Journal of Surgical Dermatology 2022 V7I1

Page 1


Editorial Board Editors-in-Chief Prof. Shahin Aghaei Iran University of Medical Sciences, Tehran Iran, Islamic Republic of

Prof. Jacek Cezary Szepietowski Wroclaw Medical University Poland

Associate Editors Dr. Felipe Bochnia Cerci Hospital Santa Casa de Curitiba Brazil

Dr. Beatrice Nardone Northwestern University, Feinberg School of Medicine United States

Editorial Board Members Dr. Aaron Tan University College London (UCL) United Kingdom

Dr. Ally-Khan Somani Indiana University School of Medicine United States

Dr. Abdulhadi Hazzaa Jfri Icahn School of Medicine at Mount Sinai Saudi Arabia

Dr. Andrea Sisti University of Siena Italy

Dr. Achih H. Chen Augusta University United States

Dr. Bahman Sotoodian University of Alberta, Edmonton Canada

Dr. Ahmed Hassan El-Sabbagh Mansoura University Hospital Egypt

Dr. Aravazhi Ananda Dorai Tropicana Medical Centre Malaysia

Dr. Aikaterini Tsiogka Paracelsus University Hospital, Salzburg Austria

Dr. Armin Kraus Otto-von-Guericke University Germany

Dr. Ajmal Rashid Combined Military Hospital Sialkot Pakistan

Dr. Artur Diaz-Carandell Hospital Parc Tauli Spain


Volume 7 Issue 1 • 2022

Journal of Surgical Dermatology

Editors-in-Chief Prof. Shahin Aghaei Iran University of Medical Sciences, Tehran Iran, Islamic Republic of Prof. Jacek Cezary Szepietowski Wroclaw Medical University Poland


Volume 7 Issue 1 • 2022

Journal of Surgical Dermatology https://jsurgdermatol.com/index.php/JSD

Contents EDITORIAL 1

Treatment of keloids: What’s news? Shahin Aghaei

RESEARCH HIGHLIGHTS 3

Analysis of chemokine receptors from angiosarcoma as the potential tumor marker

ORIGINAL RESEARCH ARTICLE 5

Expression of chemokine receptors in angiosarcoma Tomoo Kishi, Yuki Yamamoto, Chikako Kaminaka, Seiko Toyozawa, Hiroshi Matsunaka, Fukumi Furukawa

12

A randomized, double-blind, comparative study for efficacy assessment of two hyaluronic acid nasolabial fillers Saman Ahmad Nasrollahi, Mansour Nassiri Kashani, Taraneh Yazdanparast, Setareh Ameri, Alireza Firooz

17

The diagnostic accuracy of the mobile phone teledermatoscopy Hamza Yildiz, Memet Ersan Bilgili, Hasan Aktug Simsek

22

Volumetric estimation of autologous fat for augmentation of contour defects of face Shilpi Bhadani, Sujata Sarabahi, Savita Arora, Vinay Kumar Tiwari, Anmol Chugh

REVIEW 29

Treatment modalities for hyperpigmented skin lesions: A brief overview Yan Teng Khoo, Ahmad Sukari Halim


38

Cutaneous immune system: Age specificities Markelova Elena Vladimirovna, Yana Alexandrovna Yutskovskaya, Birko Oksana Nikolaevna, Bajbarina Elena Valerjevna, Natalya Sergeevna Chepurnova

45

Fiddler’s neck: Cultural influences modify clinical presentation influences Sundeep Chowdhry, Sameeksha Chand, Paschal D’Souza

CASE REPORT 49

Nevus of Ota associated with intracranial melanoma: Case report and review of the literature Ravi S. Krishnan, Christy Badgwell, Daniel Yoshor, Ida Orengo

PERSPECTIVE 52

Facial laser surgery Shree Harsh, Surendra B. Patil

SHORT COMMUNICATION 61

Laser microporation: A promising field in transdermal drug delivery Mozhdeh Sepaskhah

CORRESPONDENCE 63

Giant cell tumor of tendon sheath—Use of fine-needle aspiration cytology for diagnosis Neha Meena, Pooja Arora



doi: 10.18282/jsd.v7.i1.179

Editorial

Treatment of keloids: What’s news? Shahin Aghaei Iran University of Medical Sciences, Tehran, Islamic republic of Iran

Keloids are still therapeutic glitches, mostly disfiguring lesions which cause physical, functional and psychological burdens. Most patients with keloids are worried about cosmetic, some have grievances of itchy pain or a burning sense around them, though. The firmness can range from pliable to rigid. Most lesions tend to nurture gradually over a few months to a year. Most of them finally discontinue growing and stay unchanging or even withdraw to some extent[1,3]. No particular therapeutic modality is best for all lesions. The place, extent, penetration of the lesion, age of the patients and the previous reaction to treatments conclude the type of next step of therapy. The main key would be prevention, but intralesional steroid injections are usually the first-line strategy in the treatment of restricted keloid or hypertrophic scars. Other currently used treatments consist of occlusive silicon bandages, compression therapy , cryotherapy, surgical excision, radiation, laser surgery, interferons (IFN), 5-fluorouracil (5-FU), retinoic acid, doxorubicin, bleomycin, verapamil, retinoic acid, imiquimod 5% cream, tamoxifen, tacrolimus, botulinum toxin injection, hydrogel scaffolding, and over-the-counter treatments (such as onion extract, Lemon Juice, Baking Soda, and the combination of hydrocortisone, silicon, and vitamin E)[4]. Some promising treatments comprise anti-angiogenic factors, such as the inhibitors of vascular endothelial growth factor (VEGF) (for example bevacizumab), inhibitors of mannose-6-phosphate (M6P), combination of butyrate and docosahexaenoic acid, topical captopril, and phototherapies such as: (photodynamic therapy [PDT], intense pulsed light [IPL], ultraviolet A [UVA]-1 therapy, narrowband ultraviolet B [UVB] therapy). Inhibitors of transforming growth factor (TGF)–beta, inhibitors of tumor necrosis factor (TNF)–alpha (etanercept), recombinant human epidermal growth factor (rhEGF), and recombinant human interleukin (rhIL)–10 are some other newer modalities, which are focused at reducing collagen production[4,5]. A new study of keloids reveals that combined therapy of intralesional triamcinolone and verapamil injections results in noteworthy scar improvement with a long-term unchanging result[6]. Topical captopril could be considered as a prospective

therapy for keloid lesions[5]. According to a recent study, captopril may decrease the expression of angiotensin, platelet-derived growth factor (PDGF), transforming growth factor beta 1 (TGF-β1) and heat shock protein 47 (HSP47), and more inhibit the proliferation and collagen production of fibroblasts in keloids, which were the key in keloid creation[7]. In another new research, favorable effects of the combination of 5-FU and verapamil merit further survey[8]. Mesenchymal stem cells would be a valuable source in regenerative medicine, and the medium acquired from stem cells seemingly hinders inflammation. Keloids are made up of abnormal fibrosis, produced by fibroblasts in reaction of inflammation. In a study, the authors assessed if this medium from amnion-derived stem cells prevents proliferation and activation of keloid fibroblasts and is a capable keloid treatment for administration as a topical agent [9] . Another study revealed that keloid excision followed by brachytherapy for resistant keloids is better than intralesional cryotherapy, further research on the efficacy of intralesional cryotherapy for primary keloids is warranted, though. Brachytherapy is radiotherapy using a radioactive source[10]. There are millions of patients in the world suffered from keloids. However, there is a loss of treaty in the treatment. Furthermore, keloid investigation has left legacies in comprehending of its pathogenesis.

References 1. Atiyeh BS, Costagliola M, Hayek SN. Keloid or hypertrophic scar: The controversy: Review of the literature. Ann Plast Surg 2005; 54(6): 676–680. doi: 10.1097/01. sap.0000164538.72375.93. 2. Alhady SM, Sivanantharajah K. Keloids in various races. A review of 175 cases. Plast Reconstr Surg 1969; 44(6): 564– 566. 3. R o b l e s D T, B e r g D . A b n o r m a l w o u n d h e a l i n g : Keloids. Clin Dermatol 2007; 25: 26–32. doi: 10.1016/ j.clindermatol.2006.09.009. 4. Torii K, Maeshige N, Aoyama-Ishikawa M, Miyoshi M, Terashi H, et al. Combination therapy with butyrate and docosahexaenoic acid for keloid fibrogenesis: An in vitro study. An Bras dermatol 2017; 92(2): 184–190. doi: 10.1590/ abd1806-4841.20176198. 5. Ardekani GS, Aghaei S, Nemati MH, Handjani F, Kasraee B. Treatment of a postburn keloid scar with topical captopril:

Copyright © 2022 Aghaei S. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Treatment of keloids: What’s news?

Report of the first case. Plast Reconstr Surg 2009; 123(3): 112e–113e. doi: 10.1097/PRS.0b013e31819a34db. 6. Kant SB, van den Kerckhove E, Colla C, Tuinder S, van der Hulst RRWJ, et al. A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: A retrospective study. Eur J Plast Surg 2018; 41: 69–80. doi: 10.1007/s00238-017-1322-y. 7. Chen J, Zhao S, Liu Y, Cen Y, Nicolas C. Effect of captopril on collagen metabolisms in keloid fibroblast cells. ANZ J Surg 2016; 86(12): 1046–1051. doi: 10.1111/ans.12670. Epub 2014 May 23. 8. Alexandrescu D, Fabi S, Yeh LC, Fitzpatrick RE, Goldman MP. Comparative results in treatment of keloids with intralesional 5-FU/Kenalog, 5-FU/Verapamil, enalapril

alone,verapamil alone, and laser: A case report and review of the literature. J Drugs Dermatol 2016; 15(11): 1442–1447. 9. Sato C, Yamamoto Y, Funayama E, Furukawa H, Oyama A, et al. Conditioned medium obtained from amnion-derived mesenchymal stem cell culture prevents activation of keloid fibroblasts. Plast Reconstr Surg 2018; 141(2): 390–398. doi: 10.1097/PRS.0000000000004068. 10. Bijlard E, Timman R, Verduijn GM, Niessen FB, Hovius SER, et al. Intralesional cryotherapy versus excision with corticosteroid injections or brachytherapy for keloid treatment: Randomised controlled trials. J Plast Reconstr Aesthet Surg 2018; pii: S1748-6815(18)30046-9. doi: 10.1016/ j.bjps.2018.01.033.

Keywords: keloids; lesion; treatment Citation: Aghaei S, Treatment of keloids: What’s news? J Surg Dermatol 2022; 7(1): 179; http://dx.doi.org/10.18282/ jsd.v7.i1.179. Received: 22nd December 2021; Published Online: 9th January 2022 Correspondence to: Shahin Aghaei, roonik Skin Clinic, #78, Asad-abadi Ave., Tehran, Islamic republic of Iran, shahinaghaei@yahoo.com

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doi:10.18282/jsd.v7.i1.179


RESEARCH HIGHLIGHTS Analysis of chemokine receptors from angiosarcoma as the potential tumor marker Low-risk method presents quick turnaround of the degenerative disease, researchers found

A

round 35% of non-metastatic angiosarcoma’s survival rate has been reported by researchers to be five years due to its poor prognosis and that it is “a rapidly progressing malignant skin

tumor.”

“Angiosarcoma is a rare malignant skin tumor and appears as a pink-dark red erythema in the frontal region over the forehead in the beginning and it frequently develops in the elderly” described by Tomoo Kishi and his co-authors from Department of Dermatology, Wakayama Medical University, Japan in an original research article published in the Journal of Surgical Dermatology. The authors wrote “Angiosarcoma is accompanied by edema and then form erosion, exudative and a crust”. At advance stages of angiosarcoma, “nodules with ulceration occur”, they added. According to global medical resource portal Medscape.com, “These tumors have a high local recurrence rate and metastasis because of their intrinsic biologic properties and because they are often misdiagnosed, leading to a poor prognosis and a high mortality rate.” In addition, according to the global sarcoma advocate

Liddy Shriver Sarcoma Initiative, patients are usually diagnosed with angiosarcoma at a later stage where the disease has spread throughout the body. Therefore, it is a need to find a better solution to overcome this poor prognosis problem. The presence of cancer is detected by the help of tumor markers. As explained by National Cancer Institute, tumor markers are made by both normal and cancer cells, but the production of tumor markers are higher in cancerous conditions. Most of the tumor markers are proteins such as chemokines that can be found in the blood, tumor tissue and body fluid of some cancer patients. “Chemokines are substances inducing the migration of specific white blood cells and lymphocytes, and it has been reported that chemokine and chemokine receptor expressions play important roles in the outgrowth, infiltration, and metastasis of malignant tumors” authors described. The authors also added that chemokines represents cytokine proteins with chemotactic activity and, in the late 1980s, the study of chemokines started with the discovery of a factor inducing neutrophil migration and activation, interleukin (IL)-8. Subsequently, studies since then have greatly advanced and “more than 50 chemokines

“Once angiosarcoma develops, it rapidly progresses and results in a poor outcome, but no useful marker has been identified, and the accumulation of knowledge is urgently needed.” -Tomoo Kishi and co-authors

Image credit: Philippe Delavie via Pixabay

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RESEARCH HIGHLIGHTS have been identified.” In a previous investigation done by the authors on expressions of CXCR4, CCR6, CCR7 and SDF-1 in malignant melanoma, they initially found that CXCR4 was a useful marker for malignancy. As explained by the authors, “CXCR4 is a specific receptor of the chemokine SDF-1, and it is expressed on the cell membrane of white blood cells and undifferentiated hematopoietic cells.” Nevertheless, the authors claimed that an analysis of chemokines and chemokine receptors in angiosarcoma has not been performed yet. No useful marker has yet been identified, added Tomoo Kishi and his co-authors. Using 12 tumor tissue samples of angiosarcoma from patients of Wakayama Medical University Hospital, the authors aimed to investigate chemokine receptor expression, and if it is expressed, to histologically discuss its association with the age, sex, development site, and histologic type. The tumor tissues were collected via biopsy or surgery from patients with mean age of 75.7 years old. As a control, “16 healthy skin samples were analyzed,” explained the authors. From their investigation, they found out that CXCR4 expression was positive in 6 of the 12 samples. Among of those 6 samples, there were 4 cellular rich type and 2 were vascular rich type. In addition, they reported that the expression of CCR6 and CCR7 were negative in all samples.

The authors also mentioned that the expression of CXCR4/SDF-1 was slightly higher in malignant melanoma when a tumor thickness of 2 mm or less, histological classification of the node or non-node type, and the presence or absence of distant metastasis was within two years. Besides that, the authors also investigated the association of the expressed chemokines with demographic parameters such as age, sex, development site and histologic type. They found out that there is no significant difference associated with the age, sex, development site or histologic type in the expression of either CXCR4, CCR6, CCR7, or SDF-1. Finally, the authors claimed that, although CXCR4 is regarded as an index of tumor aggressiveness of malignant melanoma, it was suggested that chemokine receptors, such as CXCR4, do not serve as a useful marker of angiosarcoma. Their research ultimately highlights the need for further investigation on the usability of these chemokines as a marker as a tumor marker for angiosarcoma. “We have to collect more cases of angiosarcoma and analyze them immunohistochemically,” they write. “More development of a new chemokine and tumor marker shall be needed in this disease,” the authors concluded. ■ Yuki Yamamoto, Chikako Kaminaka, Seiko Toyozawa, Hiroshi Matsunaka, and Fukumi Furukawa are co-authors of this featured research article which is published on pages 5–11 in this JSD issue.

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doi: 10.18282/jsd.v7.i1.127

ORIGINAL RESEARCH ARTICLE

Expression of chemokine receptors in angiosarcoma Tomoo Kishi1,2*, Yuki Yamamoto1, Chikako Kaminaka1, Seiko Toyozawa1, Hiroshi Matsunaka1, Fukumi Furukawa1 1

Department of Dermatology, Wakayama Medical University, Wakayama, Japan

2

Department of Dermatology, Kainan Municipal Medical Center, Kainan, Japan

Abstract: Angiosarcoma is a rapidly progressing malignant skin tumor associated with a poor prognosis. We report an immunohistochemical investigation of chemokine receptors in angiosarcoma. The aim is to investigate chemokine receptor expression and, if it is expressed, to histologically discuss its association with age, sex, development site, and histological type. Analyzed were 12 angiosarcoma samples (mean patient age: 75.7 years old) collected by biopsy or surgery from patients at our department by comparing with 4 granuloma telangiectaticum samples (mean patient age: 37.5 years old) and 16 healthy skin samples as controls. CXCR4, CCR6, CCR7, and SDF-1 expressions were immunohistochemically investigated. CXCR4 expression was positive in 6 of the 12 samples. CCR6 and CCR7 were negative in all samples. SDF-1 was positive in 4 samples. Out of the 6 CXCR4-positive samples, 4 were SDF-1-positive. No significant difference associated with age, sex, development site, or histological type was noted in the expression of CXCR4, CCR6, CCR7, or SDF-1. Although CXCR4 is regarded as an index of tumor aggressiveness of malignant melanoma, it is suggested that chemokine receptors, such as CXCR4, do not serve as useful markers of angiosarcoma. Keywords: CXCR4; chemokine receptor; angiosarcoma; immunohistochemistry Citation: Kishi T, Yamamoto Y, Kaminaka C, Toyozawa S, Matsunaka H, et al. Expression of chemokine receptors in angiosarcoma. J Surg Dermatol 2022; 7(1): 127; http://dx.doi.org/10.18282/jsd.v7.i1.127. *Correspondence to: Tomoo Kishi, Department of Dermatology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012 Japan; tomoo@nnc.or.jp

Received: 15th June 2021; Accepted: 1st August 2021; Published Online: 21st August 2021

Introduction Angiosarcoma is a rare malignant skin tumor appearing as a pink-dark red erythema in the frontal region over the forehead initially and it frequently develops in the elderly. It is accompanied by edema and then forms an erosion, an exudation, and a crust; when it advances, nodules with ulceration occur. It is very malignant, recurring at a local site at a high rate, and causes hemopneumothorax due to lung metastasis in many cases, while also being a disease associated with very poor prognosis[1].

Chemokines are substances inducing the migration of specific white blood cells and lymphocytes, and it has been reported that chemokine and chemokine receptor expressions play important roles in the outgrowth, infiltration, and metastasis of malignant tumors[2-8]. Among them, CXCR4 is a specific receptor of the chemokine SDF-1 (CXCL12), and it is expressed on the cell membrane of white blood cells and undifferentiated hematopoietic cells. Its stimulation with SDF-1 induces chemotaxis and promotes proliferation and survival. We previously investigated expressions of CXCR4, CCR6, CCR7, and SDF-1 in malignant melanoma, and reported that CXCR4 is a useful marker and serves as

Copyright © 2022 Kishi T, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Expression of chemokine receptors in angiosarcoma

an index of malignancy[9]. We also reported that expressions of these chemokines may serve as markers of tumor advancement (predicting tumor aggressiveness) of malignant fibrous histiocytoma and dermatofibrosarcoma protuberans[8]. Nakatsugawa stated that CXCR4 and SDF-1 expressions on squamous cell carcinoma of the tongue are associated with lymph node metastasis, thus serving as a prognostic factor[10]. In reports on tumors other than mucocutaneous tumors, their expressions increased in cases of metastasis of breast and colorectal cancers, suggesting their involvement in tumor metastasis[2]. Analysis of chemokines and chemokine receptors in angiosarcoma has not been performed. Once angiosarcoma develops, it rapidly progresses and results in a poor outcome; however, no useful marker has been identified, and the accumulation of knowledge is urgently needed. In this study, we immunohistochemically investigated chemokine receptors in angiosarcoma, particularly CXCR4, CCR6, CCR7, and SDF-1 (CXCL12). Using tumor tissue of angiosarcoma, the expressions of CXCR4, CCR6, and CCR7 and a ligand of CXCR4, SDF-1 (CXCL12), were investigated. As clinical control, the expressions in a benign vascular proliferative tumor, granuloma telangiectaticum, were similarly analyzed immunohistologically. Normal control skin samples were also obtained. In addition, the presence or absence of an association with age, sex, development site, and histological type was also investigated.

Materials and methods Along with 16 healthy skin samples as controls, 12 angiosarcoma samples (mean patient age: 75.7 years old) and 4 granuloma telangiectaticum samples (mean patient age: 37.5 years old) collected by biopsy or surgery at Wakayama Medical University Hospital’s Department of Dermatology, were analyzed. The details of each case are shown in Table 1. The samples were immunohistologically analyzed after obtaining informed consent from the patients and their families. Immunohistochemical staining was performed following the method reported by Toyozawa et al.[8,9]. Each sample was fixed with formalin and embedded in paraffin. After deparaffinization, 4-µm-thick sections were prepared and subjected to immunohistochemical staining with control, anti-CXCR4 antibody (polyclonal, Gene TEX, Incorporated, San Antonio, TX, USA), anti-CCR6 antibody (polyclonal, Gene TEX), anti-CCR7 antibody (polyclonal, Gene TEX), and anti-SDF-1 antibody (polyclonal, Santa Cruz Biotechnology, Incorporated, Santa Cruz, CA, USA). The expressions were evaluated using the catalyzed signal amplification (CSA) method. For the evaluation, three specialized physicians from Department of Dermatology, who

Table 1. Patient and tumor characteristics Patient characteristics Angiosarcoma 12 Total number of sites Median age (years) Range Gender: Female Male

Pyogenic granuloma 4

75.7 61–89

37.5 15–54

7/12 5/12

2/4 2/4

8/12 3/12 1/12 0/12

0/4 3/4 1/4 0/4

8/12 4/12

0/4 4/4

6/12 6/12

0/4 4/4

Location: Head Face Trunk/neck/extremities Feet Histopathologic type: Cellular rich type Vascular rich type Biopsy/Operation: Biopsy Operation

were unable to access the clinical findings of the patients, randomly selected and observed five visual fields in each section at 400X magnification[9]. In terms of histological type, the histology tissue section judged as poorly differentiated angiosarcoma was defined as cellular rich type, whereas well-moderately differentiated angiosarcoma was defined as vascular rich type[11]. The correlations of stainability of each antibody with age, sex, development site, and histological type were statistically analyzed using Fisher’s exact test.

Ethics statement This study was approved by the ethics review board of Wakayama Medical University.

Results Immunohistologically investigated were 12 angiosarcoma samples, 4 granuloma telangiectaticum samples, and 16 normal skin control samples. The results of staining of the normal skin, granuloma telangiectaticum, and angiosarcoma (vascular rich and cellular rich types) are shown in Figures 1–4, respectively. The results of staining of the normal skin are shown in Figure 1. Figures 1A–1D show staining of CXCR4, CCR6, CCR7, and SDF-1 observed at 200X magnification, respectively. No specific positive reaction with any antibody was observed. Figure 2 shows the results of staining of granuloma telangiectaticum. The hematoxylin and eosin-stained (HE-stained) sample observed at low

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Kishi T, et al.

magnification (20X), at a high magnification (400X), and the control are shown in Figures 2A–2C, respectively. The results of CXCR4, CCR6, CCR7, and SDF-1 are shown in Figures 2D–2G, respectively; none of these were stained. Figure 3A shows the clinical view of an angiosarcoma that developed on the head of a 78-year-old female. Figure 3B shows HE staining of a specimen collected from the lesion shown in Figure 3A, and it was diagnosed as the vascular rich type. Figure 3C shows the HE-stained sample observed at a high magnification (400X). Figure 3D shows the control. Figure 3E–3H shows the results of CXCR4, CCR6, CCR7, and SDF-1, respectively. CXCR4 and SDF-1 expressions were positive, but CCR6 and CCR7 expressions were negative. Figure 4A shows the clinical view of an angiosarcoma that developed on the head of a 75-year-old female. Figure 4B shows HE staining of a specimen collected from the lesion shown in Figure 4A, and it was considered to be the cellular rich type. Figure 4C shows the HE-stained sample observed at a high magnification (400X). Figure 4D shows the control. Figures 4E–4H show the results of CXCR4, CCR6, CCR7, and SDF-1, respectively. CXCR4 expression was positive, but CCR6, CCR7, and SDF-1 expressions were negative. As shown in Tables 2 and 3, CXCR4 was intensely stained in the cytoplasm or nucleus in 6 of the 12 angiosarcoma samples, being expression-positive. Cellular rich type were determined in 4 of these 6 samples, and 2 were the vascular rich type. CCR6 and CCR7 were negative. SDF-1 expression was positive in 4 of the 12 samples. All these SDF-1 expression-positive cases were also positive for CXCR4 expression. In contrast, all of CXCR4, CCR6, CCR7, and SDF-1 expressions were negative in granuloma telangiectaticum. CXCR4 and SDF-1 expressions are summarized in Tables 2 and 3, respectively. A significant correlation of the presence and absence of expression was noted between CXCR4 and SDF-1. Both CCR6 and CCR7 expressions were negative in all cases. Regarding the association of CXCR4, no significant difference due to age, sex, development site, or histological type was noted. Similarly, no significant difference was noted in CCR6, CCR7, or SDF-1.

Figure 1. CXCR4, CCR6, CCR7, and SDF-1 immunoexpression in the normal skin (200X). No expression of (A) CXCR4, (B) CCR6, (C) CCR7, and (D) SDF-1 were observed in the normal skin.

Discussion Chemokines represent cytokine proteins with chemotactic activity, and their study started in the late 1980s with the discovery of interleukin (IL)-8, a factor inducing neutrophil migration and activation. Subsequently, studies on the molecular pathology of inflammation and immunity have markedly advanced, and more than 50 chemokines have been identified.

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Expression of chemokine receptors in angiosarcoma

Kaminaka et al. histologically investigated the effect of phenol therapy, which is a noninvasive treatment of solar keratosis, Bowen’s disease, and squamous cell carcinoma, and they also investigated chemokine receptors immunohistochemically at the same time[12]. Compared with normal skin and completely remitted cases, the tumor was thick and CXCR4 was strongly expressed on the first examination, similar to that in squamous cell carcinoma, and they reported that the tumor thickness and CXCR4 expression were associated with the treatment effect.

Figure 2. The HE-stained sample of granuloma telangiectaticum under (A) 20X magnification, (B) 400X, and (C) control (400X). No expression of (D) CXCR4, (E) CCR6, (F) CCR7, and (G) SDF-1 were observed in granuloma telangiectaticum.

CXCR4 is a specific receptor of the chemokine SDF-1, and it is expressed on the cell membrane of white blood cells and undifferentiated hematopoietic cells. Its stimulation with SDF-1 induces cancer cell chemotaxis and promotes further proliferation and survival of cancer cells[2]. CCR6 is a receptor of CCL20 and it plays an important role in the movement of immunocompetent cells[2]. Reduction of CCR6 expression in head-and-neck squamous cell carcinoma has been reported[7]. Reportedly, CCR7 is a receptor of CCL19 and CCL21, and it is involved in lymphocyte migration[2]; additionally, the enhancement of CCR7 expression in breast cancer, which is likely to metastasize to lymph nodes, has been reported[2]. Regarding malignant skin tumors, the involvement of the expression of chemokine receptors such as CXCR4 and CCR7 in tumor growth and metastasis of squamous cell carcinoma, malignant melanoma, and fibrous system malignant tumors has been reported[4,5,7,8], but the details of the distribution of expression and function have not been elucidated. Toyozawa et al. investigated CXCR4, CCR6, CCR7, and SDF-1 expressions in 19 cases of malignant melanoma, and reported that the frequency of CXCR4/SDF-1 expression was significantly higher in the first of the following parameters: a tumor thickness of 2 mm or less, histological classification of the node or non-node type, and the presence or absence of distant metastasis within two years[9]. On the other hand, CCR6 and CCR7 were associated with several parameters but these were not as favorable as markers compared with CXCR4/SDF-1.

Figure 3. (A) Clinical feature of angiosarcoma in the head of a 78-year-old female. The HE-stained sample of angiosarcoma under (B) 100X magnification, (C) 400X, and (D) control (400X). It was diagnosed as the vascular rich type. The expressions were positive for (E) CXCR4 and (H) SDF-1, but (F) CCR6 and (G) CCR7 expressions were negative.

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Kishi T, et al.

Nakatsugawa investigated CXCR4 and SDF-1 expressions in 53 patients with squamous cell carcinoma of the tongue, in which the frequency of cervical lymph node metastasis was significantly higher in those with SDF-1 gene expression, and the five-year cumulative survival rate was significantly lower in patients with both SDF-1 and CXCR4 gene expressions, than those with no expression of either gene[10]. Regarding the other factors, no association of SDF-1 and CXCR4 expressions with any clinicopathological factor was noted during gene analysis or immunohistochemical staining. Nakatsugawa stated that his findings suggest that the association between SDF-1 gene expression and lymph node metastasis of squamous cell carcinoma of the tongue and SDF-1/CXCR4 expression serves as a prognostic factor. In our study on angiosarcoma, CXCR4 was expressed in half of the cases. CXCR4 was intensely stained in the cytoplasm or nucleus, being positive, in 6 of the 12 samples. Cellular rich type were determined in 4 of these 6 samples, and 2 were the vascular rich type. The association of CXCR4 with age, sex, development site, and histological type was investigated, but no significant difference due to any of these parameters was noted. In addition, CCR6 and CCR7 expressions were negative. SDF-1 expression was positive in 4 of the 12 samples, and all these SDF-1 expression-positive cases were also positive for CXCR4 expression. On the other hand, in granuloma telangiectaticum, which is a representative of benign vascular proliferative disease, CXCR4, CCR6, CCR7, and SDF-1 were negative in all cases. CXCR4 and SDF-1 expressions were significantly correlated with the clinical views in malignant skin tumors such as malignant melanoma, solar keratosis, Bowen’s disease, squamous cell carcinoma, and malignant fibrous histiocytoma; however, no correlation with the clinical view of angiosarcoma was noted. It was hence, suggested that CXCR4, CCR6, CCR7, and SDF-1 do not serve as a useful tumor marker. Indeed, an investigation of a new chemokine and tumor marker for angiosarcoma is needed.

Conclusion

Figure 4. (A) Clinical feature of angiosarcoma in the head of a 75-year-old female. The HE-stained sample of angiosarcoma under (B) 20X magnification, (C) 400X, and (D) control (400X). It was diagnosed as the cellular rich type. The expression of (E) CXCR4 was positive, but (F) CCR6, (G) CCR7, (H) and SDF-1 expressions were negative.

In our study on angiosarcoma, CXCR4 was expressed in half of the cases. The association of CXCR4, CCR6, CCR7, and SDF-1 with age, sex, development site, and histological type was investigated; however, no significant difference due to any of these parameters was noted. We have to collect more cases of angiosarcoma and analyze them immunohistochemically. Additionally, we have to investigate the usability of these chemokines as a marker. More development in the study of a new chemokine and tumor marker shall be needed for this disease.

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Expression of chemokine receptors in angiosarcoma

Table 2. Clinicopathologic features and CXCR4 expression n (%)

Age (years)

Clinical type

p

< 70 ≥ 70

3/12 (25%) 9/12 (75%)

1 (33%) 5 (56%)

2 (67%) 4 (44%)

1.000

Male Female

5/12 (42%) 7/12 (58%)

3 (60%) 3 (43%)

2 (40%) 4 (57%)

1.000

Head Face Trunk/neck/extremities Feet

8/12 (67%) 3/12 (25%) 1/12 (8%) 0/12 (0%)

4 (50%) 2 (67%) 0 (0%) 0 (0%)

4 (50%) 1 (33%) 1 (100%) 0 (0%)

0.513

8/12 (67%) 4/12 (33%)

4 (50%) 2 (50%)

4 (50%) 2 (50%)

1.000

Gender Location

Number of CXCR4 expression Positive Negative n (%) n (%)

Cellular rich type Vascular rich type

*p≤ 0.05 between groups Table 3. Clinicopathologic features and SDF-1 expression Number of SDF-1 expression n (%) Age (years)

p Positive n (%)

Negative n (%)

< 70

3/12 (25%)

1 (33%)

2 (67%)

≥ 70

9/12 (75%)

3 (33%)

6 (67%)

Male

5/12 (42%)

2 (40%)

3 (60%)

Female

7/12 (58%)

2 (29%)

5 (71%)

Head

8/12 (67%)

2 (33%)

6 (67%)

Face

3/12 (25%)

2 (67%)

1 (33%)

Trunk/neck/extremities

1/12 (8%)

0 (0%)

1 (100%)

Feet

0/12 (0%)

0 (0%)

0 (0%)

Cellular rich type

8/12 (67%)

2 (25%)

6 (75%)

Vascular rich type

4/12 (33%)

2 (50%)

2 (50%)

Gender

Location

Clinical type

1.000

1.000

0.325

0.548

*p≤0.05 between groups

Author contributions

this article.

The study was conceived and designed by Kishi T, Yamamoto Y, Kaminaka C, Toyozawa S and Furukawa F. The manuscript was prepared by Kishi T. The statistical analysis was performed by Matsunaka H.

References 1.

Conflict of interest

2.

The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of

3.

Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D (editors). Rook’s textbook of dermatology. 9th ed. Oxford, UK: Wiley-Blackwell; 2016. p. 137.36-38. Zlotnik A. Chemokines and cancer. Int J Cancer 2006; 119(9); 2026–2029. doi: 10.1002/ijc.22024. Müller A, Homey B, Soto H, Ge N, Catron D, et al. In-

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volvement of chemokine receptor in breast cancer metastasis. Nature 2001; 410(6824): 50–56. doi: 10.1038/35 065016. Scala S, Ottaiano A, Ascierto PA, Cavalli M, Simeone E, et al. Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res 2005; 11(5): 1835–1841. doi: 10.1158/1078-0432.CCR-04-18 87. Muller A, Sonkoly E, Eulert C, Gerber PA, Kubitza R, et al. Chemokine receptors in head and neck cancer: Association with metastatic spread and regulation during chemotherapy. Int J Cancer 2006; 118(9): 2147–2157. doi: 10.1002/ijc.21514. Feng LY, Ou ZL, Wu FY, Shen ZZ, Shao ZM. Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival. Clin Cancer Res 2009; 15(9): 2962–2970. doi: 10.1158/1078-0432.CCR-08-2495. Wang J, Xi L, Hunt JL, Gooding W, Whiteside TL, et al. Expression pattern of chemokine receptor 6 (CCR6) and CCR7 in squamous cell carcinoma of the head and neck identifies a novel metastatic phenotype. Cancer Res 2004; 64(5): 1861–1866. doi: 10.1158/0008-5472.CAN-03-29 68.

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Toyozawa S, Yamamoto Y, Ishida Y, Kondo T, Nakamura Y, et al. Immunohistochemical analysis of CXCR4 expression in fibrohistiocytic tumors. Acta Histochem Cytochem 2010; 43(2): 45–50. doi: 10.1267/ahc.10003. Toyozawa S, Kaminaka C, Furukawa F, Nakamura Y, Matsunaka H, et al. Chemokine receptor CXCR4 is a novel marker for the progression of cutaneous malignant melanomas. Acta Histochem Cytochem 2012; 45(5): 293–299. doi: 10.1267/ahc.12004. Nakatsugawa S. 舌 扁 平 上 皮 癌 に お け る SDF-1/CXCR4 発現と臨床病理的因子との関連につ い て (Japanese) [On the relationship between SDF-1/CXCR4 expression and clinicopathological factors in squamous cell carcinoma of the tongue]. Dokkyo J Med Sci 2012; 39(1): T1–T11. Elder DE. In: Elenitsas R, Johnson Jr BL, Murphy GF, Xu X, (editors). Lever’s histopathology of the skin. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2009. p. 1040–1043. Kaminaka T, Toyozawa S, Yoshi Y, Kunimoto K, Furukawa F, et al. フェノールによる日光角化症とボ ーエン病の治療効果とケモカインレセプターに関す る免疫組織化学的検討 (Japanese) [Phenol peels for the treatment of actinic keratosis and Bowen’s disease: Correlation with chemokine receptors expression]. Skin Cancer 2011; 26(3): 327–332. doi: 10.5227/skincanc er.26.327.

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doi: 10.18282/jsd.v7.i1.170

ORIGINAL RESEARCH ARTICLE

A randomized, double-blind, comparative study for efficacy assessment of two hyaluronic acid nasolabial fillers Saman Ahmad Nasrollahi1,2, Mansour Nassiri Kashani1, Taraneh Yazdanparast1, Setareh Ameri1, Alireza Firooz1,2* Pharmaceutical, Cosmeceutical and Hygienic Products Clinical Evaluation Lab (DermaLab), Center for Research & Training in Skin Diseases & Leprosy, Tehran University of Medical Sciences, Tehran, Iran 2 Cosmetic Products Research Center, Food and Drug Organization, MOH & ME, Tehran, Iran 1

Abstract: Hyaluronic acid fillers are considered safe for use in cosmetics as described in the safety assessment. This study was aimed to assess and compare the efficacy and safety of two hyaluronic acid (HA) fillers on mild nasolabial folds. Ten women aged 30-50 years with mild nasolabial folds participated for injection of A and B gels into right or left nasolabial folds. The volume and surface of nasolabial folds were measured by CSI software and the density and thickness of dermis assessed by skin ultrasonography before and 2, 12, and 24 weeks after injection. The data were analyzed using SPSS software version 20, and p-value <0.05 were considered as significant. Global assessment showed over 50% improvement in patients injected with both gel A and B. At 2 weeks after injecting gel A the volume and surface of wrinkles decreased significantly. In the side injected with gel B, this reduction was significant at 2 and 12 weeks after injection. In addition, 24 weeks after injection of both gels the dermis echo-density increased and the dermis thickness decreased. This study indicated the significant positive filling effect of both HA fillers in decreasing the clinical signs of wrinkles at nasolabial folds. Comparing both fillers, there were not any statistically significant differences in any of measurements, but the persistence of gel B to improve the wrinkle appearance was slightly better than gel A. Keywords: hyaluronic acid; filler; ultrasonography Citation: Nasrollahi SA, Kashani MN, Yazdanparast T, Ameri S, Firooz A. A randomized, double-blind, comparative study for efficacy assessment of two hyaluronic acid nasolabial fillers. J Surg Dermatol 2022; 7(1): 170; http://dx.doi. org/10.18282/jsd.v7.i1.170. *Correspondence to: Alireza Firooz, Dermatologist, Professor of Center for Research & Training in Skin Diseases & Leprosy, Tehran University of Medical Sciences (TUMS), # 415 Taleqani Ave, Tehran, Iran; alifiruz@yahoo.com Received: 1st September 2021; Accepted: 16th October 2021; Published Online: 3rd November 2021

Introduction Skin aging includes a flattening of the epidermal-dermal interface and some breakdown of the dermal tissue; this layer is a protective and nutritive tissue with main components of collagen, elastin and hyaluronic acid to provide flexibility and elasticity of the skin and protects skin against dehydration[1,2]. The majority of age-dependent changes happen in the dermis and include breakdown of collagen and elastin, reduction in skin thickness, loss of hyaluronic acid and consequently skin volume and

dehydration in the dermis which extrinsically lead to create wrinkles[1-3]. Hyaluronic acid is the most important glycosaminoglycan (GAG) which causes skin elasticity and has the unique capacity to contain water and make the skin hydrated. In addition it has a role in cell growth and function of membrane receptors, also leads to stability of cellular structures and creates a viscoelastic network for collagen and elastin fibers to connect to each other; these benefits make hyaluronic acid as excellent dermal filler[4, 5]. One of the signs of aging is vertical lines on either side

Copyright © 2022 Nasrollahi SA, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Nasrollahi SA, et al.

of the mouth which is called nasolabial folds or laugh line. Injectable fillers in treatment for facial rejuvenation have become an increasingly prevalent feature to grow the population wanting to reverse the aging process. Through recent advances in injection techniques, newer types of dermal fillers have been approved, providing practitioners the option of administering soft tissue fillers such as cross linked hyaluronic acids with minimal inconvenience to the patient [6,7]. This study was designed to assess and compare the efficacy and safety of two soft tissue fillers on mild nasolabial folds using non-invasive measurement techniques.

Materials and methods Study design and injection technique This randomized clinical trial was performed in the Pharmaceutical, Cosmeceutical and Hygienic Evaluation Lab (DermaLab) of Center for Research & Training in Skin Diseases & Leprosy, Tehran University of Medical Sciences (TUMS) from May 2013 to April 2014. After signing the written informed consent and according to the Wrinkle Severity Rating Scale, 10 women aged 30-50 years with mild nasolabial folds and and skin type III-IV were recruited. The exclusion criteria were a recent history of any skin disease or operation in the previous 3 months, any systemic disease that can affect skin status, pregnancy, any other previous cosmetic intervention on the nasolabial fold such as HA, collagen and fat injection, laser therapy, peeling, or non-ablative rejuvenation procedures in the year prior to start day of the study and a history of smoking. Participants received 1 ml of gel A (Hyamax Deep Line manufactured by Laboratories Hyamed, Switzerland) randomly on one of nasolabial folds and gel B (Yvoire Classic S manufactured by LG Life Sciences, South Korea) was injected in the opposite side. Both fillers contained 22 mg/ml HA and all injections were done with standard technique for dermal fillers. The subjects were uninformed about the gel types and instructed not to use any pharmaceutical, cosmeceutical or hygienic products on their skin on the night prior to the injection. To anaesthetize the region, a thin layer of Janucaine cream (containing lidocaine 2% and prilocaine 2%, Janus pharmaceutical company, Iran) was applied to both nasolabial folds and occluded for 30 minutes.

Assessment All assessments were done prior to the treatment and 2, 12 and 24 weeks after injections (follow up visits). A frontview digital photo of the face was taken for comparing before-after photos by two independent dermatologists according to the Physician Global Assessment (PGA) five-point scale: 1- Worse: exacerbation, 2- No change: improvement of 24% or less, 3- Fair: improvement of 2549%, 4- Good: improvement of 50- 74%, 5- Excellent:

doi:10.18282/jsd.v7.i1.170

improvement of 75% or more [8]. High-resolution images of the nasolabial fold were taken by VisioFace (CK electronic GmbH, Cologne, Germany) then the volume and surface of wrinkles were measured by the related Complete Skin Investigation (CSI) software. The change in volume and surface of wrinkles at each time point after injection were calculated as: Value after injection – value before injection / value before injection Furthermore 22 MHz skin ultrasonography (DUB Skin Scanner, tpm, Luneburg, Germany) of nasolabial folds dermis were done at baseline and final visit (24 weeks after injection) to measure the dermis echo-density and thickness [9]. The subject’s satisfaction of treatment was assessed by Visual Analogue Scale (VAS)[10] on a 0-10 scale which 0 is dissatisfied and 10 is extremely satisfied. Finally any possible adverse effects were asked and recorded on the 1-3 scale (1: mild, 2: moderate, 3: severe).

Statistical analysis The obtained data were entered in SPSS software version 20 and then mean score of parameters before and after intervention was analyzed by the paired T-test and p-value <0.05 was considered significant.

Ethics The study was conducted in accordance with the ethical principles provided by Good Clinical Practice (GCP) and the Declaration of Helsinki and all volunteers provided written informed consent.

Results All volunteers completed study period and there was no deviation from protocol. Regarding the safety, one participant reported mild bruising and the other one reported swelling, pain and mild stiffness at injection sites of gel A, which cleared spontaneously in a few days. As depicted in figure 1, the volume and surface of wrinkles at 2, 12 and 24 weeks after injecting gel A decreased compared to baseline, which was statistically significant only 2 weeks after injection (-45.94±20.74%, p– value = 0.000 for volume of wrinkles and -45.02±20.43%, p–value = 0.001 for surface of wrinkles). In the side injected with gel B; this reduction in wrinkles objective parameters was significant at week 2 (-39.67±21.51%, p – value = 0.003 for volume of wrinkles and -39.56±17.16%, p–value = 0.001 for surface of wrinkles) and week 12 (-31.6±31.37%, p –value = 0.019 for volume of wrinkles and -34.68±23.59%, p–value = 0.004 for surface of wrinkles); 24 weeks after injection gel B, just the reduction in surface of wrinkles was significant (-22.23±23.14%, p– value = 0.037). In addition, 24 weeks after injection of gel A the echodensity of dermis increased significantly (119.32±164.8%, p–value = 0.028), and there was a non-significant decrease

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A randomized, double-blind, comparative study for efficacy assessment of two hyaluronic acid nasolabial fillers

in the dermis thickness. The same changes occurred after injecting gel B, significant increase in dermis density (78.00±97.06%, p–value = 0.036), and non-significant decrease in the dermis thickness (Tables 1). Comparing both fillers, there were not any statistically significant differences in any of measurements. The results of PGA considered the grade of correction of nasolabial folds and stability of both gels at 2, 12 and 24 weeks after injection (Table 2). This improvement was good or excellent (over 50% improvement) in 8, 6, and 6 of 10 patients injected with gel A, and in 9, 7 and 7 of 10 patients injected with gel B after 2, 12, and 24 weeks, respectively (Figure 2 and Table 2 ). The mean of PGA scores were not significantly different between two gels. The mean patient satisfaction score at 2, 12 and 24 weeks after injection of gel A were 6.25 ±1.75, 7.88 ± 2.02 and 7.6 ±1.89, respectively. 2, 12 and 24 weeks after injecting of gel B, these records were 7.4 ±1.34, 7.44 ±1.66 and 7.5 ±1.95, respectively (p <0.05).

the fact that aging is a continuous process, temporary fillers should be preferred over permanent ones[13]. Hyaluronic acid (HA)-based gels are now the gold standard and most commonly used dermal fillers in the US[14]. In this before-after trial, the volume and surface of wrinkles in nasolabial folds have been reduced both objectively and subjectively 2, 12, and 24 weeks after injection of two HA fillers (Figure 1). These results can be due to the restoration of volume using dermal fillers which can rebalance facial proportion, increase symmetry and by reducing wrinkles, produce a younger appearance[11]. The obtained results have been confirmed by physician assessments (Table 2), in accordance with biometric assays. In addition there was not any statistically significant difference between these two products, and both of them were able to reduce the symptoms of wrinkles. The increased echo density of dermis can be due to the presence of hyaluronic acid composition in mentioned area. Furthermore, HA in the dermis can stimulate collagen synthesis; the cumulative effect of hyaluronic acid and collagen lead to the increase in the dermis density to mentioned rate (Table 1)[15]. In contrast, both gels reduced the dermis thickness at the injection area due to the pressure effect of fillers on dermis which is the main role of fillers to treat the wrinkles. This finding has been reported previously[16]. The participant’s satisfaction after injecting both fillers was considerable and no significant side effects

Discussion In the past decade there has been a major shift in facial rejuvenation toward less invasive and even nonsurgical procedures with less downtime and less pain [11]. It is understandable that increased popularity of soft-tissue fillers is due to the effective results of restoring lost volume and correcting contour deficiencies to the aging face[12]. Due to

Table 1.

The change in the echo-density and thickness of dermis 2, 12 and 24 weeks after injecting gel A in comparison with gel B.

The % of Variable

Dermis density Dermis thickness

Table 2.

change of gel A after 24 weeks Mean ± SD* 119.32% 164.80± -10.90% ±19.61

The % of P –value (before-after

change of gel B after 24 weeks

comparison)

P –value (before-after

P –value (before-after

comparison)

comparison)

Mean ± SD 0.028

78% ±97.06

0.036

0.178

0.081

-8.35% ±16.26

0.127

0.697

The physician global assessment of correction level and stability of gels A and B 2, 12 and 24 weeks after injection

1- Worse: exacerbation 2- No change: improvement of 24% or less 3- Fair: improvement of 25-49% 4- Good: improvement of 50-74% 5- Excellent: improvement of 75% or more The mean of PGA

week 2

week 12

week 24

(n=10)

(n=10) Gel

(n=10)

Gel A

Gel B

Gel A

2 7 1

1 8 1

1 3 5 1

B 1 2 6 1

3.9

4

3.7

3.9

Gel A

Gel B

1 3 6 -

1 2 6 1 3.7

3.5

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Nasrollahi SA, et al.

Figure 1. The change in the A) volume and B) surface of nasolabial folds 2, 12 and 24 weeks after injecting gel A in comparison with gel B.

*: considered as significant percent of the change (p-value< 0.05)

Figure 2. The photographs of nasolabial folds of a representative participant at baseline (A), 2 weeks (B), 12 weeks (C) and 24 weeks (D) after injection A and B gels. The nasolabial folds were treated on contralateral sides of the face with gel A in the participant right side and gel B in left

were reported after injection. Bruising at the injection site was infrequent and disappeared spontaneously in a few days. Our obtained results indicate no statistically significant difference between two HA fillers but a little better results of gel B in reducing wrinkle volume and surface compared to gel A can be due to different manufacturing processes with major influence on the characteristics of the biopharmaceutical final product, so even minor manufacturing processing differences may impact biological activity, safety and effectiveness of finished product[17].

Conclusion In conclusion due to the differences between before and after injection and lack of major side effects in both gels, they can be safe and effective products to remove the wrinkles at nasolabial area. Totally because of the superior beauty results of HA fillers, they are still the best dermal aesthetic device to increase the volume of soft tissue. On the other hand they are absorbed and therefore cannot be a permanent solution to remove wrinkles.

doi:10.18282/jsd.v7.i1.170

Acknowledgement The authors appreciate from Pariz Medical Equipment Co. and Omid Salamat Co., for financial support in present study.

References 1. Stern R, Maibach HI. Hyaluronan in skin: aspects of aging and its pharmacologic modulation. Clin Dermatol 2008; 26(2): 106–122. doi: 10.1016/j.clindermatol.2007.09.013. 2. Fisher GJ, Varani J, Voorhees JJ. Looking older: Fibroblast collapse and therapeutic implications. Arch Dermatol 2008; 144(5): 666–672. doi: 10.1001/archderm.144.5.666. 3. Bailey AJ. Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 2001; 122(7): 735–755. doi: 10.1016/S0047-6374(01)00225-1. 4. Masson F. Skin hydration and hyaluronic acid. Ann Dermatol Venereol 2010; 137(Suppl 1): S23–25. doi: 10.1016/S01519638(10)70005-3. 5. Lupo MP. Hyaluronic acid fillers in facial rejuvenation. Semin Cutan Med Surg. 2006; 25: 122–126. doi: 10.1016/ j.sder.2006.06.011. 6. Walter RJ, Matsuda T, Reyes HM, Walter JM, Hanumadass M. Characterization of acellular dermal matrices (ADMs) prepared by two different methods. Burns 1998; 24(2): 104– 113. doi: 10.1016/S0305-4179(97)00110-1. 7. Ascher B, Cerceau M, Baspeyras M, Rossi B. Soft tissue

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A randomized, double-blind, comparative study for efficacy assessment of two hyaluronic acid nasolabial fillers

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filling with hyaluronic acid. Ann Chir Plast Esthet 2004; 49(5): 465–685. doi: 10.1016/j.anplas.2004.09.001. Choi YJ, Lee JY, Ahn JY, Kim MN, Park MY. The safety and efficacy of a combined diode laser and bipolar radiofrequency compared with combined infrared light and bipolar radiofrequency for skin rejuvenation. Indian J Dermatol Venereol Leprol 2012; 78(2): 146–152. doi: 10.4103/0378-6323.93630. Dreno B, Araviiskaia E, Berardesca E, Bieber T, Hawk J, Sanchez-Viera M, et al. The science of dermocosmetics and its role in dermatology. J Eur Acad Dermatol Venereol 2014; 28(11): 1409–1417. doi: 10.1111/jdv.12497. Reips UD, Funke F. Interval level measurement with visual analogue scales in Internet-based research: VAS Generator. Behav Res Methods 2008; 40(3): 699–704. doi: 10.3758/BRM.40.3.699. Monstrey SJ, Pitaru S, Hamdi M, Van Landuyt K, Blondeel P, Shiri J, et al. A two-stage phase I trial of Evolence30 c o l l a g e n f o r s o f t - t i s s u e c o n t o u r c o r r e c t i o n . P l a s t Reconstr Surg 2007; 120(1): 303– 311. doi: 10.1097/01. prs.0000264402.97692.b6. Narins RS, Baumann L, Brandt FS, Fagien S, Glazer S, Lowe NJ, et al. A randomized study of the efficacy and safety of injectable poly L-lactic acid versus human-based collagen implant in the treatment of nasolabial fold wrinkles. J

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Am Acad Dermatol 2010; 62(3): 448–462. doi: 10.1016/ j.jaad.2009.07.040. Sales AG, Lotierzo PH, Gimenez R, Camargo CP, Ferreira MC. Evaluation of poly-L-lactic acid implant for treatment of the nasolabial fold: 3-year follow-up evaluation. Aesthetic Plast. Surg 2008; 32(5): 753–756. doi: 10.1007/s00266-0089182-2. Baumann LS, Shamban AT, Lupo MP, Monheit GD, Thomas JA, Murphy DK, et al. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatol Surg 2007; 33(2): S128–35. doi: 10.1097/00042728200712001-00004. Croce MA, Dyne K, Boraldi F, Quaglino D Jr, Cetta G, Tiozzo R, et al. Hyaluronan affects protein and collagen synthesis by in vitro human skin fibroblasts. Tissue & Cell 2001; 33(4): 326–331. doi: 10.1054/tice.2001.0180. Kim J. Effects of Injection Depth and Volume of Stabilized Hyaluronic Acid in Human Dermis on Skin Texture, Hydration, and Thickness. Arch Aesthetic Plast Surg 2014; 20(2): 97–103. doi: 10.14730/aaps.2014.20.2.97. Dranitsaris G, Dorward K, Hatzimichael E, Amir E. Clinical trial design in biosimilar drug development. Invest New Drugs 2013; 31(2): 479–487. doi: 10.1007/s10637-012-9899-2.

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doi: 10.18282/jsd.v7.i1.178

original research article

The diagnostic accuracy of the mobile phone teledermatoscopy Hamza Yildiz1*, Memet Ersan Bilgili1, Hasan Aktug Simsek2 1 2

Department of Dermatology, Yunus Emre Government Hospital, Turkey Department of Pathology, Eskisehir Yunus Emre Government Hospital, Turkey

Abstract: The positive predictive value (PPV) of smart mobile phone teledermatoscopy is not known. The main purpose of the present study was to investigate the sensitivity and positive predictive values (PPVs) of smart mobile phone teledermatoscopy. Over a period of 6 months, up to three clinical and dermatoscopic images were obtained of 67 skin lesions from 67 patients using a mobile phone camera and standard pocket dermatoscopy device. Out of the 67 patients, 44 were men (65.67%) and 23 were women (34.32%). The mean age of the patients was 39.56±22.19 years (ranging from 18 to 92). The majority of the lesions (71.64%; n=48) were benign, while 11.94% (n=8) of the biopsies were premalignant and 16.41% (n=11) of the lesions were malignant. The sensitivity for the diagnosis of benign, premalignant, and malignant lesions were 93.8%, 100%, and 100%, respectively. PPVs for the diagnosis of benign, premalignant, and malignant lesions were 93.8%, 100%, and 100%, respectively. The sensitivity and PPVs of all lesions were 95.9% and 95.7%. The accuracy of the teledermatoscopic consultation with a mobile phone is very high. We therefore think that it can be a cost effective and useful method in the consultation at distance. Keywords: skin lesions; smart mobile phone; teledermatology; teledermatoscopy Citation: Yildiz H, Bilgili Me, simsek HA, The diagnostic accuracy of the mobile phone teledermatoscopy. J surg Dermatol 2022; 7(1): 178; http://dx.doi.org/10.18282/jsd.v7.i1.178. *Correspondence to: Hamza Yildiz, Department of Dermatology, Yunus Emre Government Hospital, Turkey; hamzayildiz@ gmail.com Received: 23rd September 2021; Accepted: 4th November 2021; Published Online: 24th November 2021

Introduction Dermatoscopy ensures better visual image of deeper structures of the skin. Nowadays, it is commonly used and widely accepted screening device in dermatology[1]. To overcome the problem of maldistribution of dermatologist, teleconsultation technologies (teledermatology with or without teledermatoscopy) are being used [2]. Tele­ dermatoscopy improves the diagnostic accuracy for pigmented or non-pigmented skin lesions[3]. Digital dermatoscopy systems, attached high-end digital cameras and computer are expensive. These complex and expensive techniques may not importantly upgrade management plans and diagnosing. They are also not yet easily approachable. Currently, standard pocket dermatoscopy tools and mobile camera phones are widely distributed, easily available, cheap, reachable, and effective[1,4,5]. In this study, we assessed the sensitivity and positive

predictive values (PPVs) of mobile teledermatoscopy (using a mobile camera phone and standard pocket dermatoscopy device).

Methods This study was a prospective, open-label, non-randomized controlled clinical study of the diagnostic accuracy of mobile teledermatoscopy. Ethical approval was obtained from Eskisehir Osmangazi University Clinical Research, Ethical Committee (September 26, 2012; protocol no., 2012/272) for this study. The study period was from January 2015 to December 2015. The study protocol complied with the ethical guidelines of the Declaration of Helsinki of the World Medical Association. Patients were selected randomly from the outpatient clinic at the department of dermatology, Eskisehir Military Hospital, Eskisehir, Turkey. Patients with suspicious skin lesion deemed to need a biopsy or excision were included to study.

Copyright © 2022 Yildiz H, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The diagnostic accuracy of the mobile phone teledermatoscopy

Clinical and dermatoscopic figures of each lesion and clinical information were sent to a teledermatologist for decision-making.

Clinical information form Clinical information (patient history, sex, age, location and lesion onset etc.) were written in the standard information form for each patient. This form contained clinical information such as age, sex, presenting complaint (does it itch, burn, and hurt?), brief summary of patient’s lesion history, localization, onset time (when did it start?), dissemination pattern of the lesion, provocative factor, previous treatment(s), occupation, additional findings, skin types, personal and family history of skin cancer.

Clinical and dermatoscopic images Clinical and dermatoscopic images of the lesions were obtained for each lesion (Figure 1). Standard guidelines and previous studies were followed for digital imaging. Two macro images (distance and close-up) at 8.0 megapixel resolutions (4320 X 3240 pixels), 180 dpi (dots per inch), Joint Photographic Experts Group (JPEG) format were obtained for each lesion using a mobile phone (Galaxy Note 4, Samsung). Two dermatoscopic images were also taken for each lesion with the same mobile phone and a lens attachment (Dermlite DL1, 3Gen Inc).

Figure 1. A: A macro image (close-up) of a basal cell carcinoma B. Dermatoscopic image of the same lesion with the same smart mobile phone and a lens attached.

The standard information forms and clinical and dermatoscopic images of the lesions were sent to teledermatologist. The teledermatologist reported one primary and one differential diagnosis. The results were then compared with a gold standard data to evaluate the teledermatoscopy method. In the present study, not only face-to-face examination but also histopathology was used as a gold standard data. The positive predictive values (PPVs) and

sensitivity of the smart mobile phone teledermatoscopy were calculated. The sensitivity is the probability of the physicians certainly identifying all of the positive diagnosis of a skin lesion. It is described as true positive (TP) / [TP + false negative (FN)]. (Table 1)[6]. The PPV is more important than the sensitivity, in clinical setting. It is described as TP / [(TP + false positive (FP)] (Table 1). The sensitivity does not foresee the proportion of accuracy of a particular doctor’s diagnosis but the PPV determines the proportion of trueness attributed to a medical doctor particular[6].

Statistical analysis Data were entered into an Excel spreadsheet and analysed with the statistical Package for SPSS 11.0 statistical software (SPSS Inc., Chicago, IL). The normal distribution of the quantitative data was tested by using the ShapiroWilk test. The Mann-Whitney U test was used for quantitative data without normal distribution. The Chisquare test was used to compare qualitative data. A P value less than 0.05 was assessed statistical significant. The data are represented as the mean values ± standard deviation (SD).

Results Sixty seven patients with 67 skin lesions were enrolled in the study. Data were collected from January 1, 2015, to December 1, 2015. The average age of these participants was 39.56±22.19 (between the age of 18-92) years. Of the 67 patients, 23 were women (34.32%) and 44 were men (65.67%). The average age of the women was 43.60±2.43 (between the age of 10-86) years. The average age of the men was 37.45±2.09 (between the age of 18-92) years. The average duration of the malignant, premalignant and benign skin lesion were 4.60±5.61 (ranging from 1 to 20), 4.75±2.71 (ranging from 3 to 10), and 10±7.33 (ranging from 0.25 to 35) years, respectively. The average age of all skin lesions was 8.96±7.21 (ranging from 0.25 to 35) years. One malignant melanoma (MM), 9 basal cell carcinomas (BCC), 1 squamous cell carcinoma (SCC), 4 keratoacanthomas, 2 actinic keratoses, 2 dysplastic nevi, 5 seborrheic keratoses, 39 nevi and 4 other benign skin lesions (2 dermatofibromas, lentigo simplex, and trichoepithelioma) were included in the study group. The histopathologic diagnoses are shown in the Table 2. Based on whether the lesions were malignant, premalignant or benign, lesions divided into 3 subgroups. BCCs, SCCs and MMs were deemed malignant lesions. Keratoacanthomas, actinic keratoses and dysplastic nevi were classified as premalignant lesions. Nevi, lentigo simplex, trichoepitheliomas, seborrheic keratoses, and dermatofibromas were deemed benign lesions. The majority of the lesions (71.64%; n=48) were benign, while 11.94% (n=8) of the biopsies were premalignant and 16.41% (n=11) of the lesions were malignant (Table 2). BCC was the most common malignancy (13.43; n=9) in the present study. Localizations of the lesions are shown in Table 3. The

18 doi:10.18282/jsd.v7.i1.178


Yildiz H, et al.

Table 1. Diagram demonstrating how the sensitivity, specificity, positive predictive value and negative predictive value are related. Condition (as determined by "Gold standard") (Face-to-face examination with histopathological diagnosis) Condition Positive Condition Negative Test Outcome (Diagnosis of the teledermatologist)

Test Outcome Positive

True Positive (TP)

False Positive (FP)

Positive predictive value: TP / (TP + FP)

Test Outcome Negative

False Negative (FN)

True Negative (TN)

Negative predictive value: TN / (FN + TN)

Sensitivity: TP / (TP + FN)

Specificity: TN / (FP + TN)

Table 2. Histopathologic diagnoses of the lesions are represented. Histopathological Diagnoses

n

%

Malignant (total)

11

16.41

Malignant melanoma

1

1.49

Basal cell carcinoma

9

13.43

Squamous cell carcinoma

1

1.49

Premalignant (total)

8

11.94

Keratoacanthoma

4

5.97

Dysplastic nevus

2

2.98

Actinic keratosis

2

2.98

48

71.64

Nevus (total)

39

58.20

●Intradermal nevus

28

41.79

●Compound nevus

5

7.46

●Junctional nevus

4

5.97

Benign (total)

●Blue nevus

2

2.98

Seborrheic keratosis

5

7.46

Other benign skin lesions*

4

5.97

67

100

Total

Table 3. Localizations of the lesions are shown. Histopathological Diagnosis

Head and neck

Chest, abdomen, and back

Lower extremity

Upper extremity

Malignant melanoma Basal cell carcinoma Squamous cell carcinoma Keratoacanthoma Dysplastic nevus Actinic keratosis Seborrheic keratosis Nevus Other skin lesions

1 8 1 4 1 4 26 2

1 11 -

1 1 1 1

1 1 1 1

19


The diagnostic accuracy of the mobile phone teledermatoscopy

PPVs and the sensitivity values for benign premalignant, and malignant skin lesions are shown in Table 4. Table 4. The sensitivity values and the PPVs for malignant, premalignant, benign skin lesions and all lesions are represented. Sensitivity (%)

PPV (%)

Malignant

100

91.6

Premalignant

100

80

Benign

93.8

100

All lesions

95.5

95.7

Discussion TD has been successfully used for remote diagnosis and consultation[7,8]. Moreno-Ramirez et al.[9] have reported that store-and-forward TD is an effective, accurate, reliable and valid approach for routine management of patient referrals dermatology clinics. Dermatoscopy is the most widely accepted and most frequently used screening tool in dermatology as it allows better visualization of deeper structures of the skin[1]. Previous studies have demonstrated that dermatoscopy improves the diagnostic accuracy for pigmented melanocytic and non- melanocytic skin lesions[3]. The ability to diagnose and assess benign skin lesions accurately and to distinguish them from malignant skin lesion is vital. Perednia reported that primary care physicians had uncertainty regarding management of more than one in three patients with dermatological lesions. Perednia assessed that it is notable that just one-tenth of these patients was sent the referral[1,10]. TD is a very important method because it is shortening the waiting intervals to the surgical treatment, avoiding unnecessary visit to the hospital, and overcoming the some other problems such as geographic maldistribution and lack of dermatologist[11]. We believe that TD methods should rely on low-cost, simple and high-sensitivity diagnostic procedures. Digital dermatoscopy systems, attached high-end digital cameras and computer are expensive. They are also not yet easily approachable[1]. Currently, standard pocket dermatoscopy tools and mobile camera phones are widely distributed, easily available, cheap, reachable, and effective[1,4]. Senel et al. investigated the contribution to the management and reliability of the diagnosis of non– melanocytic skin tumors (150 patients). They found that the reliability (kappa) enhanced dramatically when dermatoscopy was added (p < 0.05). The accuracy of diagnosis was dramatically enhanced by the additional of dermatoscopic figures, from 85% to 94% for dermatologist A and from 88% to 95% for dermatologist B[11]. Kromer et al. assessed 113 skin tumours using mobile phone camera. They compared mobile teledermatoscopy

20

with histopathologic results. The both groups showed equally high sensitivity. The sensitivity of benign nonmelanocytic, benign melanocytic, malign non-melanocytic, and malignant melanocytic lesions were 76%, 87%, 97%, and 100%, respectively. They reported clinical and dermoscopic tele-evaluations and reported that clinical image tele-evaluation might be the method of choice for mobile tumour screening (kappa, 0.84)[1]. Wu et al. used smart mobile phone in 29 patients with atypical nevi. The diagnostic concordance was 0.87 (Kappa). They suggested that mobile eledermatoscopy is feasible and effective as a method for short-term monitoring of clinically atypical nevi[3]. Alexander et al. investigated the accuracy of TD (dermatologist 1; 50.7, dermatologist 2; 60.9%) and face-toface (66.7%) dermatological examinations. They assessed that mobile teledermatoscopy solution may be useful as a triage tool[4]. The negative predictive value (NPV) is the rate of patients with negative test results who are truly diagnosed. The PPV is the rate of patients with positive test outcomes who are truly diagnosed[12]. Guggenmoos-Holzmann et al. and Har-Shai et al. recently stated that the PPV is the suitable and objective illustrator of clinical diagnoses. The PPV is more patient-focused and is often more relevant to patient care[13,14]. The PPVs and sensitivity values the for benign skin lesions (100%, 93.8%), premalignant (80%, 100%), and malignant (91.6%, 100%) were very high in the present study. These studies suggested that the diagnostic accuracy proportions of teledermatoscopy with mobile phone were high. It can be used by primary physicians in daily practice. Our study has some limitations. Changes in the staff may have affected the pathological diagnosis though the pathological assessments were performed by experienced pathologists in this study. Our pathologist was a dermatopathologist. The small number of lesions was another limitation of the study. We enrolled only the patients with suspicious skin lesion deemed to need a biopsy or excision. In conclusion, the accuracy of the teledermatoscopic consultation with a mobile phone is very high. We therefore think that it can be a cost effective and useful method in the consultation at distance.

Conflict of interest The authors declare that there is no conflict of interest.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References 1. Kromer S, Frühauf J, Campbell TM, Massone C, Schwantzer G, et al. Mobile teledermatology for skin tumour screening: Diagnostic accuracy of clinical and dermoscopic image teleevaluation using cellular phones. Br J Dermatol 2011; 164(5): 973–979. doi: 10.1111/j.1365-2133.2011.10208.x. 2. Dekio I, Hanada E, Chinuki Y, Akaki T, Kitani M, et al. Usefulness and economic evaluation of ADSL-based doi:10.18282/jsd.v7.i1.178


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3.

4. 5.

6.

7.

8.

live interactive teledermatology in areas with shortage of dermatologists. Int J Dermatol 2010; 49(11): 1272–1275. doi: 10.1111/j.1365-4632.2010.04572.x. R o s e n d a h l C , Ts c h a n d l P, C a m e r o n A , K i t t l e r H . Diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. J Am Acad Dermatol 2011; 64(6): 1068–1073. doi: 10.1016/j.jaad.2010.03.039. Börve A, Terstappen K, Sanberg C, Paoli J. Mobile teledermoscopy-there’s an app for that! Dermatol Pract Concept 2013; 3(2): 41–48. doi: 10.5826/dpc.0302a05. Massone C, Hofmann-Wellenhof R, Ahlgrimm-Siess V, Gabler G, Ebner C, Soyer HP. Melanoma screening with cellular phones. PloS One 2007; 2(5): e483. doi: 10.1371/ journal.pone.0000483. Bilgili ME, Yildiz H, Cengiz BP, Saydam IM. Effect of preoperative evaluation by a dermatologist on diagnostic accuracy. Dermatol Surg 2014; 40(12): 1402–1408. doi: 10.1097/DSS.0000000000000168. Wu X, Oliverias SA, Yagerman S, Chen L, DeFazio J, et al. Feasibility and efficacy of patients-initiated mobile teledermoscopy for short-tern monitoring of clinically atypical nevi. JAVA Dermatol 2015; 151(5): 489–496. doi: 10.1001/ jamadermatol.2014.3837. Yildiz H, Abuaf OK, Bilgili ME. The use of teledermatology in daily practices among dermatologist in Turkey. Turk J

Dermatol 2014; 8: 7–11. doi: 10.4274/tdd.1526. 9. Moreno-Ramirez D, Ferrandiz L, Ruiz-de-Casas A, NietoGarcia A, Moreno-Alvarez P, et al. Economic evaluation of a store-and-forward teledermatology system for skin cancer patients. J Telemed Telecare 2009; 15(1): 40–45. doi: 10.1258/ jtt.2008.080901. 10. Prednia DA, Allen A. Telemedicine technology and clinical applications. JAMA 1995; 133: 171–174. doi:10.1001/ jama.1995.03520300057037. 11. Ş e n e l E , B a b a M , D u r d u M . T h e c o n t r i b u t i o n o f teledermatoscopy to the diagnosis and management of nonmelanocytic skin tumours. J Telemed Telecare 2013; 19(1): 60–63. doi: 10.1177/1357633X12474961. 12. Altman DG, Bland JM. Diagnostic tests 2: Predictive values. BMJ 1994; 309(6947): 102. doi: 10.1136/bmj.309.6947.102. 13. Har-Shai Y, Hai N, Taran A, Mayblum S, Barak A, et al. Sensitivity and positive predictive values of presurgical diagnosis of excised benign and malignant skin tumors: A prospective study of 835 lesions in 778 patients. Plast Reconstr Surg 2001; 108(7): 1982–1989. doi: 10.1097/00006534200112000-00022. 14. Guggenmoos-Holzmann I, van Houwelingen HC. The (in) validity of sensitivity and specificity. Stat Med 2000; 19: 1783– 1792. doi: 10.1002/1097-0258(20000715)19:13<1783::AIDSIM497>3.0.CO;2-B.

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doi: 10.18282/jsd.v7.i1.168

original research article

Volumetric estimation of autologous fat for augmentation of contour defects of face Shilpi Bhadani, Sujata Sarabahi*, Savita Arora, Vinay Kumar Tiwari, Anmol Chugh Department of Burns, Plastic and Maxillofacial Surgery, VMMC and Safdarjung Hospital, New Delhi, India

Abstract: Autologous fat transfer for correcting contour defects of face has gained wide popularity in aesthetic surgery. However, quantification of fat requirement and its survival is still a fertile area for research to improve the predictability of volume retention of injected fat. There have been no detailed studies of the calculation for the amount of fat to be injected and percentage of fat retained. The objective of this study was to quantify the amount of fat required for correcting a facial deformity and amount retained postoperatively over a period of 6 months. Thirty patients were recruited in a prospective study where in, the fat requirement for augmenting the soft tissue defect was assessed using USG preoperatively and followed up at 1, 3 and 6 months by the same technique. It was found that USG is a simple, objective, reliable, cost-effective method of assessing the fat requirement and retention in autologous fat transfer. Keywords: fat transfer; augmentation; volumetry Citation: Bhadani S, Sarabahi S, Arora S, Tiwari VK, Chugh A. Volumetric estimation of autologous fat for augmentation of contour defects of face. J Surg Dermatol 2022; 7(1): 168; http://dx.doi.org/10.18282/jsd.v7.i1.168. *Correspondence to: Sujata Sarabahi, Department of Burns, Plastic and Maxillofacial Surgery, VMMC and Safdarjung Hospital, New Delhi 110048, India; ssarabahi@yahoo.co.in Received: 15thth November 2021; Accepted: 7th January 2022; Published Online: 22nd January 202229th May 2017; Accepted: 30 August

Introduction

The current practice of fat transplantation for augmentation of contour deformities at various sites in the body is a rediscovery of the method which has been used by plastic surgeons for more than a century. The origin of the procedure may be difficult to establish but it is to Neuber that Plastic surgeons owe this minimally invasive method. Neuber’s first report[1] in the 23rd congress of the German surgical society in 1893 included this procedure in the armamentarium of the plastic surgeons. Later other surgeons like Czerny[2] (1895) who used hip lipoma for mammary reconstruction, Lexer[3] (1910) who transplanted abdominal fat (12 × 13 cm) to nasolabial groove and subsequently more surgeons practised this procedure. Due to the disappointing results of the retention of the transplanted fat the initial interest in the procedure gradually waned. Peer [4] was the first to realise and describe the importance of measuring the viability of the transplanted fat and reported a survival of 50% volume after one year. Illouz [5] in 1983 invented the technique of liposuction using a cannula and this new technique

changed the concept of fat grafting. It changed from being transplanted as a fragment to being re-injected as a tissue. In 1997, Coleman [6] added another dimension to this procedure when he introduced the atraumatic handling of this fragile tissue which consisted of sampling, centrifugation and transfer. Fat processing to increase the survival of the transplanted tissue is now considered critical. The method popularised by Coleman in couple of decades has helped fat transfer re-establish its usefulness in the armamentarium of the plastic surgeons and has become the gold standard for autologous fat transfer. However, due to the various methods of harvesting, processing and injection, there is a great disparity in the reported result of fat grafting in terms of survival and outcomes[7–10]. If we are able to quantify the amount of fat required to correct a particular contour deformity and the amount of the injected fat that is expected to survive we can move in the treatment ladder from art to science. There are a few reports in literature which have aimed to measure the long term survival of fat by different methods which include clinical observation, photography, Ultrasonography, CT & MRI[11–21]. However, no study has

Copyright © 2022 Bhadani S, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

22


Bhadani S, et al.

been done to predict the volume required to correct the contour deformities and subsequently measure its survival in a cost-effective manner. Our study aims to achieve both these ends, using USG as a tool to measure the quantity of fat required and measure the survival.

Material and methods This is a prospective study carried out with a sample size of 30 patients between the ages of 15–45 years who required fat graft for various facial defects e.g. depressed scar, Hemifacial atrophy, facial clefts, hemifacial microsomia and other contour abnormalities of the face. Inclusion Criteria : 1. Patients with facial defects in the age group mentioned 2. Willing to be recruited in the study and undergo more than one procedure if required for the correction of the defect 3. Patients who were cosmetically concerned about their condition.

4. Willing to accept donor site fat harvest

Exclusion Criteria: 1. Patients beyond mentioned age groups 2. Not willing to undergo more than one or procedure or donor site harvest Subjective and objective assessments were done by photography and Ultrasonography, respectively, both preoperatively and post-operatively at 1 month, 3 months and 6 months. The preoperative assessment for the volume deficit was also done by facial mould, where wax was used to fill the deficient side to match in contour with the normal side and volume displacement method was used to calculate the volume of wax used for filling the defect. The volume of the contour defect was measured by USG where to calculate the fat volume a three dimensional measurement of the affected area and the corresponding normal area was taken assuming that fat acquires the shape of an ellipsoid in most areas of the face. The area to be assessed was divided in multiple sections (maximum 3) and length and the breadth of each section was measured with a tape and depth of all sections was assessed by ultrasound. To calculate the volume of each section the formula used for an ellipsoid was applied i.e. 4/3π (r1 × r2 × r3). The volume of all sections was then aggregated to get the total volume of soft tissue in the marked area. (Figure 1).The difference in volume of both the affected and the normal side gave us the soft tissue deficit. The plan included injecting this volume deficit + 30% extra adipose tissue into the affected area. Fat was harvested from various sites viz. lower ab­ dominal wall, gluteal region & thigh depending on the quantity required in different patients. Standard one hole 2 mm leur lock syringe cannula apparatus in accordance with the Coleman’s method was used for the fat harvest. The harvested fat was centrifuged at 3000 rpm for 3 min and pure adipose tissue was injected with an injecting cannula (size 0.9–1.2 mm) in the deficient areas in different soft tissue planes to increase the contact area of fat doi:10.18282/jsd.v7.i1.168

Figure 1. Diagram showing the method of calculating the volume of the defect

transferred for better vascularisation. Post operatively USG was used again for the assessment of the fat retained at 1, 3 and 6 months by using the same calculations as mentioned above. We calculated the volume retained after deducting the initial volume of fat that was present preoperatively. At 6 months fat was reinjected in those patients in whom the result after first injection was not satisfactory. The volume for second injection was calculated based on percentage fat absorbed at the end of 6 months after first injection.

Results (Table 1) The patients recruited in the study required fat grafting for augmenting soft tissue defect in the face due to various conditions. Ten patients were suffering from Hemifacial Microsomia (Figures 2–5) while fifteen patients had depressed post traumatic scars (Figures 6 and 7). There were 2 patients each of facial clefts & Parry Romberg’s disease and 1 patient required augmentation following excision and radiotherapy for rhabdomyosarcoma (Figures 8 and 9). Patients for purely aesthetic consideration are not available in a government hospital set up. There were 18 males and 12 females included in the study and the mean age was 23 years. The donor area was abdomen in 17 patients, thigh in 11 patients and gluteal region in 5 patients. In three patients fat was taken from more than one site. There were no complications observed in the donor areas. In the recipient area there was one case of transient facial nerve palsy which resolved in 5 days. The mean difference in volume calculated was 19.55 mL. The range of volume injected was 6 mL–60 mL, the average being 25.3 mL. At the end of one month the mean volume retained was observed to be 20 mL (80%). The mean volume at the end of 3 months was 16 mL (63.2%) and at the end of 6 months was 14 mL (55.3%). The maximum absorption of the transplanted fat occurred in the first three months following the procedure. Good contouring was achieved in the cases of malar deficiency and jaw line augmentation. It was observed that there was comparatively lesser absorption of fat (average 37.3%) following injection for hemifacial microsomia where the underlying tissues were healthy and vascular compared to depressed scars (52.3%) and Romberg’s disease (52.7%). At the end of 6 months assessment there was significant difference (p = 0.002). A higher pressure was required to inject under the scarred area and the passes

23


Volumetric estimation of autologous fat for augmentation of contour defects of face Table 1.

Details of patients Volume retained at 6 months

8

Reinjection of fat (double the estimated volume ) 13

9

22

5

8

6

15

15

0

-

-

22

16

16

2

-

-

20

16

13

13

2

-

-

20

33

29

20

20

5

8

5

9

10

12

10

6

6

3

-

-

20F

40

38

52

45

30

30

10

16

10

19M

18

20

26

22

16

16

2

-

-

21M

30

30

39

30

22

22

8

13

8

21/F

10

12

13

10

10

7

3

-

-

Volume Volume Volume (mL) at (mL) at 3 (mL) 1 month months at 6 months

Difference in volume from desired

36

30

22

20

24

35

31

24

15

16

20

18

29M

18

18

24

28M

15

15

16F

25

18F

No. Etiology

Diff Injected Age/sex Diff in volume volume in volume by Mould (mL) by USG

1

18/F

28

25

22F

27

25F

11

Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Hemifacial Microsomia Depressed Scar

12

Depressed Scar 26/M

8

9

11

9

6

6

2

-

-

13

Depressed Scar 35/M

9

7

12

10

7

7

2

-

-

14

Depressed Scar 27/M

14

15

19

15

10

5

9

18

10

15

Depressed Scar 21/M

20

18

26

22

18

18

2

-

-

16

Depressed Scar 26/M

21

20

27

16

16

10

11

22

10

17

Depressed Scar 33/M

26

25

34

20

13

13

13

26

15

18

Depressed Scar 16/F

24

20

32

16

13

10

14

-

-

19

Depressed Scar 19/F

13

11

17

10

10

7

6

12

13

20

Depressed Scar 20/M

12

10

16

10

7

7

5

10

6

21

Depressed Scar 36/M

20

17

26

20

12

10

10

20

8

22

Depressed Scar 18/M

24

22

18

16

13

10

14

28

15

23

Depressed Scar 22/M

30

28

39

35

32

30

0

-

-

2 3 4 5 6 7 8 9 10

24


Bhadani S, et al.

Table 1. Continued. Volume retained at 6 months

24

Depressed Scar 20/F

25

23

33

26

23

14

11

Reinjection of fat (double the estimated volume ) 22

25

Depressed Scar 22F

16

15

21

16

16

10

6

12

6

26

Parry Romberg’s Disease

16/M

12

10

16

10

7

5

7

-

-

27

Parry Romberg’s Disease

26/M

45

40

60

50

42

38

7

14

7

28

Post Radiation 22/F damage

22

22

28

25

21

14

8

16

9

29

Facial cleft

15/M

6

6

8

4

4

3.5

2.5

-

-

30

Facial cleft

26/M

4.5

4.5

6

4

3

2.7

1.2

-

-

Diff Injected Age/sex Diff in volume volume in volume by Mould (mL) by USG

No. Etiology

A

Volume Volume Volume (mL) at (mL) at 3 (mL) 1 month months at 6 months

Difference in volume from desired

10

B

Figure 2. Preoperative photograph of patient of hemifacial microsomia

A

B

Figure 3. Same patient 1 year after injection of fat

doi:10.18282/jsd.v7.i1.168

25


Volumetric estimation of autologous fat for augmentation of contour defects of face

Figure 8. Soft tissue defect due to radiation damage

Figure 4. Patient of hemifacial microsomia pre-operatively

Figure 9. 1 year after 2 sittings of fat injection

Figure 5. Patient 1 year after 2 sittings of fat injection

A

Discussion

B

Figure 6. Post traumatic scar on chin pre-operatively

A

B

Figure 7. 1 year after 2 sittings of fat injection

26

of the injecting cannula also led to subcision of the scars. However, subsequent injections under the same scarred areas were comparatively easier and the first procedure led to decrease in the adherence of the scar, hence more passes were possible in the second sitting. Adipose tissue has been lauded by the plastic surgeons as an ideal filler; it is safe, effective, reproducible, devoid of any reactions, non-teratogenic, non-infectious and potentially removable. Due to the high degree of patient satisfaction it has gained wide spread popularity among both the doctor and the patient. The procedure is minimally invasive and because of no donor site morbidity has high acceptance in the patient population. However, even after existence for more than a century among the treating surgeons, it has eluded us of its predictability. The treating surgeon right from the time he starts attending a potential patient often finds asking himself, how much is actually enough? How many touch ups will be required? Finally, it is the method of trial and error that the surgeon often practices when it comes to fat transfer. It is due to unreliable survival of the transplanted fat that literature on autologous fat transplantation is still experiment rich and evidence poor. Kaufman et al.[22] have outlined that quantitative evidence of the survival is lacking and optimisation of results needs to be supported by large scale clinical assessment that can quantify the volume of fat surviving after the transfer. Most of the present day studies quote anything between 20–80% of the survival of fat[13,16,21–23]. Majority of these studies rely


Bhadani S, et al.

on subjective assessment of photographs and patient’s and surgeon’s subjective opinion to predict the percentage of fat surviving[13–21]. Radiological assessment has also been used by some to quantify the fat volume which includes assessment by MRI and CT scan[19–21]. There has however been no detailed study which calculates the requirement of fat for augmentation in a particular area and the survival of that transplanted fat. MRI, although a reliable method is not cost-effective in repeated assessments and there is risk of exposure to radiation when employing CT scan repeatedly. Ultrasound on the other hand is safe, reliable, cost-effective method which can be repeated to assess volume of retained fat at intervals. Our study aims at predicting the volume required to augment a given area to make it comparable to the normal side. The predictability of absorption would help in assessing the amount of extra fat needed to be injected over and above the required volume (which in aesthetic indications would be judged clinically by the surgeon) in order to take care of the volume that is expected to be absorbed after a procedure). With our follow up we have been able to predict the added percentage of fat required in the initial sitting of lipofilling so that the future touch ups are either obviated altogether or reduced to a minimum. Ultrasound is an easily available, cost effective and safe method and with its ready availability it becomes a handy tool in assessment which can be carried out by the surgeon himself. Though mould technique was also used by us to calculate the volume deficit, it was found to be too cumbersome and not very reliable for small defects. The method used for fat harvest was standard Coleman’s method to exclude any confounding factor due to the technique involved. Since there is a wide range of absorption seen when it came to technique of harvesting of the fat we use gentle manual suction for fat harvest. Controversy also surrounds the processing of the fat before transfer to the recipient site. However, studies support the centrifugation and it has been found that centrifugation helps eliminate the unwanted debris and increases the concentration of fat transferred in a particular volume. Histological difference in the fat centrifuged at 3000 rpm and 4200 rpm was not significant in a study by Yoshimura et al.[25]. The injection was done in multiplanar manner to increase the surface area of contact between the fat and the native tissue to help increase the vascularisation of the graft. We do not believe in washing the fat before injection to maintain a closed system of processing and transfer to maintain the sterility. The aim was also to expose the fat as little as possible to procedures that may be a confounding factor in assessing the reasons for absorption and we followed Coleman’s method for the same. In our findings, we noted that the soft tissue edema post injection took about 10–12 days to settle. The maximum amount of absorption occurred in the first 3 months which is consistent with the results of previous studies. After the 3 months the absorption increases in a gentle curve to 6 months with about 45% getting absorbed at the end of 6 months. All patients maintained a stable weight in the six months period. In cases where there was no scarring in the recipient areas e.g. hemifacial microsomia, there doi:10.18282/jsd.v7.i1.168

was less percentage of absorption (37.3%). In areas which were scarred it was more to the tune of 52.3%. This can be explained by the fewer number of blood vessels in the scarred areas because of fibrosis of tissues and resultant less vascularisation of graft. The subcision was done in the scarred cases by the injecting cannula itself. In some cases it was even difficult to inject the amount of fat calculated by USG. The methods defined a criteria of injection calculated volume plus extra volume, so to maintain the homogeneity in the study these were excluded. Although they can be a part of a separate study in the same series. In Parry romberg’s disease the absorption was also high (52.5%) and it could be explained by the fact that the underlying tissues are atrophic which doesn’t allow injection in many planes. We have carried out reinjection in 16 patients and in the second sitting area was assessed for volume deficit and injected double the deficit in the scarred areas and 60% extra in case of hemifacial microsomia to compensate for predicted absorption (Table 1). Ten patients have completed 1 year follow up and seem to be satisfied with the result and do not require more touch-ups at present. The volume has stabilised around the required amount. In the rest 14 patients repeat ultrasound after 6 months showed no change in the volume of injected fat which was seen at 6 months. Since the initial assessment was with USg, we prefered to keep the method of assessment of the fat by the same method although MrI may be added to validate the same. This shows that the volume of transplanted fat gets stabilized after 6 months. The donor sites varied in cases depending on fat availability and patient preference. Literature gives evidence that the fat from different areas has no significant difference in absorption thus fat was harvested from abdomen, thigh or gluteal regions[26,27].

Conclusion Autologous fat transplantation has gained popularity among the plastic surgeons and its use has been expanding for augmentation of different body parts. However, if we are able to predict and assess its absorption we can help reduce the number of sittings to deliver what the patient is actually looking for. With ultrasound being readily available, it can be a tool in this assessment and guide the surgeon in the first and subsequent sittings of the treatment.

Conflict of interest The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

References 1. Neuber G. u¨ber dieWiederanheilung vollsta¨ndig vom Ko¨rper getrennter, die ganze Fettschicht enthaltender Hautstu¨cke [in German]. About the re-healing completely separated from the body, the whole fat layer containing skin pieces. Zbl f Chirurgie 1893; 30: 16. 2. Czerny V. Plastischer Ersatz der Brustdru¨ se durch ein Lipom [in German]. Plastic replacement of breast dysfunction by a lipoma. Arch f klin Chirurgie 1895; 50: 544–550. 3. Lexer E. Die freien Transplantationen. Stuttgart: Enke, 1919–

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Volumetric estimation of autologous fat for augmentation of contour defects of face

1924: 264–547. 4. Peer LA. Transplantation of tissues. Baltimore: Williams & Wilkins, 1955: 396Y–398. 5. Illouz YG. The fat cell ‘‘graft’’: A new technique to fill depressions. Plast Reconstr Surg 1986; 78: 122–123. 6. Coleman Sr. Facial recontouring with lipostructure. Clin Plast Surg 1997; 24: 347–367. 7. Har-Shai Y, Lindenbaum ES, Gamliel-Lazarovich A, Beach D, Hirshowitz B. An integrated approach for increasing the survival of autologous fat grafts in the treatment of contour defects. Plast Reconstr Surg 1999; 104(4): 945–954. doi: 10.1097/00006534-199909040-00008. 8. Eremia S, Newman N. Long-term follow-up after autologous fat grafting: Analysis of results from 116 patients followed at least 12 months after receiving the last of a minimum of two treatments. Dermatol Surg 2000; 26: 1150–1158. doi: 10.1046/ j.1524-4725.2000.00277.x. 9. Rubin A, Hoefflin SM. Fat purification: Survival of the fittest. Plast Reconstr Surg 2002; 109(4): 1463–1464. doi: 10.1097/00006534-200204010-00049. 10. Ersek RA. Transplantation of purified autologous fat: A 3-year follow-up is disappointing. Plast Reconstr Surg 1991; 87(2): 219–227. 11. Niechajev I, Sevcuk O. Long-term results of fat transplantation: clinical and histologic studies. Plast reconstr Surg 1994; 94(3): 496–506. 12. Nicareta B, Pereira LH, Sterodimas A, Illouz YG. Auto­ logous gluteal lipograft. Aesthetic Plast Surg 2011; 35(2): 216–224. doi: 10.1007/s00266-010-9590-y. 13. Coleman SR. Long-term survival of fat transplants: Controlled demonstrations. Aesthetic Plast Surg 1995; 19(5): 421–425. doi: 10.1007/BF00453875. 14. Pereira LH, Radwanski HN. Fat grafting of the buttocks and lower limbs. Aesthetic Plast Surg 1996; 20(5): 409–416. doi: 10.1007/s002669900056. 15. Scarborough DA, Schuen W, Bisaccia E. Fat transfer for aging skin: technique for rhytids. J Dermatol Surg Oncol 1990; 16(7): 651–655. doi: 10.1111/j.1524-4725.1990.tb00095.x. 16. Gormley DE, Eremia S. Quantitative assessment of augmentat ion therapy. J Dermatol Surg Oncol 1990; 16(12): 1147–1151. doi: 10.1111/j.1524-4725.1990.tb00027.x.

17. Slack GC, Tabit CJ, Allam KA, Kawamoto HK, Bradley JP. Parry-romberg reconstruction: Beneficial results despite poorer fat take. Ann Plast Surg 2013; EPUB [ahead of print] 18. Choi M, Small K, Levovitz C, Lee C, Fadl A, et al. The volumetric analysis of fat graft survival in breast reconstruction. Plast Reconstr Surg 2013; 131(2): 185–191. doi: 10.1097/PRS.0b013e31829fe2c0. 19. Fontdevila J, Serra-Renom JM, Raigosa M, Berenguer J, Guisantes E, et al. Assessing the long-term viability of facial fat grafts: An objective measure using computed tomography. Aesthet Surg J 2008; 28(4): 380–386. doi: 10.1016/j.asj.2008.05.002. 20. Pierrefeu-Lagrange AC, Delay E, Guerin N, Chekaroua K, Delaporte T. Radiological evaluation of breasts re­ constructed with lipomodeling. Ann Chir Plast Esthet 2006; 51(1): 18–28. doi: 10.1016/j.anplas.2005.10.001. 21. hörl hW, Feller AM, Biemer e. Technique for liposuction fat reimplantation and long-term volume evaluation by magnetic resonance imaging. Ann Plast Surg 1991; 26(3): 248–258. 22. Kaufman MR, Miller TA, Huang C, Roostaeian J, Wasson KL, et al. Autologous fat transfer for facial recontouring: Is there science behind the art? Plast Reconstr Surg 2007; 119(7): 2287–2296. doi: 10.1097/01.prs.0000260712.44089. e7. 23. Peer L. Loss of weight and volume in human fat grafts with postulation of a cell survival theory. Plast reconstr Surg 1950; 5(3): 217–230. 24. Chajchir A. Fat injection: Long-term follow-up. Aesthetic Plast Surg 1996; 20(4): 291–296. doi: 10.1007/BF00228458. 25. Kurita M, Matsumoto D, Shigeura T, Sato K, Gonda K, et al. Influences of centrifugation on cells and tissues in liposuction aspirates: Optimized centrifugation for lipotransfer and cell isolation. Plast Reconstr Surg 2008; 121(3): 1033–1041. doi: 10.1097/01.prs.0000299384.53131.87. 26. Rohrich RJ, Sorokin ES, Brown SA. In search of improved fat transfer viability: A quantitative analysis of the role of centrifugation and harvest site. Plast Reconstr Surg 2004; 113(1): 391–395. doi: 10.1097/01.PRS.0000097293.56504.00. 27. Ullmann Y, Shoshani O, Fodor A, Ramon Y, Carmi N, et al. Searching for the favorable donor site for fat injection: In vivo study using the nude mice model. Dermatol Surg 2005; 31: 1304–1307. doi: 10.1111/j.1524-4725.2005.31207.

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REVIEW

Treatment modalities for hyperpigmented skin lesions: A brief overview Yan Teng Khoo1*, Ahmad Sukari Halim2 1

Beauty with Yan Plastic Surgery Clinic, Kinta Medical Centre, Perak, Malaysia

2

Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia

Abstract: Skin hyperpigmentation involves a broad range of skin conditions, including epidermal pigmented lesions, dermal pigmented lesions, and mixed pigmented lesions. Treatment includes various modalities such as brightening cream, chemical peeling, and laser therapy. Responses to various treatment modalities can be quite varied depending on the type of treatment and the degree of pigmentation. Sometimes a lesion can lighten or even partially disappear, while other lesions may recur. This paper provides a brief overview of treatment modalities available for hyperpigmented skin lesions including the importance of photoprotection, various types of brightening creams, suitable types of chemical peels, specific laser therapies targeted for skin hyperpigmentation, and surgery. Keywords: skin hyperpigmentation; photoprotection; brightening cream; laser Citation: Khoo YT, Halim AS. Treatment modalities for hyperpigmented skin lesions: A brief overview. J Surg Dermatol 2022; 7(1): 35; http://dx.doi.org/10.18282/jsd.v7.i1.35. *Correspondence to: Yan Teng Khoo, Beauty with Yan Plastic Surgery Clinic, Kinta Medical Centre, 20, Jalan Chung

Thye Phin, 30250, Ipoh, Perak, Malaysia; beautywithyan@gmail.com Received: 6th June 2021; Accepted: 29th July 2021; Published Online: 18th August 2021

Introduction The management of skin pigmentation disorders poses a significant challenge to both patients and doctors. A doctor’s goal to achieve successful elimination of pigmentary lesions rests on two basic principles: 1) minimising detrimental effects of sunlight radiation, and 2) optimising conditions of the pigmentary disorder with available treatment modalities. Although currently available sun protection skin care products are increasingly varied and sophisticated, its primary function remains to reduce the adverse effects of sun radiation. Skin pigmentation disorders manifest as skin lesions arising from the melanocytic system of the skin. It can be classified as hyperpigmentation lesions (i.e., extrinsic and intrinsic factors imposed on the body that cause excessive pigmentation) or hypopigmentation lesions (i.e., underlying conditions that inhibit pigmentation resulting in decreased melanin production). Pigmentation

is the result of melanin pigment production in the melanocytes of the epidermis. Melanin synthesis is stimulated by sunlight and is controlled by the pituitary gland via melanocyte-stimulating hormone (MSH). Melanin synthesis is also influenced by endocrine secretions, including oestrogen and androgen. The number of melanocytes is the same between races; however, the amount of melanin production varies upon stimulation. The melanin in the skin has protective effects from sunlight radiation. The rising trend is that epidermal pigmentation has a direct relationship with the degree of sun exposure. Skin pigmentation affects all ethnic and racial groups; however, skin pigmentation disorders primarily affect fair- skinned populations. The closer the light-skinned races are to the equator, the higher the incidence of skin pigmentation. However, increased pigmentation can be due to causes other than melanin. Table 1 listed the factors that contribute to hyperpigmentation disorders. Treatment modalities of epidermal melanin-induced hyperpigmentation have

Copyright © 2022 Khoo YT and Halim AS. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Treatment modalities for hyperpigmented skin lesions: A brief overview

emphasised on not only curative therapy but also preventive measures from sun exposure. The new trend of treating pigmented epidermal lesions has improved exponentially with the advancement of research and development of skin care products and lasers. Photosensitive pigmentation is commonly localised on areas of the body exposed to the sun, primarily on the face (forehead, cheeks, and upper lip), hands, and back. In darker Asian, and Mediterranean skin types, the appearance of solar lentigines, seborrheic keratosis, and melasma are particularly common. This paper will present a brief overview of the treatment modalities for acquired skin pigmentation. Table 1. Causes of skin hyperpigmentation Causes of increased melanin production Non-melanin causes

Acquired

Congenital/ Inherited

Melasma Post-inflammatory pigmentation Solar lentigines Ephelides

Mongolian spots Naevus of Ota Naevus of Ito Spindle cell naevus Blue naevus

Primary haemochromatosis Hepatic cirrhosis Chronic renal failure

Lichen planus Fixed drug eruption Erythromelanosis follicularis faciei et colli Pellagra Poikiloderma of Civatte

Halo naevus Café au lait Peutz-Jegher’s syndrome Albright’s syndrome

Alkaptonuria Lamellar ichthyosis Epidermolytic hyperkeratosis Drug and heavy metal toxicity Canthaxanthin Pituitary tumours

Riehl’s melanosis

Photoprotection Sun protection is of utmost importance in the treatment of skin hyperpigmentation. The use of full spectrum sunscreens should be emphasised before, during, and after procedures. Only sunscreen has a confirmed benefit in the treatment of skin hyperpigmentation. Daily use of sunscreen with a sun protection factor (SPF) of at least 15 is valuable for sun protection. Sunscreen must be applied to all exposed skin including the lips, scalp, and ears. Sunscreen should be applied 15–30 min before sun exposure and reapplied every 2 h. The reapplication of sunscreen is required after swimming or heavy sweating. Outdoor activity during peak tanning or burning hours, between 10 a.m. and 4 p.m., should be minimised or avoided. All patients who are active outdoors should wear additional sun-protective apparel to reduce sunlight

radiation exposure. Tanning beds could aggravate skin hyperpigmentation.

Brightening agents Topical brightening agents serve a crucial role in achieving the lightening of skin hyperpigmentation. These are composed of natural or synthetic bleaching components which mainly suppress melanocytic activity and help reduce hyperpigmentation. These agents are commonly used as topical products to achieve optimal results after prolonged application. Commonly used brightening agents include hydroquinone, kojic acid, licorice extract, arbutin, ascorbic acid, glycolic acid, niacinamide, azelaic acid, retinoids, and others.

Hydroquinone Hydroquinone has the advantage of being well tolerated, easily available with prescription, and inexpensive. These agents are composed of extractions from plants such as tea and coffee, and have an inhibitory effect on tyrosinase which lead to the reduction of melanosomes. Melanocytes are present in the basal layer of the epidermis, producing melanosomes containing melanin which is synthesised from tyrosine with the action of tyrosinase. Hydroquinones are usually combined with tretinoin to achieve optimal depigmentation results. At a concentration of 4%–6%, hydroquinone is effective in treating skin hyperpigmentation, including postinflammatory hyperpigmentation, melasma, freckles, age spots, and acne scars. However, prolonged use of hydroquinone (for more than three months) has been associated with exogenous ochronosis (persistent blue-black pigmentation) in Fitzpatrick groups V and VI[1].

Kojic acid Kojic acid is a type of bleaching agent harvested from Japanese fungus, namely Penicillium and Aspergillus[2]. These bleaching agents are mild inhibitors of the formation of pigments in plant and animal tissues, and are used in cosmetics to brighten skin colour. These bleaching agents have a mild inhibitory action on tyrosinase. Kojic acid at a concentration of 4% or in combination with alpha hydroxy acid (AHA) can cause skin exfoliation to accelerate the lightening result. Kojic acid is used to treat skin disorders such as melasma[3].

Licorice extract Licorice is the root of Glycyrrhiza glabra[4]. Most

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licorices are used as flavouring agents for tobacco, candies, sweeteners, and herbal medicines. The main component of licorice is glabridin which has been reported to prevent ultraviolet light B-induced skin pigmentation. Clinical trials have demonstrated that licorice has promising tyrosinase inhibition and that it has an influence on both melanogenesis and skin inflammation[5,6]. Licorice is very effective in treating post-inflammation hyperpigmentation but it is expensive. Skin hyperpigmentation could be optimised with licorice extract at concentrations ranging from 10%–40%[7]. The reduction of hyperpigmentation is also accelerated when licorice extract is combined with kojic acid and vitamin E in topical applications.

Arbutin Arbutin is an extract from a bearberry plant of the genus Arctostaphylos. It is also found in wheat and Bergenia crassifolia[8]. Arbutin has a skin-lightening effect by decreasing both tyrosinase activity and melanin content. Hence, it is used in skin-lightening treatments at concentrations of 3%–7% and has been reported to be effective in treating liver spots and freckles[9]. Hydroquinone has been banned by the European Committee due to the risks of side effects. Arbutin is an alternative and gentler form of hydroquinone. Arbutin has advantages with long-term usage, and it can be used once or twice daily. In vivo experimental studies have demonstrated that arbutin is a safe and effective brightening treatment for hyperpigmented lesions[9,10].

Ascorbic acid Ascorbic acid (vitamin C), derived from fruits and green leafy vegetables, is a type of water-soluble vitamin and is present as a potent antioxidant in human skin[3,11]. Ascorbic acid inhibits melanin synthesis by interfering with the action of tyrosinase. The disadvantages of ascorbic acid are that it is rapidly oxidised, highly unstable, and its hydrophilic property limits its skin penetration[3,12]. Hakozaki et al. have demonstrated an enhanced skin-lightening effect by increasing transepidermal penetration and vitamin C efficacy using ultrasound[13].

Glycolic acid Skin-lightening treatments would have more effective results if preceded by thorough exfoliation. Glycolic acid is derived from sugar cane. It is a weak organic acid, and is reportedly effective in treating solar lentigines, melasma, and post-inflammatory hyperpigmentation[14]. At low

concentrations, it promotes exfoliation of pigmented keratinocytes and facilitates brightening cream penetration. However, any brightening cream treatment must be stopped at least three days prior to chemical peeling treatment to prevent complications such as epidermolysis.

Niacinamide (vitamin B3) Niacinamide is an amide form of vitamin B3 (niacin) and is a water-soluble vitamin. It can be found in trace amounts in fish, nuts, mushrooms, and root vegetables[15,16]. Niacinamide has various beneficial medical applications. It has anti-inflammatory actions and may be beneficial to patients with inflammatory skin conditions such as acne vulgaris[17]. Hakozaki et al. demonstrated in vitro that niacinamide exhibited effective skin-lightening activity by inhibiting the transfer of melanosomes to adjacent keratinocytes by 35%–68%[18,19]. In a clinical study, Navarrete-Solís et al. reported that 8 weeks of treatment with 4% niacinamide cream showed good to excellent improvement in 44% of patients with melasma, compared to 55% from a 4% hydroquinone cream treatment [20].

Azelaic acid Azelaic acid is derived from wheat, rye, and barley. It has been used for treating melasma and postinflammatory hyperpigmentation. It is an alternative to hydroquinone treatment for skin pigmentation. It works as a tyrosinase inhibitor. A clinical study conducted by Breathnach has shown that a topical application of 20% azelaic acid is superior to 2% hydroquinone in patients with melasma[1,21]. Another clinical trial conducted by Baliña et al. found no significant differences between treating melasma with 20% azelaic acid cream and 4% hydroquinone cream. 65% of patients treated with azelaic acid were reported to have achieved good to excellent results versus 73% of patients treated with hydroquinone that achieved similar results[22].

Retinoids Retinoids are composed of chemical compounds related to vitamin A. It is widely used in medicine, and its beneficial effects are primarily attributed to the regulation of epithelial cell growth. Topical applications of these agents are indicated for dermatological conditions with increased cell turnover such as psoriasis[23] and inflammatory skin disorders such as acne[24]. Retinoids are also ideal for treating photoaging and skin wrinkles[25,26]. The inhibition of tyrosinase action provides an effective environment for reducing

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Treatment modalities for hyperpigmented skin lesions: A brief overview

hyperpigmentation. Other mechanisms of action include a dispersion of pigmented granules in keratinocytes, a reduction in pigment transfer, and an acceleration of epidermal exfoliation[27]. Retinoids are suitable as long-term medications and have favourable safety profiles. When applying topical retinoids, a 0.025% concentration should be utilised initially as local adverse effects, including erythema, pruritus, and dryness, occur frequently during the early treatment phase[28]. Subsequently, treatment can be increased gradually every week up to a daily use of the cream at a concentration of 0.1%. Pathak et al. demonstrated that the treatment of melasma should include a topical formulation of cream containing 2% hydroquinone and 0.05% to 0.1% retinoic acid[29].

Other active ingredients Other ingredients under in vitro investigation include linoleic acid which is an unsaturated fatty acid, extracts from a type of Chilean snail, Helix aspersa, and lumixyl which is a synthetic oligopeptide that exhibits inhibitory activity against human tyrosinase.

Chemical peels Chemical peeling is a popular option for facial rejuvenation and treatment of superficial hyperpigmentation. A wide spectrum of chemical peels is available, producing variable effects on the skin. Fine and coarse facial rhytides and uneven skin pigmentations that are not effectively treated surgically can be treated with chemical peels. Chemical peeling affects the epidermis and superficial dermis by smoothing irregularities and altering skin pigmentation. Different solutions are used to target skin injury at specific depths, resulting in the removal of damaged skin with pigmentation. Superficial and medium-depth chemical peels are desirable due to their safety records, effectiveness, relatively low costs, and rapid recovery times. Major indications for chemical peel treatments are solar lentigines and other signs of photodamage including rhytides, scarring, actinic keratosis, melasma, and acne vulgaris. In the early phase of photodamage, skin which exhibits pigmentary changes without wrinkles will respond effectively to repetitive superficial peels[30]. Lesions arising from deeper layers of the skin, such as actinic keratosis and melasma, require treatment with one or more medium-depth peels. All patients should be adequately prepared prior to chemical peeling. Gentle facial washing is required prior to a superficial chemical peel. For medium peels, residual oils, make-up, and debris must be removed

thoroughly prior to applying chemical peel solutions. The following discussion will specifically provide an overview of chemical peeling solutions suitable for treating skin hyperpigmentation.

Glycolic acid at 20%–70% Glycolic acid peels use materials derived from sugarcane. Weekly or biweekly peels using 40%–70% unbuffered glycolic acid is a method of superficial peeling. Penetration depth is related to the concentration and duration of the treatment. A patient’s skin will naturally develop tolerance to glycolic acid peels. Therefore, a regime should start with a low-strength glycolic peel of 20%–30% applied for 2 min. Patient’s level of pain and erythema are the two main factors determining the endpoint of glycolic acid peels. A typical peel regime includes 6 peels with each peel one month apart. At subsequent visits, patient’s tolerance to pain and their recovery time can be evaluated. If the patient tolerated the previous glycolic acid peel well, the subsequent peel can be escalated to 40%–50% glycolic acid, or maintained at the same concentration of the previous glycolic acid peel (i.e., 20%–30%) and left on the skin longer, for approximately 5–6 min. Glycolic acid peels require dilution with water or neutralisation with 5% sodium bicarbonate[31]. Glycolic acid is found in many cosmetics at low concentrations. A low concentration of glycolic acid may be used as a primer for a chemical peel or for laser resurfacing.

Salicylic acid at 20%–30% Salicylic acid is a type of beta-hydroxy acid. It has an anti-inflammatory effect and thus helps to diminish inflammation-induced hyperpigmentation. Joshi et al. demonstrated that salicylic acid peels at 20% to 30% are safe and clinically effective for patients with Fitzpatrick skin types IV to VI and post-inflammatory hyperpigmentation[32]. Salicylic acid peels can remove the stratum corneum and stratum granulosum with an exfoliation process. This will stimulate the generation of new epithelium. Kligman et al. demonstrated that single and multiple salicylic acid peels at 30% applied at 4-week intervals resulted in significant improvements of pigmentation in patients with moderately photodamaged skin[33].

Blue peel Variable results often occur with various chemical peels due to lack of control over the depth of the peel. Trichloroacetic acid (TCA)-based blue peel facilitates the

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treatment of the papillary dermis and immediate reticular dermis. TCA-based blue peel is formed by mixing TCA at a fixed concentration (15%–20%) and volume with the blue peel base which contains glycerine, saponins, and a non-ionic blue colour base. This forms a homogenous TCA-oil-water solution for slow penetration and an even coating. An even blue colour demonstrates the uniformity of an application. Hence, the depth of the peel can be easily recognisable. Blue peel has no systemic side effects or toxicity[34]. Frosting occurs as a result of protein denaturation and coagulation. Pink frost develops as the papillary dermis is reached. This will become white frosting as the peel acts at the immediate reticular dermis. The time required for the blue peel solution to begin exerting its action due to initial acid neutralisation by dermal protein is approximately 2 min. Erythema will last for 3–7 days. The use of topical antibiotics and acyclovir should be considered as bacterial and viral infections are common. With increasing peel depth, scarring and pigment change become more likely. A typical regime includes two or three blue peels, and the peels are typically spaced 6–8 weeks apart for maximum effect.

pigmentation[36]. However, scarring and depigmentation are commonly observed in argon laser-treated lesions. These unwanted side effects are due to the strong absorption of argon lasers by melanin and the diffusion to surrounding tissues. Table 2. Various laser resurfacing systems for treating skin hyperpigmentation Laser types

Clinical Applications

Continuous wave Argon

514

Birthmarks, port wine stains

Flashlight-pumped pulsed dye (green)

510

Benign epidermal pigmented lesions

Copper vapour

511

Lentigines

Krypton

520

Epidermal pigmented lesions

KTP:YAG

532

Benign pigmented lesions

CO2 (pulsed)

10,600

Various epidermal and dermal lesions

Quality-switched (Q-switched) Ruby

694

Benign pigmented lesions, dark tattoos

Alexandrite

755

Benign pigmented lesions, dark tattoos

1,064

Pigmented dermal lesions, dark tattoos

Lasers Lasers are based on Einstein’s theory of stimulated emission of radiation. In 1960, Theodore Harold Maiman invented and developed light amplification by stimulated emission of radiation (LASER) using a synthetic ruby crystal[35]. Maiman’s invention led to the subsequent development of various types of lasers. Laser resurfacing removes discolourations, age spots, and photodamaged skin. There are specific lasers for pigmented skin lesions such as lasers with blue, green, red, and near-infrared wavelengths. Various laser systems can be applied to treat skin hyperpigmentation (Table 2). However, lasers should be applied with caution as they will result in paradoxical effect of hyperpigmentation following treatment if no proper information was given to patients.

Wavelength (nm)

Nd:YAG

Flashlight-pumped pulsed dye lasers (green) Flashlight-pumped pulsed dye lasers (green) (FPPDLs) are delivered in short single pulses or a train of pulses at high peak powers. These green-dyed lasers contain fluorescent dyes which are absorbed in water and alcohol. Therefore, the 510 nm wavelength is absorbed well by melanin, making it suitable for treating benign pigmented skin lesions[36]. It penetrates to a depth of 0.75–1.0 mm. In Fitzpatrick V–VI skin, this treatment may damage melanocytes, leading to hypopigmentation.

Copper vapour lasers Continuous wave lasers Continuous wave lasers supply an uninterrupted beam of laser light without pulses. Long exposures to these lasers can result in thermal damage to adjacent tissues.

Argon lasers An argon laser at a wavelength of 514 nm produces blue-green light. Continuous wave argon lasers and argon lasers are pulsed using a mechanical shutter target melanin. Therefore, argon lasers have been used in the past to treat port-wine stains and superficial

Copper vapour lasers generate light at a wavelength of 511 nm, similar to that of FPPDLs, but the pulses are much shorter at 22 ns compared with 450 μs for FPPDLs. These continuous wave copper vapour lasers emit pulses at very high frequencies (5,000–15,000 Hz). Therefore, these lasers present a higher risk of hypertrophic scarring[37]. Copper vapour lasers at 511 nm have been effective in treating lentigines.

Krypton lasers Krypton lasers are a type of continuous wave lasers.

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These lasers emit light at 520 nm (green) which is effective for treating pigmented epidermal lesions[36]. The common problem with krypton lasers is the heating of the skin surface due to strong scattering of light. Hence, skin cooling prior and during this procedure is of utmost importance.

KTP:YAG lasers Potassium-titanyl-phosphate (KTP) lasers have a wavelength of 532 nm which targets melanin. These lasers are effective in treating benign skin hyperpigmentation such as melasma. In cases of melasma, KTP functions by generating gentle heat in melanosomes with long pulses (millisecond) rather than causing mechanical destruction of the target chromophores. KTP lasers greatly reduce redness and pigmentation compared to Nd:YAG lasers in patients requiring skin rejuvenation[38].

CO2 The active laser medium is a mixture of carbon dioxide, nitrogen, and helium gases. This combination of gases generates a laser beam with a wavelength of 10,600 nm which is in the middle of the infrared spectrum and is therefore invisible. With a hand piece, the beam is aimed to transmit helium ion light. The target chromophore of the CO2 laser is water. The laser spot is focused at a depth of 0.1–2.0 mm in the skin, and the specific amount of thermal build-up determines whether the treatment results in ablation, cutting or coagulation at the cellular level. The mainstay of CO2 laser is ablative tissue resurfacing; therefore, it is effective for both benign epidermal and dermal hyperpigmentation such as various benign naevi[39].

Quality-switched (Q-switched) lasers When one of the resonating mirrors is non-reflective for an interval of pumping, the stored energy is emitted at extremely high levels of laser energy in a nanosecond. These lasers allow thermal relaxation time; therefore, these lasers carry very little collateral damage to the adjacent tissue and subsequent scarring is rare[40,41]. Taylor et al. demonstrated the mechanism of pigment removal via laser application[42]. The short pulses of high energy cause rapid thermal expansion of the pigment granules and result in photoacoustic fragmentation of the pigments. These fragments are then removed by redistribution, transepidermal elimination, and phagocytosis[41]. The advantages of laser treatment include greater precision, higher efficacy, and lesser scarring than other treatment modalities. However,

suspicious pre-malignant and malignant skin lesions are absolute contraindications for laser treatment. Multiple laser treatment sessions are required at 3–4 weeks intervals. Typically, 5 to 6 treatments are performed to achieve noticeable results. Minimal erythema and oedema are commonly noted immediately after laser treatment, and tend to resolve several hours thereafter.

Q-switched ruby lasers The ruby laser was the first laser developed. It was initially a continuous wave and was then developed to be Q-switched. Q-switched ruby lasers emit light at a wavelength of 694 nm which is useful for treating epidermal and dermal pigmented lesions[43].

Q-switched alexandrite Alexandrite laser uses a Q-switching system and emits light at a wavelength of 755 nm which is effective in treating benign pigmented lesions such as freckles[44].

Nd:YAG lasers The neodymium: yttrium aluminium garnet (Nd:YAG) laser emits light in the near-infrared band at a wavelength of 1,064 nm. Q-switched Nd:YAG lasers function by a mechanism similar to that of Q-switched ruby lasers. However, it was developed to avoid melanin absorption and further reduce the resulting hypopigmentation that is common with Q-switched ruby laser treatments. It has multiple clinical applications including treating pigmented lesions and tattoos[45-49].

Frequency-doubled Nd:YAG lasers When fitted with a K-diphosphate crystal which doubles the frequency and halves the wavelength to 532 nm, Q-switched Nd:YAG lasers are effective in treating epidermal hyperpigmented lesions[43] and red, orange, and yellow tattoos. It is uncommon to have complications with repeated treatments. Skin preconditioning is an essential part of laser therapy for skin hyperpigmentation. Applications of retinoic acid (vitamin A) with glycolic acid preconditioning regimes are often used before laser resurfacing or chemical peels. These agents increase skin metabolism, accelerate cellular division, boost collagen synthesis, and reduce the thickness of stratum corneum. In doing so, subsequent therapies are more effective. Tretinoin 0.005% (Renova) is a topical agent that is effective for treating photodamaged skin and mottled pigmentation[50]. Pretreatment with retinoids may help to reduce posttreatment hyperpigmentation but it may contribute to

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postoperative erythema. It is also contraindicated during early pregnancy due to its teratogenic effect. Renova is an excellent treatment for solar-induced lentigines on the dorsum of the hands. Overall, laser therapy for skin hyperpigmentation is an expensive consumable.

Surgery Surgery is indicated for dermatologic lesions such as large congenital naevus, dysplastic naevi syndrome, melanoma, pre-malignant skin lesions, and malignant skin lesions.

Discussion With rapid development of cosmetic products, skin procedures, and medical devices, the desire to have beautiful skin is achievable. Skin rejuvenation can be achieved by improving external appearances without complications. However, there are several important factors that should be taken into consideration in patient evaluation of hyperpigmentation disorders. These include specific skin type, skin complexion based on the Fitzpatrick scale, skin texture, skin thickness, degree of photoaging, severity of facial rhytides, aesthetic outcome, relative cost of treatment, patient expectation, and time consumption. The purpose of treating hyperpigmentation lesions is to control local factors that result in excessive melanin production. The ideal treatment for hyperpigmentation lesion would achieve this goal by applying the following effects: 1. Eliminate melanin-induced hyperpigmentation; 2. Protect skin against further injury from sun radiation and post-inflammation hyperpigmentation; 3. Reduce oedema and erythema; 4. Promote integrity of the surrounding tissue. There are numerous medical-grade brightening agents and sun protection agents available. In addition, there are different types of laser therapies available to treat hyperpigmentation disorders. The purpose of treating hyperpigmentation is to develop an optimal treatment that eliminates pigmentary lesions. Non-surgical methods are the most desirable methods. Among non-surgical methods, non-invasive treatments are the most sought after. In contrast with invasive treatments, no downtime is required after non-invasive procedures. Generally, hyperpigmented lesion treatments can be categorised into five groups: 1) photoprotection, 2) topical brightening agents, 3) chemical peeling, 4) laser therapy, and 5) surgery.

Conclusion Skin hyperpigmentation is a very common skin disorder in all Fitzpatrick skin types. Various treatment modalities have been studied and have shown improvements in reducing pigmentation. However, no single treatment is effective for all types of dermal hyperpigmentation. A brief overview of the treatment modalities for hyperpigmentation has been provided. Patients with long-standing hyperpigmentation will need to undergo continued treatment depending on the duration of treatment, cost, patients’ compliance, and clinicians’ experience. Laser treatments and chemical peels remain popular for the treatment of skin hyperpigmentation. These treatments can achieve good synergistic results in combination with brightening creams. Lastly, clinicians should educate patients about the importance of photoprotection to optimise treatment.

Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

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doi: 10.18282/jsd.v7.i1.161

REVIEW

Cutaneous immune system: Age specificities Markelova Elena Vladimirovna1, Yana Alexandrovna Yutskovskaya1, Birko Oksana Nikolaevna2, Bajbarina Elena Valerjevna2, Natalya Sergeevna Chepurnova1* 1 2

FSBEI HE Pacific State Medical University of the Ministry of Health of the Russian Federation, Vladivostok Professor Yutskovskaya’s Clinic, Ltd, Moscow

Abstract: The review is dedicated to the modern concepts in understanding the age-related changes of skin protective functions, with an emphasis on the impairments in interaction between the immune cells of innate and acquired immunity, resulting in a decrease in antigen-specific T cell immune surveillance in the skin. We discuss the various defects of T cells and their environment as well as focus on the issue of possible correction of T-reg and other cells activity in the skin which would increase the level of immune surveillance in elderly persons and reduce the risk of malignant neoplasms or skin infections developing. Keywords: skin; innate and adaptive immunity; aging Citation: Vladimirovna ME, Yutskovskaya YA, Nikolaevna BO, Valerjevna BE, Chepurnova NS, Cutaneous immune system: Age specificities. J Surg Dermatol 2022; 7(1): 161; http://dx.doi.org/10.18282/jsd.v7.i1.161. *Correspondence to: Chepurnova Natalya Sergeevna, Normal and Pathological Physiology Department, FSBEI HE Pacific State Medical University of the Ministry of Health of the Russian Federation, 2 Ave Ostryakova, Vladivostok; dr.cns@ yandex.ru Received: 4th August 2021; Accepted: 30th September 2021; Published Online: 27th October 2021

Introduction Substantial sensitivity increases to infections and malignant neoplasms observed in elderly persons designates skin protective properties decline during aging. This review focuses on the modern concepts in understanding the agerelated changes of skin protective functions focusing on how the impairments in interaction between the immune cells of innate and acquired immunity result in a decrease in antigen-specific T-cell immune surveillance in the skin. A criterion for the inclusion of literature sources in this review was research in the field of skin immunology in a young and aging people, exclusion criteria were studies in the field of immunology and the pathogenesis of skin diseases.

Skin and immunity Cutaneous integument forms the body interface with the environment and performs the main barrier function. Skin defends the body, making it impervious from a multitude of harmful exogenic substances, maintains homeostasis and prevents from moisture and heat loss. In addition, it is a highly specialized immune system, composed of resident, activated or migrated to a tissue leucocytes (Table 1). These cells are distributed in the epidermal and dermal

skin layers and participate in the mechanisms of innate and acquired immunity. They are responsible for a “self” and “non-self”, being fundamentally important, as skin every day contacts with exogenic substances. Close interrelation between these two ways of innate and acquired immunity realization plays an important role in activation and strengthening of cutaneous integument immune response. Skin immune function decreases in elderly persons, re­s ult­ing in the growth of bacterial (Streptococcal and Staphy­lo­coc­cal cellulitis) and fungal (mostly Candida) infection[3], contributing to an increase in cases of malignant neo­p lasms of the skin[4]. One of the key mechanism of skin aging is a reduction in a cell self-renewal. Progressive decrease of a cell proliferative activity causes the elevation in the old cells count and driving of adaptation, hypotrophy, and other processes [5]. Aging skin is noted to involve mononuclear infiltration, Langerhans cells count decreasing as well as changes in production of immunocompetent cytokine cells responsible for proliferation and dif­f er­ en­t­iation of skin cells [6] . Cutaneous immune system, morphologically presented with skin-associated lymphoid tissues (SALT), from the one side, is a rather autonomic structure of the bodily immune system, from the other side, it is closely morphologically and regulatory interconnected with the bodily immune system. Disturbances of normal cutaneous immune reactions result in an onset of diverse

Copyright © 2022 Vladimirovna ME, et al. This is an Open Access article distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Vladimirovna ME, et al. Table 1.

Cells of innate and acquired skin immunity[1,2]

Innate immunity

Resident Keratinocytes Endothelial cells – vascular – lymphatic Dendritic cells Mast cells Tissue macrophages

Acquired immunity T-lymphocytes ? – Reflects the probability in this case dermatological diseases and in the most of aesthetic problems, a premature skin aging being among them. With aging cells start to secrete a complex of cytokines and growth factors, modifying tissue microenvironment. This phenomenon is named senescence-associated secretory phenotype (SASP)[7,8]. Gomez (2007) correlates advanced age with the hyperproduction of proinflammatory cytokines (determining this process as “Inflamm-aging”), such as IL-1β, IL-6 and TNFα [9]. Bojarskih and coworkers [7] have compared the transcriptional profiles of young and aged human fibroblasts of three cell lines by means of the replicative aging model. The authors concluded that fibroblast aging has been accompanied with the manifested elevation of gene expression, coding secreted proinflammatory cytokines IL-6 (in 3.7 times; р = 0.05), IL-8 (in 2.5 times; р = 0.04) and insufficient rise of gene expression IL-1β (in 1.3 times; р = 0.04). Among proteins secreted by the aging cell, there are cytokines stimulating inflammatory response, some growth factors as well as secreted proteases and non-soluble components of the extracellular matrix. Therefore, aged cells exhibit capacity to alter their microenvironment and to regulate the characteristics of the adjusting cells by paracrine mechanisms[7]. All this demonstrates that skin immunity defects are progressing with increasing age.

Antigen-presenting skin cells and aging The basic components of the cutaneous innate immunity are Langerhans cells (LC), dendritic cells (DC), and resident macrophages (RM). These antigen-presenting cells produce inflammatory mediators in response to toll-like receptors (TLRs)-signals, antigen-presence and provide T-cell co-stimulation both in skin and in drain lymph nodes. This section summarizes the results of several investigations, underlining the unique role of the antigenpresenting skin cells. Skin DC count and phenotype are comparable in the young and elderly persons but migration, phagocytosis, and capability to stimulate T-cells may decrease[10,11]. Even if migration capability of aged DC being corrected, they are less effective in the antineoplastic immunity providing, correlating with the additional functional defect, associated with the selective dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) expression decreasing[12]. DC comparison in the elderly doi:10.18282/jsd.v7.i1.161

Activated Monocytes Granulocytes – basophils – eosinophils – neutrophils Mast cells Epithelioid cells

Migrated NK-cells Dendritic cells

T-lymphocytes

T-lymphocytes

? Promonocyte

persons revealed the migration disturbances to MIP-1β, notwithstanding the equivalent CCR7 expression[12]. Plasmocytic dendritic cells (PDC) are the unique subpopulation of DC, though their count in the normal skin being a few. Nevertheless, they play an important role in the viral infections (for example, herpes zoster virus) and inflammatory skin diseases (psoriasis, systemic lupus erythematosus and lichen planus) [13,14] . PDC are also observed in skin tumors (melanoma, basal-cell cancer and squamous cell carcinoma)[13,14]. Skin lesions induce the immediate PDC activation and transient IFN type 1 secretion, enabling wound healing [1,6]. In contrast to classical DC, cytokine secretion of PDC undoubtedly appear to deplete with aging[6,13]. Jing et al. [12] reported the number of circulating PDC and IFNα production to decrease in the elderly persons. It is an obvious example why persons of advance age have frequent herpes zoster virus activation, displaying PDC function disturbances in the skin: their migration, activation and cytokine secretion. Multiple functions of the macrophages disturb with aging, including TLR decreasing (or reduced cytokine response to TLR-stimulation), phagocytes functional ability as well as chemokine and cytokine secretion decreasing[13]. HRT-model demonstrates reduced macrophage ability in the antigen-activated elderly human skin to cytokine secretion, such as TNFα, accompanying the response to the antigen[15]. TNFα strengthens the collagenolytic activity of matrix metalloproteinase (ММР)-1, presumably by ММР-3 activating, producing collagen type 1 gradual loss in human skin [16,17–19]. Reactive oxygen species (ROS), resulting because of the cell oxidative metabolism, are of an extreme importance in the aging process. ROS induce transcription factor с-Jun by means of mitogen-activated protein kinase (МАРK), affecting the elevated ММР-1, ММР-3 and ММР-9 expression[16]. Montecino-Rodriguez et al.[20] do not exclude transforming growth factor (TGF)β role in the aging mechanisms of the immune system. Langerhans cells (LC) are the myeloid DC derived, populated permanently epidermally, closely interconnected with the keratinocytes. Until now, LC were considered the main antigen-presented skin cells responsible for the development of the immune response to the invaded pathogen[7]. The traditional concept considers LC to invade and proceed the antigen, then to migrate to the lymph node, presenting antigen to Т-cells[5,7]. Per the latest data, LC play the key role in the inducing IL-22 secretion by

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Cutaneous immune system: Age specificities

the T-cells (Th22) which is an important element in the skin immune response. Other investigators suppose LC to play an important role in the suppressing of the immune response[6,7]. Thus, LC take part in UV-induced suppression, implementing via regulatory Т-cells (T-regs) [6,7] . LC capacity to migrate into the drain nodes decreases in the elderly[9]. Summarizing these data, it might be supposed that a wide range of disturbances can appear in the leucocyte skin population while aging, although it is not clear, how it contributes to a greater dependency on the skin infections or malignant tumors[21]. One of the defense mechanisms of the skin is the development of antimicrobial peptides-defensins and katelicidin that represent key molecular factors of immunity with a strong antimicrobial properties [22]. Yamshikova et al. [23] have shown that antimicrobial peptides inhibit bacterial-induced production of cytokines and stimulate angiogenesis and wound healing. Defensins are divided into two groups: a-defensins and -defensins – which are chemotaxiс for monocytes, T cells and immature DC[24,25]. Also defined q-defensins – a macrocyclic peptides expressed by leukocytes and bone marrow of primates, but not yet finalized, neither for the human, nor to other higher classificated primates[26]. There are four different types of a-defensin (human neutrophile peptides 1-4-HNP1-4)[27]. β-defensins (human b-defensins (human -defensins 1-3-HBD-1-3) produced mainly by epithelial cells of the mucous membranes of the gastrointestinal, urogenital and respiratory tract[24,26]. HBD-1 is synthesized by epithelium, which is in constant contact with the medium or the microbial flora, as well as white blood cells, and it is all regulated by lipopolysaccharides and peptidoglycans. HBD2, as well as HBD-1 can be found in the skin, pancreas, leukocytes, and bone marrow. NBD-3 was detected in the heart, liver and placenta, and NBD4 – in the testes, epididymis, lung tissue tumors and gastric epithelial cells[27]. In human skin, during wound healing, antimicrobic peptides are synthesized, in particular HBD-3 is expressed by LL-37-amino acid sequence and participates in transactivation of the epidermal growth factor receptor. Furthermore, defensins in keratinocytes promote development FNOα, IFNγ, IL-1, IL-13 and IL-22. Katelicidin and HBD-1-4 are also present in the skin at low concentrations, in healthy humans, but injury or infection dramatically increases their synthesis[27]. Gibson et al. [28] found a strong bactericidal effect of β-defensins in the skin in the treatment of burn wound colonizated by Staphylococcus aureus. Clausen et al.[29] found changes in the level of β-defensins in the skin in atopic dermatitis, and the researchers found correlation between level of β-defensins and severity of atopic dermatitis. Patients with psoriasis show significantly reduced defensins level in the skin layer, which explains the high susceptibility to infectious diseases of the skin. Wittersheim et al. [30] reported that the level of antimicrobial peptides in human skin depends on the age, with β-defensins twice higher in the elderly people. Ultrastructure of the basal cells witnesses their active part in keratin synthesis as well as in preparation to other

40

specific proteins synthesis. Basal layer is populated by stem cells of the G0-period. During mitosis, part of the cells transforms into transitional cells, the other part of the cell persists in the G0-period. Phenotype α6 10G7 cells are shown to represent epidermal stem cells, composing the 8% of basal keratinocytes. Currently, the receptors to the vitamin D are detected on the stem cells. Nonetheless, all known nowadays markers fail to differentiate precisely the stem cells from the transitional ones. Keratinocytes synthesize membrane bound IL-1α, facilitating their own participation in the antigen presentation. Besides, keratinocytes synthesize IL-1β, IL-3, IL-8, IL-15 and IL19 [31]. It is worth noting, that keratinocyte synthesized IL-1 enhances prostaglandin synthesis by the fibroblasts of the papillary layer. Prostaglandin, in its part, stimulates keratinocyte proliferation and differentiation. Keratinocyte recognition of pathogens by means of TLR 2 and TLR 4 results in proinflammatory cytokines production, among which precedence must be given to IL-8, responsible for the neutrophils, basophils, and leucocytes bringing to the epidermis. All changes occurring with age, are characterized by the violation of the epithelial-stromal relations that underlie the formation of wrinkles. Type IV collagen is found in all basement membranes and plays an important role in adhesion, migration, differentiation and growth of cells. When photodamaging the skin occurs a reduction of thickness and level of border between derma and epidermis and particularly type IV collagen at the base of wrinkles. Byrne et al.[32] investigated the ability of ternary complex peptide (TCP) IV to stimulate collagen production in fibroblasts of the skin and its effects on the skin photoaging. Their results showed that stimulation of individual peptides of TCP does not lead to destruction of collagen IV. The combination of individual peptides is necessary to synergistically stimulate the production of collagen IV. The researchers suggest that the TCP can play a role in strengthening the border between derma and epidermis through its ability to stimulate collagen production. Thus, it is possible that the decrease of immunity of the skin during aging may be related to impairment of innate immunity cells such as professional antigen-presenting cells, epithelial cells and fibroblasts.

T-cells of the skin in the process of aging Normally, skin of a healthy person residents plenty of CD4+ and CD8+ Т-cells. It has been estimated that approximately 20 billion of resident Т-cells present in the skin of a healthy person, and about twice more are in the bloodstream[7]. Intraepidermal lymphocytes present in the basal and suprabasal layers. They are thymus-dependent lymphocytes, subdividing into T-helpers (Th), Т-killers and T-reg. T-helpers, in turn, subdivide into progenitor cells Тh (Th0), effector lymphocytes, and memory lymphocytes. Тh0 (expressing CD4) influenced by IL-2 and IL-12 differentiate into Тh of the first type, not only secreting IL, IL-3, IFNγ and TNF, but also stimulating Т-killers maturation and production of IgM, IgG and IgA by В-lymphocytes. Тh of the second type produce IL-3, ILdoi:10.18282/jsd.v7.i1.161


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4, IL-6 and stimulate different immunoglobulins synthesis by plasma cells. Т-reg, suppressing the immune response, express CD8, CD45PA[31,33,34]. Т-killers cause disturbance of allogenic cell permeability, resulting in their osmotic shock and subsequent necrocytosis[31]. Elucidating the T-helpers’ new functions (for example, Th17, Th22 and T-reg cells) leads to the reframing of Т1/Т2 paradigm, having been used for a long time for pathogenesis definition as well as cause of the infectious inflammatory and even tumor skin diseases[34]. Hereby, all abovementioned specificities of epidermis structural organization advocate in favor of its active part in the skin protective function.

Toll-like receptors and aging Endothelial activation and skin homeostasis transformation at the point of the antigen exposure, promoting leucocytes access from the bloodstream, are thought to be due to the secretion of proinflammatory cytokines by innate immunity cells, triggering the “alarm signals”[1,2]. TLRs are one of the most common convertors of the “alarm signals”[6,34], being the result of antigen exposure to the traumatized skin. TLRs are expressed by the different cells of innate immunity, including monocytes, macrophages, DC, and LC as well as keratinocytes. TLR-expression or TLR-induced inflammatory mediators’ production by innate immunity cells are supposed to decline with age[35]. Moreover, the recent studies have demonstrated production decline of inflammatory cytokines, such as TFNα, IL-6 and IL-12, from the circulating DC in elderly persons stimulated by the different TLR-ligands[36]. Consequently, skin immunity declines with aging is likely to be associated with the insufficiency of the innate immunity cells due to TLRsignals lesion. Majority of human Т-cells expresses CCR8 and acts as immunological surveillance cells, detecting epidermal APC, and triggering the safety program of the immune system, involving monocytes, granulocytes, inflammatory Т-cells and antibodies[6]. Т-cells of immunological surveillance play a dual role in this scheme. Firstly, responding the antigen impact, they start the inflammatory cascade by secreting TNFα and IFNγ, resulting in other leucocytes engagement. Secondly, these cells migrate into drain lymph nodes where they can proliferate or stimulate activation of antigen-specific Т and В-cell respond. Age skin immunity disturbances are likely to be also associated with the alterations of the resident Т-cells. Intermittent long-life antigen stimulation might impair Т-cells in two ways[37]. Firstly, they become functionally depleted and loss their dominant functions significant for the immune defense[7]. Functional depletion is a way to limitation of the effector Т-cells’ respond, commonly correlating with the elevating of expression of the surface receptors’ inhibitors. Although, it may be a defense mechanism against au­toim­ mune processes, but it jeopardies effectiveness of antiinflammatory and antitumor immunity [36,38]. Secondly, repetitive Т-cell stimulation can cause loss of replicative capacity of some antigen-specific Т-populations because of telomeres shortening and/or DNA damage (process known as a replicative aging)[21,34]. It is interesting, that doi:10.18282/jsd.v7.i1.161

escalating telomeres shortening is observed during immune skin response due to the inhibiting by IFN of the first type telomerase enzyme[21]. Nowadays, it is doubtful whether resident or activated during immune response to antigen skin Т-cells could deplete or age in the elderly persons, insight into this phenomenon is very essential. At present, elevation of the memory Т-cells count is a well-known aging sign[6]. These cells generated after the first contact with the antigen are sustainable for a long time after the initial task, providing a source of effectors responding quickly to the antigen re-exposure. Over the time, exposure to the range of pathogens results in a diversity of the immune repertoire including the increased pool of the defensive memory cells. However, chronic stimulation with the viral infections, for example cytomegaloviruses, may deplete naïve cell pool and cause proliferation of the oligoclonal memory cells. This phenomenon is an important factor contributing to the CD8+ memory cells accumulating in the elderly persons[8], but also CD8+ Т-cells antigen independent proliferation may be evidenced[21,31].

Regulatory Т-cells (Т-reg) are ac­cu­mu­ lat­ed in the skin with aging T-reg play a key role in a force of the immune response development. 5%–10% of the resident Т-cells in the human skin in norm expresses Foxp3 and demonstrates other characteristics of the regulatory Т-cells[15]. These regulatory cells also proliferate during the response of delayed-type hypersensitivity (DHS) type. The investigations showed that Т-reg circulate between the skin and lymph nodes and vice versa both at rest and in the immune response[16]. These Т-reg directly inhibit both T-cells and antigen-presenting cells, such as DC and macrophages. With the Т-reg depletion, neutrophil infiltration rises significantly as the secondary response to the concentration rise of neutrophil chemoattractants (CXCL1 and CXCL2)[14]. Elderly human and mice demonstrate the elevating of the ratio Т-reg in the skin in norm[34]. Т-reg can prevent effective primary proliferation/functioning of the resident antigen-specific Т-cells or inhibit activation of the innate immunity respond, resulting in immunity decline. Negative effect of Т-reg accumulation in the effective immune response is clearly described in the oncological diseases. Т-reg count rising is reported to be noticed in primary melanoma, in metastatic melanoma, and in basal cellular carcinoma[39]. Moreover, in squama-cellular skin carcinoma 50% of the Т-cells presents Foxp3+[34]. Imiquimod topical treatment has shown to be effective in such patients, depleting Т-reg percentage and decreasing their suppressive function[39]. Causes and mechanisms of the Т-reg accumulation in the skin and the other tissues in the elderly human and mice are not thoroughly obvious[15]. Т-reg are known to be induced in the skin by the UV-rays and then such Т-reg influence DC via IL-10, activating more Т-reg through this “tolerant” DC [40]. Moreover, circulating Т-reg may be directed preferentially into the skin, as their majority expresses the cutaneous lymphocyte-associated antigen

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Cutaneous immune system: Age specificities

(CLA). Summarizing all these data, it could be concluded that Т-reg accumulation in the skin with aging may contribute into the insufficiency of the immune respond by the inhibiting of both Т-cells, and the cells of the innate immune system.

Antigen-specific response declining of the human skin in the process of aging is the reason of immune surveillance reduction The studies have shown that the elderly people have a reduced capability to maintain DHS – responds after antigen exposure[35]. This is manifested by the reduction of the erythema intensity and induration at the point of the antigen exposure as well as Т-cells count depletion in the infiltrate proved by the immune-histologic methods. Since activation and skin strengthening immunity have been known to be an integrated step-by-step process, the experimental models in vivo proved to be more informative. Relatively useful is the experimental model of the DHS with the intradermal antigen exposure[35,40]. The extend of the DHS respond is determined by the diameter of the skin area infiltrate and erythema proliferation at the antigen injection site in 48 hours of its injection in human and edema severity of the auricles or feet in 24 hours in mice[40]. There are some differentiations in the kinetics and the nature of the disease in human and in mice, probably because of the different sites of the antigen injection but cell infiltrates are similar in both species[40]. From the histological point of view, antigen exposure and skin integument injury induce nonspecific warning signals to the attraction and activation of the innate immunity cells, and on the earliest stages (4–6 hours) most of such cells are neutrophils[17,20]. Cell infiltration depends on the proinflammatory cytokines production, such as IFNγ and TNFα, stimulating adhesion molecule expression on the endothelium and increasing vascular permeability on the local level[1,2]. Е-selectin is expressed on the capillary endothelium not later than 1–2 hours after antigen injection, and within 12 hours adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are activated too. These molecules interact with lymphocyte function-associated antigen 1 (LFA-1) and very late antigen-4 (VLA-4) on the monocytes and lymphocytes, helping to ensure the concentration of these cells in the skin [15]. Simultaneously with the endothelium activation and transformation at the site of the antigen exposure, antigen-presenting cells transport antigen from the skin to the lymph node, presenting it to the activated Т-cells migrating after that via blood vessels to the inflammatory lesion[2]. Т-cells infiltration in DHS is a biphasic process, including early proliferation by these cells, emerging around dermic blood vessels approximately within 12 hours after antigen exposure[2] and the subsequent accumulation peak of the antigen-specific Т-cells which might be associated with these cell proliferation in the skin[1,2]. Maximum macrophages count is revealed within 24 hours, but in 48 hours the prevailing cells in the infiltrate

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are Т-cells[2,39]. The current scientific studies of the skin HSV-1 infection have proved that HSV-specific cells migrated to the site of antigen injection, staying resident in the skin till the antigen elimination[1,6]. These long-living resident cells promote rapid response in the skin to the subsequent exposure of the same pathogen, presented by the tissue dendritic cells, and drive processes of the inflammatory cascade[2]. The immune response in the DHS type in the elderly human and mice has shown to have disturbances, these processes can reflect insufficient development of the immune memory to the antigen with aging. The published data prove that DHS reaction to the bacteria, fungi, and viral antigens decreases with aging, despite the same capability of the Т-cells to respond the same antigens in vitro [15]. It is noteworthy to suppose that the skin reactivity decrease is a local, not a systemic immunity defect, and it emphasizes the opportunity to highlight the disturbances of migration of the specific Т-cells to the skin after the antigen exposure. It has been unproved that decrease of Т-cells capability to migrate after DHS is associated with the insufficiency of the expression of the chemokine receptors or integrin by the circulating Т-cells [15]. Moreover, Т-cells in the elderly persons also retained their migrative properties while passing through a monolayer of endothelial cells in vitro[15]. It is conceivable that instead of the DHS-response insufficiency, there is a decrease of the endothelium activation. Endothelium activation is driven by Е-selectin, VCAM and ICAM adhesion molecules are the key chains in the Т-cells transmigration to the cell. TNFα and IFNγ are the basic inductors of the endothelium activation and DHS-response in young persons, these cytokines are predominantly secreted by the macrophages [21]. In the elderly persons, their secretion was significantly decreased at the site of antigen injection after its exposure, despite the macrophages count stayed at the normal level [21]. Macrophages isolated from the skin, remained fully capable to secrete these cytokines and stimulated TLR-ligands in vitro, supposing their inhibition in vivo. Relevance of TNFα for the effective skin immune response has been proved by the isolated cases of the observation of the sensitivity increase in rheumatoid patients to the cutaneous infections and tumor masses while being treated by the anti-TNFmedications[13]. An explanation to the proinflammatory cytokines’ se­ cre­tion decrease in response to antigen exposure in the elderly persons might be Т-reg ratio elevation, inhibiting macrophage activation, and cytokine secretion. Т-reg have demonstrated to inhibit TNFα secretion, transmitting macrophages and creating the anti-inflammatory profile[10].

Conclusion Immunological skin aging is a multifactorial process and it is evident that different cells become defect with aging. DHS reaction and memory Т-cells respond are impaired in the elderly persons. Defects might not be inhered in the Т-cells, but are rather in their environment, in the site of antigen exposure, thus resulting in the insufficient doi:10.18282/jsd.v7.i1.161


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endothelium activation and failure of the adequate migration of the circulating Т-cells to the place of destination. Skin immune respond reducing to the antigen may be related both to the adaptive and to the innate immunity, Т-reg count elevating, revealed in a wider range of the elderly persons. Thus, all the mechanisms of immune system weakening, including the older age, are not completely known. Ample evidence poses the number of questions as to whether the Т-reg and others cells activity correction in the skin could increase the immunological surveillance in the elderly persons, improve its quality and reduce risk of malignant tumor or cutaneous infection development.

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doi: 10.18282/jsd.v7.i1.165

REVIEW

Fiddler’s neck: Cultural influences modify clinical presentation influences Sundeep Chowdhry, Sameeksha Chand, Paschal D’Souza* ESIPGIMSR, Basaidarapur, New Delhi, India

Abstract: Fiddler’s neck which is also referred to as a “violin hickey” is a benign dermatologic occupational disease associated with the use of certain instruments like the violin, viola, cello etc. It is believed to be a type of allergic contact dermatitis, manifesting as an acute or chronic eczematous lesion typically at the submandibular and/or supraclavicular region on the side of neck. It can present as erythema, oedema and/or vesicles in the acute stage and as scaling, lichenification, hyperpigmentation and scarring in the chronic stage. Acne mechanica has also been considered by some authors as a presentation of fiddler’s neck. Occasionally, there may be associated swelling redness or a cystic lesion that makes it difficult to differentiate from lymphedema or a salivary gland tumor. PubMed search for articles about this entity resulting in instrument-induced dermatitis yielded few results of this forgotten entity which mimics a love bite (love hickey). For diagnosis, history of the usage of a string instrument which is held between the shoulder and neck, local physical examination and a positive patch test are pre-requisites. Management of fiddler’s neck includes application of topical mild steroid, emollient, proper instrument handling, neck padding, changing the material and polish of the instrument, and/or reducing the amount of playing time. Surgical intervention is usually not advisable unless cystic or tumorous lesions are the manifesting feature. The authors intend to revisit this entity and report an improvised modality that is being used by these instrumentalists in India which may help in prevention of this condition. Keywords: Fiddler’s neck; violin hickey; instrument induced dermatitis; allergic contact dermatitis; acne mechanica Citation: Chowdhry S, Chand S, D’Souza P. Fiddler’s neck: Cultural influences modify clinical presentation influences. J Surg Dermatol 2022; 7(1): 165; http://dx.doi.org/10.18282/jsd.v7.i1.165. *Correspondence to: Paschal D’Souza, Clinica ESIPGIMSR, Basaidarapur, New Delhi, India; paschaldsouza@yahoo.com

Received: 7th September 2021; Accepted: 8th October 2021; Published Online: 30th October 2021

Introduction The use of various musical instruments may be associated with certain skin conditions like contact dermatitis of the hands and lips, callosities, cellist’s chest, guitar nipple and Garrod’s pads. Musicians can develop skin lesions associated with the type, size, positioning and duration of the usage of their instruments [ 1–8]. Fiddler’s neck is a dermatologic entity associated with the use of instruments like the violin, viola and cello[6,7]. It usually manifests as a red mark which subsequently heals with hyperpigmentation or develops

into an eczematous lesion in the submandibular and/or the supraclavicular region. The submandibular form is more commonly seen and it usually develops under the angle of the mandible where the instrument comes in contact with the chin while the supraclavicular form is usually seen on the upper chest[9]. At times, there can be associated intense oedema and thus it may be difficult to differentiate from lymphadenopathy, malignancy, or pathology of the salivary glands[8–11]. Fiddler’s neck marks function as an “identifying sign” of a violinist in public view without seeing his/her instrument. This sign was even considered to be an

Copyright © 2022 Chowdhry S, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Fiddler’s neck: Cultural influences modify clinical presentation influences

indicator of the violinst’s skill, “battle scars” or “a badge of honour won” from constant practice and performances by some people on the one hand, but on the other hand, many friends giggle, family members gape and strangers stare at the marks and misconstrue them with the mimicker of love bites (love hickey). It is important to recognize this benign cutaneous condition so as to avoid unnecessary investigations and intervention. On review of literature regarding aetiopathogenesis of this entity, it is essential to highlight a novel modality being used by violin playing instrumentalists in certain countries like India which may be useful in preventing the development of this condition amongst those musicians/instrument players who encounter this skin problem.

Literature review We conducted a PubMed search using the key words: fiddler’s neck, violin, viola, cello, musical instruments, hickey and contact dermatitis.

Discussion Fiddler’s neck was first described by Peachey and Matthews in 1978 while analysing violin and viola students in England[12]. Gambichler et al. reported the incidence of fiddler’s neck to be 14.7% while Rimmer and Spielvogel observed this condition to be present in all 9 violinists and violists they studied[6, 13]. Knierim et al. have considered fiddler’s neck as a variant of acne mechanica[14,15]. Viola players are more susceptible to fiddler’s neck in comparison to violin players because viola is larger and heavier in comparison to violin. The submandibular location is due to mechanical pressure and shearing forces acting on the skin. Predisposing factors include prolonged duration of contact, poor hygiene, excessive perspiration and poor technique of instrument placement [7,12,14, 16 ] . It has been hypothesized that the instruments which are bigger in size like the violin have a greater tendency to cause this pathology in comparison to smaller instruments[12,16]. As this condition is provoked by physical forces of pressure and shear, local erythema, hyperpigmentation and lichenification are more commonly seen than an eczematous lesion[8,12]. Occasionally, however, edema, inflammatory papules, pustules and scaling may develop resulting in consequent scarring[7,8,12]. Histology of lesion commonly shows hyperkeratosis, acanthosis and follicular plugging[12]. Other features include a foreignbody reaction, abscess formation, cyst and granuloma formation [16,17] . Histology is similar to that of contact

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dermatitis showing acanthosis, spongiosis, dilated superficial blood vessels and inflammatory infiltrate with lymphocytes and eosinophils[16]. Abscess and cyst formation is usually associated with acne mechanica [14,16,17] . Even though submandibular fiddler’s neck is a benign condition, there may be occasional pain and secondary infection[7,16,17]. The supraclavicular lesion in such cases is a type of allergic contact dermatitis (ACD) to the metal brackets used to attach the chin rest to the base of the violin or viola or the polish resin coated on the wooden body of the instrument. Players allergic to ebony and rosewood are susceptible for developing Type 1 hypersensitivity after coming in contact with the body of the musical instruments. Other materials causing allergic reaction include nickel, exotic woods, cane reed or resin[7,9, 16,17] . If the chin rest screws are the source of allergy then they can be replaced by hypoallergenic titanium screws. Clinically, it presents as a pruritic, eczematous, scaly plaque with or without vesicles. There may be single or multiple lesions, depending on the number of metal brackets attached to the instrument. Hypertrophic scars or keloids may also occur in rare cases[7,11]. Diagnosis is mainly clinical and where a high suspicion of this entity is kept in mind, a detailed history regarding the type of instrument, duration of playing the instrument and positioning of the instrument must be elicited to corroborate with the clinical features. A patch test can be performed to determine allergy to metals, varnish, resins and exotic woods. Rarely, a biopsy may be needed to exclude other skin diseases[10]. Hot weather, tiredness, playing emotional music and playing in smaller groups are reported to exacerbate fiddler’s neck as individual stress is higher. The differential diagnoses of fiddler’s neck include branchial cleft cyst, diseases of salivary glands including parotid gland like sialolithiasis and adenolymphoma, lichen planus, contact dermatitis, herpes siplex, insect bites and stings[16,18]. The management of fiddler’s neck includes preventive strategies and symptomatic management of lesions. Instructions must be provided regarding proper positioning of the instrument as certain position like “drooping” can cause this condition[8]. In addition, equipping the instrument with appropriate chin and shoulder rests which are hypoallergic or non-allergic in nature is most desirable. Also, if possible, it is recommended to reduce contact with the instrument[7,8,9,11,16]. If the underlying predisposing factors are corrected, the lesions usually abate on their own and often do not occur in the first place themselves[7,8]. Surgical intervention may rarely be required in cases where a cyst has developed. It is also advised in branchial

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cleft cyst, diseases of salivary glands including parotid gland like sialolithiasis and adenolymphoma. Compared with submandibular fiddler’s neck which is caused by mechanical pressure and shear stress, supraclavicular fiddler’s neck is usually caused by contact dermatitis. The latter can be treated with application of topical steroid creams and emollients. We evaluated four patients in our outpatient department who play the violin. The average duration for which they have been playing the instrument is 15 years. The average time for which they practice is 3–4 hours per day. None of our patients knew about this entity and never experienced it practically either. A common point of observation amongst all these violinists was the use of a plastic “guard” (Figure 1) that they always affix at the end of their instruments (violin), at the site that comes in contact with their skin in the neck and upper shoulder region (Figure 2). The use of this guard is primarily to increase the thickness of that end of the instrument so that strain on the neck due to excessive tilting is reduced. A second advantage offered by this temporary fixture is that the surface of the guard is designed so as to enhance the grip of the neck on the violin body which prevents the instrument to slip under the chin due to sweat. This is especially important in a tropical country like India where there is increased sweating due to the hot and humid climate and violinists often have to perform in stage shows which are mostly in open setups. Jue et al. recommended the use of a “strad pad” to absorb perspiration and to cushion the skin from friction[7]. Finally, this plastic guard also helps to prevent damage to the polish and shine of the instrument which is lessened due to the sweat and friction over a period of time. The use of such a device may be offering an additional benefit by acting as a form of barrier between the skin and the probable potential allergens present in the material of instruments. Furthermore, it might be acting as a cushion to prevent friction between the skin and the instrument thereby reducing the impact of the shearing forces on the skin.

Figure 2. Violinist using plastic guard

Conclusion Fiddler’s neck or Violin hickey is a type of allergic contact dermatitis commonly seen in instrumentalists using the violin, viola and cello. Sweating, friction, pressure, type of instrument material, prolonged duration of contact and improper positioning of the playing instrument may contribute in the development of this condition. We strongly recommend the routine usage of “strad pads” or “guards” when playing instruments like the violin, viola, cello etc. during practice and otherwise. This addendum (plastic guard) reduces the physical exertion by preventing neck strain due to excessive bending unilaterally, improves the grip of the neck on the instrument, avoids slipping of one end of the instrument in sweaty conditions, maintains the shine of the instrument and most importantly, prevents the development of the fiddler’s neck. The “plastic guard” or any other soft cushion grips on one end of these musical instruments will virtually eliminate the occurrence of fiddler’s neck in those musicians who play such instruments either as a hobby or do so professionally.

Conflicts of interest The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

References 1 Figure 1. Plastic guard

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Lombardi C, Bottello M, Caruso A, Gargioni S, Passalacqua G. Allergy and skin diseases in musicians. Eur Ann Allergy

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2 3 4

5

6

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8 9

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Clin Immunol 2003; 35(2): 52–55. Bork K. Stigmas, symptoms and diseases of the skin in musicians. Hautarzt 1993; 44(9): 574–580. Crépy MN. Skin diseases in musicians. Eur J Dermatol 2015; 25(5): 375–383. doi: 10.1684/ejd.2015.2559. Cohen PR. Harpist’s finger: Case report of a traumainduced blister in a beginner harpist and review of string instrument-associated skin problems in musicians. Cutis 2008; 82(5): 329–334. Lieberman HD, Fogelman JP, Ramsay DL, Cohen DE. Allergic contact dermatitis to propolis in a violin maker. J Am Acad Dermatol 2002; 46(2 Suppl Case Reports): S30– 31. Gambichler T, Uzun A, Boms S, Altmeyer P, Altenmüller E. Skin conditions in instrumental musicians: A self-reported survey. Contact Dermatitis 2008; 58(4): 217–222. Jue MS, Kim YS, Ro YS. Fiddler’s neck accompanied by allergic contact dermatitis to nickel in a viola player. Ann Dermatolo 2010; 22(1): 88–90. doi: 10.5021/ad.2010.22.1. 88. Stern J. The edema of fiddler’s neck. J Am Acad Dermatol 1979; 1(6): 538–540. Caero JE, Cohen PR. Fiddler’s neck: Chin rest associated irritant contact dermatitis and allergic contact dermatitis in a violin player. Dermatol Online J 2012; 18(9): 10.

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12

13 14

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Myint CW, Rutt AL, Sataloff RT. Fiddler’s neck: A review. Ear Nose Throat J 2017 Feb; 96(2): 76–79. Yeo DK, Pham TP, Baker J, Porters SA. Specific orofacial problems experienced by musicians. Aust Dent J 2002; 47(1): 2–11. doi: 10.1111/j.1834-7819.2002.tb00296.x. Peachey RD, Matthews CN. Fiddler’s neck. Br J Dermatol 1978; 98(6): 669–674. doi: 10.1111/j.1365-2133.1978.tb03 586.x. Rímmer S, Spielvogel RL. Dermatologic problems of musicians. J Am Acad Dermatol 1990; 22(4): 657–663. Knierim C, Goertz W, Reifenberger J, et al. Fiddler’s neck (German). Hautartz 2013; 64(10): 724–726. doi: 10.1007/s0 0105-013-2647-5. Crěpy MN. Skin diseases in musicians. Eur J Dermatol 2015; 25(5): 375–383. doi: 10.1684/ejd.2015.2559. Moreno JC. Gata IM, García-Bravo B, Camacho FM. Fiddler’s neck. Am J Contact Dermat 1997; 8(1): 39–42. doi: 10.1016/S1046-199X(97)90035-X. Gambichler T, Boms S, Freitag M. Contact dermatitis and other skin conditions in instrumental musicians. BMC Dermatol 2004; 4: 3. doi: 10.1186/1471-5945-4-3. Tennstedt D, Cromphaut P, Dooms-Goossens A, Lachapelle JM. Dermatoses of the neck affecting violin and viola players (fiddler’s neck and contact dermatitis). Derm Beruf Umwelt 1979; 27(6): 165–169.

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doi: 10.18282/jsd.v7.i1.180

Case Report

Nevus of Ota associated with intracranial melanoma: Case report and review of the literature Ravi S. Krishnan1*, Christy Badgwell2, Daniel Yoshor3, Ida Orengo2 Virginia Mason Medical Center, Seattle, Washington, United States Department of Dermatology, Baylor College of Medicine, Houston, Texas, United States 3 Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, United States 1 2

Abstract: There is a known association between nevus of Ota and melanomas involving the brain parenchyma and/or the meninges. We present the unusual case of a 32-year-old African-American female with a nevus of Ota and a contralateral parenchymal, primary CNS melanoma. We discuss the unique features of this case and provide a brief review of the literature regarding nevi of Ota and associated CNS melanoma. Our patient is a 32 year-old, African-American female with a left-sided nevus of Ota who presented with a three month history of headaches and paresthesias involving her left face and arm. An MRI of the brain revealed a hemorrhagic mass in the right temporal lobe, which, after craniotomy, was determined to be a melanoma. Extensive imaging, ophthamologic examination and full-body skin examination revealed no other foci of melanoma. To our knowlege, this is the only case of a nevus of Ota associated with contralateral parenchymal melanoma in an African-American patient. The association of contralateral parenchymal primary CNS melanoma with nevus of Ota is extremely unusual. Futhermore, despite the association of nevus of Ota with CNS melanoma, the literature does not support routine screening of patients with nevus of Ota for CNS melanoma with imaging modalities. Keywords: nevus of Ota; melanoma; skin Citation: Krishnan RS, Badgwell, Yoshor D, Orengo I. Nevus of Ota associated with intracranial melanoma: Case report and review of the literature. J Surg Dermatol 2022; 7(1): 180; http://dx.doi.org/10.18282/jsd.v7.i1.180. *Correspondence to: Ravi Shankar Krishnan, Virginia Mason Medical Center, Seattle, WA 98101, United States; ravi.krishnan@gmail.com Received: 18th October 2021; Accepted: 5th December 2021; Published Online: 16th December 2021

Case Report The patient is a 32-year-old African-American female with no significant past medical history who had severe headaches and episodes of numbness on the left side of her face and left arm for several months prior to presentation. Of note, the patient had a large nevus of Ota on the left side of her face that had been present since birth (Figure 1). She stated that the nevus had been unchanged for at least a decade. On exam, there was slate-blue patch which covered most of the left half of her face. Most of the left sclera displayed similar blue pigmentation as did a portion of her soft palate. The patient had no pigmented lesions concerning for melanoma on full body skin exam. The patient's neurological exam was normal, except for subtle sensory deficits on the left face and arm. An MRI of the brain revealed a 5 cm hemorrhagic mass located in the right superior temporal gyrus. A subsequent staging work-up including CT scans of the chest, abdomen, and pelvis failed to reveal any other foci of melanoma, so it

was concluded that the melanoma originated intracranially. The patient underwent craniotomy for extirpation of this lesion, and histopathological examination revealed it to be a melanoma. The patient did well initially; however, the melanoma recurred with leptomeningeal dissemination several months after surgery, and the patient expired.

Discussion We present the case of an intracranial melanoma in a woman with unilateral nevus of Ota. Our case is unique in that the melanoma is contralateral to the patient’s nevus of Ota and located in the brain parenchyma. Nevus of Ota, often referred to as oculodermal melano­ cytosis, usually occurs as a flat or slightly raised blue-black or slate-gray unilateral discoloration in the distribution of the first and second divisions of the trigeminal nerve[1]. It is formed by melanoblasts that fail to migrate to the dermoepidermal junction and instead remain in the dermis[2]. Melanoblasts are the precursors of melanocytes, and

Copyright © 2022 Krishnan RS, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Nevus of Ota associated with intracranial melanoma: Case report and review of the literature

Figure 1. A large nevus of Ota on the left side of the patient's face

their arrested migration can cause pigmentary abnormalities in the nerve fibers, meninges, ocular structures, and inner ear[2]. Intracranial melanomas originate from the proliferation of melanocytic elements normally present in the lepto­ meninges (i.e. melanoblasts of neural crest origin) which can develop neoplastic patterns [3] . Leptomeningeal melanosis, a disproportionate number of melanotic cells in the meninges, has been considered a hamartomatous state characterized by excessive formation of melanoblasts that may predispose an individual to CNS melanomas[4]. Likewise, dural melanomas are thought to originate from abnormal dural melanin pigmentation[5]. There are 15 previously reported cases of intracranial melanomas associated with nevus of Ota [5–11] . These tumors have been located in the cerebral hemisphere, the optic chiasm, and the pineal gland[5–11]. The majority of CNS tumors associated with nevus of Ota have been leptomeningeal[6]. In nearly half of reviewed meningeal melanomas associated with Ota’s nevus, a dural attachment and origin have been documented[5]. To our knowledge, our patient is the fifth reported case of intraparenchymal CNS melanoma associated with nevus of Ota[6,7]. In the prior four cases, the leptomeninx had associated pigmentation or melanoma. With the recurrence of intracranial melanoma in our patient, there was leptomeningeal dissemination. However, it is not known if she had leptomeningeal pigmentation associated with the melanoma at initial presentation. While previously reported cases have been associated with pigmentation of the leptomeninx, it has been demonstrated by magnetic resonance that intraparenchymal melanin deposition can occur independently of detectable leptomeningeal melanosis [12,13]. Therefore, it may be possible that our patient presented with intraparenchymal melanoma without associated leptomeningeal melanosis. To our knowledge, our patient is the third reported case of contralateral CNS melanoma associated with nevus of Ota[6,8]. Each of the two cases previously reported, Sang et al. in 1977 and Balmaceda et al. in 1993, were thought to have been a unilateral nevus of Ota associated with bilateral

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diffuse leptomeningeal melanocytosis, one area of which underwent malignant degeneration[6,8]. Although the prognosis of intracranial melanoma is poor, the prognosis of solitary intracranial melanoma or dural melanoma is better than that of diffuse leptomeningeal melanoma, likely because the former lesions are more accessible to direct surgical removal[14,15]. However, the survival of patients with solitary intracranial melanomas depends largely on the extent of surgical treatment and the location of the tumor[3]. In a study of 81 patients who underwent surgery for solitary intracranial melanomas, the overall survival rate was more than 12 months in 20% of cases (16/81) and less than 1 month in 13.6% (11/81) of cases[3]. Disease free intervals for dural melanoma have been reported as 16–18 months postoperatively[15]. Patients with leptomeningeal melanoma have a median symptomfree course of 5 months and a median postoperative survival of 1 month[16]. Given the poor prognosis of intracranial melanoma, the question arises as to whether or not patients with nevus of Ota should undergo screening CT or MRI for intracranial masses. To the best of our knowledge, there is not literature in strong support of implementing such screening measures. Our review of the literature revealed that our case represents only the sixteenth case of intracranial melanoma associated with nevus of Ota. In light of the rarity of the association of the two, it might be more prudent to advise clinicians to have a high index of suspicion in a patient with a nevus of Ota presenting with neurologic findings rather than to suggest widespread head imaging of asymptomatic patients with a nevus of Ota.

Conflict of interests The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

References 1. Rivers J, Bhayana S, Martinka M. Dural melanoma associated with ocular melanosis and multiple blue nevi. J Cutan Med Surg 2001; 381–385. doi: 10.1177/120347540100500501. doi:10.18282/jsd.v7.i1.180


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2. Rahimi-Movaghar V, Karimi M. Meningeal melanocytoma of the brain and oculodermal melanocytosis (nevus of Ota): Case report and literature review. Surg Neurol 2003; 59: 200–210. doi: 10.1016/S0090-3019(02)01052-2. 3. Rodriguez y Baena R, Gaetani P, Danova M, Bosi F, Zappoli F. Primary solitary intracranial melanoma: Case report and review of literature. Surg Neurol 1992; 38(1): 26–37. doi: 10.1016/0090-3019(92)90208-5. 4. Willis RA. The borderland of embryology and pathology (Second Edition). London: Butterworths, 1962: 377–382. 5. Theunissen P, Spincemaille G, Pannebakker M, Lambers J. Meningeal melanoma associated with nevus of Ota: Case report and review. Clin Neuropath 1993; 12(3): 125–129. 6. Balmaceda CM, Fetell MR, Powers J, O’Brien JL, Housepian EH. Nevus of Ota and leptomeningeal melanocytic lesions. Neurology 1993; 43: 381–386. doi: 10.1212/WNL.43.2.381. 7. Shaffer D, Walker K, Weiss GR. Malignant melanoma in a Hispanic male with nevus of Ota. Dermatology 1992; 185: 146–150. doi: 10.1159/000247433. 8. Sang DN, Albert DM, Sober AJ, McMeekin TO. Nevus of Ota with contralateral cerebral melanoma. Arch Ophthalmol 1977; 95: 1820–1824. doi: 10.1001/archopht.1977.04450100122017. 9. Enriquez, R, Egbert B, Bullock J. Primary malignany melanoma of central nevous system: Pineal involvement in a patient with nevus of Ota and multiple skin nevi. Arch Pathol 1973; 95: 392–395.

10. Sagar HJ, Ilgren eB, Adams CB. Nevus of Ota associated with meningeal melanosis and intracranial melanoma. J Neurosurgery 1983; 58: 280–283. doi: 10.3171/jns.1983.58.2 .0280. 11. A runkuma M J , R a nja n A , J a c ob M , R a js hekhar V. Neurocutaneous melanosis: A case of primary intracranial melanoma with metastasis. Clin Oncol (R Coll Radiol) 2001; 13: 52–54. doi: 10.1053/clon.2001.9215. 12. Koksal N, Bayram Y, Isik M, Dogru M, Bostan O, et al. Neurocutaneous melanosis with transposition of the great arteries and renal agenesis. Pediatr Dermatol 2003; 20(4): 332–334. doi: 10.1046/j.1525-1470.2003.20412.x. 13. Demirci A, Kawamura Y, Sze G, Duncan C. MR of parenchymal neurocutaneous melanosis. Am J Neuroradiol 1995; 16(3): 603–606. 14. Allcutt D, Michowiz S, Weitzman S, Becker L, Blaser S, et al. Primary leptomeningeal melanoma: An unusually aggressive tumor in childhood. Neurosurgery 1993; 32(5): 721–729. doi: 10.1227/00006123-199305000-00004. 15. Macfarlane R, Marks PV, Waters A. Primary melanoma of the dura mater. Br J Neurosurgery 1989; 3: 235–238. doi: 10.3109/02688698909002801. 16. Kiel FW, Starr LB, Hansen JL. Primary melanoma of the spinal cord. J Neurosurg 1961; 18: 616–629. doi: 10.3171/ jns.1961.18.5.0616.

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doi: 10.18282/jsd.v7.i1.137

PERSPECTIVE

Facial laser surgery Shree Harsh*, Surendra B. Patil Department of Plastic and Maxillofacial Surgery, Government Medical College and Hospital, Nagpur, India

Abstract: Lasers have a number of clinical applications on the face, ranging from aesthetic uses such as the rejuvenation of ageing face to functional ones such as the correction of bleeding vascular malformations. The vast growing uses of lasers on the face emphasises the need to have knowledge of the subject. Though the vast spectrum of lasers is very difficult to compile in an article, the authors give an overview of the application of lasers in the facial region and discuss the most defining treatment of the individual disease processes. Keywords: face; laser; surgery Citation: Harsh S and Patil SB. Facial laser surgery. J Surg Dermatol 2022; 7(1): 137; http://dx.doi.org/10.18282/ jsd.v7.i1.137.

*Correspondence to: Shree Harsh, Department of Plastic Surgery, G.MC Nagpur, India; s007harsh@gmail.com Received: 29th July 2021; Accepted: 23rd September 2021; Published Online: 1st October 2021

Introduction Background and history Laser is an abbreviation for “light amplification by stimulated emission of radiation”. It generates light energy in the photon beam form. The concepts to build laser was postulated in 1917 by Albert Einstein, which was published in The Quantum Theory of Radiation. Maser, an acronym for microwave amplification by stimulated emission of radiation, was devised by Charles H Townes and Arthur L Schalow in 1958. Townes along with Aleksandr Mikhailovich Prokhorov and Nikolay G Basov were awarded Nobel Prize in 1964 for their contribution in quantum electronics which helped in the discovery of Laser and Maser[1]. Helium-neon laser, the first gas laser which produced a continuous beam, was developed by physicists William Bennett and Ali Javan in 1961. Argon laser was thereafter discovered, followed by 10,600-nm carbon dioxide (CO2) laser by engineers Kumar Patel et al. in 1964[2]. Neodymium-doped yttrium aluminium garnet (Nd:YAG) was developed by scientists JE Geusic, HW Marcos and LG Van Uitert in 1964 and was used first for the control of gastrointestinal bleed. Dye lasers were discovered by physicists PP Sorokin and JR Lankard as well as FP Schafer et al., in 1966[3].

Later, excimer lasers, copper vapour lasers and other lasers were discovered and continued to be added to the armamentarium of the treating doctors. The principle of selective photothermolysis was proposed in 1983 by Anderson and Parrish where they explained the process of selective destruction of certain tissues by absorption of a particular wavelength by a chromophore[4]. To standardise the practice of laser, many societies were established such as The Laser Institute of America, International Society for Laser Medicine and Surgery, American Society for Laser Medicine and Surgery, and The American National Standard Institute for the organisation and evolution of lasers.

Facial laser surgery The use of lasers on the face has a very wide spectrum. They are amongst the most popular options in aesthetic practice for facial rejuvenation. They can also be used for the treatment of vascular and pigmented lesions, removing unwanted hair, treatment of facial scar and for the treatment of some dermatological disorders. We will discuss them in the article.

Safety in laser surgery Safety in laser surgery is of paramount importance. It comes in the top priorities for any clinician. The Federal Laser Product Performance Standard classifies med-

Copyright © 2022 Harsh S and Patil SB. This is an Open Access article distributed under the terms of the Creative Commons Attribu-tionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ical lasers on the basis of the ability to cause damage to ocular and cutaneous structures (Table 1). Class I laser does not cause damage. Class II lasers can cause ocular damage only if someone overcomes the natural aversion response towards bright light. Class III (mainly IIIb) lasers can cause ocular damage, and class IV lasers can be harmful to eyes and skin and has potential fire hazard. Ocular hazard by long wavelength lasers (CO2 and Erbium-doped yttrium aluminium garnet (Er:YAG)) can cause corneal burns. Holmium: YAG (Ho:YAG) laser can cause injury to the lens and cornea. It spares the retina. Short wavelength lasers can cause retinal damage[5]. Appropriate safety eyewear should be used for the protection of the eyes of all members who are inside the chamber where the session is going on. Fire hazard is associated mostly with the use of high power systems. Fire safety should be a priority inside the chamber. Fire extinguisher should be available near the laser room. The chamber should have restricted entry at the time of the procedure to avoid any accidental exposure. Evacuation systems and ultra–low particulate air filter should be used to evacuate the plume and protective devices should be used by all members of the team. International standards can be followed by observing the guidelines laid by the International Electrotechnical Commission for manufacturers, clinicians and administrators.

Discussion Laser for rejuvenation of the face The features of the aging face appear due to a combination of intrinsic and extrinsic factors[6]. These include wrinkles, malar depression, actinic changes, excess of skin, furrows, accumulation of submental fat and the showing of mandibular teeth. Sagging occurs due to the loss of skin elasticity, which decreases from an early age[7]. Wrinkles (Figures 1 and 2) appear due to the decrease of procollagens I and III and collagen VII[8]. Fitzpatrick skin phototypes[9] are used to classify the responses to sun exposure by the skin (Table 2).There are many lasers available for skin resurfacing. They can be used in the treatment of skin wrinkles, acne scars, actinic and seborrheic keratosis, photo-aging and lentigines. Table 3 summarises the different types of lasers.

Ethics statement The figures of the patients exhibiting various conditions are from the Department of Plastic and Maxillofacial Surgery, Government Medical College and Hospital, Nagpur, India. Informed consent was taken from the patients (or their parents, in the case of minor patients).

Figure 1. Aging face with wrinkles

Table 1. Laser safety

Class of Laser

Safety profile

I

Safe

II

Safe but harmful if natural aversion response to light averted

III

Harmful to eyes

IV

Harmful to eyes, skin. Figure 2. Aging face with wrinkles and lentigines

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Facial laser surgery

Table 2. Fitzpatrick skin types Type

Scores

Skin colour

Effect to UVA

Reaction to sun

Skin tone

I

0–6

Caucasian, blond/red hair, freckles, fair skin , blue eyes

Very sensitive

Always burns, never tans

Very fair

II

7–13

Caucasian

Very sensitive

Usually burns, tans minimally

Fair

III

14–20

Darker Caucasian, light Asian

Sensitive

Burns moderately, tans uniformly

Fair to medium

IV

21–27

Mediterranean, Asian, Hispanic

Moderately sensitive

Rarely burns, always tans well

Medium

V

28–34

Middle Eastern, Latin, light-skinned black, Indian

Minimally sensitive

Very rarely burns, tans very easily

Olive or dark

VI

35–36

Dark-skinned black

Least sensitive

Never burn, always tans

Very dark

Table 3. Summary of lasers Laser type CO2

Wavelength (nm) 10,600

Erbium:YAG

2940

Nd:YAG

1064, 1320,1440

IPL

500–1200

PDL

585, 595

KTP

532

Alexandrite Diode

755 600–1020

Indications Skin resurfacing, wrinkles Mild-to-moderate rhytids, scars, pigmentation Wrinkles, pigmentation Dyspigmentation, wrinkling, telangiectasia, hair removal Vascular lesions, wrinkling, dyspigmentation Photo-damaged red-brown discolouration Tattoo, hair removal Facial rhytids, telangiectasia, hair removal

Ablative techniques This is more aggressive as compared to non-ablative lasers. CO2 laser (10,600 nm) vaporises the epidermis and dermis layer by layer. It rejuvenates the skin by epidermal regeneration and reorganisation, and by the strengthening of collagen bundles. It is more useful in severe facial wrinkles, challenging skin textures, and dyspigmentation[10]. Fractional ablative lasers provide adequate skin resurfacing safely as compared to the unfractionated models used earlier. Non-ablative laser spares the epidermis, decreases fine wrinkles, chang-

54

Pulse duration (ms) 50 .25

Complications Edema, erythema, pruritus, contact dermatitis, hyperpigmentation Minimal burning

50

Pain, redness, itching, swelling

1–300 45 20–50 3 30

Erythema, discomfort, blisters, pain, hyperpigmentation, crusting, purpura Pain, purpura, swelling Edema, pain, crusting, erythema, telangiectasia Pain, redness, swelling, itching Hyperpigmentation, erythema, edema

es the texture and tone of skin and treats dyspigmentation. The scarring produced in continuous wave (CW) laser is more when compared to the short-pulsed CO2 laser. Currently, high power pulse (ultrapulse) and CW CO2 laser (acupulse) are used. The outermost layer of the epidermis and some part of superficial dermis are removed. Activated fibroblasts help in the deposition of collagen and elastin tissue[11]. The papillary dermis is affected to a minimum in newer lasers. The superpulsed lasers based on selective photothermolysis result in pure steam vaporisation and the adjacent tissue is affected

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Harsh S and Patil SB

minimally[12] Ultrapulse CO2 lasers for midfacial region are treated with 90 mJ/45W with first-pass density setting of 7, and less for the upper and lower eyelids and even lesser for hairline and jawline. In the second pass, lesser density is required as compared to the first. Some wrinkles may require a third pass. Postoperative period may be complicated with swelling (which subsides in a week), erythema, pruritus and contact dermatitis. Post-inflammatory hyperpigmentation, which occurs 2–3 weeks post-therapy, may be decreased with prior treatment of retinoic acid and hydroquinone[13]. Er:YAG lasers It has a wavelength of 2,940 nm with water as its chromophore. It is used for superficial rhytids, actinic keratosis, dyschromia and Favre-Racouchot disease[14]. The penetration and ablation is more superficial compared to CO2. About 10–20 µm of thermal damage is caused by 10– 40 µm of skin impact. Skin tightening is achieved by the second and third pass. Wrinkles are reduced up to 50% in 2–3 passes[14]. Er:YAG has less crusting and erythema compared to CO2 laser[15]. Erbium can be combined with CO2 to give uniformity in the treatment of different areas of the face. Fractional photothermolysis It was developed by Relent technologies. The wavelength is 1,550 nm. It is among the recent options for skin rejuvenation[16]. It treats only a fraction of skin. The thermal side effects are decreased. Non-ablative techniques These include plasma skin regeneration, pulse dye laser, Nd:YAG, intense pulsed light (IPL), light-emitting diode(LED) devices and photodynamic therapy. It involves the sparing of epidermis, and affects the dermis directly, which helps in early recovery. The mechanism is by targeting chromophores such as melanin, haemoglobin and collagen. The wavelength is in the visible to infrared region, targeting the upper and middle part of the dermis. There is the activation of dermal fibroblasts, which helps in healing. Plasma skin regeneration Nitrogen plasma delivers energy to the skin. There is no chromophore mediator and the energy is delivered in a uniform and smooth way to the dermis by pulses of plasma. It is a non-ablative method used to treat facial rhytids, benign facial skin lesions and actinic keratosis. Pulse dye laser Long pulse dye laser is used for the treatment of facial doi:10.18282/jsd.v7.i1.137

lentigines and wrinkles. There is no scarring or changes in skin pigmentation post-operatively[17]. There is an increase in dermal collagen with the use of 585-nm pulsed dye laser (PDL) between days 0–90 with maximum increase in the periorbital region[18]. Intense pulse light Dyschromia, ephelides, senile and solar lentigines can be treated with intense pulsed light (IPL)[19]. It is a non-coherent light with a wavelength between 500–1,200 nm. It works on the basis of selective photothermolysis targeting haemoglobin, melanin and water. Skin tightening in IPL occurs due to the contracture of the heated collagen fibers. Photoaging due to telangiectasia and pigmentation shows significant improvement within three treatments[20]. Side effects include mild crusting, blistering, erythema and purpura, all of which are transient and self-limiting. Potassium titanyl phosphate The 532-nm lasers produce energy pulses with small spots. They target oxyhemoglobin and melanin. Patients with Fitzpatrick types I to III are good candidates for these lasers[21]. They are effective in treating photo-damaged red and brown discolourations. Side effects of the therapy include erythema and edema. Light-emitting diode Light-emitting diode (LED) was invented in 1962. It stimulates collagen synthesis and accelerates fibroblast-myofibroblast transformation. The wavelengths are 590, 633 and 830 nm. For fine wrinkles, the periorbital area show more improvement than nasolabial area[22]. LED has shown to decrease erythema, edema, pain and bruising following blepharoplasty and periocular resurfacing by Er:YAG/CO 2 laser[23]. Near-infrared laser Rejuvenation with this laser is produced by long-lasting elastin stimulation. Significant improvement in the skin texture and wrinkles has been observed [24]. The increase in collagen and elastin improves skin texture, although without significant improvement in hyperpigmented lesions[25]. Photodynamic therapy It involves use of light with photosensitising substance ( amino levulonic acid). It has an additional advantage of destroying precancerous cells, in addition to the treatment of sun-damaged fine lines and pigmentation. The more ablative the laser is, the better results it gives. This, however, comes at a cost of longer time of

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recovery for these patients. The fractional lasers provide the best combination to give optimal results.

Treatment of pigmentation Solar lentigines Though there are many topical therapies available, the treatment of solar lentigines by laser provides almost complete clearance. The options include Q-switched lasers, long-pulsed lasers and HGM K1 krypton lasers. Long-pulsed dye laser have shown near complete clearance of the lesion and reduced machine-produced index factor[26]. Q-switched Nd:YAG with 532-nm wavelength is a good option for light-skinned patients with lentigines, and 1064nm for darker-skinned patients. Q-switched Nd:YAG is better than fractional CO2 laser for treating solar lentigines[27]. Solar elastosis CO2, Nd:YAG, diode, IPL and Er:YAG can be used for solar elastosis. Diode laser has the advantage of preserving the epithelial layer with resurfacing effects, same as that of CO2 laser[28]. Melasma Treatment options for melasma include: 1. 2. 3. 4. 5.

Q-switched ruby laser Erbium:YAG – refractory melasma PDL – recurrent melasma Fractional laser IPL

Children should be treated when the hemangioma fails to regress. PDL with wavelength ranging from 585–600 nm with pulse width of about 0.45 ms[21] can be used to treat these lesions. Residual scarring can be treated by CO2 or Erbium lasers. Laser photocoagulation is the method of choice to treat port-wine stain. Argon laser can be used for the treatment of hypertrophied nodule of thickened port-wine stain. However, the disadvantage with Argon, CO2 and Nd:YAG is scarring[31]. Best results are with flashlamp-pulse dye laser[32]. Patients are treated at interval of 4–6 weeks or on clinical judgement. Venous malformation Nd:YAG can be used for deeper and superficial lesions with 595–1,064-nm laser (Figure 4). Lymphatic malformation Laser is useful in treating superficial lymphatic malformation of the head and neck area. 10,600-nm CO2 laser is of help for treating mucosal lesions. Facial telangiectasia and rosacea Vascular laser can be used to deal with facial telangiectasia. CO2 and Erbium:YAG can be used to treat rhinophyma (Figure 5). PDL remains the gold standard for the treatment of vascular lesions, though erythema and purpura may persist for a couple of weeks after treatment.

Lasers should be used in patients of melasma who are refractory to topical therapies.

Use of lasers in facial acne Potassium titanyl phosphate (KTP) laser may act through selective photothermolysis of the blood vessels or by a photodynamic effect on Propionibacterium acnes[29]. The 585-nm PDL has been used in treatment of acne scar[30]. It also decreases post-acne erythema. 1450-nm diode laser and 1540-nm Erbium glass laser are also used for acne with the latter causing decreased oiliness. They can be used in the inflammatory phase of acne by acting on haemoglobin and water as chromophores and for the management

Figure 3. Hemangioma of the upper eyelid

Laser for treatment of vascular lesions on the face Hemangioma It is the most common type of vascular tumor (Figure 3).

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Figure 4. Venous malformation of the tongue

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Harsh S and Patil SB

Laser for tattoo on the face Traumatic tattoos can be due to carbon, graphite, etc. They can be removed with Q-switch Alexandrite laser[33]. Tattoos applied by a professional are deeper and are more difficult to remove. Exogenous ink is the chromophore. Quality switch lasers have been used traditionally to treat these tattoos. Multiple settings are required for complete removal of pigments. The appropriate lasers for different colours of tattoo are as follows: 1. 2. 3. 4. 5. 6. 7.

Black and dark blue pigment: QS ruby, QS Nd:YAG (1,064 nm) and QS Alexandrite[34] Orange and red brown: 1064-nm QS Nd:YAG doubled in frequency Red: Nd:YAG[35] Green pigment: Alexandrite[35] Purple and violet: Q-switched ruby laser[35] Light coloured/pale: QS Alexandrite and QS Nd:YAG laser[36] Newer modalities: a. Multi-pass treatment - multiple passes in one session[37] b. Picosecond laser

3. 4. 5. 6.

Fibrotic scar: Fractional laser Hyperpigmentation and discolouration in post-burn scars: IPL and Q-switch Hypertrophic scars[38]: Nd:YAG (1,064 nm) and CO2 Post-traumatic scars[39]: Erbium glass (1,540 nm)

IPL, PDL and Erbium glass (1,540 nm) have shown decent results.

Figure 5. Rhinophyma of the nose

Black, dark blue and red can all be removed with QS ruby, Nd:YAG and Alexandrite lasers.

Laser for unwanted hair on the face Alexandrite (755 nm), diode (800 nm) and ruby (694 nm) lasers can be used to remove unwanted hairs on the face (Figure 6). Cutaneous hyper/hypopigmentation is more in these short wavelength lasers as compared to longer wavelength laser such as Nd:YAG (1,064 nm) laser. IPL and Q-switched Nd:YAG are other options for hair removal with good results. Patients should be educated about the multiple treatment sessions and minor side effects such as itching, edema and redness after the procedure. People with higher Fitzpatrick skin types are more responsive to diode and Nd:YAG.

Figure 6. Black hairy nevus of the face

Laser for facial scar Facial scars can be a result of trauma, post-surgery, post-burn or after any inflammatory process (Figures 7 and 8). Though many invasive and non-invasive treatment options are available, they are associated with recurrence, side effects, as well as failure rates.

Specific lasers for different scars 1. 2.

Post-burn scars: CO2 laser Immature post-burn scar: Nd:YAG (1,064 nm)

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Figure 7. Post-traumatic facial scar

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Facial laser surgery

personnel and the patient are of paramount importance and laser safety protocols should be followed every time the procedure is performed. Caution should be taken when evaluating the patient with unrealistic expectations.

Author contributions Both S Harsh and SB Patil contributed to the drafting of manuscript.

Conflict of interest The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article. Figure 8. Post-burn hypertrophic scar on the face

References

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[41]

The Nd:YAG laser and CO2 laser can be used to treat cylindroma (Figure 9) in the head and neck region[40,41].

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6.

7. Figure 9. Cylindroma of the head and neck region

Conclusion

8.

Lasers have become a powerful tool for many procedures on the face. Proper training of the care provider along with the staff and maintaining acceptable standards in the clinic makes the process safe. The risk-benefit ratio, the usefulness and the adverse effects of the procedure should not only be kept in mind at the time of procedure but are also explained to the patient and documented in detail prior to the procedure. The safety of medical

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SHORT COMMUNICATION

Laser microporation: A promising field in transdermal drug delivery Mozhdeh Sepaskhah Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Keywords: laser; microporation; transdermal drug delivery Citation: Sepaskhah M. Laser microporation: A promising field in transdermal drug delivery. J Surg Dermatol 2022; 7(1): 139; http://dx.doi.org/10.18282/jsd.v7.i1.139. Correspondence to: Mozhdeh Sepaskhah, Department of Dermatology, Shahid Faghihi Hospital, Zand Avenue, Shiraz 71348 44119, Iran; sepaskhah_m@yahoo.com

Received: 21st July 2021; Accepted: 19th September 2021; Published Online: 25th September 2021

Introduction Topical therapy is an expanding field not only in dermatology but also in other fields of medicine[1,2]. An expanding list of systemic medications have been applied topically in several dermatologic conditions[1]. Drugs applied topically have the advantage of fewer side effects, and bypassing the first-pass effect. Also, painless drug delivery which is especially encouraging in children, makes transdermal drug delivery even more appealing[3]. However, transdermal dermal drug delivery has limitations, including decreased penetration of larger and water-soluble molecules and poor penetration of agents in areas like nails[4,5]. Researchers have tried to overcome the limitations and enhance percutaneous drug delivery by using different carriers or microporation[6,7].

Microporation Microporation devices create micron-sized pores or channels in the skin to facilitate the transport of hydrophilic molecules and macromolecules[4]. Microporation has been performed by different mechanisms, including laser ablation, radiofrequency, iontophoresis, mechanical needling, thermal microporation, phonophoresis, electroporation and high pressure gas/powder or

liquid[7].

Laser microporation Laser microporation is among the recently used microporation techniques. Historically, a pulsed argon fluoride excimer laser was first used in 1987 for stratum corneum ablation[8]. Since then, other lasers including Q-switched ruby, Neodymium-doped yttrium aluminium garnet (Nd:YAG) lasers and carbon dioxide (CO2) lasers were also used for microporation[8]. However, the most widely used lasers for microporation are erbium-doped yttrium aluminium garnet (Er:YAG) lasers which are preferred due to less heating of the surrounding skin. One of the most frequently used laser devices for transdermal drug delivery is a fractional Er:YAG laser named Precise Laser Epidermal System (P.L.E.A.S.E.®, Pantec Biosolutions, Ruggell, Liechtenstein)[9,10]. To date, most of the studies evaluated laser microporation in vitro or in vivo (animal studies).There are few clinical studies assessing the efficacy of microporation in human[11,12].

Advantages and disadvantages As noted previously, laser microporation presents many advantages including delivering drugs to the target tissue

Copyright © 2022 Sepaskhah M. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http: //creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Laser microporation: A promising field in transdermal drug delivery

i.e. dermis, decreased dose of drug administered, decreased risk of systemic side effects, penetration of medications in tissues like nail and fibrosing tissues and presenting a relatively painless method[3-5,13]. While laser microporation is considered a promising technique in promoting drug absorption via skin, potential side effects of ablative lasers remain the main limitation. The most common side effects include discomfort, erythema, edema, dyspigmentation, scarring and herpes virus reactivation[14]. Also, possible risk of local and/or systemic side effects due to increased amount and depth of the penetrated medication may be a concern[15].

Conclusion Laser microporation is a recently investigated, promising technique for improving transdermal drug delivery, although, optimal drug dosing, laser treatment protocol and safety of the technique need to be determined clinically. Therefore, conducting strong randomized controlled clinical trials, especially in assessing laser microporation effect on transdermal drug delivery of dermatological medications in the future, will help to confirm laser microporation as a new method for enhancing drug delivery in clinical practice.

5.

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9.

10.

Conflict of interest The author declares no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

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Chiu HY, Tsai TF. Topical use of systemic drugs in dermatology: A comprehensive review. J Am Acad Dermatol 2011; 65(5): 1048.e1–1048.e22. doi: 10.1016/j.jaad.20 10.08.034. Zech NH, Murtinger M, Uher P. Pregnancy after ovarian superovulation by transdermal delivery of follicle-stimulating hormone. Fertil Steril 2011; 95(8): 2784–2785. doi: 10.1016/j.fertnstert.2011.03.073. Subramony JA. Needle free parenteral drug delivery: Leveraging active transdermal technologies for pediatric use. Int J Pharm 2013; 455(1–2): 14–18. doi: 10.1016/j.ijpharm.2013.07.055. Banga AK. Microporation applications for enhancing drug delivery. Expert Opin Drug Delivery 2009; 6(4):

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343–354. doi: 10.1517/17425240902841935. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Delivery 2008; 5(11): 1267–1282. doi: 10.1517/17425240802497218. Singh MD, Mital N, Kaur G. Topical drug delivery systems: A patent review. Expert Opin Ther Pat 2016; 26(2): 213–228. doi: 10.1517/13543776.2016.1131267. Singh TRR, Garland MJ, Cassidy CM, Migalska K, Demir YK, et al. Microporation techniques for enhanced delivery of therapeutic agents. Recent Pat Drug Delivery Formulation 2010; 4(1): 1–17. doi: 10.2174/187 221110789957174. Scheiblhofer S, Thalhamer J, Weiss R. Laser microporation of the skin: Prospects for painless application of protective and therapeutic vaccines. Expert Opin Drug Delivery 2013; 10(6): 761–773. doi: 10.1517/17 425247.2013.773970. Chen X, Shah D, Kositratna G, Manstein D, Anderson RR, et al. Facilitation of transcutaneous drug delivery and vaccine immunization by a safe laser technology. J Controlled Release 2012; 159(1): 43–51. doi: 10.1016/ j.jconrel.2012.01.002. Hsiao CY, Sung HC, Hu S, Huang CH. Fractional CO2 laser treatment to enhance skin permeation of tranexamic acid with minimal skin disruption. Dermatology 2015; 230(3): 269–75. doi: 10.1159/000371386. Oni G, Rasko Y, Kenkel J. Topical lidocaine enhanced by laser pretreatment: A safe and effective method of analgesia for facial rejuvenation. Aesthetic Surg J 2013; 33(6): 854–861. doi: 10.1177/1090820X13496248. Cunha PR, Scabine Pessotti N, Bonati Mattos C, Salai AF. New approach in the treatment of refractory vitiligo: CO2 laser combined with betamethasone and salicylic acid solution. Dermatol Ther 2017; 30: e12410. doi: 10.1111/dth.12410. Park JH, Chun JY, Lee JH. Laser-assisted topical corticosteroid delivery for the treatment of keloids. Lasers Med Sci 2017. In Press. doi: 10.1007/s10103-017-2154-5. Riggs K, Keller M, Humphreys TR. Ablative laser resurfacing: High-energy pulsed carbon dioxide and erbium:yttrium-aluminum-garnet. Clin Dermatol 2007; 25(5): 462–473. doi: 10.1016/j.clindermatol.2007.07.003. Zaleski-Larsen LA, Fabi SG. Laser-assisted drug delivery. Dermatol Surg 2016; 42(8): 919–931. doi: 10.1097/ DSS.0000000000000556.

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doi: 10.18282/jsd.v7.i1.138

Correspondence

Giant cell tumor of tendon sheath—Use of fine-needle aspiration cytology for diagnosis Neha Meena1*, Pooja Arora2 1 2

Central Hospital, North Western Railway, Jaipur (Rajasthan), India Department of Dermatology, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India

*Correspondence to: Neha Meena, Central Hospital, North Western Railway, Jaipur (Rajasthan) - 302006, India; nehadermatologist@gmail.com Received: 13th July 2021; Published Online: 9th August 2021 Dear Editor, Giant cell tumour of the tendon sheath (GCTTS) is a slowgrowing, usually painless benign lesion of soft tissues[1]. We report the case of a 38-year-old male with a painless, slowly enlarging swelling on right thumb in order to highlight the role of fine-needle aspiration cytology (FNAC) in diagnosing GCTTS. A 38-year-old male presented with a painless, slowly enlarging swelling on his right thumb from last six months. There was no history of injury to the affected area. On

examination, there was a 3-cm × 1-cm mass with normal overlying skin on the ulnar aspect of the right thumb at interphalangeal joint (Figure 1). It was non-tender, firm, well-circumscribed and fixed to the underlying structures with non-adherent overlying skin. X-ray of the right hand showed soft tissue swelling in the right thumb. Ultrasonography revealed a lobulated, well-defined, hypoechoic lesion in close approximation of the underlying tendon. However, the integrity of the underlying tendon was maintained. FNAC was suggestive of giant cell tumor of tendon sheath.

Figure 1. Mass on right thumb Copyright © 2022 Meena N and Arora P. This is an Open Access article distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

63


Giant cell tumor of tendon sheath—Use of fine-needle aspiration cytology for diagnosis

Giant cell tumour of the tendon sheath (GCTTS) is a slowly growing, usually painless benign lesion of soft tissues [1]. It is the second most common tumour of the hand after ganglion cysts. It affects individuals between the age of 30 and 50 years old and is more common in females [1]. GCTTS presents as a firm, nodular mass occurring more commonly on the volar aspect of fingers and hands[2]. The various etiological factors include trauma, neoplastic, inflammatory and metabolic disease, but it is best considered idiopathic[2]. Histologically, GCTTS is composed of multinucleated giant cells, histiocytes polyhedral, fibrotic material and hemosiderin deposits[1]. There is no report of GCTTS becoming malignant. Rate of recurrence is reported up to 45% of cases. Excision is the treatment of choice[1]. Byers et al. classified GCTTS into two types: localized nodular (common in hand) and diffuse (common in joints) [3] . Al-Qattan proposed a new classification for GCTTS: Type-I as single tumour, which is round or multi-lobulated, and Type-II where there are two or more distinct tumours which are not joined[4]. Ultrasonography can detect whether the tumour is solid or cystic, and to note if there are satellite lesions. It also describes the relationship of the lesion to the surrounding structures[5]. Information regarding the extent of contact with the underlying tendon and the percentage of circumferential involvement is possible with sonography[5]. GCTTS appears as a solid homogeneous hypoechoic mass on ultrasonography[6]. In GCTTS, FNAC shows a polymorphic population composed of mononuclear histiocyte-like cells, hemo­ siderin-laden macrophages, foamy macrophages and a few multinucleated giant cells[7,8]. FNAC can be used as a diagnostic tool for an early and accurate detection of GCTTS as the cytological features, and clinico-radio­­ logical correlation are sufficiently diagnostic[7,8]. Thus, FNAC helps in preoperative planning to prevent re­ currence [8]. Differential diagnoses of GCTTS include ganglion, lipoma, foreign body granuloma, tophaceous gout, haemangioma, glomus tumour, enchondroma, osteoid osteoma, osteoblastoma, schwannoma, and cir­ cum­s cribed fibromatosis [6]. Due to its location in the

64

extremities, GCTTS also needs to be differentiated from epithelioid sarcoma, synovial sarcoma, clear-cell sarcoma, and rhabdomyosarcoma[7]. Osteoclast-type giant cells are normally absent in each of these four neoplasms, but they are frequently present in GCTTS[7]. We report this case to highlight the role of FNAC in diagnosing GCTTS.

Conflict of interest The authors declare no potential conflict of interest with respect to the research, authorship and/or publication of this article.

References 1. Di Grazia S, Succi G, Fraggetta F, Perrotta RE. Giant cell tumor of tendon sheath: Study of 64 cases and review of literature. G Chir 2013; 34(5–6): 149–152. doi: 10.11138/gchi r/2013.34.5.149. 2. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of the tendon sheath (localised nodular tenosynovitis): Clinicopathological features of 71 cases. J Clin Pathol 2001; 54(5): 404–407. doi: 10.1136/jcp.54.5.404. 3. Byers PD, Cotton RE, Deacon OW, Lowy M, Newman PH, et al. The diagnosis and treatment of pigmented villonodular synovitis. J Bone Joint Surg Br 1968, 50(2): 290–305. 4. Al-Qattan MM. Giant cell tumors of tendon sheath: Classification and recurrence rate. J Hand Surg 2001; 26(1): 72–75. doi: 10.1054/jhsb.2000.0522. 5. Middleton WD, Patel V, Teefey SA, Boyer MI. Giant cell tumors of the tendon sheath: An analysis of sonographic findings. AJR Am J Roentgenol 2004; 183(2): 337–339. doi: 10.2214/ajr.183.2.1830337. 6. Darwish FM, Haddad WH. Giant cell tumour of tendon sheath: Experience with 52 cases. Singapore Med J 2008; 49(11): 879–882. 7. Gupta K, Dey P, Goldsmith R, Vasishta RK. Comparison of cytologic features of giant-cell tumor and giant-cell tumor of tendon sheath. Diagn Cytopathol 2004; 30(1): 14–18. doi: 10.1002/dc.10411. 8. Iyer KV, Kapila K, Verma K. Fine-needle aspiration cytology of giant cell tumor of the tendon sheath. Diagn Cytopathol 2003; 29(2): 105–110. doi: 10.1002/dc.10319.

doi:10.18282/jsd.v7.i1.138


Journal of Surgical Dermatology

Focus and Scope Journal of Surgical Dermatology (JSD) is focused on publishing up-to-date and clinically-relevant information on all dermatological procedures. The Journal aims to play a significant role in reporting cases involving reconstructive and cosmetic skin surgeries, as well as skin cancers. Moreover, reports on scientifically novel topics will be published periodically. All submitted original research articles, reviews, perspectives and case reports will be peer-reviewed and if accepted, will be published as Open Access articles. Some key words for JSD include, but are not limited to: Ambulatory phlebectomy Blepharoplasty Body contouring Botulinum toxin injections Chemical peelings Cryosurgery Dermabrasion and microdermabrasion Dermoscopy Dressing Excisional surgeries Fat injections Flaps Hair transplantation Iontophoresis Laser surgeries Liposuctions

Mechanical resurfacing Mesotherapy Microneedeling technology Micropigmentation Mohs micrographic surgery Nail surgery Phlebology Photodynamic therapy Platelet rich plasma therapy Sclerotherapy Skin cancers Skin grafts Soft tissue augmentation Subcision and acne scar surgery Ultrasound therapy Ultraviolet therapy

About the Publisher PiscoMed Publishing Pte. Ltd. is an international publisher based in Singapore, with operations in China and Malaysia. Since its inception in 2011, PiscoMed has dedicated itself towards advancing medical research and clinical practice worldwide via the publication of high quality literature, aimed at academics and medical practitioners. Our vision is to transform scientific research findings into quality-assessed communications for the continuous dissemination of new knowledge and state-of-the-art discoveries.



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