and the study was not statistically powered for a formal noninferiority analysis. Nevertheless, the randomized, double-blind design and the consistency of results across all endpoints support the robustness of the findings. Future multicenter studies with larger and more diverse populations are warranted to confirm and expand these results. CONCLUSION The depigmenting serum containing tranexamic acid, niacinamide, 4-butylresorcinol, and hydroxy acids was effective in reducing clinical and colorimetric parameters and improving the quality of life in patients with melasma after 12 weeks of treatment. Its efficacy was comparable to that of 4% hydroquinone while also demonstrating a faster initial depigmenting effect and a residual benefit after treatment discontinuation. These findings support serum QC as a safe and effective alternative for the management of melasma. l

Schalka S, Steiner D, Furmanczyk M, Brown A, Foyaca M, Casals JP.

REFERENCES: 1. Cassiano DP, Espósito ACC, Silva CN, Lima PB, Dias JAF, Hassun K, et al. Update on Melasma-Part II: treatment. Dermatol Ther (Heidelb). 2022;12(9):1989-2012. 2. Wang RF, Ko D, Friedman BJ, Lim HW, Mohammad TF. Disorders of hyperpigmentation. Part I. Pathogenesis and clinical features of common pigmentary disorders. J Am Acad Dermatol. 2023;88(2):271-88. 3. Chang YF, Lee TL, Oyerinde O, Desai SR, Aljabban A, Bay CP, et al. Eﬃcacy and safety of topical agents in the treatment of melasma: What's evidence? A systematic review and meta-analysis. J Cosmet Dermatol. 2023;22(4):1168-76. 4. Desai SR, Chan LC, Handog E. Optimizing melasma management with topical tranexamic acid: an expert consensus. J Drugs Dermatol. 2023;22(4):386-92. 5. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19(8):753–7. 6. Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012;14(3):150–4. 7. Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M. Comparison of therapeutic effects of liposomal Tranexamic Acid and conventional Hydroquinone on melasma. J Cosmet Dermatol. 2015;14(3):174-7 8. González-Molina V, Martí-Pineda A, González N. Topical treatments for melasma and their mechanism of action. J Clin Aesthet Dermatol. 2022;15(5):19-28. 9. Navarrete-Solis J, Castanedo-Cazares JP, Torres-Alvarez B, Oros-Ovalle C, Fuentes-Ahumada C, Gonzalez FJ, et al. A double-blind, randomized clinical trial of niacinamide 4% versus hydroquinone 4% in the treatment of melasma. Dermatol Res Pract. 2011;2011:379173. 10. Konda S, Geria AN, Halder RM. New horizons in treating disorders of hyperpigmentation in skin of color. Semin Cutan Med Surg. 2012;31(2):133-9. 11. Lee SJ, Son YH, Lee KB. 4-n-butylresorcinol enhances proteolytic degradation of tyrosinase in B16F10 melanoma cells. Int JCosmet Sci. 2017;39(3):248-55.

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Khemis A, Kaiafa A, Queille-Roussel C. Evaluation of efficacy and safety of rucinol serum in patients with Melasma: A randomized controlled trial. Br J Dermatol. 2007;156:997-1004. Huh SY, Shin JW, Na JI. Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of Melasma: a randomized controlled split-face trial. J Dermatol. 2010;37:311-5. Houshmand EB. Effect of glycolic acid, phytic acid, soothing complex containing emulsion on hyperpigmentation and skin luminosity: a clinical evaluation. J Cosmet Dermatol. 2021;20(3):776-80. Narda M, Trullas C, Brown A, Piquero-Casals J, Granger C, Fabbrocini G. Glycolic acid adjusted to pH 4 stimulates collagen production and epidermal renewal without affecting levels of proinflammatory TNF-alpha in human skin explants. J Cosmet Dermatol. 2021;20(2):513-21. Kar HK, Gupta L, Chauhan A. A comparative study on efficacy of high and low fluence Q-switched Nd:YAG laser and glycolic acid peel in melasma. Indian J Dermatol Venereol Leprol. 2012;78:165-71. Desai S, Ayres E, Bak H. Effect of a tranexamic acid, kojic acid, and niacinamide containing serum on facial dyschromia: a clinical evaluation. J Drugs Dermatol. 2019;18(5):454-9. Furmanczyk M, Brown A, Bustos J, de Henestrosa ARF, Trullas C, Granger C. Efficacy and tolerability of a depigmenting gel serum comprising tranexamic acid, niacinamide, 4-butylresorcinol, phytic acid, and a mixture of hydroxy acids that targets the biological processes regulating skin melanogenesis. J Cosmet Dermatol. 2024;23(6):2058-65. Pandya AG, Hynan LS, Bhore R. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol. 2011;64(1):78-83 Piérard GE. EEMCO guidance for the assessment of skin colour. J Eur Acad Dermatol Venereol. 1998;10(1):1-11. Zhu Y, Zeng X, Ying J, Cai Y, Qiu Y, Xiang W. Evaluating the quality of life among melasma patients using the MELASQoL scale: a systematic review and meta-analysis. PLoS One. 2022;17(1):e0262833.

AUTHOR’S CONTRIBUTION: Sergio Schalka 0000-0003-2425-7962 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript Denise Steiner 0000-0001-6450-9234 Approval of the final version of the manuscript, Critical revision of the manuscript Marta Furmanczyk 0000-0003-3524-514X Approval of the final version of the manuscript, Conception and design of the study, Effective participation in the conduct of the study, Critical revision of the manuscript Anthony Brown 0000-0002-1271-310X Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Critical review of the literature, Critical revision of the manuscript Monica Foyaca 0009-0005-3244-6626 Approval of the final version of the manuscript, Conception and design of the study, Critical review of the literature, Critical revision of the manuscript Jaime Piquero Casals 0000-0002-4481-5602 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Clinical aesthetic effects of oral collagen oligopeptides on wrinkle appearance in women aged 45-60 years: a randomized, double-blind, placebo-controlled trial

Efeitos clínicos de oligopeptídeos de colágeno oral na aparência de rugas em mulheres de 45-60 anos: ensaio clínico randomizado, duplo-cego, controlado por placebo DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180573 ABSTRACT Introduction: Oral collagen supplementation has been investigated as a strategy to support skin appearance, although clinical effects are generally modest. In aesthetic dermatology, both the magnitude and temporal pattern of changes are relevant. Objective: To assess the effects of oral supplementation with collagen oligopeptides on facial wrinkle appearance in women aged 45-60 years. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted in 102 women. Participants received collagen oligopeptides (2.5 g/day) or a placebo for 12 weeks.Wrinkle intensity was the primary endpoint, assessed using standardized digital imaging. Dermal density and collagen-related optical signals were analyzed as exploratory outcomes. Results: A significant reduction in wrinkle intensity was observed in the active group at week 8. A reduction was already apparent at week 4, although not statistically significant, and values remained numerically lower at week 12.The placebo group showed minor variations. Exploratory parameters showed numerical increases but were not statistically significant. Conclusion: Collagen oligopeptide supplementation was associated with a reduction in wrinkle intensity, with an early effect that was partially maintained over time, indicating a measurable aesthetic benefit. Keywords: Skin Aging; Collagen; Dietary Supplements; Peptides; Dermis

RESUMO Introdução: A suplementação oral de colágeno tem sido investigada como estratégia para suporte à aparência da pele, embora os efeitos clínicos sejam geralmente modestos. Em dermatologia estética, a magnitude e o padrão temporal das alterações são relevantes. Objetivo: Avaliar os efeitos da suplementação oral com oligopeptídeos de colágeno na aparência de rugas faciais em mulheres de 45-60 anos. Métodos: Ensaio clínico randomizado, duplo-cego e controlado por placebo com 102 mulheres. As participantes receberam oligopeptídeos de colágeno (2,5 g/dia) ou placebo durante 12 semanas. A intensidade das rugas foi o desfecho primário, avaliado por meio de imagens digitais padronizadas. A densidade dérmica e os sinais ópticos associados ao colágeno foram analisados como desfechos exploratórios. Resultados: Observou-se redução significativa na intensidade das rugas no grupo ativo na semana 8. A redução já era observável na semana 4, sem significância, e os valores permaneceram numericamente inferiores na semana 12. O placebo apresentou variações discretas. Os parâmetros exploratórios apresentaram aumentos numéricos, sem significância estatística. Conclusão: A suplementação com oligopeptídeos de colágeno associou-se à redução da intensidade das rugas, com efeito precoce e manutenção parcial ao longo do tempo, indicando benefício estético mensurável. Palavras-chave: Envelhecimento da Pele; Colágeno; Suplementos Nutricionais; Peptídeos; Derme

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Original Article Authors: Vivian Zague1 Ana Lúcia Tabarini Alves Pinheiro2 Juliana Rodrigues Pinto2 Viviane Cristina Albarici2 Gustavo Facchini2 Samara Eberlin2

Genu-in - JBS S/A, Research and Development, São Paulo (SP), Brazil 2 Kosmoscience Group, Research and Development, Valinhos (SP), Brazil 1

Correspondence: Vivian Zague E-mail: vivian.zague@genu-in.com / gustavo@kosmoscience.com

Funding: None Conflict of interest: None Research Ethics Committee approval CAAE Number: 70137923.4.0000.5514 Submitted on: April 29, 2026 Final decision: July 9, 2026

How to cite this article: Zague V, Pinheiro ALTA, Pinto JR, Albarici VC, Facchini G, Eberlin S. Clinical aesthetic effects of oral collagen oligopeptides on wrinkle appearance in women aged 4560 years: a randomized, double-blind, placebo-controlled trial. Surg. Cosmet Dermatol. 2026;18(3):e20260573.

Zague V, Pinheiro ALTA, Pinto JR, Albarici VC, Facchini G, Eberlin S.

INTRODUCTION Skin aging arises from a complex interplay between intrinsic biological mechanisms, such as genetic programming, hormonal fluctuations, and chronological decline, and extrinsic stressors including ultraviolet exposure, environmental pollution, and behavioral factors.Together, these factors progressively impair dermal architecture, leading to reduced elasticity, thinning of the dermis, and the formation of clinically visible wrinkles.1 Among the various manifestations of skin aging, wrinkle appearance remains one of the most relevant and perceptible endpoints in aesthetic dermatology, serving as a key parameter for assessing the efficacy of interventions. Given the multifactorial nature of skin aging, nutritional interventions and functional food ingredients capable of modulating extracellular matrix (ECM) homeostasis have gained increasing attention as complementary strategies for maintaining skin health. In this context, the ability of such interventions to produce measurable changes in skin appearance, particularly under controlled clinical conditions, represents an important translational challenge in the field.1–3 Collagen, the predominant fibrillar protein of the dermal ECM, plays a central structural role in maintaining the mechanical integrity and firmness of the skin.With advancing age, collagen synthesis decreases while enzymatic degradation accelerates, resulting in fragmentation of collagen fibers and progressive loss of tensile strength. These age-related alterations in collagen dynamics are closely associated with clinically observable deterioration in skin appearance, contributing to skin laxity, reduced tone, and deeper wrinkle formation.2 Among nutritional interventions targeting ECM integrity, hydrolyzed collagen peptides (CPs) have gained increasing attention. Derived from enzymatic cleavage of native type I collagen, these peptides possess low molecular weight and are efficiently absorbed following oral ingestion. After ingestion, specific collagen-derived peptides can be detected in plasma and have been reported to accumulate within the dermis, where they are thought to function as biochemical messengers, potentially interacting with fibroblast activity and supporting ECM-related processes, as suggested by experimental and translational studies.3–6 Experimental data provide biological plausibility for the proposed mechanisms. In vitro studies have shown that collagen peptides can enhance fibroblast activity, increasing type I procollagen synthesis while reducing the expression or activity of matrix metalloproteinases (MMP-1 and MMP-2). Zague et al.7 showed that collagen hydrolysates promoted ECM protein deposition in fibroblasts from both sun-protected and photoaged skin, with greater effects under UV-induced stress, supporting a potential modulatory role of collagen-derived peptides under conditions of dermal challenge. Low-molecular-weight peptides containing hydroxyproline are particularly relevant because they have been shown to interact with fibroblast-associated pathways and modulate ECM-associated processes, providing a structure-function rationale based primarily on experimental models, which is relevant to the interpretation of functional food applications.7,8

More recently, Zague et al.9 expanded these findings by integrating molecular and clinical evidence. In a randomized controlled trial involving 85 women, daily ingestion of collagen oligopeptides (Col-OP, 2.5 g/day) was associated with improvements in skin firmness and elasticity compared with placebo, while hydration showed a consistent, though not statistically significant, improvement. Complementary gene expression analyses indicated upregulation of extracellular matrix components (procollagen I, decorin, biglycan) and TIMP-1, alongside downregulation of MMP-1 and versican, providing molecular-level support for a coordinated modulation of dermal matrix-related pathways, which may contribute to the clinical effects observed.9 Taken together, these results strengthen the biological plausibility of collagen peptides as potential modulators of ECM homeostasis and overall skin quality. Nevertheless, inconsistencies among studies, stemming from differences in peptide profiles, dosage regimens, and methodological designs, have led to substantial variability in reported clinical outcomes. Recent meta-analyses emphasize the need for standardized formulations and rigorously controlled trials to confirm efficacy and to further characterize, rather than definitively establish, the molecular basis of observed effects.9–11 Given the need for objective imaging-based assessments and dermal biomarkers capable of sensitively capturing ECM-related changes in vivo, this study tested the hypothesis that daily oral supplementation with collagen oligopeptides (2.5 g/ day for 12 weeks) would promote a measurable reduction in facial wrinkle intensity, with particular emphasis on the temporal pattern of response, compared with placebo. Changes in dermal density and collagen-related optical markers were evaluated as complementary, exploratory endpoints, to support biological plausibility and provide an integrated assessment of structural and optical skin-related changes, rather than to establish definitive mechanistic effects. MATERIALS AND METHODS Test Substance The investigational product consisted of food-grade collagen oligopeptides (Col-OP; manufacturer details withheld for blinded review), supplied as a powder and derived from bovine type I collagen by controlled enzymatic hydrolysis. The investigational product was supplied in single-dose sachets, each containing 2.5 g of Col-OP, to be dissolved in water before oral intake. The placebo was also supplied as a powder in identical sachets and was matched in appearance, taste, and texture to maintain blinding. The resulting peptide mixture had an average molecular weight of approximately 4 kDa, with about 40% of fragments below 1 kDa. The peptide profile of Col-OP was analytically characterized, confirming a reproducible distribution of low-molecular-weight collagen-derived oligopeptides consistent with the specifications of a standardized bovine type I collagen hydrolysate. This level of physicochemical characterization was considered sufficient for the purposes of the present

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clinical investigation. Although individual peptide sequences are proprietary, previous studies have shown that low-molecular-weight collagen-derived peptides can reach the bloodstream after oral ingestion12 and have been associated with modulation of ECM-related pathways, including fibroblast activity and MMP/ TIMP balance.7,9 These prior observations provide biological plausibility but should not be interpreted as direct mechanistic evidence within the present clinical trial. The placebo was an isocaloric, organoleptically identical powder composed of maltodextrin and containing no collagen peptides.The placebo was matched in appearance, taste, and texture to ensure adequate blinding of participants and investigators. No bioactive compounds, flavors, or other functional excipients with potential biological activity were included.

weeks using a computer-generated randomization sequence. The unequal 49:53 distribution reflected the use of simple randomization and did not result from exclusions according to predefined eligibility criteria. Both test materials were provided in identical sachets, each containing a single daily dose (2.5 g) to be dissolved in water and consumed in the morning. Randomization was computer-generated using a predefined random sequence, and both participants and investigators remained blinded to group allocation throughout the study. Allocation concealment was ensured using sequentially numbered, identical sachets prepared by an independent pharmacist, and compliance was monitored at each visit through systematic sachet counts and standardized adherence questionnaires. Study visits were conducted at baseline, week 4, week 8, and week 12 under controlled environmental conditions.

Study Design and Participants The protocol was reviewed and approved by the Research Ethics Committee of Universidade São Francisco, located in Bragança Paulista, São Paulo, Brazil (CAAE number 70137923.4.0000.5514; approval no. 6.123.303, issued on June 16). All volunteers provided written informed consent prior to enrollment. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines, and in compliance with all applicable national regulatory requirements. This study was a single-center, randomized, double-blind, placebo-controlled clinical trial. One hundred and two women aged 45–60 years, representing Fitzpatrick skin phototypes II–V, were screened and randomized (49 to the Col-OP group and 53 to the placebo group). The computer-generated sequence used an equal allocation probability (1:1), without blocking or forced balancing of final group sizes; therefore, a small numerical imbalance resulted by chance, with 49 participants allocated to the Col-OP group and 53 to the placebo group. Baseline clinical assessments were performed prior to randomization to confirm comparability between treatment arms. Exclusion criteria included pregnancy or lactation, any active dermatological condition, or ongoing medical or cosmetic procedures that could affect the outcomes. The use of topical retinoids, chemical peels, or similar interventions within 4 weeks prior to baseline was prohibited.Throughout the trial, participants were instructed to avoid excessive UV exposure, artificial tanning, and dietary or topical products aimed at anti-aging effects. The use of basic skincare products habitually used by the participants, limited to cleansers, moisturizers, and sunscreens, was permitted, provided that these products had been part of their routine before enrollment and remained unchanged throughout the study. Participants were further instructed to maintain consistent dietary habits, contraceptive methods, and skincare routines throughout the study period. Adherence to these restrictions was monitored at each study visit, and noncompliance was prospectively defined as a criterion for exclusion from the study. Participants were randomly assigned with an intended 1:1 allocation probability to receive either Col-OP or placebo for 12

Assessments Study visits were conducted at baseline and at weeks 4, 8, and 12. All instrumental assessments were performed under standardized environmental conditions following predefined operating procedures. Wrinkle intensity was quantified using standardized high-resolution digital imaging coupled with dedicated analytical software (ImageJ 1.47v, National Institutes of Health, Bethesda, MD, USA). All photographs were acquired under controlled illumination, at a fixed camera distance, and with standardized facial positioning using a mechanical head stabilizer. Image processing was performed using a pre-specified macro that quantified the Rq parameter (root-mean-square roughness). Rq corresponds to the root-mean-square of the profile-height deviations within the analysis area and was used as the primary quantitative descriptor of wrinkle intensity and the primary clinical endpoint of the study. Dermal density was assessed using a 22-MHz high-frequency ultrasound device, the Ultrascan UC22 (Courage + Khazaka Electronic GmbH, Köln, Germany). Three consecutive measurements were obtained at each anatomical site and averaged to minimize technical and operator-dependent variability. In parallel, collagen-related optical signals were indirectly estimated by diffuse reflectance spectroscopy (DRS) using the FluoroMax-4 spectrofluorometer (HORIBA Scientific, Edison, NJ, USA). The excitation wavelength was set to 290 nm, emission spectra were recorded from 300–500 nm, and all spectra were normalized to the maximal tryptophan fluorescence peak prior to ratio calculation. Spectra were collected in triplicate at each anatomical site and averaged to minimize instrument-related variability. The collagen-to-tryptophan ratio was calculated as a noninvasive, exploratory optical marker associated with dermal collagen-related signals and should not be interpreted as a direct measure of collagen biosynthesis or structural remodeling. Based on collagen-to-tryptophan ratio values obtained from 10 anatomically defined facial regions (Figure 1), an exploratory aging map was generated. The resulting map (Figure 4) was rendered as a color-coded image, with a scale ranging from 0.0 (indicating very low collagen-related signal, represented in white)

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to 3.0 (indicating very high collagen-related signal, represented in dark blue). Wrinkle intensity was designated as the primary clinical endpoint of the study, with particular emphasis on its temporal evolution throughout the intervention period. Dermal density and the DRS collagen-to-tryptophan ratio were defined as secondary, exploratory endpoints intended to provide supportive biological context and an integrated interpretation of instrumental findings, rather than definitive mechanistic evidence. All evaluators were trained before study initiation and followed standardized operating procedures throughout the study. Instrument calibration and quality control procedures were performed according to the manufacturers’ recommendations. Statistical Analysis Data were analyzed using analysis of covariance (ANCOVA) and linear mixed-effects models, incorporating group, time, and their interaction (group × time) as fixed factors and participant as a random effect. The mixed-effects framework was used to evaluate the overall temporal trajectory of responses across study visits, allowing for the assessment of time effects and potential group × time interactions, in addition to between-group comparisons at individual time points. Between-group contrasts were expressed as adjusted means and change-from-ba-

Figure 1: Anatomically defined facial regions for diffuse reflectance spectroscopy (DRS). Ten standardized facial regions were selected to capture variability in wrinkle formation and dermal remodeling across anatomically distinct zones. Normalized fluorescence spectra for collagen and tryptophan were acquired at each site under standardized conditions. Triplicate spectra were collected and averaged to reduce local variability and improve measurement consistency. The resulting collagen-to-tryptophan ratio was used as an exploratory optical marker and served as the basis for generating the facial aging map presented in Figure 4

seline estimates, accompanied by 95% confidence intervals and standardized effect sizes (Hedges’ g), to facilitate interpretation of effect magnitude alongside statistical significance, with particular emphasis on the primary endpoint. P-values were corrected for multiple comparisons within each endpoint across time points using the Holm-Bonferroni method. All models included baseline values as covariates where appropriate. Model assumptions, including normality, homoscedasticity, and independence of residuals, were evaluated using standard diagnostic procedures, such as inspection of residual distributions, assessment of variance homogeneity, and screening for influential observations. For percentage-based outcomes (collagen-to-tryptophan ratio), residual distributions were additionally inspected for skewness; no substantial deviations from model assumptions were identified. Missing data were handled under the assumption of missing at random (MAR). The linear mixed-effects models were estimated using restricted maximum likelihood, allowing the inclusion of all available observations without the need for data imputation. All statistical tests were two-sided, with a predefined significance level of α = 0.05. Primary analyses followed the intention-to-treat principle using available-case analysis under the mixed-effects framework. Sensitivity analyses using mixed-effects models were performed to confirm the robustness of the primary ANCOVA findings. All statistical procedures were defined a priori before data unblinding and applied consistently across endpoints. All analyses were performed using R software version 4.3.1 (R Foundation for Statistical Computing,Vienna, Austria). A post-hoc power analysis was conducted using the observed effect size for wrinkle intensity at week 8 (Hedges’ g ≈ 0.28). Based on the final sample size (n = 49 in the active group and n = 53 in the placebo group), α = 0.05, and a two-tailed ANCOVA design, the statistical power achieved was estimated at approximately 65% for the observed effect size. This level of statistical power reflects the ability to detect of modest treatment effects as limited by the sample size and is consistent with effect magnitudes typically reported in nutritional and aesthetic intervention trials. However, it remains below the conventional 80% threshold, indicating limited sensitivity for detecting small between-group differences, particularly for secondary exploratory endpoints and later time-point comparisons, and should be interpreted accordingly.12 Expected effect sizes for planning were derived from previous randomized controlled trials evaluating collagen peptides, including Proksch et al.,13 Asserin et al.,14 and Zague et al.,9 which reported effect sizes between 0.25 and 0.45 for wrinkle- and elasticity-related endpoints using daily doses of 2.5–5 g. Assuming a conservative anticipated effect size of 0.30, α = 0.05, and 80% statistical power, a minimum of 45–50 participants per group was estimated to be required. The final sample size of the present study fell within this recommended range for detecting modest primary endpoint effects, while acknowledging reduced sensitivity for secondary exploratory outcomes and small between-group differences at later time points.

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RESULTS Study Population Out of 102 randomly assigned women, 49 were allocated to Col-OP and 53 to placebo. This 49:53 distribution reflected the use of simple computer-generated randomization with equal allocation probability and no forced block balancing, rather than post-randomization exclusion according to eligibility criteria. Four participants (2 from each group) discontinued before the 12-week visit, all for personal reasons unrelated to treatment or adverse events. No treatment-related adverse events leading to discontinuation were reported, and no serious adverse events were observed during the study period. No protocol deviations related to product intake or prohibited concomitant treatments were reported. Baseline demographic and clinical parameters, including age, Fitzpatrick phototype, and wrinkle severity, were generally comparable across groups, indicating adequate balance between groups (Table 1). No statistically significant baseline differences were observed between groups for key demographic or clinical variables. The per-protocol sample included 98 women, and all analyses followed the intention-to-treat principle with available-case analysis under the mixed-effects framework for repeated measures. Overall study retention was high, with balanced discontinuation across treatment arms, supporting the internal validity of the trial. Wrinkle Intensity A statistically significant between-group difference in change-from-baseline wrinkle intensity was observed at week 8, when Col-OP supplementation was associated with a reduction in wrinkle intensity compared with placebo. This time point represented the greatest separation between groups during the intervention period. Detailed adjusted mean changes and

Characteristic Age, years Wrinkle intensity baseline Dermal density baseline

effect size estimates are presented in Table 2. Within the active group, a directional reduction was apparent by week 4 and values remained numerically lower at week 12, whereas participants receiving placebo showed a reduction primarily at the final assessment. This temporal pattern is consistent with an early onset of response followed by a peak separation at the intermediate time point and partial maintenance over time. Figure 2A depicts the mean temporal trend, and Figure 3 presents representative images from one participant, illustrating the qualitative pattern of reduction in wrinkle depth and surface roughness, consistent with the group-level findings. Although the standardized effect size was small (Hedges’ g), negative between-group Δ values indicate a greater reduction in wrinkle intensity in the active group compared with placebo. The consistency of directional effects across multiple analytical approaches supports the robustness of the observed temporal pattern, despite the modest magnitude of change.These findings were consistent in direction across sensitivity analyses using linear mixed-effects models, which reproduced the overall temporal pattern observed in the ANCOVA results. The modest effect magnitude likely reflects inter-individual variability in baseline wrinkle characteristics and response kinetics. Such variability is commonly observed in aesthetic clinical trials involving heterogeneous skin-aging profiles. No adverse events related to imaging procedures or participant discomfort were reported. Dermal Density Ultrasound assessments revealed small increases in dermal density following Col-OP intake (Figure 2B). Although the active group exhibited numerically higher values across all post-

Table 1: Baseline characteristics of participants Active (n = 49) Placebo (n = 53) 53 (4) 53 (4) 8.78 (2.09) 8.41 (2.40) 9.63 (3.38) 10.04 (2.48)

p-value NS NS NS

All values are mean (standard deviation). NS = not significant.

Time point Week 4 Week 8 Week 12

Table 2: Changes in wrinkle intensity (ANCOVA, LS-means ± 95% CI) Active (LS-mean Placebo (LS-mean Between-group Δ p-value Δ ± 95% CI) Δ ± 95% CI) (95% CI) –0.066 –0.002 (–0.09 –0.066 0.08 (–0.15 to 0.01) to 0.08) (–0.15 to 0.01) –0.110 –0.025 (–0.09 –0.085 0.046 (–0.17 to –0.05) to 0.04) (–0.141 to –0.028) –0.095 –0.040 (–0.10 –0.055 0.09 (–0.16 to –0.03) to 0.02) (–0.14 to 0.02)

Hedges’ g (95% CI) –0.17 (–0.40 to 0.06) –0.28 (–0.51 to –0.05) –0.19 (–0.42 to 0.04)

ANCOVA: analysis of covariance; CI: confidence interval; LS: least squares. All models adjusted for baseline values; negative between-group Δ values indicate a greater reduction in wrinkle intensity in the active group compared with placebo.

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Figure 2: Temporal changes in wrinkle intensity, dermal density, and collagen-related optical signals during 12 weeks of supplementation. Wrinkle intensity (Rq parameter), dermal density assessed by high-frequency ultrasound, and collagen-related optical signals expressed as the collagen-to-tryptophan ratio obtained by diffuse reflectance spectroscopy (DRS) are presented as mean change from baseline with 95% confidence intervals at weeks 4, 8, and 12 for participants receiving collagen oligopeptides (Col-OP, 2.5 g/day) or placebo. Change-from-baseline values are shown to reduce the influence of baseline variability and to illustrate temporal response patterns across visits; negative values indicate a reduction in wrinkle intensity relative to baseline, with lower Rq values corresponding to improved skin surface topography. Wrinkle intensity was the predefined primary endpoint and showed the greatest between-group separation at week 8, when a statistically significant difference was observed (p < 0.05, Holm-Bonferroni corrected). A reduction was already apparent at week 4 and values remained numerically lower at week 12, suggesting partial maintenance of the response over time. Dermal density and collagen-related optical signals were prespecified exploratory endpoints; although between-group differences for these parameters did not reach statistical significance, both measures showed numerically consistent temporal patterns in line with the primary clinical outcome. Taken together, these findings provide an integrated view of the response trajectory over time, with statistical significance observed for wrinkle intensity and exploratory findings in complementary instrumental measures. (Figure 2C). The collagen-to-tryptophan ratio increased progressively throughout the intervention, reaching approximately 30% above baseline at week 12 in the Col-OP group, whereas the placebo group showed an increase of approximately 12%. Although between-group differences did not reach statistical significance, the temporal pattern remained consistently favorable across all post-baseline visits (Table 4). Both groups exhibited minor variability across visits, although the active group demonstrated a numerically more consistent pattern over time. The standardized effect size was small, indicating a limited detectable signal under the conditions of this study. Sensitivity analyses using mixed-effects modeling produced similar non-significant patterns, confirming the consistency of the observed temporal profiles across analytical approaches. Figure 4 illustrates the aging map generated from mean collagen-to-tryptophan ratio values in the Col-OP group, providing a complementary visual representation of spatial variation in collagen-related optical signals; the color scale was normalized for visualization purposes. This visualization was included to facilitate qualitative interpretation of spatial patterns rather than quantitative comparison. The map reflects mean values within the active group and does not represent a formal statistical comparison. Given the exploratory nature of this optical bio-

-baseline visits, these changes did not reach statistical significance, as the 95% confidence intervals included zero at every time point (Table 3). Both groups demonstrated minor numerical fluctuations over time, without a consistent directional pattern clearly favoring the active treatment. The corresponding effect size was negligible, indicating a limited detectable effect on dermal density within the 12-week intervention period. ANCOVA and mixed-effects sensitivity analyses produced consistent, non-significant results. Within-group variability was observed across visits, remaining within the expected range for ultrasound-based dermal density measurements. High-frequency ultrasound is known for operator- and site-dependent variability, which may contribute to measurement variability in dermal assessments. Overall, the ultrasound data indicate no statistically significant changes in dermal density over the study period. Collagen-Related Optical Signals Assessed by Diffuse Reflectance Spectroscopy Measurements obtained using DRS, used here as a noninvasive optical surrogate for collagen-related signal rather than as a direct measure of collagen biosynthesis or structural remodeling, indicated a numerical increase in collagen-to-tryptophan ratios in the Col-OP group compared with placebo

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Figure 3: Representative wrinkle-intensity images from a participant supplemented with Col-OP. High-resolution digital images from a representative participant at baseline (T0) and after weeks 4, 8, and 12 of supplementation. The participant was selected based on a response trajectory close to the group median for wrinkle intensity changes. Images were acquired under standardized conditions and processed using a predefined ImageJ macro to compute the Rq parameter. Three-dimensional surface rendering is shown with a color-coded topographic scale (yellow indicating elevations and dark blue indicating deeper valleys), providing a qualitative representation of changes in skin surface roughness over time. These images are intended to illustrate morphological patterns consistent with the group-level findings and do not represent a quantitative comparison.

Figure 4: Facial aging map derived from collagen-to-tryptophan ratio values (obtained by diffuse reflectance spectroscopy [DRS]). The aging map was generated from mean collagen-to-tryptophan ratio values obtained across the ten anatomically defined facial regions shown in Figure 1 for participants in the Col-OP group. The visualization represents a spatial integration of collagen-related optical signals, with the color scale ranging from 0.0 (very low signal, white) to 3.0 (very high signal, dark blue). Values were normalized for visualization purposes only to allow comparison across facial regions. This map is intended to illustrate spatial distribution patterns of collagen-related optical signals and does not represent a statistical comparison or a direct measure of collagen content or structural remodeling. Given the exploratory nature of this optical marker, the figure should be interpreted as a qualitative representation only, complementing the temporal trends observed in Figure 2C

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Time point Week 4 Week 8 Week 12

Table 3: Changes in dermal density (ANCOVA, LS-means ± 95% CI) Active (LS-mean Δ ± Placebo (LS-mean Δ Between-group Δ p-value 95% CI) ± 95% CI) (95% CI) +0.42 +0.25 +0.17 0.62 (–0.18 to +1.02) (–0.32 to +0.82) (–0.65 to +0.99) +0.48 +0.33 +0.15 0.71 (–0.10 to +1.06) (–0.25 to +0.91) (–0.70 to +1.00) +0.44 +0.36 +0.08 0.82 (–0.16 to +1.04) (–0.22 to +0.94) (–0.76 to +0.92)

Hedges’ g (95% CI) +0.05 (–0.15 to +0.25) +0.04 (–0.16 to +0.24) +0.02 (–0.18 to +0.22)

ANCOVA: analysis of covariance; CI: confidence interval; DRS: diffuse reflectance spectroscopy; LS: least squares. All models adjusted for baseline values; positive between-group Δ values indicate a higher collagen-related optical signal in the active group compared with placebo

Table 4: Changes in collagen-to-tryptophan ratio (DRS, ANCOVA, LS-means ± 95% CI) Time point Active Placebo Between-group p-value Hedges’ g (LS-mean Δ% ± 95% CI) (LS-mean Δ% ± 95% CI) Δ% (95% CI) (95% CI) Week 4 +18% +6% +12% 0.22 +0.12 (–5% to +41%) (–12% to +24%) (–15% to +39%) (–0.10 to +0.34) +9% +15% 0.18 +0.14 Week 8 +24% (–2% to +50%) (–10% to +28%) (–14% to +44%) (–0.08 to +0.36) Week 12 +30% +12% +18% 0.16 +0.18 (–5% to +65%) (–8% to +32%) (–13% to +49%) (–0.05 to +0.41) ANCOVA: analysis of covariance; CI: confidence interval; DRS: diffuse reflectance spectroscopy; LS: least squares. All models adjusted for baseline values; positive between-group Δ values indicate a higher collagen-related optical signal in the active group compared with placebo

marker, these findings should be interpreted as exploratory and supportive rather than as conclusive evidence of ECM-associated changes. DISCUSSION In this randomized, double-blind, placebo-controlled clinical trial, daily supplementation with standardized collagen oligopeptides (2.5 g/day) met the predefined primary clinical endpoint by significantly reducing wrinkle intensity compared with placebo at week 8. Improvements were already evident at week 4 and remained numerically favorable at week 12, suggesting an early onset followed by partial maintenance of the response. Dermal density showed no detectable changes, whereas collagen-related optical signals demonstrated consistent numerical increases throughout supplementation, providing complementary support for the overall pattern of clinical findings. Although the observed effect size for wrinkle reduction was modest, the corresponding change in Rq roughness reflects a measurable modification in skin surface topography. In the context of nutritional and cosmetic dermatology, such variations are frequently reported and may be associated with perceptible improvements in fine wrinkle appearance under controlled conditions. The temporal profile observed here, with early changes followed by a clearer separation at week 8, is consistent with a gradual response pattern typically associated with oral supplementation.These findings suggest that relatively small

quantitative shifts may reflect dynamic changes in skin surface characteristics that are not fully captured by secondary structural endpoints within a 12-week period. The present findings are broadly consistent with previous experimental and clinical studies investigating collagen-derived peptides. Evidence from in vitro models indicates that these peptides can modulate ECM-related pathways, including collagen synthesis and matrix metalloproteinase activity.7,8 Clinical studies have also reported improvements in parameters such as elasticity, hydration, and wrinkle appearance after 8 to 12 weeks of supplementation.13,14 However, the magnitude of these effects is generally modest, reflecting the progressive and cumulative nature of nutritional interventions compared with procedural or topical approaches. For example, Proksch et al. reported improvements in skin elasticity at doses ranging from 2.5 to 5 g/day, along with residual effects observed after discontinuation.13 In a subsequent analysis, reductions in periorbital wrinkle volume were observed at weeks 4 and 8, accompanied by increased levels of procollagen I and elastin. Similarly, Asserin et al. described improvements in skin hydration, dermal density, and collagen network organization, supported by ex vivo findings.14 Taken together, these studies suggest a temporal pattern in which early changes may emerge within the first month and become more evident between weeks 8 and 12, consistent with the temporal profile observed in the present study. Additional evidence from other clinical contexts supports the broader relevance of collagen supplementation. A longer-term randomized trial in cellulite found improvements

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in skin waviness and dermal density, particularly in individuals with lower BMI.15 More recently, supplementation with hydrolyzed fish cartilage has been associated with improvements in wrinkle-related parameters and dermal echogenicity.16 These findings indicate that the effects of collagen-derived peptides may extend across different anatomical sites and structural outcomes, although inter-study variability remains substantial. In this context, the results of the present study are generally in line with the literature, although the magnitude of change was comparatively smaller. Several factors may contribute to this difference, including variations in peptide composition, dosage, baseline characteristics of participants, and analytical methodologies. In particular, the lack of statistically significant effects on dermal density contrasts with some previous reports.14,15 It should be considered, however, that the present study was not specifically powered to detect differences in secondary endpoints, particularly those related to structural outcomes. In addition, the 12-week duration may not have been enough to capture slower ECM remodeling dynamics. The spectroscopic findings should be interpreted as exploratory and as still providing complementary biological context for the clinical outcomes. Collagen-related optical signals showed a progressive numerical increase throughout supplementation, reaching approximately 30% above baseline after 12 weeks in the active group, whereas in the placebo group it increased by approximately 12%. Although between-group differences did not reach statistical significance, the consistent temporal pattern observed across all post-baseline visits suggests that subtle ECM-related changes may accompany the observed reduction in wrinkle intensity. Given the inherent variability associated with optical measurements, larger studies incorporating complementary molecular biomarkers, such as procollagen I, TIMP-1, and MMPs, are warranted to further characterize the biological relevance of these findings. The strengths of this study include its randomized, double-blind design, the use of objective imaging-based endpoints, and the application of a predefined statistical framework combining ANCOVA and mixed-effects modeling. The integration of multiple assessment modalities, including imaging, ultrasound, and spectroscopy, also provides a broader perspective on skin-related changes. However, several limitations should be acknowledged. These include the moderate sample size for secondary endpoints, the single-center design, and the use of proprietary image-processing methods, which may limit comparability across studies. In addition, the absence of direct biomarker validation restricts mechanistic interpretation, and the study population, limited to women aged 45–60 years, may limit the generalizability of the findings. From a translational standpoint, the convergence of modest clinical improvements with existing biological plausibility supports further investigation in larger and more diverse populations. Future trials would benefit from longer follow-up periods, standardized imaging methodologies, and the inclusion of validated structural and molecular endpoints. Such approaches

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may help to better define the relationship between measurable biological changes and clinically perceptible outcomes. In summary, daily supplementation with collagen oligopeptides for 12 weeks was associated with a small but measurable reduction in wrinkle intensity, reaching statistical significance at week 8. No significant changes were observed in dermal density, and collagen-related optical signals showed a consistent numerical increase without statistical significance. These findings are consistent with a modest, time-dependent response profile and should be interpreted in light of the limited effect size and the exploratory nature of the secondary endpoints. Importantly, these findings complement our previous randomized clinical study using the same collagen oligopeptide ingredient, which found improvements in skin firmness, elasticity, and ECM-related gene expression, thereby expanding the clinical evidence across complementary skin-aging endpoints. Further studies are warranted to better define the magnitude, durability, and clinical relevance of these effects. CONCLUSION Daily supplementation with a standardized collagen oligopeptide (Col-OP; 2.5 g/day for 12 weeks) was associated with a statistically significant reduction in wrinkle intensity at week 8 compared with placebo. Although the magnitude of change was limited, the temporal pattern is consistent with an early response followed by partial maintenance over time. No significant effects were observed for dermal density, while collagen-related optical signals showed a consistent numerical increase that did not reach statistical significance. These findings should be interpreted as exploratory and supportive. Overall, the results indicate that oral collagen supplementation may contribute to measurable, albeit modest, improvements in skin appearance under the conditions of this study. Further research is needed to better define the magnitude, durability, and biological relevance of these effects. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this manuscript, the authors used ChatGPT (OpenAI, GPT-4 or a later version) as an AI-assisted tool to support language refinement and improve clarity of expression.The tool was used exclusively for editing purposes, including grammar correction, sentence restructuring, and improvements in readability in English. No AI tools were used for data analysis, data generation, interpretation of results, or generation of scientific content. All outputs were critically reviewed and edited by the authors, who take full responsibility for the accuracy, integrity, and originality of the final manuscript. l Acknowledgments The authors would like to thank all study participants and the clinical staff for their contributions.

Zague V, Pinheiro ALTA, Pinto JR, Albarici VC, Facchini G, Eberlin S.

REFERENCES: 1. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138:1462–70. 2. Varani J, Dame MK, Rittie L, Fligiel SEGG, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006;168:1861–8. 3. Ohara H, Matsumoto H, Ito K, Iwai K, Sato K. Comparison of quantity and structures of hydroxyproline-containing peptides in human blood after oral ingestion of gelatin hydrolysates from different sources. J Agric Food Chem. 2007;55:1532–5. 4. Mari WK, Muneshige S, Shin K, Yasuki T, Hideyuki S, Fumiki M, et al. Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats. J Agric Food Chem. 2010;58:835–41. 5. Taga Y, Iwasaki Y, Shigemura Y, Mizuno K. Improved in vivo tracking of orally administered collagen hydrolysate using stable isotope labeling and lc-ms techniques. J Agric Food Chem. 2019;67:4671–8. 6. Virgilio N, Schoen C, Steen B van der, Kleinnijenhuis AJ, Holthoon FL van, Vleminckx S, et al. Unravelling the bioavailability of amino acids and bioactive peptides from collagen hydrolysate in coffee in healthy volunteers. Food Res Int. 2025;211:116478. 7. Zague V, Amaral JB, Rezende Teixeira P, Oliveira Niero EL, Lauand C, Machado-Santelli GM. Collagen peptides modulate the metabolism of extracellular matrix by human dermal fibroblasts derived from sun-protected and sun-exposed body sites. Cell Biol Int. 2018;42:95–104. 8. Fisher GJ, Quan T, Purohit T, Varani J, Kang S, Voorhees JJ. Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Am J Pathol. 2009;174:101–14.

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Zague V, Pinheiro ALTA, Pinto JR, Facchini G, Eberlin S. Oral Collagen oligopeptides as a modulator of skin health: a Comprehensive Evaluation of Clinical and Molecular Effects. J Med Food. 2025;28:869–76. Brueckheimer PJ, Silva TC, Rodrigues L, Zague V, Filho CI, Silva C. The effects of type I collagen hydrolysate supplementation on bones, muscles, and joints: a systematic review. Orthop Rev (Pavia). 2025;17:129086. Miranda RB, Weimer P, Rossi RC. Effects of hydrolyzed collagen supplementation on skin aging: a systematic review and meta-analysis. Int J Dermatol. 2021;60:1449–61. Iwai K, Hasegawa T, Taguchi Y, Morimatsu F, Sato K, Nakamura Y, et al. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem. 2005;53:6531–6. Proksch E, Schunck M, Zague V, Segger D, Degwert J, Oesser S. Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. Skin Pharmacol Physiol. 2014;27:113–9. Asserin J, Lati E, Shioya T, Prawitt J. The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials. J Cosmet Dermatol. 2015;14:291–301. Schunck M, Zague V, Oesser S, Proksch E. Dietary supplementation with specific collagen peptides has a body mass index-dependent beneficial effect on cellulite morphology. J Med Food. 2015;18:1340–8. Franco PMBGM, Barboza CRS, Kakuda L, Cadioli GF, Costa GMD, Bouvret E. Oral supplementation with hydrolyzed fish cartilage improves the morphological and structural characteristics of the skin: a double-blind, placebo-controlled clinical study. Molecules. 2021;26:1134.

AUTHOR’S CONTRIBUTION: Vivian Zague 0009-0001-1958-0207 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Critical review of the literature, Critical revision of the manuscript. Ana Lúcia Tabarini Alves Pinheiro 0000-0002-0226-2544 Statistical analysis, Conception and design of the study, Acquisition, analysis and interpretation of data, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature. Juliana Rodrigues Pinto 0000-0002-6387-7243 Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript. Viviane Cristina Albarici 0000-0001-6181-8859 Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript. Gustavo Facchini 0000-0003-0111-7596 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript. Samara Eberlin 0000-0001-7001-801X Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Critical review of the literature, Critical revision of the manuscript.

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Effectiveness of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy: a 5-year experience Eficácia do ácido poli-L-láctico no tratamento da lipoatrofia facial associada ao HIV: uma experiência de cinco anos DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180557 ABSTRACT Introduction: HIV-associated facial lipoatrophy can impair social relationships, treatment adherence, and mental health, frequently leading to depression. Correction of facial lipoatrophy is associated with significant improvement in quality of life. Objectives: To evaluate the efficacy of poly-L-lactic acid (PLLA) in correcting HIV-related facial lipoatrophy. Methods: Sixty-one patients with HIV-associated facial lipoatrophy received PLLA injections once a month until clinical improvement. The primary endpoint was the need for retreatment. Two independent dermatologists and the researcher classified lipoatrophy according to photographs. Malar skinfold thickness was measured with an adipometer. Results: All patients showed improvement in facial lipoatrophy after receiving a mean of 7.9 vials of PLLA. Skinfold thickness improved by 105%. Maximum follow-up was 58 months, and the mean duration of the effect was 33.4 months. Patients who discontinued HAART or had higher CD4+ cell counts at baseline presented better responses. Lower responses were observed in patients with very severe lipoatrophy and thinner skin. Conclusion: PLLA treatment is an effective and durable alternative for patients with moderate HIV-associated facial lipoatrophy, but of limited effectiveness for patients with thin skin and very severe lipoatrophy. Keywords: HIV-Associated Lipodystrophy Syndrome; Polylactic Acid-Polyglycolic Acid Copolymer; Antiretroviral Therapy, Highly Active; Skinfold Thickness

RESUMO Introdução: A lipoatrofia facial associada ao HIV prejudica as relações sociais, a adesão ao tratamento e a saúde mental, frequentemente levando à depressão. A correção da lipoatrofia facial está associada a uma melhora significativa na qualidade de vida. Objetivos: Avaliar a eficácia do ácido poli-L-láctico (PLLA) na correção da lipoatrofia facial associada ao HIV. Métodos: Sessenta e um pacientes com lipoatrofia facial associada ao HIV receberam injeções mensais de PLLA até obterem melhora clínica. O desfecho primário foi a necessidade de retratamento. Dois dermatologistas independentes e o pesquisador classificaram a lipoatrofia com base em fotografias. A espessura da prega cutânea malar foi medida com adipômetro. Resultados: Todos os pacientes apresentaram melhora da lipoatrofia facial após recebem, em média, 7,9 frascos de PLLA. A espessura da prega cutânea melhorou 105%. O seguimento máximo foi de 58 meses e a duração média do efeito foi de 33,4 meses. Melhores respostas ocorreram em pacientes que suspenderam a HAART ou que apresentavam contagem inicial de CD4+ mais elevada. Respostas inferiores foram observadas em casos de lipoatrofia muito grave e pele fina. Conclusão: O PLLA constitui uma alternativa eficaz e duradoura para a lipoatrofia facial moderada associada ao HIV, mas apresenta resultados limitados em pacientes com pele muito fina e lipoatrofia grave. Palavras-chave: Copolímero de Ácido Poliláctico e Ácido Poliglicólico; Síndrome de Lipodistrofia Associada ao HIV; Espessura de Dobras Cutâneas;Terapia Antirretroviral de Alta Atividade 291 195 191

Original Article Authors: Márcia C N Yoshioka¹ (in memoriam) Samira Yarak¹ Adriana Maria Porro¹ Jane Tomimori¹ ¹ Escola Paulista de Medicina, Universidade Federal de São Paulo, Department of Dermatology, São Paulo (SP), Brazil ² Training Center on Aids/STD, Dermatology, São Paulo (SP), Brazil

Correspondence: Samira Yarak E-mail: s.yarak@unifesp.br

Funding: None Conflict of interest: None Research Ethics Committee approval CAAE Number: IRB #079/2001 Submitted on: February 7, 2026 Final decision: August 17, 2026

How to cite this article: Yoshioka MCN, Yarak S, Porro AM, Tomimori J. Effectiveness of poly-Llactic acid for the treatment of HIV-associated facial lipoatrophy: a 5-year experience. Surg Cosmet Dermatol. 2026;18(3):e20260557.

Yoshioka MCN, Yarak S, Porro AM, Tomimori J.

INTRODUCTION Highly active antiretroviral therapy (HAART), a combination regimen comprising 2 or more classes of antiretroviral medications with different targets in the HIV replication cycle, was introduced in the mid-1990s for the treatment of HIV infection.1 Lipodystrophy was first described in people living with HIV (PLHIV) in 1998.2 Initially, it was believed that protease inhibitors were the main cause, but nucleoside analogues3,4 and HIV itself are also responsible.5 Lipodystrophy is an association of fat redistribution and metabolic disturbances, such as insulin resistance and hypertriglyceridemia. Fat redistribution is characterized by lipoatrophy of the legs, arms and face, and lipohypertrophy of the abdomen, breasts and neck, consequently developing a characteristic buffalo hump. Lipoatrophy is by far the most bothersome of these alterations, interfering with social relationships and adherence to treatment and causing depression.6,7 Treatment of facial lipoatrophy is, therefore, associated with improvement in quality of life. There is no proven strategy for the effective treatment of facial lipoatrophy in PLHIV. Poly-L-lactic acid (PLLA) is a biocompatible and biodegradable polymer derived from the L-lactic and D-lactic isomers, and it has been used as a therapeutic approach to restore lost facial volume, improving patients' appearance and quality of life. The use of PLLA is recommended for the treatment of HIV-associated facial lipoatrophy and has been approved in the United States since 2004.8 There are many studies8-18 regarding PLLA and PLHIV, mostly related to safety and efficacy, but most of them have follow-up periods of up to 2 years. There is a lack of standardization regarding the quantity of PLLA indicated for each patient and the assessment of outcomes.The lack of an easy-to-use objective method to measure regional fat is a major difficulty in the assessment of lipodystrophy in PLHIV.19 Improvement of cheek skinfold, measured by an adipometer, and improvement of the lipoatrophy severity score of the malar region, assessed with photographs, were used as evaluation methods to determine treatment response.The aim of this study was to evaluate measurement methods for lipoatrophy related to PLHIV receiving HAART, to establish factors related to better PLLA performance, and to identify clinical conditions related to PLLA injection durability.

Assessment of lipoatrophy severity was based on digital photographs of the frontal and lateral aspects of the face, obtained using a Sony Cyber-shot DSC F707T digital camera. The evaluation focused exclusively on the cheek region. To minimize bias, 3 dermatologists analyzed the photographs—2 independent specialists and the author, who administered the PLLA injections, measured cheek skinfold thickness, and conducted follow-up consultations. Patients were given clinical scores from 0 to 20, according to the affected area and depth, classified as mild (0-5), moderate (5.1-10), severe (10.1-15), and very severe (15.1-20) lipoatrophy. Digital photographs taken immediately before the first treatment and 1 month after the final injection were considered the pre- and post-treatment assessments, respectively. In addition, the evaluation included cheek skinfold measurements at both time points. A scientific adipometer (Cescorf) was positioned along a virtual line extending from the lower portion of the earlobe to the nostrils, with the measurement taken 1 centimeter lateral to the nostrils. Each vial of PLLA (Sculptra, Sanofi-Aventis) was reconstituted with 3 mL of sterile water at least 4 hours before the procedure. Immediately before the procedure, 1 mL of 2% lidocaine was added to the vial, and it was thoroughly shaken. Each patient received one vial per cheek at each visit, except at the last one, when half a vial could be injected into each cheek, according to the judgment of the dermatologist. The injections were made at the junction of the deep dermis and the subcutaneous tissue, with a 25-gauge needle. The injection sites covered the entire affected region, with 1-cm intervals, 0.1 mL of suspension each time, in 4 directions. Patients were treated at 4-week intervals. The number of PLLA vials was determined during the follow-up visits, and the decision to stop treatment was made jointly by the patient and the physician. After the injections, vigorous massage was performed in order to evenly distribute the PLLA. Patients were instructed to apply ice and massage the area twice a day, for 3 days, as well as to avoid excessive exposure to sunlight and heavy exercise. Patients were evaluated every 2 months during the first year, and every 6 months until retreatment was indicated. The indication for retreatment, agreed upon by both the patient and the physician, was considered an endpoint. Pearson correlation and the paired t-test were used for statistical analysis, and the level of significance was set at p < 0.05.

METHODS This study is a prospective, non-randomized clinical trial involving PLHIV with moderate to severe facial lipoatrophy. Sixty-one PLHIV with moderate to very severe lipoatrophy without prior fillers, received cheek injections of PLLA. Treatment was administered between October 2002 and October 2004, with follow-up and data collection completed in February 2008. Key parameters analyzed included age, sex, HIV infection duration, CD4+ cell count, viral load, HAART regimen, and body mass index (BMI). All patients were treated at the Reference Center on AIDS/STD, São Paulo, Brazil and gave written informed consent.The study was approved by the institutional review board (IRB #079/2001).

RESULTS The mean age of the 61 patients was 44.6 (9.3) years (range, 30 to 71), and 86.9% were male. Twenty-four patients (39.3%) were classified as having moderate lipoatrophy, 22 (36.1%) as having severe lipoatrophy, and 15 (24.6%) as having very severe lipoatrophy. Fifty-eight patients completed the treatment, 3 were lost to follow-up because of cardiovascular disease, depression, and abandonment of HIV treatment (4.9%). The mean duration since HIV infection diagnosis was 111.3 months, and patients had experienced signs of lipoatrophy for

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30.6 months before the beginning of the study (median = 24 months). The mean nadir CD4+ cell count was 176.3 × 106/L, and the median was 114 × 106/L before HAART. On the other hand, the mean CD4+ cell count increased to 495.6 × 106/L, and only 5 patients presented with a CD4+ cell count of less than 200 × 106/L when the study began. Viral load was below 400 copies/mm3 in 33 patients (54.1%), and the median detectable viral load was 8005 copies/mm3. All but one patient was treated with stavudine for a mean of 44.4 months, and the remaining patient was treated with zidovudine for 61 months. Fifteen patients discontinued HAART for periods ranging from 2 to 51 months, due to various reasons: drug toxicity, inadequate adherence, and structured treatment interruption. In some patients, HAART was introduced when the CD4+ cell count was above 350 × 106/L, when early treatment was recommended, despite the CD4+ cell count criteria.1 In some of these patients, HAART was interrupted. We observed that patients who had their antiretroviral therapy suspended had a correlation between the time of suspension and the duration of results (Pearson correlation coefficient r = 0.771; p < 0.001). Patients received a mean of 7.9 PLLA vials until clinical improvement. They were treated in 2 to 7 sessions, with a total of 4 to 13 vials of PLLA. Before the procedure, the mean clinical evaluation score was 11.9, representing severe lipoatrophy (Figure 1a). After treatment, the mean score was 4.2, showing significant improvement (p < 0.001) (Figure 1b). The mean skinfold thickness was 6.09 mm before the treatment, increasing to 11.03 mm at the end (81%; p < 0.001, paired t-test). The maximum improvement in

skinfold thickness was 12.47 mm, obtained 15.9 months after the end of the treatment, corresponding to 105% improvement. We observed an inverse correlation between clinical scores and pre-treatment skinfold thickness (r = -0.675; p < 0.001) (Figure 2). The quantity of PLLA used was related to the severity scores for lipoatrophy (r = 0.609; p < 0.001) as assessed by the photographs. The correlation was not significant when compared to skinfold thickness (r = -0.359; p = 0.06). There was a negative correlation between pre-treatment skinfold thickness and the clinical assessment score from post-treatment photographs (r = -0.589; p < 0.001). There was also a good correlation between pre- and post-treatment clinical scores, showing that patients with worse pre-treatment scores also had the worse post-treatment scores (r = 0.740; p < 0.001). Patients did not present papules or nodules as complications of the procedure, and immediate effects, such as ecchymosis, pain, and edema, were not considered. Fifty-three patients completed follow-up until the indication for a new treatment. Five patients did not complete follow-up because of death from myocardial infarction, diagnosis of rectal cancer, renal failure, change of residence, and treatment with polymethylmethacrylate. The maximum follow-up period was 58 months, and the mean follow-up period was 31.7 months. The results were maintained for 25 to 48 months in most patients (n = 44). The mean duration of the effect was 33.4 months. In February 2008, when we stopped collecting data, 2 patients had not required retreatment yet. There was a trend toward a weak correlation between age and durability of effect (r = -0.275; p = 0.047).There was no association between durability of the PLLA treatment and time of lipoatrophy,

Figure 1: Clinical aspects. A - Pre-treatment (score = 16); skinfold measurement site; B - Post-treatment (score = 5.0). 313 197 193

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Figure 2: Comparison between lipoatrophy severity and pre- and post-treatment skinfold measurements (in mm).

time of diagnosis of HIV infection, CD4 nadir, viral load, or BMI. On the other hand, CD4+ cell count at the time of treatment with PLLA was weakly correlated with durability of results (r = 0.342; p = 0.013). The quantity of PLLA was weakly inversely correlated with duration of results (r = -0.356; p = 0.009).The clinical severity score before treatment was inversely correlated with the durability of PLLA injection (r = -0.525; p < 0.001).

vudine has been implicated as the major nucleoside analogue responsible for mitochondrial toxicity,22 and consequently for the development of lipodystrophy. All patients, except one, had received stavudine for more than 3 years. It has been shown that prolonged use of HAART, especially stavudine, is associated with lipodystrophy.23 There is no gold-standard method for assessing facial lipoatrophy. For this reason, many authors have suggested different approaches, such as sonography,15 magnetic resonance imaging (MRI),24 computed tomography (CT),25 and anthropometry.25 Pre-treatment evaluation using an adipometer and digital photographs revealed an inverse correlation between clinical severity scores and cheek skinfold thickness, demonstrating that these methods are not only effective but also cost-efficient and easy to implement in clinical practice. Although radiologic imaging has been utilized for assessing facial lipoatrophy, each technique presents specific limitations.15,21-23 Moreover, these methods—including high-frequency ultrasound—are often too expensive for routine clinical application. In their study, Mest and Humble11 showed a 65.1% improvement in measured skinfold at the end of treatment and 73% at 12-month follow-up. These authors limited the maximum quantity of PLLA injected, and there were patients who would need to undergo more treatment sessions. To date, there is no standardization regarding the quantity of PLLA injection, dilution for the treatment of HIV-associated lipoatrophy, or number of sessions, making comparisons with other studies difficult. Levy et al. used a quantity of PLLA similar as that used in this study, and the results lasted more than 2 years.13 In this study, the number of applications was determined based on patient satisfaction, with their agreement as a key factor in the decision-making process. The extended follow-up period enabled a thorough assessment of PLLA injection longevity, which lasted nearly 3 years. We suggest that the optimal number of treatment sessions should be determined through a collaborative decision-making process,

DISCUSSION The use of PLLA for HIV-associated lipoatrophy and cosmetic purposes has been widely reported in the literature, although the data regarding long-term follow-up is scarce.8-14 Our longest follow-up was almost 5 years, and during this period we did not observe any major adverse effects. The most frequently reported complication after PLLA injection in the literature8-13 is the development of palpable and/or visible papules and/or nodules. The risk of papule and nodule formation is directly linked to the physicochemical properties of the polymer, its degradation rate, reconstitution method, application site, and the patient's immunological response.16-18 We believe that these complications did not occur in this study because of prior dilution of PLLA to a compatible volume, correct placement of the product at the junction of the deep dermis and subcutaneous tissue, and avoidance of sites of thin skin, such as orbital and temporal areas. In addition, the host's immunological response may have played a role in preventing adverse reactions.16-18 Patients in this study had been diagnosed with HIV infection for a mean time of almost 10 years. Most had improved their immunological status after HAART, as the majority had an undetectable viral load when undergoing PLLA injections. The severity and duration of HIV infection and effective viral suppression have been described as risk factors for HIV-associated lipoatrophy,19,20 as we have seen in this study. The use of nucleoside analogues can alter mitochondrial function in adipocytes and eventually cause apoptosis.21 Sta-

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balancing patient satisfaction with medical expertise. The quantity of PLLA required to achieve the desired outcome was closely linked to lipoatrophy severity scores, as assessed through digital photographs. However, no significant correlation was observed between this requirement and pre-treatment skinfold measurements. This discrepancy may stem from individual variations in skin thickness,26 as patients with comparable skinfold measurements can exhibit different degrees of lipoatrophy. Moreover, aging—both natural and accelerated by HIV infection— can weaken skin firmness, leading to sagging and compromising the accuracy of skinfold assessments.The progressive loss of structural support both affects measurement precision and diminishes skin responsiveness to PLLA treatment, ultimately reducing its bio-stimulatory effectiveness and volumetric enhancement. In some patients, even when we used a greater quantity of PLLA, despite increasing skin thickness, clinical improvement was not as evident. There was also a negative correlation between pre-treatment skinfold measurements and clinical assessment scores based on post-treatment photographs, suggesting that the thinner the skin, the worse the outcome of treatment with PLLA. For this reason, a complete evaluation of lipoatrophy, including the adipometer and clinical assessment, should be performed. Therefore, a multifactorial clinical evaluation is essential to determine the most appropriate treatment protocol for each patient. After treatment, assessment of the photographs showed improvement in all patients (p < 0.001), the score changing from 11.9 to 4.2 on the severity scale. However, patients presenting with worse pre-treatment scores also improved less after treatment, even when a greater quantity of PLLA was used. It has been suggested that patients with severe fat loss do not achieve good results with PLLA and that better results are seen in patients who have had lipoatrophy for a shorter period of time.27 We believe that there is a limit to clinical improvement for each individual and, once it is reached, the clinical aspect does not improve, regardless of how much PLLA is injected. When analyzing factors that could interfere with durability, we observed that patients who had their antiretroviral therapy suspended had longer-lasting results, in proportion to the length of suspension. Clinical improvement lasted for more than 48 months in 3 patients, and all of them had had their HAART suspended for 21 to 51 months. We believe that the efficacy observed in these patients is associated both with the improvement of lipoatrophy and the potential partial recovery of fat.28,29 Studies on PLLA durability indicate that its clinical effects generally do not exceed 30 to 40 months.14,30 However, an alternative hypothesis suggests that PLLA may persist in the tissue longer than assumed, and that available studies should focus solely on clinical outcomes without considering the long-term presence of the biomaterial in the tissue. As the PLLA mechanism of action is based on neocollagenesis,31 one could expect a worse response in older adults, given the impairment of collagen production and increased degradation.32 Inevitably, we have seen this tendency, but with a weak correlation. The CD4+ cell count at the moment of treatment with

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PLLA was weakly correlated with the durability of the treatment with PLLA, and the severity of lipoatrophy was inversely correlated with durability. Based on these findings, we can suggest that the better the patient’s immunological status, the longer-lasting the response, and also that more severe lipoatrophy results in a less durable treatment effect. Facial lipoatrophy lacks a standardized measurement method, and proposed approaches such as MRI, ultrasound, and CT have limitations and high costs. Our analysis revealed an inverse correlation between clinical scores and adipometer measurements, supporting digital photography and anthropometric evaluation as practical, cost-effective alternatives for clinical assessment. We observed that patients who received more PLLA vials presented less durable treatment effects, contrary to expectations. It is possible that, once an optimal quantity of PLLA has been injected, intrinsic features of each person determine the outcome. The patients who received more PLLA were also those with the worst severity scores. In other words, patients with more severe lipoatrophy have worse results.Thus, the study confirms the efficacy of PLLA in treating moderate to severe facial lipoatrophy in HIV-positive patients; however, thin skin and severe lipoatrophy impose certain limitations, requiring complementary therapeutic approaches. In some cases, the effects of PLLA persisted for up to 48 months, underscoring its importance in the aesthetic and psychosocial management of these patients. LIMITATIONS Individual differences in skin thickness mean the assessment of skinfold measurements across different patients is inherently variable, limiting its precision as a comparative metric. Similarly, imaging modalities, despite their advanced capabilities, remain constrained by the absence of standardized measurement protocols and their high cost, restricting their feasibility for routine clinical application. Although the sample size in this study was relatively small, the long duration of the study provided a robust framework for evaluating the long-term effects of PLLA, partially offsetting this limitation. Additional constraints include the lack of a control group and the absence of standardized injection protocols, both of which could impact treatment reproducibility and the comparability of outcomes. CONCLUSIONS PLLA injections improve malar lipoatrophy in PLHIV receiving HAART. This study identified features associated with better responses, such as immunological status and suspension of HAART. On the other hand, skin thickness and lipoatrophy severity are associated with worse responses to PLLA. Severity of lipoatrophy is also related to the use of more PLLA vials and a shorter duration of results. Based on these findings, we can suggest that treatment with PLLA is a good option in patients presenting mild or moderate HIV-associated lipoatrophy, but good results will not be achieved in patients presenting severe lipoatrophy and thinner skin. l

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REFERENCES 1. Ho DD. Time to hit HIV, early and hard. N Engl J Med. 1995;333:450-1. 2. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12:F51-8. 3. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;13:1659-67. 4. Joly V, Flandre P, Meiffredy V, Leturque N, Harel M, Aboulker JP, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS. 2002;16:2447-54. 5. Pinti M, Salomoni P, Cossarizza A. Anti-HIV drugs and the mitochondria. Biochim Biophys Acta. 2006;1757:700-7. 6. Martínez E, Garcia-Viejo MA, Blanch L, Gatell JM. Lipodystrophy syndrome in patients with HIV infection: quality of life issues. Drug Saf. 2001;24:157-66. 7. Collins E, Wagner C, Walmsley S. Psychosocial impact of the lipodystrophy syndrome in HIV infection. AIDS Read. 2000;10:546-50. 8. Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E, Pauchard M, Schoen H, et al. Polylactic acid implants (New-Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA. AIDS. 2003;17:2471-7. 9. Guaraldi G, Orlando G, Fazio D, Lorenzi I, Rottino A, Santis G, et al. Comparison of three different interventions for the correction of HIV-associated facial lipoatrophy: a prospective study. Antivir Ther. 2005;10:753-9. 10. Negredo E, Higueras C, Adell X, Martinez JC, Martinez E, Puig J, et al. Reconstructive treatment for antiretroviral-associated facial lipoatrophy: a prospective study comparing autologous fat and synthetic substances. AIDS Patient Care STDS. 2006;20:829-37. 11. Mest DR, Humble G. Safety and efficacy of poly-L-lactic acid injections in persons with HIV-associated lipoatrophy: the US experience. Dermatol Surg. 2006;32:1336-45. 12. Carey DL, Baker D, Rogers GD, Petoumenos K, Chuah J, Easey N, et al. A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy. J Acquir Immune Defic Syndr. 2007;46:581-9. 13. Levy RM, Redbord KP, Hanke W. Treatment of HIV lipoatrophy and lipoatrophy of aging with poly-L-lactic acid: A prospective 3-year follow-up study. J Am Acad Dermatol. 2008;59:923-33. 14. Vleggaar D; Bauer U. Facial enhancement and the European experience with Sculptra (poly-l-lactic acid). J Drugs Dermatol. 2004;3:542-7. 15. Martinez E, Bianchi L, García-Viejo MA, Bru C, Gatell JM. Sonographic assessment of regional fat in HIV-1-infected people. Lancet. 2000;356:1412-3. 16. Christen MO. Collagen stimulators in body applications: a review focused on Poly-L-Lactic Acid (PLLA). Clin Cosmet Investig Dermatol. 2022;15:997-1019. 17. Oh S, Lee JH, Kim HM, Batsukh S, Sung MJ, Lim TH, et al. Poly-L-lactic acid fillers improved dermal collagen synthesis by modulating M2 macrophage polarization in aged animal skin. Cells. 2023;12:1320.

18. Lin CY, Lin JY, Yang DY, Lee SH, Kim JY, Kang M. Efficacy and safety of poly-D,L-lactic acid microspheres as subdermal fillers in animals. Plast Aesthetic Res. 2019;6:16. 19. Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS. 2001;15:1389-98. 20. Wierzbicki AS, Purdon SD, Hardman TC, Kulasegaram R, Peters BS. Clinical aspects of the management of HIV lipodystrophy. Br J Diabetes Vasc Dis. 2008;8:113-19. 21. Villarroya F, Domingo P, Giralt M. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity.Trends Pharmacol Sci. 2005;26:88-93. 22. Buffet M, Schwarzinger M, Amellal B, Gourlain K, Bui P, Prévot M, et al. Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy. J Clin Virol. 2005;33:60-4. 23. Lichtenstein KA. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr. 2005;39:395-400. 24. Bickel M, Eisen J, Stephan C, Crespi CM, Lutz T, Klauke S, et al. A standardized, comprehensive magnetic resonance imaging protocol for rapid and precise quantification of HIV-1-associated lipodystrophy. HIV Med. 2007;8:413-9. 25. Padilla S, Gallego JA, Masiá M, Gutiérrez F. Single-slice computed tomography and anthropometric skinfold analysis for evaluation of facial lipoatrophy in HIV-infected patients. Clin Infect Dis 2004;39:1848-51. 26. Lee Y, Hwang K. Skin thickness of Korean adults. Surg Radiol Anat. 2002;24:183-9. 27. Borelli C, Kunte C, Weisenseel P, Thoma-Greber E, Korting HC, Konz B. Deep subcutaneous application of poly-L-lactic acid as a filler for facial lipoatrophy in HIV-infected patients. Skin Pharmacol Physiol. 2005;18:273-8. 28. Kim MJ, Leclercq P, Lanoy E, Cervera P, Antuna-Puente B, Maachi M et al. A 6-month interruption of antiretroviral therapy improves adipose tissue function in HIV-infected patients: the ANRS EP29 Lipostop Study. Antivir Ther. 2007;12:1273-83. 29. Skiest DJ, Krambrink A, Su Z, Robertson KR, Margolis DM. A5170 Study Team Improved measures of quality of life, lipid profile, and lipoatrophy after treatment interruption in HIV-infected patients with immune preservation: results of ACTG 5170. J Acquir Immune Defic Syndr. 2008;49:377-83. 30. Engelhard P, Humble G, Mest D. Safety of Sculptra: a review of clinical trial data. J Cosmet Laser Ther. 2005;7:201-5. 31. Wu XS, Wang N. Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part II: biodegradation. J Biomater Sci Polym Ed. 2001;12:21-34. 32. Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000;114:480-6.

AUTHOR’S CONTRIBUTION: Márcia C. N. Yoshioka (in memoriam) Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature. Samira Yarak ORCID: 0000-0002-5657-6645 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript. Adriana Maria Porro ORCID: 0000-0003-0736-4790 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Jane Tomimori ORCID: 0000-0002-2407-6646 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript.

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

The effectiveness of a whitening and anti-aging double-layer serum and cream containing gammaaminobutyric acid (GABA) 3%, dimethylaminoethanol (DMAE) 2%, cysteamine 2.5%, and bakuchiol 1% A eficácia de um sérum e creme de dupla camada com ação clareadora e antienvelhecimento contendo ácido gama-aminobutírico (GABA) 3%, dimetilaminoetanol (DMAE) 2%, cisteamina 2,5% e bakuchiol 1% DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180574 ABSTRACT Background: Combination therapies targeting multiple pathways of skin aging and hyperpigmentation are increasingly explored. However, the combined efficacy of gamma-aminobutyric acid (GABA), dimethylaminoethanol (DMAE), cysteamine, and bakuchiol remains limited. Objectives: To assess the efficacy of a double-layer serum and cream containing GABA 3%, DMAE 2%, cysteamine 2.5%, and bakuchiol 1% on skin brightness, pore count, and wrinkles. Methods: In this 8-week, double-blind, randomized, placebo-controlled trial, 50 participants were randomized, and 44 completed the study. Subjects received either the active formulation or a placebo. Outcomes included wrinkle scores, pore counts, skin brightness (L-value), and melanin index assessed at baseline and weeks 2, 4, 6, and 8. Data were analyzed using repeated-measures MANOVA. Results: A significant time-by-group interaction was observed for L-value (p < 0.001), with the treatment group showing a modest increase (+1.63) compared to minimal change in controls (-0.49). Wrinkle scores changed over time in both groups without clinically meaningful between-group differences. No significant treatment effects were observed for pore counts or melanin index. Conclusion: The formulation improved measured skin brightness but did not demonstrate significant depigmenting or structural anti-aging effects over 8 weeks, suggesting primarily cosmetic benefits. Keywords: GABA Agents; Cysteamine; Aging

RESUMO Introdução: As terapias combinadas que visam múltiplos mecanismos de envelhecimento cutâneo e de hiperpigmentação para o clareamento da pele e o antienvelhecimento são cada vez mais exploradas. Contudo, a eficácia combinada de ácido gama-aminobutírico (GABA), dimetilaminoetanol (DMAE), cisteamina e bakuchiol ainda é limitada. Objetivo: Avaliar a eficácia de um sérum e creme em camadas (double-layer) contendo GABA 3%, DMAE 2%, cisteamina 2,5% e bakuchiol 1% em relação à luminosidade da pele, diminuição dos poros e redução das rugas. Métodos: Neste ensaio clínico randomizado, duplo-cego e controlado por placebo com duração de 8 semanas, 50 participantes foram randomizadas e 44 completaram o estudo. Os desfechos incluíram rugas, poros, luminosidade (valor L) e índice de melanina, avaliados na data de início e nas semanas 2, 4, 6 e 8. Os dados foram analisados com o uso de MANOVA de medidas repetidas. Resultados: Houve interação tempo × grupo significativa para o valor L (p < 0,001), com aumento modesto no grupo tratamento (+1,63) e mudança mínima no controle (-0,49). As rugas variaram ao longo do tempo em ambos os grupos, sem diferença clinicamente relevante. Não houve efeito significativo nos poros ou no índice de melanina. Conclusão: A formulação melhorou a luminosidade da pele, sem evidência de efeito despigmentante ou antienvelhecimento estrutural em 8 semanas. Palavras-chave: Agentes GABAérgicos; Envelhecimento; Cisteamina

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Original Article Authors: Widya Widita¹ Andi Hardianty¹ Anis Irawan Anwar¹ Andi Alfian Zainuddin² Wong Lip Wih³ Cynthia Sandra Kuncoro¹ Annisa Alviariza¹ Adhisti Prihastuti¹ Andi Dhidit Dwiputra¹ ¹ Hasanuddin University, Dermatology, Venereology and Aesthetics, Makassar, South Sulawesi, Indonesia ² Hasanuddin University, Department of Public Health and Community Medicine, Makassar, South Sulawesi, Indonesia ³ Lipwih Synergylab Company, Lipwih Synergylab Company, Bekasi, West Java, Indonesia

Correspondence: Widya Widita E-mail: widya.widita@med.unhas. ac.id

Submitted on: April 30, 2026 Final decision: July 29, 2026

How to cite this article: Widita W, Hardianty A, Anwar AI, Zainuddin AA, Wih WL, Kuncoro CS, Alviariza A, Prihastuti A, Dwiputra AD. The effectiveness of a whitening and anti-aging double-layer serum and cream containing gamma-aminobutyric acid (GABA) 3%, dimethylaminoethanol (DMAE) 2%, cysteamine 2.5%, and bakuchiol 1%. Surg Cosmet Dermatol. 2026;18(3):e20260574.

Widita W, Hardianty A, Anwar AI, Zainuddin AA, Wih WL, Kuncoro CS, Alviariza A, Prihastuti A, Dwiputra AD.

INTRODUCTION Skin aging and pigmentary disorders remain major concerns in dermatological practice and cosmetic science. Common complaints include skin aging, wrinkles, pigmentation, dryness, and dull complexion. Many researchers continue to seek various strategies and solutions to address these issues.1 Brighter skin is still regarded as an aesthetic advantage among certain ethnic groups, particularly in women of Asian and African descent with Fitzpatrick skin types IV–VI.2 The preference for lighter skin among Indonesian women reflects broader beauty standards prevalent across Asia, where the market for skin-brightening products is expanding rapidly. A clinical study conducted in Yogyakarta involving 74 Indonesian women demonstrated the demand for skin lightening products.3,4 Changes in the epidermal and dermal layers due to the aging process result in structural and functional alterations in the skin. New research has emerged focusing on various active compounds such as gamma-aminobutyric acid (GABA), dimethylaminoethanol (DMAE), cysteamine, and bakuchiol.2 GABA is widely distributed among cortical neurons, reducing neuronal excitability by decreasing the frequency of neuronal action potentials. In dermatological applications, GABA has been shown to significantly enhance dermal cell proliferation, delay skin aging processes, alleviate epidermal cell senescence, and improve skin hydration.5,6 DMAE is considered an indirect precursor of acetylcholine. It contributes to dermal collagen synthesis and plays a role in anti-aging mechanisms.7 Bakuchiol is a natural phenolic meroterpene isolated from the fruits of the plant Psoralea corylifolia. It is recognized for its wide range of pharmacological effects, including anti-aging, anti-inflammatory, antioxidant, antimicrobial, and anti-cancer activities. Cysteamine is known as an effective and safe agent for treating melasma by reducing melanin content. Depigmentation occurs through inhibition of tyrosinase activity.7 The use of serums and creams aimed at skin brightening and anti-aging has increased substantially in many countries, including Indonesia. However, studies demonstrating the effectiveness of combined GABA, DMAE, cysteamine, and bakuchiol as brightening and anti-aging agents remain limited. Therefore, the aim of this study was to assess the effectiveness of a brightening and anti-aging double-layer serum and cream containing these active components. OBJECTIVE To determine whether, compared with placebo, an 8-week double-layer serum-cream regimen containing GABA 3%, DMAE 2%, cysteamine 2.5%, and bakuchiol 1% improves skin L-value at week 8 and affects wrinkle score, pore score, melanin index, and harms in women aged 30-50 years with Fitzpatrick phototypes III-V.

MATERIALS AND METHODS Trial design and setting This was a single-center, 2-group, parallel, superiority, double-blind, randomized, placebo-controlled trial with 1:1 individual allocation and 8 weeks of follow-up.The trial was conducted at the Department of Dermatology and Venereology, Faculty of Medicine, Hasanuddin University/Hasanuddin University Hospital, Makassar, South Sulawesi, Indonesia, from March to August 2025. The study was approved by the Health Research Ethics Committee, Faculty of Medicine, Hasanuddin University (93/ UN4.6.4.5.31/PP36/2025). All participants provided written informed consent.The trial was registered retrospectively at ClinicalTrials.gov (NCT07477288) in March 2026. Patient and public involvement Patients and members of the public were not involved in the design, conduct, analysis, interpretation, or reporting of this trial. Changes to the protocol No important changes were made to the eligibility criteria, interventions, primary or secondary outcomes, follow-up duration, or target sample size after the trial had begun. Participants Eligible participants were women aged 30-50 years with Fitzpatrick skin phototypes III-V who attended participating dermatology clinics, were willing to follow the study regimen, and signed informed consent forms. The protocol also specified no use of vitamin C, selenium, or other antioxidant supplements during the preceding month. Exclusion criteria were pregnancy, breastfeeding, menopause, hormonal therapy or hormonal contraception, use of topical or systemic skin-whitening treatment during the preceding month, hyperpigmented lesions at the measurement sites (including melasma, lentigines, or ephelides), and a history of hypersensitivity to GABA, DMAE, cysteamine, or bakuchiol. Sample size The protocol calculated a minimum of 20 participants per group using assumed response proportions of 80% and 40%, a 2-sided alpha of 0.05 (Zα = 1.96), and 80% power (Zβ = 0.84). After a 10% allowance for attrition, the target was 22 participants per group (44 total). Recruitment was increased to 25 participants per group. Fifty participants were ultimately randomized. Randomization, allocation, and blinding Participants were assigned in a 1:1 ratio by simple randomization to the active group (Group A) or to the placebo group (Group B). Participants and outcome assessors were blinded. Active and placebo products were supplied using identical-looking packaging. Simple randomization was used without stratification or blocking. Participants and outcome assessors were blinded to treatment allocation. 236 202 198

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Interventions Participants in both groups cleansed their faces with 5 drops of the supplied facial wash in the morning and evening. The active group then applied 2 drops of active serum to the entire face, waited 1 minute, and applied one fingertip unit of active cream to the entire face. The same sequence was repeated twice daily for 8 weeks. The active products contained GABA 3%, DMAE 2%, cysteamine 2.5%, and bakuchiol 1%. The placebo group followed the same sequence of cleansing, serum application, waiting, and cream application using placebo products without the active ingredients. Adherence was assessed by participant self-report during follow-up visits; a quantitative adherence threshold was not specified. The use of concomitant whitening agents and antioxidant supplements was not allowed, as defined in the eligibility criteria. Treatment adherence was assessed by participants at each follow-up visit. Outcomes and assessments The prespecified primary outcome for this report was the change in skin brightness (L-value) from baseline to week 8. Secondary outcomes were changes in wrinkle score, pore score, and melanin index. Assessments were performed at baseline and weeks 2, 4, 6, and 8. Skin brightness was measured with a Chromameter (Konica Minolta, Japan), for which L = 0 represents black and L = 100 represents white. Melanin index was measured with a Mexameter MX 18 (Courage + Khazaka, Germany). The protocol specified measurements on the forehead and both cheeks, repeated 3 times at the same locations. Wrinkle and pore scores were obtained using the Janus-III Facial Analysis System (PIE Co., South Korea). At each visit, participants were asked about tolerability and adverse events, including itching or stinging, erythema, irritation, and blistering. Serious adverse events and treatment discontinuations due to harms were monitored throughout the 8-week period.

viations. Between-group comparisons at individual visits used independent-samples t tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data. Repeated-measures multivariate analysis of variance (MANOVA) using Pillai’s trace assessed time, group, and time-by-group effects. Two-sided p < 0.05 was considered statistically significant, and partial eta squared was reported as an effect-size measure. The efficacy analysis was a complete-case analysis of participants with data through week 8, analyzed in their randomized groups; no missing-data imputation or sensitivity analysis was performed. Between-group differences in baseline-to-week-8 change and 95% confidence intervals were calculated post hoc from the corresponding repeated-measures contrast error terms. No interim analysis or stopping guideline was used. RESULTS Of the 50 participants, 44 completed the 8-week follow-up and were included in the final analysis (Figure 1). During follow-up, 3 participants in the active group and 3 in the placebo group were lost to follow-up. Baseline characteristics were comparable between groups. The mean age of the participants in Group A was 38 years, compared to 39 years for Group B. All participants were categorized as Fitzpatrick skin phototype III. BMI, ethnicity, baseline hyperpigmentation severity, and categorical skin type were not recorded in the study dataset. Changes over time were observed in pore counts, wrinkle scores, L-value, and melanin index across both groups during the 8-week period. Adverse events were monitored throughout the study period. No serious adverse events were reported. Efficacy outcomes At week 8, the mean L-value increased from 48.21 to 49.84 in the active group, corresponding to a mean change of

Assessed for eligibility (n = 50)

Clinical photography Facial photographs were obtained at baseline through week 8 using a Nikon D3100 camera with an 18–55-mm lens and the Janus-III Facial Analysis System. Photographs were obtained using the same facial position, camera distance, illumination, and background at each visit. Harms and adherence No serious adverse events were reported. The number and type of non-serious adverse events, withdrawals due to harms, and quantitative adherence data were not available in the supplied analysis output. Statistical analysis Analyses were performed using SPSS version 22.0. Continuous variables are summarized as means and standard de-

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Randomized (n = 50)

Allocated to treatment (n = 25)

Allocated to control (n = 25)

Lost to follow-up (n = 3)

Completed study (n = 22)

1. CONSORT FlowDiagram Diagram FigureFigure 1: CONSORT Flow

Widita W, Hardianty A, Anwar AI, Zainuddin AA, Wih WL, Kuncoro CS, Alviariza A, Prihastuti A, Dwiputra AD.

Table 1: Comparison of wrinkle scores in study participants during the 8-week treatment period Group A

Group B

Table 2: Comparison of pore scores in study participants during the 8-week treatment period

Total

Group A

Group B

Total

56,136

53,955

55,045

Wrinkle W-0

63,136

66,318

64,727

Pores W-0

Wrinkle W-2

63,864

66,364

65,114

Pores W-2

56,773

54,273

55,523

Wrinkle W-4

64,455

65,636

65,045

Pores W-4

57,227

54,091

55,659

Wrinkle W-6

64,773

65,636

65,205

Pores W-6

57,682

54,182

55,932

Wrinkle W-8

65,318

66,000

65,659

Pores W-8

58,273

54,682

56,477

Figure 2: Changes in wrinkle scores (blue = Group A, green = Group B) in study participants during the 8-week treatment period. Source: authors' own archive

Figure 3: Changes in pore scores (blue = Group A, green Group B) in study participants during the 8-week treatment period. Source: authors' own archive

+1.63. In the placebo group, the mean L-value decreased from 48.62 to 48.13, corresponding to a mean change of −0.49. The between-group difference in change was 2.11 units (95% CI, 0.90–3.33; p = 0.001). A significant time-by-group interaction was also observed (p < 0.001). The mean wrinkle score changed from 63.14 to 65.32 in the active group and from 66.32 to 66.00 in the placebo group. The between-group difference in change was 2.50 points (95% CI, 1.33–3.67; p < 0.001), representing an improvement. The clinical relevance of the difference observed remains uncertain (Figure 2). No statistically significant time-by-group interaction was observed for pore score (p = 0.236). No significant treatment effect was observed for melanin index over the 8-week follow-up. At baseline, wrinkle scores were comparable between groups (mean [SD]: treatment 63.14 [6.01] vs. control 66.32 [4.55]). Wrinkle scores changed over time (within-subject effect, Pillai’s trace; p = 0.009) (Table 1, Figure 2). Wrinkle scores changed over time in both groups (within-subject effect, p = 0.009). While a significant time-by-group interaction was observed for wrinkle scores (p < 0.001),

the clinical magnitude of this change was minimal and did not represent a substantial reduction in wrinkle severity over the 8-week period. Baseline pore counts were similar between groups (treatment 56.14 [10.82] vs. control 53.96 [12.23]). Pore measurements changed over time (within-subject effect; p = 0.006), reflecting an overall change across visits (Table 2, Figure 3). However, the time-by-group interaction was not significant (p = 0.236), and no consistent between-group differences were observed at individual time points, indicating that the temporal change observed was not attributable to the assigned treatment. Mean baseline L-values were similar (treatment 48.21 [4.25] vs. control 48.62 [2.49]). The overall effect of time on L-values approached but did not reach conventional significance (p = 0.065). Crucially, there was a time-by-group interaction (p < 0.001), indicating that treatment and control groups had different brightness trajectories over time (Table 3, Figure 4). In absolute terms, the treatment group showed a small increase in L-values from baseline to week 8 (≈ +1.63), while the control group showed minimal change (≈ −0.49), which is

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Table 3: Comparison of L-value scores in study participants during the 8-week treatment period

Table 4: Comparison of melanin index scores in study participants during the 8-week treatment period

Group A

Group B

Total

Group A

Group B

Total

L-value W-0

48,207

48,615

48,411

Mexameter W-0

218,544

211,288

214,916

L-value W-2

48,544

48,413

48,478

Mexameter W-2

219,182

220,424

219,803

L-value W-4

48,965

47,509

48,237

Mexameter W-4

224,136

226,818

225,477

L-value W-6

49,642

48,411

49,027

Mexameter W-6

222,015

216,015

219,015

L-value W-8

49,835

48,129

48,982

Mexameter W-8

216,682

214,955

215,818

Figure 4: Changes in L-Value scores (blue = Group A, green = Group B) in study participants during the 8-week treatment period. Source: authors' own archive

Figure 5: Changes in melanin index scores (blue = Group A, green = Group B) in study participants during the 8-week treatment period. Source: authors' own archive

consistent with an increase in measured skin brightness even without a significant reduction in melanin index. Although statistically measurable, the magnitude of L-value change was relatively modest, and its clinical perceptibility remains uncertain. Baseline Mexameter values were similar between groups (treatment 218.5 [63.4] vs. control 211.3 [34.7]) (Table 4, Figure 5). The overall time effect showed a trend towards improvement (p = 0.051), but the time-by-group interaction was not significant, and there were no statistically significant between-group differences at individual visits.Thus, Mexameter readings did not show a clear treatment effect over 8 weeks. Representative standardized clinical photographs from 2 participants in the active group and 2 participants in the placebo group at baseline and week 8 are shown in figures 6 and 7.These photographs are presented for visual illustration only and were not used as substitutes for the prespecified quantitative outcome measures.

whereas in extrinsic aging results from the loss of redox equilibrium caused by environmental factors, such as ultraviolet (UV) radiation.8 Skin pigmentation is largely determined by melanin synthesis in melanocytes. Abnormal pigmentation is a common symptom accompanying aging skin.9 UV and visible light upregulate melanocyte-specific genes (tyrosinase, Tyrp1, and dopachrome tautomerase) and stimulate alpha-melanocyte–stimulating hormone (α-MSH) production.10 Advanced glycation end products (AGEs) accumulate in dermal collagen and elastin, engage receptors for AGEs (RAGE) on melanocytes, and activate extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) phosphorylation, leading to increased microphthalmia-associated transcription factor (MITF) and tyrosinase expression.11 UV and intrinsic ROS activate mitogen-activated protein kinase (MAPK) pathways, leading to activator protein 1 (AP-1) formation, which stimulates transcription of several collagen-degrading enzymes including matrix metalloproteinase-1 (MMP1), -3, and -9.12 AGE-mediated intracellular buildup generates ROS, damaging dermal proteins and triggering inflammatory signaling that contributes to photoaging, such as wrinkling.11

DISCUSSION In chronological aging, reactive oxygen species (ROS) are produced mainly through cellular oxidative metabolism,

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Widita W, Hardianty A, Anwar AI, Zainuddin AA, Wih WL, Kuncoro CS, Alviariza A, Prihastuti A, Dwiputra AD.

Figure 6: Clinical photographs of Group A and B

Figure 7: Clinical photographs of Group A and B

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Thinning of the dermis is thought to be caused by reduced collagen secretion by dermal fibroblasts. Thinning of the dermis is responsible for major morphological changes in skin wrinkles.13 Skin pores are enlarged openings of the pilosebaceous follicles that can be affected by age, gender, genetics, exposure to UV light, ethnicity, and sebum secretion.14 Chronic UV exposure induces degradative enzymes in the dermis, reducing collagen and elastin and exacerbating pore dilation.15 In this trial, we observed the effects of double-layer regimen comprising a serum and cream containing GABA 3%, DMAE 2%, cysteamine 2.5%, and bakuchiol 1% on skin brightness (L-value), pore counts, and wrinkle scores. Although statistically detectable, the magnitude of L-value change was modest and may not represent a clinically meaningful improvement. The absence of significant changes in melanin index suggests that a true depigmenting effect was not demonstrated within the 8-week period. GABA has been shown to enhance filaggrin expression, thereby promoting the proper formation and function of the skin barrier.16 Treatment with GABA increases type I collagen transcript levels while suppressing the expression of MMP-1, an enzyme responsible for collagen degradation. Through this mechanism, GABA regulates type I collagen expression, contributing to improved skin elasticity.17 It also helps alleviate epidermal cell senescence and enhances skin hydration, collectively improving the overall integrity and appearance of the skin.16 GABA inhibits α-MSH–induced melanogenesis through activation of GABAA and GABAB receptors, leading to downregulation of the cAMP–CREB–MITF–tyrosinase signaling cascade and suppression of intracellular Ca²+ levels. Because Ca²+ acts as a key secondary messenger mediating melanocyte activation via G protein-coupled receptors (GPCRs) such as MC1R, its elevation promotes both melanin synthesis and melanosome transfer to keratinocytes. GABA attenuates α-MSH–driven melanin biosynthesis primarily by reducing intracellular Ca²+ signaling, underscoring its regulatory role in melanogenic modulation.18 DMAE is considered an indirect precursor of acetylcholine or an analog of the B vitamin choline. Its proposed mechanism of action involves participation in muscle contraction beneath the dermis, as well as in cell adhesion between the epidermis and dermis. Increased muscle tonicity may provide a nonsurgical lifting effect. In addition, DMAE may influence dermal collagen synthesis.7,19 It exhibits hydroxyl radical–scavenging activity that competes with proline and hydroxyproline, both of which can reduce hydroxyl radicals (•OH) and form nitroxyl radicals.This finding demonstrates the ability of DMAE to neutralize hydroxyl free radicals, thereby suggesting its anti-aging mechanism of action.7 DMAE 3% gel has been shown to be safe and effective in the mitigation of forehead lines and periorbital fine wrinkles, and in improving lip fullness and shape and the overall appearance of facial skin.19 The improvements

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in wrinkle-related outcomes are supported by the established biological effects of the active ingredients. The contributions of DMAE and GABA may be mediated by dermal firming, membrane stabilization, and modulation of neurogenic inflammation or cutaneous muscle tone, thereby complementing collagen-stimulatory actions. Cysteamine is an aminothiol compound physiologically synthesized within human cells and functions as a depigmenting agent. It has been shown to be effective and safe in the treatment of melasma by reducing melanin content. Depigmentation occurs through inhibition of tyrosinase activity, an enzyme that plays a crucial role in the melanogenesis process.20 Cysteamine is a potent endogenous antioxidant that degrades hydrogen peroxide in cells and theoretically can act as an anti-aging agent. Topical cysteamine can significantly decrease the hyperpigmentation of solar lentigines, even without a mixture of retinol or glycolic acid. Cysteamine exerts its antimelanogenic effect partly through its metal-chelating capacity. It binds transition metal ions, including iron and copper, and neutralizes hydroxyl radicals produced via Fenton-type reactions, thereby indirectly downregulating the melanogenesis cascade.21 In an open-label controlled trial, patients with melasma who received 5% cysteamine showed an 11.5% decrease in melanin content at 12 weeks compared with baseline.22 The observed increase in L-value may be explained by the known pharmacological properties of the individual components. However, this increase occurred without corresponding reductions in melanin index, suggesting that optical or surface-level effects may have contributed to the outcome. In a 16week case series involving 7 participants, topical application of a cysteamine–isobionicamide complex resulted in a noticeable reduction in pore size and enhancement of skin texture on 3-dimensional imaging, accompanied by visible softening of fine lines and wrinkles.21 Bakuchiol has been shown to inhibit melanin synthesis and suppress the formation of primary cilia in dendritic cells, leading to the inhibition of melanogenesis.23 The proposed mechanism involves the downregulation of tyrosinase expression and the inhibition of Rho-dependent signaling pathways, both of which play key roles in the regulation of melanogenesis. Furthermore, bakuchiol can block the activity of α-MSH and tyrosinase, ultimately resulting in a reduction of pigmentation intensity on the skin surface.24 A serum containing a combination of bakuchiol extract has been shown to prevent excessive expression of IL-8 and p16 in skin exposed to UVA radiation, thereby exerting a skin-firming effect. Bakuchiol also promotes the synthesis of type I, III, and IV collagen, contributing to improved dermal structure and elasticity. In addition, bakuchiol enhances skin permeability, supporting the delivery of active ingredients, and exhibits anti-aging, moisturizing, and rejuvenating properties that collectively improve overall skin condition and appearance.24 Bakuchiol has been shown to have potent antioxidant and anti-inflammatory effects and to exert retinol-like antiaging

Widita W, Hardianty A, Anwar AI, Zainuddin AA, Wih WL, Kuncoro CS, Alviariza A, Prihastuti A, Dwiputra AD.

benefits without the typical adverse reactions associated with retinoids. It serves as an effective scavenger of linoleic acid peroxyl radicals, DPPH radicals, hydroxyl radicals, and glutathionyl radicals. Moreover, its antioxidant capacity has been shown to inhibit the upregulation of MMP-9 expression in vivo.25 It also can inhibit the activity of MMP-1 more effectively than retinol.26 Although each component has demonstrated individual dermatological benefits, their combined clinical efficacy remains uncertain.The lack of significant changes in melanin index despite the presence of known depigmenting agents such as cysteamine may be explained by the relatively short duration (8 weeks), insufficient delivery of the active ingredients, or formulation-related penetration limitations. The relatively small sample size and short duration may limit the generalizability of the findings and the abi-

lity to detect subtle changes, particularly in melanin-related outcomes. Future studies with longer follow-up periods and larger sample sizes are required to confirm clinical relevance. CONCLUSION This randomized, double-blind study demonstrates that a double-layer serum and cream containing GABA 3%, DMAE 2%, cysteamine 2.5%, and bakuchiol 1% is a potential cosmetic formulation for enhancing skin brightness and modulating skin appearance. Over 8 weeks, the double-layer formulation improved skin brightness (L-value) but did not show a clinically meaningful improvement in wrinkle scores. However, no significant effects were observed on melanin index or pore counts. These findings suggest a cosmetic benefit in enhancing skin appearance rather than confirmed depigmenting effects. l

REFERENCES 1. Benito-Martínez S, Zhu Y, Jani RA, Harper DC, Marks MS, Delevoye C. Research Techniques Made Simple: Cell Biology Methods for the Analysis of Pigmentation. J Invest Dermatol. 2020;140(2):257-68.e8. 2. Wei K, Guo C, Zhu J. The Whitening, Moisturizing, Anti-aging Activities, and Skincare Evaluation of Selenium-Enriched Mung Bean Fermentation Broth. Front Nutr. 2022;9:837168. 3. Hu Y, Zeng H, Huang J, Jiang L, Chen J, Zeng Q. Traditional Asian Herbs in Skin Whitening: The Current Development and Limitations. Front Pharmacol. 2020;11:534739. 4. Etnawati K, Adiwinarni DR, Susetiati DA, Sauchi Y, Ito H. The efficacy of skin care products containing glutathione in delivering skin lightening in Indonesian women. Dermatol Reports. 2019;11(s1):8013. 5. Zolghadri S, Bahrami A, Hassan Khan MT. A comprehensive review on tyrosinase inhibitors. J Enzyme Inhib Med Chem. 2019;34(1):279. 6. Naik PP, Farrukh SN. Influence of Ethnicities and Skin Color Variations in Different Populations: A Review. Skin Pharmacol Physiol. 2022;35(2):65-76. 7. Grossman R. The role of dimethylaminoethanol in cosmetic dermatology. Am J Clin Dermatol. 2005;6(1):39-47. 8. Papaccio F, D’arino A, Caputo S, Bellei B. Focus on the Contribution of Oxidative Stress in Skin Aging. Antioxidants. 2022;11(6):1121. 9. Lee AY. Skin Pigmentation Abnormalities and Their Possible Relationship with Skin Aging. Int J Mol Sci. 2021;22(7):3727. 10. Liu W, Chen Q, Xia Y. New Mechanistic Insights of Melasma. Clin Cosmet Investig Dermatol. 2023;16:429. 11. Lee EJ, Kim JY, Oh SH. Advanced glycation end products (AGEs) promote melanogenesis through receptor for AGEs. Sci Rep. 2016;6:27848. 12. Rittié L, Fisher GJ. Natural and Sun-Induced Aging of Human Skin. Cold Spring Harb Perspect Med. 2015;5(1):a015370. 13. Lowry WE. Its written all over your face: the molecular and physiological consequences of aging skin. Mech Ageing Dev. 2020;190:111315. 14. Parvar SY, Amani M, Shafiei M, Rastaghi F, Hosseini SA, Ahramiyanpour N. “The efficacy and adverse effects of treatment options for facial pores: A review article.” J Cosmet Dermatol. 2023;22(3):763-75. 15. Qiu W, Chen F, Feng X, Shang J, Luo X, Chen Y. Potential role of inflammaging mediated by the complement system in enlarged facial pores. J Cosmet Dermatol. 2024;23(1):27-32.

16. Zhao H, Park B, Kim MJ, et al. The Effect of γ-Aminobutyric Acid Intake on UVB- Induced Skin Damage in Hairless Mice. Biomol Ther (Seoul). 2023;31(6):640-7. 17. Mills DJ. The Aging GABAergic System and Its Nutritional Support. J Nutr Metab. 2021;2021(1):6655064. 18. Molagoda IMN, Kavinda MHD, Ryu HW. Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABAA and GABAB Receptors. Int J Mol Sci. 2021;22(15):8257. 19. Liu S, Chen Z, Cai X. Effects of Dimethylaminoethanol and Compound Amino Acid on D-Galactose Induced Skin Aging Model of Rat. Sci World J. 2014;2014:507351. 20. Atallah C, Viennet C, Robin S, Ibazizen S, Greige-Gerges H, Charcosset C. Effect of cysteamine hydrochloride-loaded liposomes on skin depigmenting and penetration. Eur J Pharm Sci. 2022;168:106082. 21. Clark-Loeser L, Sfriso R, Dirlewanger L, Kasraee B. A Case Series With Cysteamine–Isobionicamide Complex: Clues for Skin‐Rejuvenating Activity. J Cosmet Dermatol. 2025;24(1):e16743. 22. Chuang ADC, Lin ET, Chang CC. Comparison between the efficacy of cysteamine cream and combined hydroquinone cream in the treatment of melasma using skin analytical systems: An open-label quasi-randomized controlled trial in Asia patients. Dermatologica Sinica. 2024;42(3):194201. 23. Kang MC, Lee JW, Lee TH. UP256 Inhibits Hyperpigmentation by Tyrosinase Expression/Dendrite Formation via Rho-Dependent Signaling and by Primary Cilium Formation in Melanocytes. Int J Mol Sci 2020;21(15):5341. 24. Putriana NA, Husni P, Mita SR. Recent Advance Bakuchiol Application as a Potential Alternative to Retinol in Skincare and Cosmetics. Published online January 18, 2024. 25. West BJ, Alabi I, Deng S, West BJ, Alabi I, Deng S. A Face Serum Containing Palmitoyl Tripeptide-38, Hydrolyzed Hyaluronic Acid, Bakuchiol and a Polyherbal and Vitamin Blend Improves Skin Quality. J Cosm Dermatol Sci Appl. 2021;11(3):237-52. 26. Draelos ZD, Gunt H, Zeichner J, Levy S. Clinical Evaluation of a Nature-Based Bakuchiol Anti-Aging Moisturizer for Sensitive Skin. Journal of Drugs in Dermatology. 2020;19(12):1181-3.

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AUTHOR'S CONTRIBUTION: Widya Widita ORCID: 0000-0002-0044-1389 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/ or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Andi Hardianty ORCID: 0009-0009-5071-9105 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Anis Irawan Anwar ORCID: 0000-0002-1830-5617 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Andi Alfian Zainuddin ORCID: 0000-0003-4436-3906 Statistical analysis, Approval of the final version of the manuscript. Wong Lip Wih Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript Cynthia Sandra Kuncoro ORCID: 0009-0002-9971-4953 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Annisa Alviariza ORCID: 0000-0001-5337-109X Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Adhisti Prihastuti ORCID: 0009-0007-9079-6995 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Andi Dhidit Dwiputra ORCID: 0009-0001-4006-002X Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Critical review of the literature, Critical revision of the manuscript.

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ISSN-e 1984-8773 APOIO CIENTÍFICO:

www.surgicalcosmetic.org.br/

Extending the reach of the East-West flap: a modiﬁed technique for larger paramedian nasal tip defects Expandindo o alcance do retalho East-West: técnica modificada para defeitos paramedianos maiores da ponta nasal DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180585

How do I do it? Authors: Valery Lynn Turner1 Pablo Vargas Mora2,3 Rubén González Cuevas2,3 1

ABSTRACT Reconstruction of paramedian nasal tip defects is challenging because of the thick, adherent skin and limited tissue mobility in this region.The East-West advancement flap is a well-established reconstructive technique but has traditionally been limited to defects smaller than 1.5 cm. We describe a modification incorporating a superiorly oriented crescent-shaped extension at the base of the inferior Burow’s triangle to redistribute closure tension and preserve adjacent healthy tissue. This modification extends the applicability of the flap to larger defects while maintaining simplicity. In the cases presented, the technique achieved satisfactory aesthetic outcomes without clinically apparent nasal tip distortion or other complications, representing a practical reconstructive option for selected larger paramedian nasal tip defects. Keywords: Mohs Surgery; Surgical Flaps; Nose

Universidad de los Andes, Department of Dermatology, Santiago (RM), Chile Universidad de Chile, Department of Dermatology, Santiago (RM), Chile Instituto Nacional del Cáncer, Unidad de Melanoma y Cáncer de piel, Santiago (RM), Chile

Correspondence: Valery Lynn Turner E-mail: valeryturnerg@gmail. com / vturner@miuandes.cl

RESUMO A reconstrução de defeitos paramedianos da ponta nasal é desafiadora devido à pele espessa e aderente e à mobilidade tecidual limitada nessa região. O retalho de avanço East-West é uma técnica reconstrutiva bem estabelecida, mas seu uso tem sido tradicionalmente limitado a defeitos menores que 1,5 cm. Descrevemos uma modificação que incorpora uma extensão em forma de crescente, orientada superiormente, na base do triângulo de Burow inferior, com o objetivo de redistribuir a tensão durante o fechamento e preservar o tecido saudável adjacente. Essa modificação amplia a aplicabilidade do retalho a defeitos maiores, mantendo a simplicidade da técnica. Nos casos apresentados, a técnica proporcionou resultados estéticos satisfatórios, sem distorção clinicamente aparente da ponta nasal ou outras complicações, representando uma opção reconstrutiva prática para defeitos paramedianos maiores e selecionados da ponta nasal. Palavras-chave: Cirurgia de Mohs; Retalhos Cirúrgicos; Nariz

Funding: None Conflict of interest: None Submitted on: May 22, 2026 Final decision: July 3, 2026

How to cite this article: Turner VL, Mora PV, Cuevas RG. Extending the reach of the EastWest flap: a modiﬁed technique for larger paramedian nasal tip defects. Surg. Cosmet Dermatol. 2026;18(3):e20260585.

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Turner VL, Mora PV, Cuevas RG.

INTRODUCTION Reconstruction of paramedian nasal tip defects is a surgical challenge due to the thick, adherent skin and limited tissue mobility in the supratip region.1 The East-West flap, also known as horizontal advancement flap, provides a conceptually straightforward and effective reconstructive option for this area; however, its use has traditionally been limited to defects smaller than 1.5 cm.2,3 We describe a modification of the East-West advancement flap for the reconstruction of larger paramedian nasal tip defects after Mohs micrographic surgery. The modified technique incorporates a superiorly oriented crescent-shaped extension at the base of the inferior triangle. This modification preserves adjacent healthy tissue while reducing excessive tension during closure, thereby extending the applicability of the East-West flap to larger defects.

TECHNIQUE The traditional East-West ﬂap involves horizontal advancement of the dorsal nasal skin and excision of two Burow’s triangles (Figure 1).The superior triangle extends vertically above the defect, whereas the inferior triangle is oriented medially toward the columella. The width of the superior triangle should correspond to that of the defect, with suﬃcient vertical height to prevent the formation of a standing cone deformity along the nasal dorsum. In the proposed modification, the straight base of the inferior Burow’s triangle is replaced by a superiorly oriented crescent extending from the midpoint of the lateral edge of the defect toward the contralateral side, with a length equal to the horizontal width of the defect (Figure 2). The height of the inferior triangle can be adjusted according to the size and location of the defect and the dimensions of the nasal tip. Narrower nasal

Figure 1: Schematic representation of the traditional East-West ﬂap

Figure 2: Schematic representation of the modiﬁed East-West ﬂap, incorporating a superiorly oriented crescent-shaped extension at the base of the inferior triangle

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tips or more distal defects may require a shorter inferior triangle, measuring 50%–70% of the height of the superior triangle. The procedure begins with excision of the superior Burow’s triangle and the modified inferior triangle with its superiorly oriented crescent-shaped base. Extensive undermining in the sub–superficial musculoaponeurotic system (sub-SMAS) plane across the nasal tip and supratip region is crucial to permit assessment of tip distortion during flap advancement and ensure closure with minimal tension.1,5 The resulting cone-shaped flap is then advanced horizontally to fill the defect. Subcutaneous closure with 4-0 or 5-0 absorbable sutures is recommended, followed by superficial closure with 6-0 nylon sutures (Figures 3 and 4).2 Postoperative management consists of conservative wound care. The surgical site is cleansed daily with sterile saline solution, without the need for specialized dressings. Nylon sutures

are removed 7–10 days postoperatively. After suture removal, the scar is supported with micropore tape, and a moisturizing barrier cream is applied for 1 month to provide optimal scar maturation. DISCUSSION The East-West flap, initially described by Robins and subsequently by Goldberg, Alam, and others, is a well-established reconstructive option for nasal supratip defects.4 The proposed modification preserves the conceptual simplicity of the traditional flap while extending its applicability to larger nasal tip defects. By replacing the conventional straight-based inferior triangle with a crescent-shaped design, the modified technique maximizes the preservation of adjacent healthy tissue while minimizing closure tension and contour distortion. A potential disadvantage of this modification is narrowing of the nasal tip in the horizontal plane. However, this effect

Figure 3: Modified East-West flap for reconstruction of a paramedian nasal tip defect. (A) Paramedian nasal tip defect before reconstruction. (B) Preoperative marking of the modified East-West flap. (C) Excision of the superior triangle and incision of the modified inferior triangle. (D) Undermining of the flap. (E) Horizontal advancement of the flap into the defect. (F) Final closure with the flap sutured in place.

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was subtle in our patients and was considered aesthetically acceptable. On postoperative evaluation, no pincushioning or clinically apparent nasal tip deformity was observed. Follow-up at 3 and 6 months demonstrated satisfactory aesthetic outcomes. Several alternative techniques are available for reconstruction of nasal tip defects, each with specific advantages and limitations. The bilobed flap provides substantial tissue mobility through double transposition but may result in longer suture lines, trapdoor deformity, and contour irregularities. The crescentic nasojugal flap is another effective option but requires incisions extending along the alar groove, which may be more difficult to conceal.4,5 The paramedian forehead flap remains an

important reconstructive option for larger or more complex defects; however, it generally requires a two-stage procedure and entails greater reconstructive complexity. CONCLUSION The modified East-West advancement flap represents a promising reconstructive option for selected larger paramedian nasal tip defects. The cases presented suggest that this modification may achieve favorable aesthetic and functional outcomes while preserving nasal contour and adjacent healthy tissue. Further studies with larger patient cohorts and longer follow-up are needed to confirm these findings and better define the indications and limitations of this technique. l

Figure 4: Modified East-West flap for reconstruction of a paramedian nasal tip defect. A - Paramedian nasal tip defect before reconstruction. B - Preoperative marking of the modified East-West flap. C - Excision of the superior and modified inferior triangles, followed by extensive undermining. D - Advancement of the flap into the defect. E - Final closure with the flap sutured in place. F - Clinical appearance 3 months after surgery, frontal view.

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REFERENCES: 1.

Boyette JR. Reconstruction of a nasal tip defect, East-West advancement ﬂap. In: Stack BC, Moreno MA, Boyette JR, Vural EA, editors. Matrix head and neck reconstruction. Cham: Springer International Publishing; 2023. p. 255–7.

Geist DE, Maloney ME. The “East-West” advancement ﬂap for nasal defects: reexamined and extended. Dermatol Surg. 2012;38:1529–34.

Magliano J, Abelenda MP, Navarrete J, Bazzano C. East-West ﬂap after Mohs micrographic surgery. Actas Dermosiﬁliogr Engl Ed. 2019;110:759–62.

Goldberg LH, Alam M. Horizontal advancement ﬂap for symmetric reconstruction of small to medium-sized cutaneous defects of the lateral nasal supratip. J Am Acad Dermatol. 2003;49:685–9.

Durbec M, Disant F. Reconstruction of lateral defects of the tip and supratip less than 1.5 cm in diameter. Eur Ann Otorhinolaryngol Head Neck Dis. 2016;133:59–61.

AUTHOR’S CONTRIBUTION: Valery Lynn Turner 0000-0002-2195-5725 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Effective participation in the conduct of the study, Critical review of the literature, Critical revision of the manuscript Pablo Vargas Mora 0000-0002-9388-2940 Approval of the final version of the manuscript, Effective participation in the conduct of the study, Critical revision of the manuscript Rubén González Cuevas 0000-0003-1707-7373 Approval of the final version of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical revision of the manuscript

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Waterdrop excision technique for repairing a split earlobe after ear stretching Técnica de exérese em gota para correção de lóbulo auricular fendido após uso de alargador DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180550 ABSTRACT The earlobe is often pierced, and complications such as significant defects may occur, particularly after the use of ear gauges. Surgical correction of these defects is challenging due to tissue loss and the risk of aesthetic deformities. We report the case of a 26-year-old man with a residual left earlobe defect following ear gauge use, successfully treated with a novel waterdrop-shaped excision technique.This approach allowed simple primary closure while preserving the natural contour and volume of the earlobe, resulting in an excellent aesthetic outcome. This technique represents a feasible alternative for intermediate earlobe defects. Keywords: Ear Deformities, Acquired; Body Piercing; Surgery, Plastic

RESUMO O lóbulo auricular é perfurado com frequência, podendo evoluir com defeitos significativos, especialmente após o uso de alargadores. A correção desses defeitos representa um desafio cirúrgico devido à maior perda tecidual e ao risco de deformidades. Relatamos o caso de um homem de 26 anos com defeito residual no lóbulo auricular esquerdo após uso de alargador, tratado por meio de uma nova técnica de exérese em formato de gota. A abordagem permitiu fechamento simples, preservação da curvatura inferior e excelente resultado estético, configurando uma alternativa viável para defeitos intermediários do lóbulo. Palavras-chave: Deformidades Adquiridas da Orelha; Piercing Corporal; Cirurgia Plástica

How do I do it? Authors: Giulia Zanata Rossi1 Vitória Castelo Branco Rocha Ibiapina do Monte1 Lorena Queiroz Furtado de Mendonça1 Anna Carolina Miola1 1

UNESP, Infectious Diseases, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu (SP), Brazil

Correspondence: Anna Carolina Miola E-mail: anna.c.miola@unesp.br

Funding: None Conflict of interest: None Submitted on: January 20, 2026 Final decision: August 13, 2026

How to cite this article: Rossi GZ, Monte VCBRI, Mendonça LQF, Miola AC. Waterdrop excision technique for repairing a split earlobe after ear stretching. Surg Cosmet Dermatol. 2026;18(3):e20260550.

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INTRODUCTION Earlobes are often pierced for either aesthetic or cultural reasons. However, this practice can lead to complications, such as a split earlobe. In this context, lobuloplasty has become an increasingly in-demand procedure, both by women and men who are dissatisfied with aesthetic defects caused in the earlobe by the use of piercings, ear gauges, or earrings.1 There are different approaches to correcting these defects, ranging from local application of 90% trichloroacetic acid to surgical procedures, such as primary closure of de-epithelialized tissue or the use of flaps or grafts.2 The choice of technique should be individualized, with the aim of achieving the best possible aesthetic outcome. Most descriptions of surgical techniques take into account clefts caused by conventional earrings. In contrast, the use of ear gauges has become very common, and defects caused by their use are often not equivalent to the typical split earlobes caused by earrings. Such defects cause greater aesthetic discomfort when the patient discontinues use of the jewelry, as they involve greater tissue loss and skin laxity, particularly in the inferior portion of the earlobe. This makes correction challenging, and unaesthetic deformities may occur as a result of the surgical procedure.3 There are few descriptions in the literature of surgical techniques specifically aimed at correcting these defects. We report the case of a patient with a defect in the left earlobe caused by previous use of an ear gauge and corrected using the drop excision technique.The technique was developed for this case and achieved a satisfactory aesthetic outcome, with preservation of the inferior curvature. We also provide a brief review of the surgical techniques described in the literature for correcting medium to large earlobe defects. SURGICAL TECHNIQUE The patient chosen for the procedure was a 26-year-old man with a history of ear gauge use for 3 years. After discontinuing use of the ear gauge, the patient noted a persistent 6-mm-diameter hole in the left earlobe, with local distortion and elongation (Figure 1), and was subsequently referred for surgical correction of the defect. During surgical planning, we observed that revitalization of the hole by conventional de-epithelialization with primary closure, as used in conventional split earlobe repair, would not be appropriate given that the size of the hole corresponded to more than one-third of the earlobe size. In addition, the use of ear gauges leads to skin laxity of the earlobe and thinning of its inferior portion, which may hinder reconstruction using techniques involving de-epithelialization of the inferior earlobe border. To avoid the complications described above, the waterdrop excision technique was developed. The defect is de-epithelialized in the shape of a water droplet, such that the widest portion of the droplet encompasses the defect to be corrected, while the tapered end is strategically positioned at the most lateral portion of the earlobe and parallel to its inferior portion, with the aim of preserving the shape of the earlobe curvature

Figure 1: Surgical marking using the waterdrop excision technique for correction of an enlarged earlobe. The tapered end of the waterdrop ends at the most lateral portion of the earlobe, with its design parallel to the most inferior portion, thereby avoiding distortion.

Figure 2: Immediate postoperative appearance: preservation of earlobe shape, without distortion.

during closure (Figure 2). In the case described, to achieve closure without deformity, a small portion of skin at the end of the inferior tip was excised to avoid redundancy during closure (Figure 3). Anesthesia was performed with lidocaine without a vasoconstrictor using greater auricular nerve block. After excision of the area previously marked during preoperative planning, simple suturing was performed between the two edges, respecting the local anatomy, with 6-0 nylon suture. The technique allowed closure with a satisfactory aesthetic outcome, preserving the inferior curvature and lobular symmetry, without overall loss of earlobe volume compared with the earlobe before the procedure, despite the substantial size of the preoperative defect (Figure 3B). After 3 months of follow-up, the aesthetic outcome remained stable, with no scar retraction or secondary deformity.

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Figure 3: Preoperative A and postoperative B images in grayscale for better identification of the auricular structures. In green: tragus; in red: helix; in yellow: inferior portion of the earlobe, sutured to the defect after excision of redundant skin tissue. It is important to note that, despite removal of excess tissue, there was no significant overall reduction in the earlobe, since the defect caused by the ear gauge increases the overall local volume (image supplemented by artificial intelligence). Table 1: Comparison of techniques for correcting split earlobes with intermediate or large defects Technique

Description

Advantages

Disadvantages

Boutray, 2020⁹

De-epithelialization of defect; transverse crescent-shaped suture on the anterior surface and longitudinal crescent-shaped suture on the posterior surface.

Technically easy; no need for flap reconstruction; suitable for intermediate defects.

May cause deformities in larger defects

Arévalo-Ortega, 2025⁶

Use of punch 4 or 5 mm after elongating the cutting blade with forceps.

Technically easy and fast; no need for complex surgical material; excellent for small to intermediate defects.

The diameter of the punch is insufficient for larger defects.

Henderson-Malata, 2010¹¹

Complete excision of the enlarged portion of the medial earlobe to the beginning of the cleft; de-epithelialization of the medial surface; the lateral margin of the earlobe, which forms part of the tunnel, is used as a random-pattern flap; L-shaped closure of the defect.

Moderate level of difficulty.

Substantially reduces the size of the earlobe.

Arasaratnam-Pek Technique, 2011¹²,¹³

De-epithelialization of the entire defect; de-epithelialization of the lateral surface of the earlobe; suturing of the lateral surface of the earlobe in a spiral pattern.

Preserves the rounded shape of the earlobe.

Technically more difficult and time-consuming.

Collins Technique, 2015¹⁴

Excision of the inferior portion of the enlarged earlobe; de-epithelialization of the defect; advancement with a posterior-superior base advanced anteriorly to be sutured to the defect.

Preserves the rounded shape of the earlobe.

Technically more difficult and time-consuming.

Williams Technique, 2010¹⁵

Excision of the inferior portion of the enlarged earlobe; de-epithelialization of the defect; edge-to-edge suturing of the defect at the center.

Technically easier than the Collins technique; allows removal of lax tissue from the inferior portion.

The earlobe may become more pointed compared with the Collins technique.

DISCUSSION The objective of this article is to describe a new technique for correcting intermediate earlobe defects, aiming for a good aesthetic outcome and restoration of the natural shape of the earlobe, and to review the techniques described in the literature.

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Few publications focus on descriptions of split earlobes, particularly after the use of ear gauges. For small defects, primary closure preceded or not by punch excision, and, for large defects, excision with advancement flaps and Z-plasties are classically used.4,5,6,7 However, there are few reports on intermediate

Rossi GZ, Monte VCBRI, Mendonça LQF, Miola AC.

* Posterior suture concave and perpendicular to the anterior one

Figure 4: Representative diagram of the main surgical techniques described for correcting split earlobes caused by ear gauge use. The green dashed lines show the areas of de-epithelialization; the red areas show the areas of tissue excised because of redundancy; the blue dashed lines indicate the suture lines for each technique (image drawn using artificial intelligence and supplemented by the authors).

defects, for which two challenges must be considered: deformation of the natural curvature of the inferior margin, which requires technical care to restore the earlobe contour; and greater local tissue loss, since ear gauges cause this characteristic as a consequence of their use.8 Classic primary closure may cause distortion, with narrowing and elongation of the earlobe and, consequently, an unsatisfactory aesthetic outcome. Different techniques for correcting intermediate defects involve rotation or transposition flaps, with preservation of the inferior border while maintaining earlobe dimensions.9 However, for the present case, such approaches would not be aesthetically appropriate because of the increased earlobe proportions, in addition to being more complex and requiring greater skill and training on the part of the surgeon. The waterdrop closure technique for earlobes was developed with the aim of respecting the original shape of the earlobe while being easier to perform than techniques such as rotation or O-Z techniques of the earlobe, which require greater refinement.4 In addition, earlobes that have been subjected to ear gauge use generally have greater laxity, making closure more difficult and often requiring greater removal of devitalized tissue,

which may preclude the use of a more complex flap.10-15 Table 1 describes the main surgical techniques for correcting split earlobes, including their advantages and disadvantages, and Figure 4 shows a representation of each surgical technique. It is crucial to maintain the inferior curvature of the earlobe during lobuloplasty procedures; therefore, the surgeon must be attentive and careful during planning, particularly in cases in which the defect causes significant tissue loss, as with the use of ear gauges. In the present case, we describe a technically simple surgical technique that has not yet been described, with promising results for correcting split earlobes caused by ear gauges. CONCLUSION Correction of defects resulting from the use of ear gauges in the earlobes is challenging, given the risk of deformities and reduction in overall earlobe volume. Waterdrop excision allows preservation of the earlobe shape without significantly compromising overall local volume, and it has a low level of technical difficulty, making it feasible for routine office practice. Comparative studies with other techniques are needed to determine the best aesthetic and functional outcomes for earlobe defects involving greater tissue loss. l

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REFERENCES: 1.

McLaren LR. Cleft ear lobes: a hazard of wearing ear rings. Plast Reconstr Surg. 1954;14(6):456.

Sadaka M, Hantash S. Freestyle perforator flap in earlobe reconstruction. BMC Surgery. 2022;22(1).

Grohmann M, Weiland T, Tuca A-C, Wimbauer JM. Earlobe Correction of the Pierced Ear: A Systematic Review of the Literature and Principles for Surgical Reconstruction. Facial Plast Surg Aesthet Med. 2023;25(2):83-9.

Boutray M, Veyssiere A, Bekara F, Graillon N. Repair of gauge earlobe medium defect. J Stomatol Oral Maxillofac Surg. 2020;121(4):430-3.

Pfeifer GM. Attitudes toward piercings and tattoos. Am J Nurs. 2012;112(5):15.

Sharma HK, Gupta D, Punj S. Orifice Preserving Double Opposing Z-Plasty for Partial Split Ear Lobe Repair: A Review of 25 Cases. Dermatol Surg. 2018;44(2):270-4.

Tan EC. Punch technique-an alternative approach to the repair of pierced earlobe deformities. J Dermatol Surg Oncol. 1989;15(3):270-2.

12. Pek W-S, Goh LHT, Pek CH. The rolling earlobe flap for dilated ear holes following ear gauging: a novel approach to aesthetically preserving earlobe soft tissue volume. Arch Plast Surg 2017;44(5):453-6.

Arévalo-Ortega I, Lada-Colunga B, Artola-Igarza JL. Optimizing earlobe repair: A modified punch technique for elongated pierced earlobe holes. J Am Acad Dermatol. 2025;92(3):e49-e50.

13. Arasaratnam RBS, Patel SK, Pramechander D, Ramotar H, Daodu KA. Repair of large holes in stretched earlobes. Clin Otolaryngol 2011;36(6):597-8.

Sharma R, Krishnan S, Kumar S, Verma M. Rotation flap lobuloplasty: technique and experience with 24 partially torn earlobes. Int J Oral Maxillofac Surg. 2014;43(10):1206-10.

14. Collins JC, Harvey J, Hilinski JM. Reconstructing the Gauge Earlobe Defect. JAMA Facial Plastic Surgery. 2015;17(2):144-8.

10. Vathulya M, Jain V, Jain P. Simple Tips for Ear Lobule Reconstruction-"Lobuloplasty Revisited." Indian J Otolaryngol Head Neck Surg. 2019;71(S2):1096-8. 11. Henderson J, Malata CM. Surgical correction of the expanded earlobe after ear gauging. Aesthet Plast Surg 2010;34(5):632-3.

15. Williams AM, Majumder S. Earlobe reconstruction following plug and tunnel piercing. J Plast Reconstr Aesthet Surg. 2010;63(3):e294-5.

AUTHOR’S CONTRIBUTION: Giulia Zanata Rossi 0000-0001-8501-2286 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature. Vitória Castelo Branco Rocha Ibiapina do Monte 0000-0002-1361-5480 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Critical review of the literature. Lorena Queiroz Furtado de Mendonça 0009-0009-5377-1945 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature. Anna Carolina Miola 0000-0001-8926-734X Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript.

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Intralesional cryosurgery in the treatment of refractory keloids

Case Report

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180565

Criocirurgia intralesional no tratamento de queloide refratário

ABSTRACT Keloids are a benign fibroproliferative response of scar tissue that extends beyond the boundaries of the original wound, characterized by a high recurrence rate despite the various available treatments, including combination therapy.We report the case of a female patient with multiple spontaneous keloids, refractory to surgical excision and intralesional corticosteroid injections, with a significant impact on quality of life. A combined approach consisting of surgical excision and intralesional cryosurgery was performed. After one year, sustained regression, volumetric reduction, and no recurrence were observed. This case highlights intralesional cryosurgery as an effective strategy in the combined management of refractory keloids.

Authors: Barbara Brunca1 Giulia Maria dos Santos Goedert1 Ana Paula Weber1 Sofia Leite Mitidieri1 André Luiz Simião1 PUC-Campinas, Dermatology, Campinas (SP), Brazil

Keywords: Keloid; Cicatrix, Hypertrophic; Cryotherapy; Cryosurgery RESUMO O queloide é uma resposta fibroproliferativa benigna do tecido cicatricial que ultrapassa os limites da ferida inicial, caracterizado por elevada taxa de recidiva apesar dos diversos tratamentos disponíveis, inclusive procedimentos combinados. Relata-se paciente do sexo feminino com queloides múltiplos e espontâneos, refratários à cirurgia e a infiltrações intralesionais de corticoides, com grande impacto na qualidade de vida. Realizou-se abordagem combinada com ressecção cirúrgica e criocirurgia intralesional. Após um ano, observou-se regressão sustentada, com redução volumétrica, estabilidade clínica e ausência de recidiva. O relato reforça essa técnica como estratégia eficaz em terapias combinadas no manejo de queloides refratários.

Correspondence: Barbara Brunca E-mail: barbarabrunca@gmail.com / andresimiao@gmail.com

Palavras-chave: Queloide; Cicatriz Hipertrófica; Crioterapia; Criocirurgia Funding source: None Conflict of interest: None

Submitted on: March 16, 2026 Final decision: July 29, 2026

How to cite this article: Brunca B, Goedert GMS, Weber AP, Mitidieri SL, Simião AL. Intralesional cryosurgery in the treatment of refractory keloids. Surg Cosmet Dermatol. 2026;18(3):e20260565.

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INTRODUCTION Keloids are benign fibroproliferative disorders characterized by growth extending beyond the boundaries of the original lesion, resulting from dysregulated wound healing and leading to excessive collagen deposition. Unlike hypertrophic scars, they do not undergo spontaneous regression and are often associated with pruritus, pain, and substantial aesthetic impact, in addition to high recurrence rates.1,2 Several therapeutic approaches have been used to treat these lesions, including intralesional corticosteroid injections, laser therapy, surgical excision, and silicone sheets. However, no single approach has shown fully satisfactory efficacy, and combinations of different therapeutic modalities are often necessary.2,3 In this context, therapeutic algorithms have been proposed to guide the sequential selection of treatments. ASAP (Assessment, Soften, Approach, Prevent) proposes a stepwise approach based on lesion assessment, scar tissue softening, targeted treatment, and recurrence prevention.4 Intralesional cryosurgery has emerged as a promising alternative because it promotes the selective destruction of fibroproliferative tissue through controlled thermal injury, followed by collagen remodeling.3,5 We report the case of a patient with multiple refractory keloids treated with surgical excision and intralesional cryosurgery, with a favorable clinical outcome.The patient agreed to the procedure and subsequent publication and signed an informed consent form.The authors followed the Declaration of Helsinki.

CASE REPORT A 26-year-old woman had developed multiple keloids since the age of 8, initially after bilateral ear piercing, with progressive involvement of other regions in the absence of further trauma. On examination, she had lesions on the earlobes, suprapubic region, vulva, right arm, and right thigh, associated with pruritus and a substantial impact on quality of life (Figures 1–4). Over 12 years, she underwent multiple surgical excisions and intralesional injections of triamcinolone and 5fluorouracil, with recurrence following all treatments. Given the persisten-ce of the condition, partial resection of the suprapubic keloid was performed, followed by primary closure with a continuous anchored suture (Figure 5). Histopathological examination re-vealed a proliferation of thick bundles of hyalinized collagen arranged in a disorganized pattern in the dermis, confirming the diagnosis of keloid. After suture removal, intralesional cryo-surgery of the suprapubic lesion, which had the greatest impact on the patient, was initiated. Intralesional cryosurgery was performed under infiltrative anesthesia with lidocaine associated with a vasoconstrictor, following antisepsis with aqueous chlorhexidine. A sterile bone biopsy needle (NEO OXUS®, Medax), 11 G × 100 mm, was inserted along the longest axis of the keloid until it completely traversed the lesion, with its distal end left exposed to reduce the risk of subcutaneous emphysema. Connected to the liquid nitro-gen cryotherapy device via silicone tubing, the needle allowed progressive freezing of the keloid tissue from the center toward the periphery (Figure 6).

Figure 1: Multiple keloids on the right thigh

Figure 2: Keloids on the right arm

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Figure 3: Right earlobe: keloid resulting from previous piercing

Figure 5: Clinical appearance of the surgical wound immediately after partial resection of the suprapubic keloid, followed by primary closure with a continuous anchored suture

Figure 4: Suprapubic and vulvar regions: extensive linear and nodular keloid

Two sessions of intralesional cryosurgery were performed at a 1-month interval. During each session, 2 60-second freezing cycles were performed, interspersed with complete thawing of the tissue. Freezing time was counted after complete freezing of the keloid, respecting its clinical boundaries and avoiding the propagation of freezing to the adjacent skin. At the end of the procedure, a dressing with sterile gauze and Vaseline was applied and maintained for 48 hours, followed

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Figure 6: Intralesional cryosurgery technique. Connection of the sterile bone biopsy needle (NEO OXUS®, Medax), 11 G × 100 mm, to the liquid nitrogen cryotherapy device via silicone tubing. Insertion of the needle to completely traverse the keloid, allowing the passage of cooled gas through the needle lumen and progressive freezing of the lesion from the center toward the periphery while preserving adjacent tissues

Brunca B, Goedert GMS, Weber AP, Mitidieri SL, Simião AL.

by daily Vaseline dressings until complete healing by secondary intention. After re-epithelialization, continuous use of silicone sheets was resumed as adjuvant therapy (Figure 7). One month after the final session, significant volumetric reduction and clinical and quality-of-life improvements were observed. During follow-up, after confirmation of a new pregnancy, invasive therapies were discontinued, and only conservative measures and use of silicone sheets were maintained. After 1 year of follow-up, the patient remained stable, with no recurrence of the treated lesions or development of new keloids (Figure 8).

duals.2,3 Likewise, widely used intralesional corticosteroid injections have variable results and depend on adherence to multiple treatment sessions, as well possible local adverse effects such as skin atrophy and telangiectasias.1,3 In this setting, cryosurgery has become an important therapeutic modality for the treatment of hypertrophic scars and keloids.6,7 Its mechanism of action is based on the formation of intracellular ice crystals, disruption of cell membranes, secondary vascular injury with microthrombosis, and subsequent tissue necrosis, ultimately leading to collagen remodeling.6,7 In addition, freezing reduces fibroblast activity and local vascularity, factors that contribute to controlling scar growth.8 Intralesional cryosurgery represents a technical advance, promoting the selective destruction of fibroproliferative tissue while relatively preserving the adjacent epidermis.6 A systematic review conducted by van Leeuwen et al.6 found significant volumetric reductions following intralesional cryotherapy, with recurrence rates lower than those observed with surgical excision alone. Khattab et al.8 corroborated these findings by demonstrating marked clinical reduction associated with decreased vascular density and reorganization of collagen fibers after treatment. The literature emphasizes better outcomes when cryosurgery is used as part of a multimodal approach.3,6 In the present

DISCUSSION Keloid management remains challenging, particularly in patients with multiple lesions, early onset, and recurrent disease. The pathophysiology involves fibroblast hyperproliferation, excessive production of type III collagen, and alterations in cytokine and growth factor signaling, resulting in persistent growth beyond the boundaries of the original lesion.1 The tendency toward recurrence after isolated therapeutic interventions is one of the main obstacles to treatment. The literature indicates that surgical excision alone is associated with high recurrence rates, often exceeding 50% and potentially reaching even higher rates in predisposed indivi-

Figure 7: Immediate postoperative clinical appearance following the first session of intralesional cryosurgery, performed after partial surgical resection of the suprapubic keloid. Mild edema and erythema of the treated lesion were observed, consistent with the immediate effects of freezing, with preservation of the adjacent tissues and no immediate complications.

Figure 8: Surgical wound after approximately 1 year of follow-up. Following partial surgical resection, two sessions of intralesional cryosurgery, and continuous use of silicone sheets, sustained volumetric reduction and a stable scar were observed, with no clinical signs of recurrence or development of new lesions in the treated area

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case, the patient underwent partial resection of the suprapubic lesion, intralesional cryosurgery, and use of silicone sheets. Although the clinical outcome was favorable, it is not possible to determine the individual contribution of each therapeutic modality or to attribute the observed results exclusively to intralesional cryosurgery. Reported adverse events include transient pain, edema, erythema, and pigmentary changes.6,7 Severe complications are rare when the technique is performed correctly. In the present case, no relevant adverse effects were observed, reinforcing the safety and applicability of the method even in a sensitive anatomical area. The favorable clinical outcome, with progressive volumetric reduction and no recurrence, highlights the importance of longitudinal follow-up in patients with a history of multiple recurrences. Lesion stability, even after the temporary discontinuation of invasive therapies during pregnancy, suggests a sustained therapeutic response to date. Although this case report does not allow broad generalization, its relevance lies in documenting therapeutic strategies applied to unusual clinical presentations. In this case, the development of multiple spontaneous keloids since childhood, without

REFERENCES: 1. Marvin AM, Price HN. Keloids and hypertrophic scars. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

a consistent association with further trauma, is noteworthy. This rare feature suggests an individual predisposition and a more aggressive fibroproliferative behavior, possibly associated with genetic factors.This profile may account for the high recurrence rate and refractoriness observed, adding to the clinical interest of the case. Nevertheless, gaps remain in the literature regarding the standardization of the optimal freezing time, number of sessions, and intervals between applications.6 The heterogeneity of the available studies highlights the need for controlled clinical trials and greater methodological uniformity to establish optimized protocols. Even so, current evidence supports intralesional cryosurgery as a promising alternative when employed as part of a multimodal therapeutic strategy for refractory keloids. CONCLUSION This report presents a simple technique combining partial surgical resection, intralesional cryosurgery, and use of silicone sheets, resulting in significant improvement, clinical stability, and no recurrence during the follow-up period, without serious adverse effects.This approach represents a feasible alternative for the management of complex cases of multiple refractory keloids. l

Oliveira GV, Metsavaht LD, Kroumpouzos G. ASAP revisited: the Brazilian sequential algorithm for treating keloids and hypertrophic scars. Clin Dermatol. 2026;44(1):192-6.

van Leeuwen MCE, van Zuijlen PPM, van Leeuwen PAM, Niessen FB. Intralesional cryotherapy for the treatment of keloid scars: a systematic review. Plast Reconstr Surg Glob Open. 2015;3(6):e437.

Oliveira GV, Metsavaht LD, Kadunc BV, Jedwab SKK, Bressan MS, Stolf HO, et al. Treatment of keloids and hypertrophic scars: position statement of the Brazilian expert group GREMCIQ. An Bras Dermatol. 2016;91(1):87-100.

van Leeuwen MCE, Bulstra AEJ, Ket JCF, Galindo-Garre F, Ritt MJPF, van Zuijlen PPM, et al. Treatment of keloids and hypertrophic scars: a review. J Plast Reconstr Aesthet Surg. 2021;74(8):1700-13.

Mohamed AM, Alsharidah AM, Al-Sufyani MA, Al-Mubarak L, Alsaif FM, Alajlan MI, et al. Cryotherapy in dermatology: updated review. Clin Cosmet Investig Dermatol. 2021;14:803-14.

Oliveira GV, Nunes TA, Magna LA, Cintra ML, Kitten GT, Zarpellon S, et al. Silicone versus nonsilicone gel dressings: a controlled trial. Dermatol Surg. 2001;27(8):721-6.

Khattab FM, Tawfik AA, Hassan MA, Mohammed GF, Elsaie ML. Intralesional cryotherapy for keloids and hypertrophic scars: clinical eﬃcacy and histologic findings. J Cosmet Dermatol. 2022;21(1):88-94.

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Brunca B, Goedert GMS, Weber AP, Mitidieri SL, Simião AL.

AUTHOR’S CONTRIBUTION: 0000-0002-2492-8474 Barbara Brunca Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript Giulia Maria dos Santos Goedert Acquisition, analysis and interpretation of data

0000-0002-6672-0276

Ana Paula Weber 0000-0002-8841-7817 Acquisition, analysis and interpretation of data Sofia Leite Mitidieri 0009-0000-2752-9391 Statistical analysis, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature, Critical revision of the manuscript André Luiz Simião 0000-0002-0246-2001 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript

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Dermal nerve sheath myxoma of the toe and its management – A case report Mixoma dérmico da bainha nervosa do dedo do pé e seu manejo – Relato de caso

Case Report Authors: Jiten Kumar Mishra1 Abhijith Valsalan1 Shamendra Anand Sahu1 Jalaz Joezer Rahmi1 1

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180536 ABSTRACT Nerve sheath myxoma (NSM) is a rare benign tumor of peripheral nerve sheath origin that typically presents as a small nodule on the extremities of young adults. We report an unusual case of dermal NSM of the toe in a 40-year-old man, present since birth. Due to its nonspecific clinical features, NSM may be difficult to diagnose before biopsy and can resemble other benign soft-tissue lesions. Histopathologic and immunohistochemical evaluation is therefore essential for establishing accurate diagnosis. Awareness of this uncommon entity and its inclusion in the differential diagnosis of small, firm subcutaneous lesions may facilitate appropriate management and help prevent misdiagnosis. Keywords: Myxoma; Neurothekeoma; Toes

RESUMO O mixoma da bainha nervosa (MBN) é um tumor benigno raro originário da bainha dos nervos periféricos, que geralmente se apresenta como um pequeno nódulo nas extremidades de adultos jovens. Relatamos um caso incomum de MBN dérmico em dedo do pé de um homem de 40 anos, presente desde o nascimento. Devido às suas características clínicas inespecíficas, o MBN pode ser de difícil diagnóstico antes da biópsia e pode assemelhar-se a outras lesões benignas de partes moles. A avaliação histopatológica e imuno-histoquímica é, portanto, essencial para o estabelecimento de um diagnóstico preciso. O conhecimento dessa entidade incomum e sua inclusão no diagnóstico diferencial de pequenas lesões subcutâneas de consistência firme podem facilitar o manejo adequado e contribuir para evitar erros diagnósticos. Palavras-chave: Mixoma; Neurotecoma; Dedos do pé

All India Institute of Medical Sciences Raipur, Burns and Plastic surgery, Raipur, Chhattisgarh, India

Correspondence: Shamendra Anand Sahu E-mail: shamendrasahu@gmail. com

Funding: None Conflict of interest: None Submitted on: November 2, 2025 Final decision: June 29, 2026

How to cite this article: Mishra JK, Valsalan A, Sahu SA, Rahmi JJ. Dermal nerve sheath myxoma of the toe and its management – A case report. Surg Cosmet Dermatol. 2026;18(3):e20260536.

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Mishra JK, Valsalan A, Sahu SA, Rahmi JJ.

CASE REPORT A 40-year-old man presented with a painless swelling over the dorsolateral aspect of the right fourth toe that had been present since birth and had progressively increased in size. The lesion had become painful approximately 1 year before presentation. There was no history of trauma, bleeding from the lesion, or similar swellings elsewhere on the body. Physical examination revealed a tender, firm-to-hard, nonpulsatile, noncompressible, smooth, lobulated subcutaneous swelling measuring 2 × 1 cm over the dorsal aspect of the right fourth toe. The swelling was adherent to the overlying skin but did not restrict toe movement (Figure 1). No similar lesions were identified elsewhere, and there was no regional lymphadenopathy. Plain radiography of the foot was unremarkable. Fine needle aspiration cytology indicated a benign spindle cell neoplasm. The lesion was completely excised on an outpatient basis under digital block anesthesia and sent for histopathologic examination. The resulting wound was primarily closed, with a small residual raw area left to heal by secondary intention. Histopathologic examination of the excised tumor showed spindle-to-stellate cells with mild nuclear atypia, scant eosinophilic cytoplasm, and bipolar and multipolar processes. The cells were embedded in a fibrillary myxoid stroma, with no areas of necrosis or atypical mitoses (Figures 2 and 3). At 2-year follow-up, there was no evidence of local recurrence (Figure 4).

nerve sheath myxoma (NSM) was subsequently recognized as a distinct entity. Further studies demonstrated subtle morphologic differences, distinct immunohistochemical profiles, and differing ultrastructural features between these two tumor types. Reported cases of NSM have involved several anatomic sites, including the extremities (finger, knee, and pretibial region), neck,1 and tongue. NSM most commonly occurs during the third and fourth decades of life, with a male‑to‑female ratio of approximately 1:1. In contrast, neurothekeomas predominantly affect the upper extremities and head and neck region, typically during the second and third decades of life, with a female predominance.2 Grossly, NSMs usually present as firm, slow-growing, painless nodules or masses measuring 0.4 to 4.5 cm. On cut section, they may contain multiple small, well-demarcated, translucent, whitish mucoid nodules. Histologically, these tumors have a characteristic multilobular structure, with individual lobules composed of spindle and stellate cells arranged in swirling, lamellar, and concentric patterns. The cells are embedded in an abundant myxoid stroma and generally exhibit mild nuclear pleomorphism and rare mitosis. Lesions may involve the epidermis, dermis, or subcutaneous tissue.3 Immunohistochemically, the tumor cells are usually strongly positive for S100 protein, glial fibrillary acidic protein (GFAP), and vimentin. Epithelial membrane antigen (EMA) is often absent or limited to a small number of perineural cells.4 In our patient, S100 staining was diffusely positive in spindle cells, whereas EMA was diffusely expressed in the perineural cells, which were more numerous at the periphery of the lesion, indicating bidirectional schwannomatous and perineural differentiation. A similar pattern of bidirectional differentiation was previously reported by Zamecnik et al.5 Electron microscopic

DISCUSSION Neurothekeomas were initially described as benign cutaneous tumors of nerve sheath differentiation; however, dermal

Figure 1: Dermal nerve sheath myxoma over the distal aspect of the right fourth toe 261 227 223

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Figure 2: Gross appearance of the excised specimen

Figure 4: Clinical appearance at 2-year follow-up, with no evidence of local recurrence

Figure 3: Histopathology showing hyperkeratotic stratified squamous epithelium with focal acanthosis and well-circumscribed myxoid lobules in the dermis containing fibrous tissue and spindle-to-stellate neoplastic cells (hematoxylin and eosin, ×10)

findings in NSM include single or duplicated external laminae surrounding the cells, desmosome-like junctions, cytoplasmic microfilaments, myelin figures, and interdigitating cytoplasmic processes.6

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More recent molecular evidence further supports the distinction between NSM and neurothekeoma. A gene expression study comparing the two tumors demonstrated that neurothekeoma expresses genes predominantly encoding glycoproteins and metalloproteinases associated with macrophages and fibroblasts. Differential expression of the S100B gene was also observed between NSM and neurothekeoma. These findings provide additional evidence that NSM is a neoplasm of peripheral nerve sheath origin and is distinct from neurothekeoma.3

Mishra JK, Valsalan A, Sahu SA, Rahmi JJ.

Complete surgical excision is usually the treatment of choice for symptomatic lesions, as incomplete excision is associated with a high risk of local recurrence.5 The histopathologic differential diagnosis of NSM includes several myxoid tumors, particularly plexiform neurofibroma, myxoid neurofibroma, myxoid schwannoma, extraneural perineurioma, and cutaneous, juxta-articular, and intramuscular myxomas.7 Cutaneous myxomas involving the dermis and subcutis may similarly consist of multiple myxoid masses containing spindle-to-stellate neoplastic cells. However, cutaneous myxomas are positive for CD34 and negative for S100 protein, providing a useful immunohistochemical distinction from NSM.8 CONCLUSION Dermal NSM is a benign myxoid neoplasm of peripheral nerve sheath origin. Its cytologic differential diagnosis includes

neurothekeoma, myxoid neurofibroma, plexiform neurofibroma, myxoid schwannoma, extraneural perineurioma, cutaneous myxoma, intramuscular and juxta-articular myxomas, cutaneous mucinosis, and hamartomas. These entities may share cytologic features, including myxoid material and benign spindle-to-stellate cells, making histopathologic and immunohistochemical evaluation essential for establishing an accurate diagnosis.9 Preoperative diagnosis can be challenging because of the lack of specific clinical or imaging features. This case highlights the importance of considering dermal NSM in the differential diagnosis of a long-standing myxoid soft-tissue lesion at an unusual site, such as the toe. Complete surgical excision is important because incomplete removal may result in local recurrence.Therefore, clinical follow-up is warranted, particularly after incomplete excision or when there is concern for residual disease.10 l

REFERENCES: 1.

Bhat A, Narasimha A, C V, Vk S. Nerve sheath myxoma: report of a rare case. J Clin Diagn Res. 2015;9(4):ED07-9.

Alsalam FA. Benign nerve sheath myxoma: Atypical giant lesion in atypical location. Gulf J Dermatol Venereol. 2016;23(2).

Kim BW, Won CH, Chang SE, Lee MW. A case of nerve sheath myxoma on finger. Indian J Dermatol. 2014 Jan;59(1):99-101.

Masamatti SS, Narasimha A, Janardhan JV. An unusual case of Nerve sheath myxoma with schwannomatous and perineural differentiation. Ann of Pathol and Lab Med [Internet]. 2017 Jan. 3 [cited 2025 Jun. 6];3(6):C319-322.

Tafti DA, Dearborn MC, Ornoff A, Moeck AR, Cecava ND. Nerve Sheath Myxoma in the Lower Extremity: A Rare Case with Description of Magnetic Resonance Imaging and Sonographic Findings. Am J Case Rep. 2021;5(22):e927922.

Suh YL, Song KY, Kim JM. Nerve sheath myxoma (neurothekeoma)--a case report. J Korean Med Sci. 1992;7(1):85-9. Suh YL, Song KY, Kim JM. Nerve sheath myxoma (neurothekeoma)--a case report. J Korean Med Sci. 1992;7(1):85-9.

J Wang, D Sarma, E Santos, B Wang. Dermal nerve sheath myxoma. Int J Dermatol. 2006;5(2).

Khashaba H, Hafez E, Burezq H. Nerve Sheath Myxoma: A rare tumor, a case report and literature review. International Journal of Surgery Case Reports. 2020 ;73:183-6.

10. Bergamin, F., Gangemi, E. N., Cerato, C., Clemente, A., Borsetti, M., Suriani, A., Taraglio, S. An unusual case of neurothekeoma of the arm in an adult. J Ortho Traumatol. 2015;17(3):287–90.

AUTHOR’S CONTRIBUTION: Jiten Kumar Mishra 0000-0001-6357-5299 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Abhijith Valsalan 0000-0001-9827-3645 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Shamendra Anand Sahu 0000-0003-0877-8725 Statistical analysis, Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Jalaz Joezer Rahmi 0000-0002-3330-0136 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical revision of the manuscript.

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Melanoma pitfalls: When danger lies in familiarity – a series of 5 cases of clinical mimicry of common dermatoses Armadilhas do melanoma: Quando o perigo está na familiaridade – série de cinco casos com mimetismo clínico de dermatoses comuns

Case Report Authors: Márcio Fellipe Menezes Viana1 Renata Ferreira Magalhães1 Andréa Fernandes Eloy da Costa França1 Lucas de Teive Argollo1 Thais Helena Buffo1 Hamilton Ometto Stolf1 1

Universidade Estadual de Campinas, Dermatologia, Campinas (SP), Brazil

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180596 ABSTRACT We report 5 cases of melanoma with initial clinical presentations suggestive of common dermatoses, including seborrheic keratosis, basal cell carcinoma, Bowen disease, actinic keratosis, and solar lentigo. In 4 cases, documented dermoscopy revealed findings discordant with the initial clinical impression and prompted biopsy; in 1 case, lesion evolution and recurrent bleeding prompted excision, confirming a thick nodular melanoma. This series highlights how familiar clinical patterns may promote diagnostic anchoring and delay suspicion. Lesion evolution, patient concern, total-body skin examination, systematic dermoscopy, and a low threshold for biopsy are practical strategies for reducing biases and improving early diagnosis. Keywords: Melanoma; Dermoscopy; Diagnostic Errors

RESUMO Relatamos cinco casos de melanoma com apresentação clínica inicial sugestiva de dermatoses comuns, incluindo queratose seborreica, carcinoma basocelular, doença de Bowen, queratose actínica e melanose solar. Em quatro casos, a dermatoscopia documentada revelou achados discordantes da hipótese inicial e motivou biópsia; em um caso, a evolução clínica e sangramentos recorrentes indicaram excisão, confirmando melanoma nodular espesso. A série destaca como padrões familiares favorecem ancoragem diagnóstica e atraso na suspeição. História evolutiva, preocupação do paciente, exame de pele total, dermatoscopia sistemática e baixo limiar para biópsia são estratégias práticas para reduzir vieses e melhorar o diagnóstico precoce. Palavras-chave: Melanoma; Dermoscopia; Erros de Diagnóstico

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Correspondence: Márcio Fellipe Menezes Viana Email: mfellipe.menezes@gmail. com / marciofm@unicamp.br

Funding: None Conflict of interest: No Submitted on: June 17, 2026 Final decision: July 16, 2026

How to cite this article: Viana MFM, Magalhães RF, França AFEC, Argollo LT, Buffo TH, Stolf HO. Melanoma pitfalls: When danger lies in familiarity – a series of 5 cases of clinical mimicry of common dermatoses. Surg Cosmet Dermatol. 2026;18(3):e20260596.

Viana MFM, Magalhães RF, França AFEC, Argollo LT, Buffo TH, Stolf HO.

INTRODUCTION Melanomas may mimic lesions commonly encountered in dermatologic practice, including basal cell carcinoma (BCC), Bowen disease, actinic keratosis (AK), seborrheic keratosis, and other benign or keratinocytic dermatoses. Such mimicry may promote cognitive biases, particularly anchoring and premature diagnostic closure, by activating familiar clinical patterns and reducing the perception of risk.1-3 Dermoscopy improves diagnostic accuracy for melanoma detection compared with clinical examination alone and, in practice, may serve as a strategy to interrupt intuitive pattern recognition when the initial clinical impression is discordant with the morphologic findings.4 In settings where dermoscopy is unavailable or has not been documented, the history of lesion evolution — corresponding to the “E” criterion of the ABCDE rule — should lower the threshold for biopsy, particularly in the presence of growth, changes in color or surface, symptoms, or bleeding.4-7 In addition, total-body skin examination may increase the detection of skin cancer even in patients presenting with a focal complaint, thereby reducing “tunnel vision” in the outpatient setting. Patient concern may also support clinical decision-making when the assessment is inconclusive.9,10 This case series is presented for its educational value and immediate applicability to routine dermatologic practice, illustrating 5 seemingly common presentations that concealed melanoma.

Case 3: A 62-year-old patient with Fitzpatrick skin phototype III presented with a mildly scaly erythematous lesion on the left upper extremity that had appeared 6 months earlier, with an initial clinical appearance suggestive of Bowen disease or superficial BCC. Documented dermoscopy revealed vascular patterns (polymorphous vessels and structureless areas) inconsistent with an isolated keratosis, prompting diagnostic biopsy. Histopathology confirmed superficial spreading melanoma in situ (Figure 3). Case 4: A 48-year-old patient with Fitzpatrick skin phototype II presented with an erythematous, pearly nodule in the left preauricular region that had developed several months earlier and was clinically consistent with BCC. Dermoscopy was documented and raised suspicion for a melanocytic/atypical lesion, prompting excisional rather than incisional biopsy, as would have

CASE SERIES This retrospective series included 5 cases treated with surgical excision. For each case, the anatomic site, clinical course, clinical pattern, dermoscopic findings, and histopathologic findings were described. Case 1: A 70-year-old patient with Fitzpatrick skin phototype II presented with multiple homogeneous brown macules resembling solar lentigines or pigmented AK, with no lesion generally standing out from the others. Dermoscopy of the left temporal region revealed features of melanocytic atypia, raising suspicion and prompting diagnostic biopsy. Histopathology confirmed lentigo maligna (Figure 1). Case 2: A 60-year-old patient with Fitzpatrick skin phototype III presented with a lesion on the left thigh that had been present for more than 5 years, with frequent bleeding secondary to manipulation. Examination revealed a large verrucous lesion clinically consistent with seborrheic keratosis; dermoscopy was not documented. Excision was indicated because of the lesion’s size, growth over time, and the patient’s informed preference. Histopathology confirmed nodular melanoma with a nevoid pattern and a Breslow thickness of 4 mm. The absence of documented dermoscopy in this case was deliberately retained in the analysis as part of the phenomenon under investigation, reinforcing the need for a low tolerance for diagnostic uncertainty when evaluating evolving lesions (Figure 2).

Figure 1. Pigmented macule in the left temporal region. Dermoscopy shows asymmetric follicular pigmentation and linear projections emerging from follicular openings. The black circle highlights asymmetric follicular pigmentation and rhomboidal structures.

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Figure 3. Mildly scaly erythematous plaque measuring approximately 1.5 cm on the left forearm (black circle). Dermoscopy shows shiny white structures and an atypical vascular pattern. Histopathology shows an atypical melanocytic proliferation predominantly involving the junction, with lentiginous growth along the basal layer and architectural disorder (asymmetric/heterogeneous distribution), with foci suggestive of pagetoid spread (isolated suprabasal melanocytes).

Figure 2. A 3-cm hyperkeratotic verrucous lesion on the left thigh. Histopathology shows a melanocytic proliferation with a papillomatous growth pattern among pseudohorn cysts, hyperkeratosis, well-demarcated borders, and an exophytic appearance. Atypical epithelioid melanocytes are located at the dermoepidermal junction, while the lesional cells decrease in size in the dermis, mimicking the maturation with depth observed in melanocytic nevi. Immunohistochemical staining for HMB-45 (×40) demonstrates maturation with depth mimicking a melanocytic nevus.

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Viana MFM, Magalhães RF, França AFEC, Argollo LT, Buffo TH, Stolf HO.

Figure 4. Erythematous papule measuring approximately 1 cm in the left preauricular region, with a pearly appearance. Dermoscopy shows atypical globules and network, a blue-white veil, and a milky-pink background. Histopathology shows a dense, nodular/expansile, asymmetric, and poorly circumscribed cellular proliferation involving predominantly the superficial and mid dermis, composed of atypical cells arranged in poorly defined sheets/nests, with scant or absent melanin pigment (consistent with a hypomelanotic pattern).

DISCUSSION The 5 cases presented illustrate a common diagnostic mechanism: clinical presentations sufficiently familiar to promote anchoring on far more prevalent diagnoses, despite ultimately representing melanoma. Although melanomas mimicking nonmelanocytic lesions account for only approximately 1.4% of cases at tertiary referral centers, their clinical relevance is disproportionate because these presentations are associated with greater Breslow thickness, a higher frequency of micrometastases, and greater sentinel lymph node positivity, reflecting the diagnostic delay inherent in clinical mimicry.1

been performed for suspected BCC. Histopathology confirmed hypomelanotic nodular melanoma with a Breslow thickness of 2.3 mm (Figure 4). Case 5: A 68-year-old patient with Fitzpatrick skin phototype II presented with an erythematous keratotic lesion on the right forearm, with an initial clinical appearance suggestive of Bowen disease or AK. Documented dermoscopy revealed vascular patterns inconsistent with this diagnosis, prompting diagnostic biopsy. Histopathology confirmed superficial spreading melanoma in situ (Figure 5).

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Figure 5. Mildly scaly erythematous plaque measuring approximately 1.2 cm on the left arm. Dermoscopy shows an erythematous background, shiny white structures, and atypical vessels. Histopathology confirmed the diagnosis of lentigo maligna melanoma in situ.

Rather than simply lacking signs of malignancy, these presentations exploit cognitive shortcuts inherent in diagnostic reasoning, particularly intuitive pattern recognition, thereby promoting biases such as anchoring and premature diagnostic closure. Although these mechanisms are fundamental to everyday medical practice, they become vulnerable when malignant lesions reproduce features typical of far more prevalent dermatoses, increasing the risk of diagnostic delay.2,3 Case 2 exemplifies this phenomenon. A verrucous lesion clinically consistent with seborrheic keratosis proved to be nodular melanoma with a Breslow thickness of 4 mm. In this context, the absence of documented dermoscopy highlights an important limitation of the initial assessment and reinforces that evolving lesions, even when apparently benign, should lower — rather than raise — the threshold for biopsy.

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Dermoscopy represents one of the main strategies for mitigating this process of diagnostic anchoring. By replacing the initial clinical impression with a systematic assessment of morphologic criteria, dermoscopy reduces exclusive reliance on intuitive pattern recognition and significantly improves diagnostic accuracy. A systematic review including more than 23,000 lesions demonstrated a significant increase in sensitivity and specificity for melanoma diagnosis when dermoscopy was added to clinical examination, simultaneously reducing missed melanomas and unnecessary excisions.4 In the present series, this benefit was evident in 4 of the 5 cases, in which documented dermoscopy altered the initial diagnostic impression by revealing structures incompatible with Bowen disease, AK, or BCC. In addition to improving diagnostic accuracy, dermoscopy assists in identifying particularly challenging melanoma variants.

Viana MFM, Magalhães RF, França AFEC, Argollo LT, Buffo TH, Stolf HO.

Melanomas mimicking seborrheic keratosis frequently exhibit structural asymmetry, atypical vessels, and absence of classic keratotic criteria, whereas amelanotic or hypomelanotic melanomas may display a pink background associated with polymorphous vessels, mimicking BCC, keratinocytic tumors, or inflammatory dermatoses.5,6 These findings reinforce that dermoscopy should be used not only to confirm the initial clinical impression but, more importantly, to identify features that contradict it. However, dermoscopy does not replace clinical history. Lesion evolution, represented by the “E” criterion of the ABCDE rule, was incorporated into the clinical assessment criteria for melanoma specifically to account for changes in size, shape, color, surface, or symptoms, including bleeding and tenderness.7 Case 2 illustrates this principle: despite the absence of documented dermoscopy, progressive growth and recurrent episodes of bleeding prompted excision, allowing the definitive diagnosis to be established. Diagnostic delay results from the interaction of patientand physician-related factors. Several patients delay seeking medical attention after noticing changes in a lesion, while empirical treatments, low clinical suspicion, and delayed referral may also contribute to diagnosis at more advanced stages.8 In this setting, patient concern should be considered an additional clinical finding, especially when associated with evolving lesions or atypical features.9 Another relevant aspect underscored by this series is the importance of total-body skin examination. In addition to redu-

cing so-called “tunnel vision” focused exclusively on the presenting complaint, this practice increases the detection of additional skin cancers, including melanomas unrelated to the initial reason for consultation, representing a simple, high-impact strategy in dermatologic practice.10 The cases presented highlight 3 practical recommendations for routine dermatologic practice: (1) systematically incorporate and document dermoscopy, particularly for apparently commonplace lesions that are atypical or evolving; (2) maintain a low threshold for biopsy when there is discordance among the clinical impression, lesion evolution, and dermoscopic findings; and (3) systematically integrate lesion evolution, patient concern, and total-body skin examination into diagnostic reasoning. The principal challenge posed by melanoma mimics is not the absence of signs of malignancy, but their ability to reproduce clinical patterns that are highly familiar to dermatologists. Familiarity, therefore, should not reduce diagnostic vigilance; rather, it should prompt more careful evaluation of evolving lesions or those with discordant findings. Integrating the clinical history, documented dermoscopy, total-body skin examination, and a low threshold for histopathologic confirmation provides a practical strategy for reducing cognitive biases, minimizing diagnostic delays, and improving melanoma prognosis. l Acknowledgments To Dr. Mercedes Cristina Mongeli Martim Paro for documenting a case presented in this article and for her enthusiasm for skin dermatoscopy.

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Detrixhe A, Libon F, Mansuy M, Nikkels-Tassoudji N, Rorive A, Arrese JE, et al. Melanoma masquerading as nonmelanocytic lesions. Melanoma Res. 2016;26(6):631-4.

Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003;78(8):775-80.

Pampena R, Lai M, Lombardi M, Mirra M, Raucci M, Lallas A, et al. Clinical and dermoscopic features associated with diﬃcult-to-recognize variants of cutaneous melanoma: a systematic review. JAMA Dermatol. 2020;156(4):430-9.

Abbasi NR, Shaw HM, Rigel DS, Friedman RJ, McCarthy WH, Osman I, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004;292(22):2771-6.

Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med. 2005;165(13):1493-9.

Dinnes J, Deeks JJ, Chuchu N, Ferrante di Ruﬀano L, Matin RN, Thomson DR, et al. Dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. Cochrane Database Syst Rev. 2018;12(12):CD011902.

Xavier MHSB, Drummond-Lage AP, Baeta C, Rocha L, Almeida AM, Wainstein AJA. Delay in cutaneous melanoma diagnosis: sequence analyses from suspicion to diagnosis in 211 patients. Medicine (Baltimore). 2016;95(31):e4396.

Carrera C, Segura S, Aguilera P, Scalvenzi M, Longo C, Barreiro A, et al. Dermoscopic clues for diagnosing melanomas that resemble seborrheic keratosis. JAMA Dermatol. 2017;153(6):544-51.

Stoecker WV, Rader RK, Rabinovitz HS, Oliviero M, Calcara DA, Malters JM, et al. Patient concern as a predictor of cutaneous malignancy. Br J Dermatol. 2016;174(1):222-4.

10. Argenziano G, Zalaudek I, Hofmann-Wellenhof R, Bakos RM, Bergman W, Blum A, et al. Total body skin examination for skin cancer screening in patients with focused symptoms. J Am Acad Dermatol. 2012;66(2):212-9.

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AUTHOR’S CONTRIBUTION: Márcio Fellipe Menezes Viana 0009-0005-1663-9591 Conception and design of the study, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Critical review of the literature. Renata Ferreira Magalhães 0000-0001-9170-932X Statistical analysis, Critical revision of the manuscript. Andréa Fernandes Eloy da Costa França 0000-0003-1657-4570 Statistical analysis, Conception and design of the study. Lucas de Teive Argollo Acquisition, analysis and interpretation of data. Thais Helena Buﬀo 0000-0002-6833-7596 Approval of the final version of the manuscript, Effective participation in the conduct of the study, Critical review of the literature. Hamilton Ometto Stolf 0000-0002-3540-2769 Approval of the final version of the manuscript, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical revision of the manuscript.

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Onychocytic matricoma of the hallux: a rare nail neoplasm at an unusual site Matricoma onicocítico em hálux: neoplasia ungueal rara em localização incomum

Case Report Authors: Heloisa Calegari Borges1 Isabelle Sousa Medeiros Torres Ferreira1 Flauberto de Sousa Marinho1 1

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180592 ABSTRACT Onychocytic matricoma (OCM) is a rare benign neoplasm of the nail matrix that presents as longitudinal pachymelanonychia with striking onychogenic capacity. Few cases have been reported in the literature, mostly involving the fingernails. Treatment consists of complete surgical excision of the lesion, which is curative in most cases. We report a case of OCM on the great toenail, contributing to the clinical and histopathologic recognition of this entity. Keywords: Nails; Rare Diseases; Neoplasms

RESUMO O matricoma onicocítico (MOC) é uma neoplasia benigna rara da matriz ungueal que se apresenta como paquimelanoníquia longitudinal e com grande capacidade onicogênica. Há poucos casos relatados na literatura, sendo a maioria em unhas das mãos. O tratamento é cirúrgico, com excisão completa da lesão, o que é curativo na maioria dos casos. O presente relato descreve um caso de MOC localizado no hálux, contribuindo para o reconhecimento clínico e histopatológico dessa entidade. Palavras-chave: Unhas; Doenças Raras; Neoplasias

Faculdade de Medicina Nova Esperança, Dermatologia, João Pessoa (PB), Brazil

Correspondence: Heloisa Calegari Borges E-mail: heloisacalegarib@gmail.com

Funding: None Conflict of interest: None Submitted on: June 4, 2026 Final decision: August 6, 2026

How to cite this article: Borges HC, Ferreira ISMT, Marinho FS. Onychocytic matricoma of the hallux: a rare nail neoplasm at an unusual site. Surg Cosmet Dermatol. 2026;18(3):e20260592.

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Borges HC, Ferreira ISMT, Marinho FS.

INTRODUCTION Onychocytic matricoma (OCM) is a benign, monodactylous neoplasm arising from the nail matrix, first described by Perrin et al. in 2012. It is characterized by striking onychogenic capacity, manifesting as thickening of the nail plate associated with longitudinal melanonychia — a clinical presentation termed longitudinal pachymelanonychia.1,2 Since its initial description, few cases have been reported in the literature, with fingernail involvement predominating. Most reported cases have occurred in adults between the fourth and sixth decades of life, with a slight male predominance.3-5 Toenail involvement is uncommon, with only a few documented cases.3-8 Alvarez et al. reported the first case in a Black patient, also involving the great toenail, confirming that OCM may occur across different skin phototypes.9 Despite its indolent behavior, OCM frequently mimics malignant tumors, such as subungual melanoma and Bowen’s disease, raising diagnostic concern and often prompting surgical intervention.4,6,9 In a recent review of 14 cases, Perrin et al. emphasized the rarity of toenail involvement, identifying only 4 cases at this site.3 We report a case of OCM on the great toenail, contributing to the clinical and histopathologic recognition of this entity.

CASE REPORT A 54-year-old man with Fitzpatrick skin phototype III presented with an asymptomatic “black line” on the left great toenail that had been present for 3 years. He reported gradual progression of the pigmentation over the preceding months. Physical examination revealed a black longitudinal band approximately 3 mm wide, associated with focal/localized thickening of the nail plate, mild distal onycholysis, and absence of Hutchinson’s sign (Figure 1). Dermoscopy showed homogeneous longitudinal melanonychia and localized subungual keratosis (Figures 2, 3, and 4). Given the clinical suspicion of pigmented onychopapilloma or OCM, an excisional biopsy was performed. After aseptic preparation and antisepsis, a proximal digital nerve block was performed, followed by distal elevation of the nail plate, revea-

Figure 1: Black longitudinal band of the nail plate with localized subungual keratosis on the left great toenail.

Figures 2 and 3: Dermoscopy of the nail plate showing longitudinal melanonychia and mild distal onycholysis.

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Figure 4: Dermoscopy of the free edge of the toenail showing localized subungual keratosis with areas of pigmentation.

Figure 6. Nail plate showing numerous nail pearls (arrows) and hyperkeratosis (hematoxylin and eosin, ×40).

melanin pigmentation and no cytologic atypia or mitotic figures; dermal elastosis and fibrosis were also identified (Figure 6). Based on the clinical, dermoscopic, and histopathologic findings, a diagnosis of OCM of the acanthotic subtype was established.The patient achieved complete healing, with no recurrence after 18 months of follow-up.

Figure 5: Intraoperative photograph showing a longitudinally oriented pigmented lesion in the nail matrix.

ling a longitudinally oriented pigmented lesion arising from the nail matrix (Figure 5). The lesion was then removed by shave excision, and the specimen was sent for histopathologic examination. Histopathologic examination revealed an intraepidermal epithelial proliferation composed of basaloid cells arranged in nests and cords, with formation of nail pearls. There was scant

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DISCUSSION Clinically, OCM presents as a solitary, monodactylous longitudinal pigmented band that may be associated with pachyonychia and distal subungual keratosis. Absence of pain and a history of trauma is common, and the clinical course is slow and asymptomatic.1,3,5 Dermoscopy findings described by Perrin et al. include round or oval white dots and clods, regular longitudinal ridges, splinter hemorrhages, and free-edge thickening of the nail plate.3 These findings reflect abnormal keratinization and localized thickening of the nail plate. As described by Spaccarelli et al., hypopigmented OCM may mimic onychomatricoma, presenting with thickening of the nail plate without visible pigmentation.6 OCM is considered the epithelial counterpart of onychomatricoma and may manifest clinically as longitudinal melanonychia, xanthonychia, or leukonychia, generally associated with localized thickening of the nail plate.3,5,7 In contrast, the pigmented subtype presents with melanonychia resulting from melanin deposition in the basal layer of the nail matrix, without melanocytic proliferation.1,4 Histopathologic examination is essential for diagnosis. OCM exhibits an intraepithelial proliferation of onychocytic cells with gradual maturation, resulting in abrupt keratinization and formation of nail pearls.1,3,4 Three main subtypes have been described: 1) acanthotic – characterized predominantly by thickened epithelium without papillomatosis; 2) acanthotic-papillo-

Borges HC, Ferreira ISMT, Marinho FS.

matous – characterized by superficial epithelial papillae containing spheres of prekeratogenous and keratogenous cells; and 3) keratogenous – characterized by a prominent keratogenous zone and delayed maturation.3,8 The present case exhibited an acanthotic pattern, whereas the acanthotic-papillomatous subtype has been the most frequently observed in the reviews by Perrin et al.3 OCM should be distinguished from subungual melanoma. In contrast to melanoma, OCM is characterized by the absence of cytologic atypia, dermal invasion, and melanocytic proliferation.4,6 Differentiation from seborrheic keratosis (SK) is also important.Whereas OCM cornifies with spheres of eosinophilic nuclei-retaining onychocytes, SK shows pseudohorn cysts. Pseudohorn cyst-like areas in OCM have 2 distinct layers, the prekeratogenous and keratogenous zones, which are absent in SK.9 Immunohistochemistry may assist in distinguishing among nail matrix tumors. OCM demonstrates positivity for

LEF-1, an onychogenic marker useful in differentiating OCM from onychocytic carcinoma and subungual keratosis.3,9 Treatment consists of complete surgical excision of the lesion and is curative in most cases.3,5 No malignant transformation or metastasis has been reported, and recurrence is rare and associated with incomplete excision. The prognosis is favorable, with preservation of the aesthetic appearance of the nail after appropriate surgical repair CONCLUSION OCM is a rare benign neoplasm of the nail matrix that may clinically mimic malignant tumors, particularly subungual melanoma. Recognition of its clinical, dermoscopic, and histopathologic patterns is essential to avoid misdiagnosis. This case reinforces the importance of including OCM in the differential diagnosis of longitudinal melanonychia and subungual pachyonychia, especially in cases involving the toenails. l

REFERENCES: 1.

Perrin C, Cannata GE, Bossard C, Grill JM, Ambrossetti D, Michiels JF. Onychocytic matricoma presenting as pachymelanonychia longitudinal: a new entity (report of ﬁve cases). Am J Dermatopathol. 2012;34(1):54–9.

Perrin C, Cannata GE, Langbein L. Acquired localized longitudinal pachyonychia and onychomatrical tumors: a comparative study of onychomatricomas and onychocytic matricomas. Am J Dermatopathol. 2016;38(6):1–8.

Perrin C, Coutts M, Boukari F, Ambrosetti D. Onychocytic matricoma: a clinical, dermoscopic, and pathological analysis of 14 cases. Am J Dermatopathol. 2024;46(5):259–70.

Kusutani N. Onychocytic matricoma as an underrecognized benign mimicker of subungual malignant melanoma and Bowen’s disease. J Dermatol. 2016;43(7):1–2.

Vieira LFdA, Jeunon T, Leverone AP, Nakamura R. Matricoma onicocítico. An Bras Dermatol. 2019;94(4):214–7.

Spaccarelli N, Wanat KA, Miller CJ, Rubin AI. Hypopigmented onychocytic matricoma as a clinical mimic of onychomatricoma. J Cutan Pathol. 2013;40(6):591–4.

Perrin C, Ambrosetti D. A new, important nail-unit tumor mistaken for a foreign body. JAMA Dermatol. 2014;150(3):1–3.

Song H, Qu F, Dang N, Sun X. Onychocytic matricoma: report of an Asian case. Ann Dermatol. 2017;29(3):355–6.

Alvarez G, Kha C, Selim MA, Fresco A. Onychocytic matricoma presenting as longitudinal melanonychia in a skin of color patient. Skin App Dis. 2023;9(3):1–6.

AUTHOR’S CONTRIBUTION: Heloisa Calegari Borges 0000-0002-8026-262X Approval of the final version of the manuscript, Preparation and writing of the manuscript, Intellectual participation in the propaedeutic and/ or therapeutic approach to the cases studied, Critical review of the literature Isabelle Sousa Medeiros Torres Ferreira 0000-0002-9597-3272 Acquisition, analysis and interpretation of data Flauberto de Sousa Marinho 0000-0002-9337-9931 Approval of the final version of the manuscript, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical revision of the manuscript

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Surgical treatment of rhinophyma: a case series Tratamento cirúrgico de rinofima: uma série de casos

DOI: http://www.dx.doi.org/10.5935/scd1984-8773.2026180543 ABSTRACT Rosacea is an inflammatory disease characterized by 4 clinical stages, with phymatous rosacea representing the final stage of progression. Its insidious and chronic course may result in exuberant rhinophyma associated with functional impairment, including nasal obstruction. This study reports a series of 5 cases of exuberant rhinophyma treated with electrosurgery, with satisfactory outcomes achieved after up to four treatment sessions. Keywords: Rhinophyma; Electrosurgery; Rosacea

RESUMO A rosácea é uma doença inflamatória caracterizada por quatro estágios clínicos, em que a última fase evolutiva é a rosácea fimatosa. A evolução insidiosa e crônica pode gerar quadros exuberantes de rinofima associado à repercussão funcional, como obstrução nasal. O presente estudo objetiva relatar uma série de cinco casos de rinofima exuberante tratados com eletrocirurgia que tiveram resultado satisfatório após até quatro sessões. Palavras-chave: Rinofima; Eletrocirurgia; Rosácea

Case Report Authors: Geovanna Mourão Ishikawa1 Airton Kenji Motizuki2 Natalia Megumi Morikawa1 João Augusto Gomes de Souza Monteiro de Brito1 Renata Mie Oyama Okajima1,2 1

Universidade do Estado do Pará, Ambulatório de Dermatologia, Belém (PA), Brazil Universidade Federal do Pará, Medicina, Belém (PA), Brazil

Correspondence: Geovanna Mourão Ishikawa E-mail: geovannapantoja30@ gmail.com

Funding: None Conflict of interest: None Submitted on: December 23, 2025 Final decision: August 20, 2026

How to cite this article: Ishikawa GM, Motizuki AK, Morikawa NM, Brito JAGSM, Okajima RMO. Surgical treatment of rhinophyma: a case series Surg Cosmet Dermatol. 2026;18(3):e20260543.

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Ishikawa GM, Motizuki AK, Morikawa NM, Brito JAGSM, Okajima RMO.

INTRODUCTION Rosacea is a chronic inflammatory disease characterized by 4 clinical stages, with phymatous rosacea representing the final stage of progression.1 This condition is characterized by hyperplasia of the sebaceous glands and connective tissue, resulting in marked skin hypertrophy; when it affects the nasal region, it is referred to as rhinophyma.2 Rhinophyma is relatively uncommon and occurs more frequently in men aged > 50 years.3 Its insidious and chronic progression may result in exuberant disease associated with functional impairment, including nasal obstruction, as well as substantial aesthetic, social, and psychological effects.3 There is no established gold-standard treatment for rhinophyma. Therapeutic approaches reported in the literature include surgical techniques, carbon dioxide (CO₂) laser therapy, trichloroacetic acid peel, and systemic treatment with retinoids and antibiotics. However, surgical treatment has been described as a more definitive approach for extensive disease.4 Therefore, this study aimed to report a series of 5 cases of exuberant rhinophyma treated with electrosurgery, with satisfactory outcomes.

CASE REPORT Five patients with rhinophyma followed at the dermatology department underwent electrosurgery. The surgical procedure was performed in all patients as follows: Local antisepsis with 2% chlorhexidine digluconate. Anesthetic block with 2% lidocaine with epinephrine administered bilaterally in the infraorbital nerve region, combined with local infiltration over the nasal dorsum. A low-frequency monopolar electrosurgical unit (Wavetronic® 120 Nano) was used in cut mode at a power setting of 20 W. A straight loop electrode, 3–5 mm in diameter, was used to remove the phymatous tissue, and a 3–5-mm ball electrode was used for hemostasis and contouring of the nose. Immediately after the procedure, restoration of the nasal contour was observed, with preservation of the nasal architecture and a uniform raw surface without areas of carbonization or active bleeding, indicating adequate hemostasis (Figure 1). An occlusive petrolatum dressing was then applied, and the wound was allowed to heal by secondary intention. In addition, oral cephalexin 500 mg every 6 hours for 7 days was

Figure 1: A - Immediate postoperative appearance after the first session of electrosurgery for rhinophyma. B - Immediate postoperative appearance after the third session of electrosurgery, demonstrating restoration of the nasal contour, preservation of the osteocartilaginous framework, and adequate hemostasis.

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prescribed to prevent secondary infection, along with collagenase/chloramphenicol ointment (0.6 U/g + 0.01 g/g) once daily until tissue re-epithelialization. Case 1: A 60-year-old man with no comorbidities had a 16-year history of rhinophyma that had progressed to nasal obstruction. He underwent 4 sessions of electrosurgery at intervals of 3–4 months, resulting in satisfactory aesthetic and functional outcomes of the nasal dorsum (Figure 2). Case 2: A 71-year-old man with no comorbidities and a 3-year history of rhinophyma underwent 2 sessions of electrosurgery 3 months apart, with a favorable outcome (Figure 3). Case 3: A 67-year-old man with a 6-year history of phymatous rosacea underwent 2 surgical treatment sessions and achieved an excellent outcome (Figure 4).

Case 4: A 63-year-old man with hypertension and a 5-year history of rhinophyma underwent 2 sessions of electrosurgery involving the nasal ala, with an interval of 5 months between procedures, and achieved a satisfactory outcome (Figure 5). DISCUSSION Rosacea is a chronic inflammatory skin disease with a multifactorial pathogenesis. The condition involves both immune system changes and neurovascular dysfunction and frequently impairs patients’ quality of life.3-6 Epidemiologically, rosacea affects approximately 5% of the global population, predominantly individuals with lighter skin phototypes (Fitzpatrick I and II), and is more common in women.5,6 Rhinophyma, however, has

Figure 2. Clinical appearance before and after surgical treatment of rhinophyma with 4 surgical sessions.

Figure 3. Clinical appearance before and after surgical treatment of rhinophyma with 2 surgical sessions.

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Ishikawa GM, Motizuki AK, Morikawa NM, Brito JAGSM, Okajima RMO.

Figure 4. Clinical appearance before and after surgical treatment of rhinophyma with 2 surgical sessions.

Figure 5: Clinical appearance before and after surgical treatment of rhinophyma involving the nasal ala with 2 surgical sessions.

Figure 6: Clinical appearance before and after surgical treatment of rhinophyma with 3 surgical sessions.

a distinct epidemiologic profile, occurring primarily in White men aged > 50 years, with reported male-to-female ratios ranging from approximately 5:1 to 30:1. Cases in men of Asian or African American ancestry have been reported but are uncommon.5-7 Rhinophyma is considered pathognomonic of rosacea and may clinically present as skin thickening associated with erythema, edema, and telangiectasia. As the condition progresses, proliferation of fibrous tissue and sebaceous glands occurs, accompanied by accentuation of follicular openings and other structures of the nasal region.5-8 Several therapeutic approaches for rhinophyma have been described in the literature, including laser therapy and oral

isotretinoin; however, surgical excision remains a mainstay of treatment.5,6,8 In this respect, electrosurgery represents an effective treatment option for rhinophyma because of its low cost, favorable safety profile, and relatively limited tissue trauma.6,9,10 Moreover, this modality meets the objectives and procedural steps of excisional treatment of rhinophyma described by Oliveira et al., including removal of excess phymatous tissue, refinement of the nasal contour, achievement of hemostasis, and provision of appropriate postoperative wound care, supporting electrosurgery as one of the main treatment modalities for this condition.5 Major complications documented with this therapeutic modality include thermal injury to the surrounding tissue

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and the risk of aesthetically unfavorable scarring. Nevertheless, reported benefits include reduced tissue trauma, greater postoperative satisfaction, and improvements in functional outcomes and quality of life.6,7,10 The cases described in this series are consistent with the literature, demonstrating excellent aesthetic and functional outcomes, as well as low treatment costs and high patient satisfaction.These findings are consistent with the favorable outcomes of similar surgical treatments reported in the medical literature.2,4,7,10

CONCLUSION Electrosurgery is an effective treatment option for rhinophyma, particularly in exuberant cases, such as those described in this series, and can provide high levels of patient satisfaction with both aesthetic and functional outcomes. Case 5: A 68-year-old man with hypertension and a 5-year history of rhinophyma underwent 3 surgical sessions at 4-month intervals and showed a favorable clinical response (Figure 6). l

REFERENCES: 1.

Chowdhary S, Alexander A. Giant rhinophyma. BMJ Case Rep. 2021;14:e239860.

Dick MK, Patel BC. Rinoﬁma. Em: StatPearls [Internet]. Ilha do Tesouro (FL): StatPearls Publishing; 2025.

Luppino I, Lacarrubba F, Verzì AE, Micali G. The clinical spectrum of phyma: a case report of rhino-metophyma and review of the literature. Skin App Disord. 2025;11(6):515-9.

Kondo RN, Borges Junior C, Leugi LG, Gubert M, Scalone FM. Eletrocirurgia em rinoﬁma: relato de dois casos. Surg Cosmet Dermatol. 2024;16:e20240312.

Benwadih S, Bouksirat M, Dani B, Boulaadas M. Management of rhinophyma. J Surg Case Rep. 2025;2025(5).

Benyo S, Saadi RA, Walen S, Lighthall JG. A Systematic Review of Surgical Techniques for Management of Severe Rhinophyma. Craniomaxillofac Trauma Reconstr. 2021;14(4):299-307

Tan J, Almeida L, Bewley A, Cribier B, Dlova NC, Gallo R, et al.Updating the diagnosis, classiﬁcation and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176:431-8.

Oliveira CMM, Almeida LMC, Bonamigo RR, Lima CWG, Bagatin E. Consensus on the therapeutic management of rosacea - Brazilian Society of Dermatology. An Bras Dermatol. 2020;95:53-69.

Cardoso TA, Yang JJH, Rossoe EWT. Electrosurgery in the treatment of giant rhinophyma: a case report. Surg Cosmet Dermatol. 2015;7(3 Supl 1):S50-2.

10. Al Hamzawi, Nabeel K, Al Baaj, Salih M. Large rhinophyma treated by surgical excision and electrocautery. Case Rep Surg. 2019;2395619.

AUTHOR’S CONTRIBUTION: Geovanna Mourão Ishikawa 0000-0001-6404-6938 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Acquisition, analysis and interpretation of data, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript. Airton Kenji Motizuki 0009-0002-7188-0984 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical revision of the manuscript. Natalia Megumi Morikawa 0000-0001-9533-3307 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical revision of the manuscript. João Augusto Gomes de Souza Monteiro de Brito 0000-0001-7286-7066 Approval of the final version of the manuscript, Preparation and writing of the manuscript, Critical review of the literature. Renata Mie Oyama Okajima 0000-0003-2168-5515 Approval of the final version of the manuscript, Conception and design of the study, Preparation and writing of the manuscript, Effective participation in the conduct of the study, Intellectual participation in the propaedeutic and/or therapeutic approach to the cases studied, Critical review of the literature, Critical revision of the manuscript.

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