Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited. Late-Onset Adverse Reactions Related to Hyaluronic Acid Dermal Filler for Aesthetic Soft Tissue Augmentation Marcos Martins Curi, DDS, MSc,  Camila Lopes Cardoso, DDS, MSc, y Cla´udia Curra, DDS, y Daniel Koga, DDS, MSc,  and Maria Beatriz Benini y Abstract: Hyaluronic acid (HA) fillers have been the choice material for soft tissue augmentation in the last decade. Although they are considered safe, there could be adverse reactions in the subsequent months or years to the treatment. However, these reactions have hardly ever been reported in the literature. This article considers 2 cases of delayed adverse reactions related to HA dermal filler for soft tissue augmentation with oral manifestation. It should be, before all, emphasized that HA filler is a safe and well-recognized treatment for soft tissue augmentation, despite the fact that delayed adverse effects may later occur after treatment, and clinicians should be aware of it when establishing a definitive oral diagnosis. Key Words: Hyaluronic acid dermal filler, Restylane, late-onset adverse reactions, oral manifestation (J Craniofac Surg 2015;26: 782–784) D uring the last decade, skin filler agents have often been used for wrinkling treatment, soft tissue augmentation, and correc- tion of atrophic scars as well as for the treatment of small cutaneous defects. 1 They can be classified into 2 main categories: biodegrad- able or resorbable (eg, bovine collagen and hyaluronic acid [HA]) and permanent or nonresorbable (eg, silicone). 2 The most suitable implanting material for soft tissue augmentation should bring a satisfactory aesthetic result; it should also have a long and persistent effect and then be safe, biocompatible, and with the least risk for having adverse reaction effects. Unfortunately, this kind of material has not yet been discovered and almost all agents may induce some degree of adverse reactions. 3,4 Hyaluronic acid has been the most frequent class of injectable product for soft tissue augmentation, accounting for 85% of such procedures in 2010. 2 It is one of the components of the normal extracellular matrix of the dermis and provides support for other tissues. It is produced by dermal fibroblasts and other cells, and it is released into the extracellular matrix. Theoretically, HA has no organ or species specificity; therefore, there is no risk for any allergic reaction. For the majority of patients, HA is fully degraded and reabsorbed within 6 months, not leaving any type of fibrosis or implant waste on the tissue. 1,2,5 In addition, few reports on adverse hypersensitivity reactions secondary to injection of HA have been reported. 2 More precisely, Restylane (Medicis Inc, Scottsdale, AZ) was the first HA gel approved by the US Food and Drug Administration (in 2003), 6 for nasofacial fold and lip augmentation. 2 It is a nonanimal stabilized HA preparation produced using microbiological engin- eering techniques and terminally sterilized. 1 Restylane has clear advantages when compared with previous animal-derived fillers; because it is a nonanimal product, the incidence of allergic reaction is reduced. 1 Authors have reported a low allergic response 7 of 1:26,000 compared with bovine collagen with a response of 3:100. 8 Furthermore, authors injected more than 450 syringes of it in a period of 2 years; they reported a high degree of fulfillment of expectations in both patients and physicians and that there were no significant complications. 1 The most common complications that appear when using HA filler are related to what the injector experiences, such as the emergence of hematoma, asymmetry, overcorrection, undercorrec- tion, and tissue necrosis. 1 Theoretically, products derived from HA are biocompatible and nontoxic and has no risk for immunogenicity. Hypersensitivity reactions and injection site inflammation are uncommon and occur in 0.05% to 0.15% of all cases. 7 Delayed reactions occurred in few cases demonstrating hypersensitivity and foreign body reactions, that is, within 6 to 24 months after the injection. 2,4,9–18 Authors reported delayed reactions in 0.6% of the cases. 9,19 In this article, we report 2 cases of delayed adverse reactions related to the use of HA filler (Restylane) with oral manifestation. CLINICAL REPORT Approval for these case reports was granted by the institutional review board of Hospital Santa Catarina, Sao Paulo, Brazil. The first patient was a 65-year-old woman who presented 2 nodular lesions on the right upper lip mucosa that appeared after an exodontia of the left second molar in the previous month. First, clinical examination revealed 2 inflamed painful nodular indura- tions with no definitive outline on her right upper lip (Fig. 1A). Then, the patient returned after a week presenting 2 further painful nodules on the left side of the same anatomic region (Fig. 1B). Hence, she underwent computed tomography, which revealed implanted material in the soft tissue of the lip (Figs. 2A, B). Later, when she was questioned about any aesthetic and/or cosmetic procedure in the past, she confirmed that she had gone through a soft tissue augmentation treatment 12 years earlier (Restylane). The patient, who finally underwent an incisional biopsy and a histologic examination, was confirmed to have granulomatous foreign body reaction related to the HA filler (Figs. 3A, B). The treatment applied thus consisted of local intralesional hyaluronidase and systemic anti-inflammatory therapy for 2 months. Remission of clinical signs and symptoms occurred after 3 months (Figs. 4A, B). The medical dermatologist responsible for the procedure confirmed the use of Restylane years ago. From the  Department of Stomatology, Hospital Santa Catarina; and y Department of Oral Surgery, University Sagrado Corac ¸a ˜o, Sao Paulo, Brazil. Received June 24, 2014. Accepted for publication September 29, 2014. Address correspondence and reprint requests to Camila Lopes Cardoso, DDS, MSc, University Sagrado Corac ¸a ˜o-Rua Irma ˜ Arminda 10-50 Bauru, Sao Paulo, Brazil; E-mail: cardoso_lopes@yahoo.com.br The authors report no conflicts of interest. Copyright # 2015 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000001358 CLINICAL STUDY 782 The Journal of Craniofacial Surgery  Volume 26, Number 3, May 2015