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Editorial Board Editor-in-Chief Egypt Shahin Aghaei (Iran) Abdelrahman Ezzat Ahmed Hassan El-Sabbagh Amira Mohamed El-Tawdy Dalia Mahmoud Shaaban Eslam Mohamad Alshawadfy Ezzat A. Badawy Hesham Moneer Ahmad Lamia Hamouda Elgarhy Mohamed Abdelraheem Shoeib Mohamed Mahmoud Hegazi Mohamed Makboul Ahmed Makboul Mohammad Ali Gaballah Rami Magdi Makkar Sara Mohamed Ibrahim Awad Serag Monier Zidan Sherif Shoukry Awad Farhana Quyum Nadia Rumman Rahul K. K. Pillai Rajnish Kumar Sanjiv Vijay Choudhary Santhosh Kumar Shamma Aboobacker Shaurya Rohatgi Shehnaz Zulfikar Arsiwala Shricharith Shetty Smriti Naswa Sourabh Jain Suman S. Thakur Sunil Kumar Kothiwala Swapnil Moghe Swetalina Pradhan Vijay Langer Vishal Mago Yuti C. Nakhwa France Iraq Belarus Georgia Dmitry Aleksandrovich Zinovkin James J. Drinane Komenan Kassi Associate Editor Sergio Chimenti (Italy) Editorial Board Members Argentina Julieta Ruiz Beguerie Australia Michael John Inskip Austria Peter P.Wolf Bangladesh Brazil Angelica Rodrigues Araujo Eloisa Leis Ayres Felipe Bochnia Cerci Felipe Ladeira De Oliveira Frederico Hassin Sanchez Kevan Guilherme Nóbrega Barbosa Lee Seng Khoo Mariana Gontijo Ramos Marisa Gonzaga da Cunha Marta Chagas Monteiro Patricia Shu Kurizky Paulo Müller Ramos Rafael Dib Porcides Canada Bahman Sotoodian Behrooz Barikbin Harsharan Pal Singh Ahluwalia Monica KY Li China Bin Chen Bin Li Cheng Feng Zhang Cheng Li Liu Cuiping Guan Hede Yan Li Xiao Li Peiji Wang Wei-Qiang Wen-Jun Xu Xiao-Jing Kang Yi Zhao Yuanjun Liu Yujun Sheng YunPeng Zhao Zhanyu Zhou Croatia Sandra Jerkovic Gulin Denmark Uffe Harboe Nygaard Audrey Gaby Gueniche Germany Armin Kraus Diamant Thaci Lukas Maria Prantl Natalia Glebovna Ilina Eleni Papakonstantinou Greece Aikaterini Tsiogka Christofer K. Tzermias Evangelia Papadavid Ioannis Emmanuel Liapakis Maria Joannis Saridi Hungary Adam Kemeny-Beke India Abhijeet Kumar Jha Ajit Vasant Bellare Amresh Kumar Singh Anil Budania Apratim Goel Arshdeep Ashish Singh Basavraj Saybanna Nagoba Bharat Bhushan Dogra Bhushan Prakashchandra Mundada BN Vedha Hari C. R. V. Narasimhalu Devinder Mohan Thappa Jayabal Pandiaraja Kiran Kaur Lohia Mala Bhalla Manas Ranjan Puhan Mathew P. Alex Murugesan Sankaran Narayan Chanadra Mishra Nikhil Gupta Pooja Arora Pradeep Kumari Raheeqa Razvi Ari Raheem Qader Muhsin Abdulhussein Al-Dhalimi Islamic Republic of Iran Abbas Karimi Ahmad Reza Parhizkar Amir Feily Babak Saedi Farhad Handjani Javad Sharifi-Rad Mohammad Biglari Mohammad Reza Namazi Nasrin Saki Niloofar Mehrolhasani Nooshin Bagharani Pegah Mosannen Mozafari Reza Ghaderi Reza M. Robati Saman Ahmad Nasrollahi Vahid Mashayekhi Goyonlo Zaheer Abbas Israel Avner Shemer Gadi Borkow Marina Landau Tzachi Shelkovitz Vasileios Antonios Pagkalos Italy Andrea Sisti Claudio Feliciani Claudio Guarneri Enrico Valerio Ernesto Maria Buccheri Fabio Guerriero Francesca Duraturo Gennaro Ilardi Giuseppe Cuccia Klaus Eisendle Luca Negosanti Marina Talamonti Matteo Becatti Michelangelo Giovanni Vestita Raffaele Rauso Roberto Amore Journal of Surgical Dermatology Roberto Cuomo Sebastian Torres Veronica Di Fede Vincenzo Nobile Japan Ayumi Yoshizaki Hiromi Baba Keiji Sugiura Robert Katsuhiro Kure Jordan Saja H. Hamed Kuwait Sardar Tanweer A.K. Sindhu Libya Elghblawi S. Ebtisam Lithuania Evelina Buinauskaite Malaysia Aravazhi Ananda Dorai Arman Zaharil Mat Saad Azizan Zalmy Noor Ehfa Bujang Safawi Fahad Saleem Noriah Bidin Primuharsa Putra Sabir Husin Athar Shah Jumaat Mohd. Yussof Taib Tarita Yan Teng Khoo Mexico Judith G. Dominguez-Cherit Mongolia Enkhtur Yadamsuren Morocco Abdelmoughit Echchaoui Awatef Kelati Netherlands Martain Loonen Peter Van De Kerkhof Pakistan Ajmal Rashid Asma Qaiser Qureshi Ghazala Butt Rehan Ud Din Saadullah Khan Poland Adam Reich Jacek Cezary Szepietowski Jerzy Mosiewicz Magdalena Żychowska Mariusz Jaworski Mateusz Cybulski Portugal Maria Lídia Palma Patrick Agostini Vitor Manuel Figueiredo Qatar Mohamed Ibrahim Allam Republic of Korea Beom Joon Kim Cheol Hwan Kim Hei Sung Kim Jung-Im Na Kun Hwang Seung Chul Rhee Vivek Kumar Morya Tak-Wah Wong You-Cheng Hseu Thailand Apirag Chuangsuwanich Chayada Chaiyabutr Kidakorn Kiranantawat Kobkan Thongprasom Romania Tunisia Alin Laurentiu Tatu Olimpiu Ioan Harcega Bouraoui Med Kotti Russian Federation Arif Turkmen Bahar Sevimli Dikicier Berna Aksoy Binnur Tuzun Engin Senel Ersin Aksam Ersin Aydin Hamza Yildiz Handan Handan Kelekçi Ismail Soner Koltas Mahmut Sami Metin Nadir Goksugur Omer Faruk Ozkan Ozgur Yilmaz Ozlem Gundeslioglu Seval Dogruk Kacar Sevil Alan Yelda Dere Zekayi Kutlubay Zekeriya Tosun Irina Sergeeva Yana Aleksandrovna Yutskovskaya Saudi Arabia Abdulhadi Hazzaa Jfri Ahmad Mohammad Al Aboud Esam A. Omar Iqbal Abdulaziz Bukhari Mohammed Ahmed Alsufyani Mohammed Mesfer Alkahtani Nahed A. Farhat Saad Sami Alsogair Salim Ali Algaadi Thamer Fahad Mubki Serbia Jadran Milos Bandic Radmilo Roncevic Singapore Chen Wee Derrick Aw Taige Cao Tanya Mangharam Talreja Turkey United Arab Emirates United Kingdom Ander Mayor-Ibarguren Artur Diaz-Carandell Gabriel Serrano Jean Luc Bernabo Juan Monreal Marta Elena Losa Iglesias Sara Guerrero-Aspizua Aaron Tan Anna Zampetti Maryam Borumand Nicole Yi Zhen Chiang Nikolaos Manoloudakis Mohammed Sami Al Abadie Nigel Yong Boon Ng Sri Lanka United States of America Dulharie Thanuja Wijeratne Ranthilaka Rasika Ranawaka Achih H. Chen Adam Christopher Miller Alan James Durkin Ally-Khan Somani Arash Taheri Beatrice Nardone Chih-Shan Jason Chen Clemens Esche Dean Michael Tomasello Dharanesh M. Gangaiah Edmond Bechir Cabbabe Farhaad Rahman Riyaz George Kroumpouzos Hanjiang Zhu Harina Vin Hend Mohamed Ibrahim Ian Atticus Maher Imran Amir Jack Leonard Arbiser Jennifer T. Haley Jordan D. Frey Ahmed Hassan Fahal Sweden Hamed Hamid Muhammed Karima Akool Al-Salihi Switzerland Bettina Rümmelein Carlo Maria Oranges Mathias Tremp Morteza Seyed Jafari Syrian Arab Republic Ahmad Al Machhour Taiwan Charles Yuen Yung Loh Gwo-Shing Chen Hui-Min Wang Stephen Chu-Sung Hu Vietnam Trung-Hau Le Thua Yemen Mohammad Ali Alshami Managing Editor Yanitha Meena Louis [email protected] Journal of Surgical Dermatology Editorial Office Hasan Ali Spain Sudan Joseph Niamtu III Julie Jefferson Katlein Franca Kaveri Korgavkar Kirsten Carly Webb Lara Devgan Lisa Mask Bull Manal Kamal Abokwidir Marc R. Avram Michael S. Kolodney Ming-Lin Liu Morgan Janelle Mccarty Pauline Raymond-Martimbeau Ravi Shankar Krishnan Robert Evans Bowen Rodney Chan Russel Brent Stokes Sara AlFadil Sheryl Diane Clark Teo Soleymani Thomas Stephen Lisse Journal of Surgical Dermatology April 2016 • Volume 1 • Issue 1 • Pages 1–54 Journal of Surgical Dermatology www.jsurgdermatol.com Contents EDITORIAL 1 From the Desk of the Editor-in-Chief: Welcome to the first issue of the Journal of Surgical Dermatology Shahin Aghaei CORRESPONDENCE 2 Correction of glabellar protrusion after botulinum toxin injection for forehead wrinkles Min Woo Kim, Sihyeok Jang, Hyun-sun Yoon, Soyun Cho, Hyun-sun Park REVIEW 4 Laser therapy for cutaneous sarcoidosis: A review Teo Soleymani, Michael Abrouk CASE REPORT 13 Recurrent verrucous carcinoma of the foot: A case report Jayabal Pandiaraja, Selvaraju Uthayam 16 Trichofolliculoma of the nasal vestibule Tan Shi Nee, Mazita Ami, Mohamad Razif Mohamad Yunus, Primuharsa Putra Sabir Husin Athar 18 Paramedian forehead flap for nasal tip reconstruction after Mohs surgery Felipe Bochnia Cerci 22 Severe local skin reaction after the application of ingenol mebutate gel treated by photodynamic therapy: A case report Luca Negosanti, Rossella Sgarzani, Matteo Santoli, Massimino Negosanti, Nicoletta Banzola, Francesca Negosanti 25 Giant seborrheic keratosis of the face – An unusual presentation Koh Khai Luen, Rashid Shawaltul Akhma, Wan Sulaiman Wan Azman ORIGINAL RESEARCH ARTICLE 29 Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique Laila M Mohammad, Lamia H Elgarhy, Dina G Saad, Walid A Mostafa 37 Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation Sara Majewski, Chantelle Carneiro, Erin Ibler, Peter Boor, Gary Tran, Mary C Martini, Salvatore Di Loro, Alfred W. Rademaker, Dennis P. West, Beatrice Nardone 43 Important aspects of Demodex diagnostics Alexey Kubanov A, Gallyamova Yulia, Anzhela Grevtseva 52 Author Guidelines Journal of Surgical Dermatology doi: 10.18282/jsd.v1.i1.61 EDITORIAL From the Desk of the Editor-in-Chief: Welcome to the first issue of the Journal of Surgical Dermatology Shahin Aghaei Iran University of Medical Sciences, Tehran, Islamic Republic of Iran Received: 18th April 2016; Published Online: 20th April 2016 It is my great pleasure to bring you the first issue of the Journal of Surgical Dermatology (JSD). JSD is a quarterly, Gold Open Access journal that is focused on publishing clinically comprehensive and up-to-date information on dermatological procedures. It has been a gratifying voyage for all of us involved to see the steady progress of the editorial process: starting with the initial assessment of the many articles by myself as the Editor-in-Chief, inviting and selecting section editors and peer reviewers, reviewing the articles, notifying the authors about changes in the manuscripts, advising them regarding revisions, and ultimately making the final decisions on whether or not the manuscripts are acceptable for publication. I would like to thank all the authors whose articles have been chosen for publication in this issue. I would like to express my gratitude to all who were kind enough to submit their manuscripts to JSD, albeit we were unable to accept some of the papers for publication. I thank them for their patience and understanding. There have been occasional technical glitches and small missteps on our part, too, due to the infancy of JSD. For those who submitted without success, our recommendation is to keep writing and submitting. I have to thank the Publisher, the Managing Editor and the Editorial Board Members for their kind support and time to review the manuscripts. I also wish to express, on behalf of everyone involved with JSD, our deep sadness by the news of JSD Associate Editor Prof. Sergio Chimenti’s recent passing. Words cannot express our sorrow. Our long term goal is to ensure that quality dermatological research is made available to individuals who would derive as much as possible for their own pursuits. Every reliable journal wishes to publish papers that are accurate and disseminate valuable information to the right reader to support the development of science. I hope, and know, that JSD, in the near future will inch a little closer to this goal. About the Editor-in-Chief : Assoc. Prof. Shahin Aghaei graduated from Shiraz University of Medical Sciences in 2004. He was awarded a Fellowship of ISD Dermatopathology from Charles University, Prague, Czech Republic, in 2008 and a Fellowship of Dermatologic Surgery from the Medical University of Graz, Austria, in 2010. He is currently an Associate Professor of Dermatology and Dermatologic Surgery at School of Medicine, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran. Copyright © 2016 Aghaei S. 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. 1 doi: 10.18282/jsd.v1.i1.22 CORRESPONDENCE Correction of glabellar protrusion after botulinum toxin injection for forehead wrinkles Min Woo Kim, Sihyeok Jang, Hyun-sun Yoon, Soyun Cho, Hyun-sun Park* Department of Dermatology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea Citation: Kim MW, Jang S, Yoon H, Cho S, Park H. Correction of glabellar protrusion after botulinum toxin injection for forehead wrinkles. J Surg Dermatol 2016; 1(1): 2–3; http://dx.doi.org/10.18282/jsd.v1.i1.22. *Correspondence to: Hyun-sun Park, Department of Dermatology, SMG-SNU Boramae Medical Center, 39, Boramae-Gil, Dongjak-gu, Seoul 156-707, Republic of Korea, [email protected]. Received: 18th December 2015; Accepted: 6th January 2016; Published Online: 16th March 2016 Dear Editor, Botulinum toxin blocks the release of the neurotransmitter acetylcholine and helps treat wrinkles[1]. The efficacy and safety of botulinum toxin injection for upper facial wrinkles were established in several studies[2-4]. Common side effects include transient headache, bruising, eyebrow ptosis and eyelid swelling[5]. No adverse life threatening events or long-term complications have been reported. However, there have been reports on site-specific side effects, except eyebrow ptosis or eyelid swelling. Kang et al. described two cases which showed exaggerated glabellar wrinkles after botulinum toxin injection for forehead horizontal lines. No specific treatment for the exaggeration of wrinkles was carried out and it was left to naturally subside[6]. In the present report, we highlighted the case of a patient whose significant glabellar protrusion was rapidly and effectively corrected with the use of botulinum toxin injection. A 66-year-old female had moderate forehead wrinkles (Figure 1). Botulinum toxin type A (Neuronox Ⓡ , Medytox, Inc., Seoul, Republic of Korea) was diluted with preservative-free sterile saline for a final concentration of 4 units/mL. A total of 6 units were administered by intramuscular injection into the upper half of the forehead (5 injection sites). After one week, forehead wrinkles were reduced. However, glabellar protrusion was noticeable. The patient expressed dissatisfaction on the remaining protrusion and appealed for a rapid solu- tion. Subsequently, an additional 6 units of botulinum toxin were injected into the corrugators (two injection sites). After one week, the protrusion disappeared and the patient was satisfied (Figures 2A and 2B). Figure 1. Maximal forehead wrinkling before treatment (5 injection points marked) Figure 2A. Improved forehead wrinkles with noticeable glabellar protrusion – one week after frontalis treatment Copyright © 2016 Kim MW, 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. 2 Correction of glabellar protrusion after botulinum toxin injection for forehead wrinkles Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References Figure 2B. Disappearance of the glabellar protrusion–one week after additional botulinum injection into the corrugators The frontalis raises the eyebrows and the upper eyelids, causing horizontal forehead lines. Its medial fibers intersect with the procerus at the glabellar region, whereas its central and lateral fibers intermingle with the corrugators in the central and lateral parts[7]. When the upper half part of the muscle is weakened with botulinum toxin for the improvement of forehead wrinkles, the lower half can be relatively hyperactivated. Glabellar protrusion can occur in this case. Previous cases reported the use of other Botulinum toxin type A products (Botox Ⓡ , Allergan, Inc., Irvine, CA, USA) and it was believed that this phenomenon can occur regardless of the product type[6]. Kang et al. reported that mild hyperactivation of corrugators nearly disappeared without treatment by week 4; however, a severe case showed that only slight improvement and significant protrusion persisted by week 4[6]. Therefore, through this observation, proactive treatment of hyperactivated muscles can increase patient satisfaction. Side effects following additional injections of the corrugators, such as eyelid ptosis, could be avoided with proper injection techniques and patients need to be informed of it. Additionally, concurrent injections into the frontalis and corrugators can be considered to prevent expected glabellar protrusion, especially in patients with noticeable corrugator activity, when reducing forehead wrinkles. Clinicians should be aware of this phenomenon and are recommended to explain this prior to treatment for better patient compliance. 1. 2. 3. 4. 5. 6. 7. Blitzer A, Binder WJ, Aviv JE, Keen MS, Brin MF. The management of hyperfunctional facial lines with botulinum toxin. A collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997; 123(4): 389–392. Carruthers A, Carruthers J. Botulinum toxin type A for the treatment of glabellar rhytides. Dermatol Clin 2004; 22(2): 137–144. doi: 10.1016/S0733-8635(03)00071-8. Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dermatol Surg 2003; 29(5): 461–467. doi: 10.1046/j.1524-4725.2003.29114.x. Carruthers JA, Lowe NJ, Menter MA, Gibson J, Nordquist M, et al. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002; 46(6): 840–849. doi: 10.1067/mjd.2002.121356. Rzany B, Dill-Müller D, Grablowitz D, Heckmann M, Caird D. Repeated botulinum toxin A injections for the treatment of lines in the upper face: A retrospective study of 4,103 treatments in 945 patients. Dermatol Surg 2007; 33(s1): S18–S25. doi: 10.1111/j.1524-4725.2006.32327.x. Kang SM, Feneran A, Kim JK, Park O, Kim JE, et al. Exaggeration of wrinkles after botulinum toxin injection for forehead horizontal lines. Ann Dermatol 2011; 23(2): 217–221. doi: 10.5021/ad.2011.23.2.217. Ascher B, Talarico S, Cassuto D, Escobar S, Hexsel D, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) Part I: Upper facial wrinkles. J Eur Acad Dermatol 2010; 24(11): 1278–1284.doi: 10.1111/j.1468-3083.2010. 03631.x. 3 doi: 10.18282/jsd.v1.i1.22 doi: 10.18282/jsd.v1.i1.20 REVIEW ARTICLE Laser therapy for cutaneous sarcoidosis: A review Teo Soleymani1*, Michael Abrouk2 1 The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, USA 2 Department of Dermatology, University of California, School of Medicine, Irvine, California, USA Abstract: Sarcoidosis is a systemic, multi-organ disease of unknown etiology characteristically defined by the development of non-caseating granulomas. The development of sarcoidosis has been associated with a number of environmental and microbacterial factors coupled with genetic susceptibility. Depending on the type, location and distribution of disease, sarcoidosis can cause functional impairment, symptomatic distress, scarring and disfigurement. The advent of lasers as precise, minimally destructive surgical tools has allowed for their development as promising alternatives that minimize the morbidity associated with current therapies. In this paper, we reviewed the role of laser therapy in the treatment of cutaneous sarcoidosis. A comprehensive search of the Cochrane Library, MEDLINE and PUBMED databases was performed to identify relevant literatures investigating the role of laser therapy in the treatment of cutaneous sarcoidosis. In our opinion, laser therapy, particularly PDL, appears to be an effective, safe and generally well-tolerated modality for the treatment of cutaneous sarcoidosis and should be considered in patients with localized cutaneous disease that is refractory to conventional treatments. Less is known about the efficacy and tolerability of ablative laser therapy for the treatment of cutaneous sarcoidosis, though the limited data appears promising as well. With that said, however, the data is limited and warrants a need for additional larger, randomized controlled studies to further invest igate the utility and efficacy of laser therapy in the treatment of cutaneous sarcoidosis. Keywords: Skin cancer; basal cell carcinoma; squamous cell carcinoma; lasers; PDL; ablative lasers; vascular lasers; CO2 laser Citation: Soleymani T and Abrouk M. Laser therapy for cutaneous sarcoidosis. J Surg Dermatol 2016; 1(1): 4–12; http://dx.doi.org/10.18282/jsd.v1.i1.20. *Correspondence to: Teo Soleymani, The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, USA, [email protected] Received: 15th December 2015; Accepted: 25th January 2016; Published Online: 28th March 2016 Introduction Sarcoidosis is a systemic, granulomatous disease of unknown etiology that is characteristically defined by the presence of noncaseating granulomas. While numerous organs may be involved, the skin, lungs and lymph nodes are the most common organs involved. Its pathogenesis is unknown but it is suspected that sarcoidosis develops after exposure to one or more inciting ―trigger‖ antigens in a genetically susceptible individual, resulting in the activation and overstimulation of inflammatory pathways that promote the formation of sarcoidal granulomas[1]. Studies have found an elevated risk of sarcoidosis in individuals who have been exposed to microbial agents and environmental antigens[1-3]. Disease susceptibility is genetically linked to some degree, and several associated genes of the HLA family have been identified[1]. Cutaneous sarcoidosis, the ―great imitator,‖ may stump even the most astute clinicians because of its diversity in manifestation. Copyright © 2016 Soleymani T and Abrouk M. 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. 4 Laser therapy for cutaneous sarcoidosis: A review The prevalence of sarcoidosis varies by geographic location, race and gender. In United States, the disease prevalence is estimated to be between 10–40 cases per 100,000, with a much higher annual incidence in African Americans (35.5–64 cases/100,000) than in whites (10.9–14 cases/100,000)[4-6]. The Scandinavian countries have the world‘s highest prevalence at 50–60 cases per 100,000 whereas the annual incidence in Japan is only one to two cases per 10,000[7,8]. Sarcoidosis is characteristically a multi-organ disease. Cutaneous disease is present in at least 20% of cases and is the initial manifestation in nearly one-third[1,9-11]. Depending on the type, location, and distribution of disease, sarcoidosis can cause functional impairment, symptomatic distress, scarring and disfigurement. Numerous therapeutic options are available for the treatment of cutaneous sarcoidosis but with varying degrees of success. Furthermore, powerful immunosuppressive treatments such as methotrexate and the biologics are not without inherent side effects, including long-term risks of infection, hepatotoxicity and potential malignancy. Since the advent of the first lasers, their use has been expanded tremendously in the field of medicine. What initially precipitated from the need for a better treatment of port wine stain birthmarks (PWS) led to the development of ―selective photothermolysis‖[12,13]. Selective photothermolysis was based on the concept that light passes through space until it is absorbed by a structure which contains light-absorbing molecules that coincide with the delivered wavelength. Intense pulses of light at preferential wavelengths absorbed by these ―target‖ structures will initiate selective thermal damage[12,13]. Confinement of thermal damage within the target lesion is achieved if a laser wavelength with selective absorption and with sufficient but not overwhelming energy is delivered with pulse duration shorter than the time it takes for the target to cool off[12,14]. The advent of lasers as precise, versatile and minimally destructive surgical tools has allowed for their development as an alternative treatment option that minimizes the morbidity associated with current therapies used to treat cutaneous sarcoidosis. In this paper, we reviewed the role of laser therapy in the treatment of cutaneous sarcoidosis. Vascular lasers for treatment of cutaneous sarcoidosis The clinical manifestations of cutaneous sarcoidosis are highly variable and consist of various subtypes including papular, plaque, lupus pernio, scar, psoriasiform, subcutaneous including erythema nodosum, and others. Of importance, lupus pernio is a very commonly presenting variant and is characterized by chronic and violaceous induration with associated telangiectasias, found predominantly on the nose and cheeks, that can often progress into disfiguring ulcerative nodular plaques on the nose and cheeks[1,15,16]. Lupus pernio can produce considerable disfigurement with significant morbidity and is often associated with chronic, progressive multi-organ systemic disease[1,15,16]. Notably, lupus pernio is frequently resistant to both topical and systemic immunosuppressive therapy[1,16,17]. The presence of increased vasculature and telangiectatic vessels are classic clinical features of lupus pernio[1,15-17]. These microscopic vessels are both ectatic and fragile, making them an ideal target for selective photodamage. It has been hypothesized that vascular selective lasers such as pulsed dye lasers (PDL) can be used to selectively target a structure‘s vascular supply. The flashlamp-pumped pulsed dye laser was the first laser specifically developed for the treatment of vascular lesions and works based on the principle of selective photothermolysis as described above. The current PDL is able to vary different parameters such as spot size, pulse duration and energy fluence, which has increased in recent years because of the development of protective cooling systems. The most frequently used wavelengths are 585 and 595 nanometers (nm), allowing the penetration depth to be a maximum of 1.5–2 mm. The potential advantage of photothermal vascular targeting over conventional excisional treatments is greater preservation of surrounding normal tissue. By selectively targeting the aberrant vasculature in lupus pernio, this approach may be an effective treatment alternative in order to minimize morbidity. It is important to note, however, that although it has been theorized that PDL treatment specifically targets blood vessels, this has not been definitely proven. Furthermore, high energies are often used (compared to, for example, treatment of telangiectasias) in combination with multiple passes and in some cases, without epidermal cooling, which may result in the injury being non-selective. Although the data is limited, several studies have investigated the role of vascular selective PDL therapy for the treatment of cutaneous sarcoidosis. The first ever reported case of laser treatment for lupus pernio came from the Department of Dermatology and Beckman Laser Institute at the University of California, Irvine in 1992[18]. A 39-year-old Caucasian woman with a 5-year history of stable, diffuse, violaceous erythema with scattered granulomatous papules limited to the nose was treated with 1 pass of PDL utilizing a 585 nm wave- 5 doi: 10.18282/jsd.v1.i1.20 Soleymani T and Abrouk M length, 5 mm spot size, 0.46 ms pulse duration at a fluence of 5–8 J/cm2[18]. There was no mention of cooling or anesthesia used. At the 4-week follow-up visit, significant fading of the erythema was noted with greatest improvement at areas that received 8 J/cm2[18]. There was no atrophy, scarring or hypopigmentation reported and the patient was pleased with the cosmetic outcome. The authors noted regression in the papular components of her pernio as well[18]. The authors reported that a second full treatment session was necessary after 7 months due to the recurrence of erythema and papules, upon which at 6-month follow-up after the second treatment, a 75% overall improvement over baseline was observed[18]. As a result from the follow-ups, the authors observed that great improvements were seen for 6–10 months after each laser treatment. However, the laser effects were temporary, which was unsurprising in a chronic granulomatous inflammatory disease. The authors concluded that performing laser treatments at periodic intervals would be an acceptable, safe and well-tolerated treatment option to provide significant improvement in the appearance of lupus pernio [18]. The second reported case of laser treatment for cutaneous sarcoidosis was published several years later in 1999[19]. In this report, a 62-year-old Caucasian woman presented with biopsy-proven lupus pernio defined clinically by violaceous induration and blanchable erythema with ectatic telangiectasias limited to the nose. The patient underwent six treatments of 585 nm PDL, each spaced 6 weeks apart, utilizing a single pass with 5-mm spot size at an average of 6.6 J/cm2[19]. There was no mention of pulse duration and no cooling or anesthesia was used. The authors reported a dramatic cosmetic improvement at the end of the 6 sessions with no evidence of scarring, atrophy or other cosmetic side effects[19]. Remarkably, a repeat biopsy from the nose taken from an area that demonstrated cosmetic improvement after laser treatment showed a paucity in vascularity within the superficial dermis compared to the initial biopsy but with a persistence of noncaseating epitheliod granulomas within the deep dermis[19]. The authors concluded that this finding was not unexpected, as the pulsed dye laser treatment likely resulted in selective thermolysis of blood vessels within the papillary and reticular dermis, which in turn reduced the clinically visible erythema but did not affect the granulomatous process. In another similar case, a 63-year-old Caucasian woman with biopsy-confirmed cutaneous sarcoidosis defined clinically by progressively enlarging erythematous nodules on her back underwent 585 nm PDL treatment using a 12 mm spot size, 0.5 ms pulse duration at 6 J/cm2. There was no mention of cooling or anesthesia. After 4 weeks, there was complete resolution of the nodules; however, subtle persistent erythema remained[20]. The patient‘s sarcoidosis remained active and the patient subsequently required systemic corticosteroid treatment with prednisone for developing necrobiosis lipoidica and iridocyclitis of her eyes. Consequently, her ocular findings and necrobiosis lipoidica resolved with steroid treatment; importantly, there was no recurrence of new nodular lesions or of the original lesions that had completely resolved through laser treatment before starting prednisone, and the patient remained free of nodular lesions 13 months after the steroids were discontinued, indicating that primary efficacy was derived from the laser treatment and not from steroids[20]. Scar sarcoidosis is characterized by the infiltration of noncaseating sarcoidal granulomas in surgical scars, tattoos, skin piercings and other sites of trauma[1]. Scar sarcoid may be difficult to be distinguished clinically from a granulomatous foreign body reaction in a scar, hypertrophic scars, keloids, or other similarly appearing cutaneous conditions. Scar sarcoid is often refractory to topical and intralesional therapies and surgical excision provides only variable success and is often associated with significant morbidity. A recently published case reported the first successful treatment of pediatric scar sarcoidosis with PDL. In this case, a 10-year-old Caucasian boy presented with a 4-year history of a 1.0 cm × 1.0 cm isolated inflammatory, violaceous, ulcerated plaque on the left buccal cheek that had developed at the site of a previous atrophic scar secondary to a primary VZV infection at age six. The lesion was biopsied and confirmed to be scar sarcoid with no evidence of polarizing foreign body material, mycobacteria or fungal infections. The patient underwent PDL treatment utilizing a 595 nm wavelength, 7 mm spot size, 0.5 ms pulse duration at a fluence of 7.7 J/cm2[21]. Cold air cooling was provided using an air-cooling device at setting 3 (SmartCool, Cynosure)[21]. Two to four pulses were delivered per session and neither pulse stacking nor double passing was used[21]. The patient received three treatments, given at 6-week intervals. No local anesthetics or systemic analgesics were needed during laser treatment[21]. The authors reported that immediately after treatment, mild to moderate purpura was observed, followed by minimal crusting[21]. After the first two treatments, the authors observed significant flattening of the lesion; after three treatments, complete clearance was achieved[21]. The authors reported that the treatments 6 doi: 10.18282/jsd.v1.i1.20 Laser therapy for cutaneous sarcoidosis: A review were well tolerated and no treatment associated side effects were noted. At one-year follow-up, there was no evidence of lesion recurrence, although the varicella scar became much more visible after the sarcoidosis resolved[21]. One of the biggest shortcomings of PDLs is the shallow depth of penetration: pulsed dye lasers penetrate up to 2 mm into the skin with yellow light wavelengths that are strongly absorbed by both oxyhemoglobin and deoxyhemoglobin[22]. Other vascular targeting wavelengths allow greater depths of penetration to target deeper vasculature. Lasers such as long-pulsed 1064 nm Nd: YAG and 755 nm Alexandr ite lasers penetrate 50% – 75% deeper into the skin than PDL. Additionally, the conversion of oxyhemoglobin to methemoglobin after irradiation with PDL creates a second target chromophore for the Nd:YAG laser. However, these lasers have a much lower absorption coefficient in blood than PDL, requiring use of higher fluences[23]. In a more recently published study, a 57-year-old Caucasian woman with a 17-year history of biopsy-confirmed cutaneous sarcoid defined clinically as lupus pernio by violaceous infiltrating plaques on her cheeks was treated with two sessions spaced 7 months apart with frequency-doubled Nd:YAG at a wavelength of 532 nm, using a 50 ms pulse duration at 12–16 J/cm2[23]. There was no mention of spot size or cooling. After the second treatment, the patient had near complete resolution of her violaceous erythema, and follow-ups for three years demonstrated no sign of relapse[23]. There was no evidence of atrophy, hypo- or hyperpigmentation, scarring or other side effects related to treatment [23]. This presents a notable finding: compared to the cases mentioned above which were treated using PDL, this patient experienced much longer lasting treatment efficacy with the utilization of Nd:YAG. This may be attributed to the greater depth of penetration of Nd:YAG lasers compared to PDL, resulting a more efficient targeting and selective photothermolysis of deeper vasculature, and/or attributed to the use of much higher fluences in this Nd:YAG case compared to the PDL cases mentioned above (Nd:YAG lasers have a lower absorption coefficient than PDL, thus inherently requiring the use of higher fluences, as mentioned earlier). However, it would be premature to draw any definitive conclusions on comparative efficacy between PDL and Nd:YAG as these are only case reports and much larger randomized controlled trials would be needed to make a decisive conclusion. Ablative lasers for treatment of cutaneous sarcoidosis Ablative lasers, consisting primarily of carbon dioxide (CO2) and Erbium Yittrium Aluminum Garnet (Er:YAG) lasers, have wavelengths that lie within the infrared range (10600 nm and 2940 nm, respectively) and thus target tissue water as the intended chromophore[24]. Although many describe ablative lasers as ―selective‖ given that water is the targeted chromophore, it is important to understand that these lasers work by ablating tissue through vaporization of tissue water. Their precision lies in the minimization of ―spillover‖ damage of tissue not in the treatment area. Delivery of high fluences with short pulse duration allows for a more precise control of tissue vaporization with minimal non-specific thermal damage to surrounding tissue. For CO2 lasers, depth of tissue ablation is superficial, in the 20 µm range[24-26]. At depths where adequate fluence is reached for heat vaporization of water, tissue is precisely ablated. At deeper depths, fluence drops and tissue is no longer vaporized but is instead coagulated, which provides associated hemostasis and collagen synthesis stimulation[24]. For Er:YAG lasers, depth of tissue ablation is even more superficial, approximately 2 µm in depth[27]. The water affinity of the Er:YAG laser is roughly 15 times greater than that of the CO2 laser[24], which allows for greater tissue vaporization but minimal coagulation. Hemostasis and, to a lesser extent, collagen stimulation are significantly reduced with Er:YAG as compared to CO2 lasers[24]. In the first ever published case series investigating the role of ablative CO2 laser resurfacing for the treatment of cutaneous sarcoidosis, two patients with longstanding and gross disfiguring lupus pernio refractory to medical therapy were treated with ablative CO2 laser with excellent subsequent post-operative outcomes[28]. The first patient was a 37-year-old Afro-Caribbean woman who presented with a 20-year history of progressively disfiguring lupus pernio of her nose that was refractory to medical therapy. The patient had significant concomitant progressive systemic disease. She underwent CO2 laser ablation scanning back and forth repeatedly with the defocused manual hand-piece at 20–25 W continuous wave to produce even removal without deep dermal injury[28]. There was no specific mention of model, spot size, pulse duration or fluence for the first patient in this case series. Treatment was continued until a natural nasal profile was achieved. The authors reported an excellent response to treatment that was maintained for 7 years post-operatively, without further re-treatment[28]. The second patient was a 52-year-old Afro-Caribbean woman who initially presented with a three-month history of disfiguring lupus pernio limited to her nose. Unlike the first patient, this patient did not have conco- 7 doi: 10.18282/jsd.v1.i1.20 Soleymani T and Abrouk M mitant systemic disease. The patient underwent a trial of medical management including topical, intralesional and systemic immunosuppressive therapy (duration unknown), to which no response resulted and her nasal lesions progressed, prompting a trial of CO2 laser ablation. For this patient, the authors used the Sharplan Silk Touch Flashscanner™ CO2 laser attachment and resurfacing hand-piece (Sharplan Laser Industries Ltd, Israel; distributed by medical equipment distributors Litechnica Ltd, Heston, Middlesex, UK) on repeat pulse (pulse duration 0.2 s) at 4 mm spot size, 19 J/cm2 and 6 mm spot size, 18 J/cm2, respectively[28]. Treatment was continued until a natural nasal profile was achieved[28]. For this patient as well, the authors reported an excellent post-operative outcome with no lesion recurrence over a 32-month follow-up period (as of publication of the case series, the patient‘s follow-up was being continued)[28]. The authors did not report any evidence of side effects such as atrophy, hypo- or hyperpigmentation, or scarring in either patient[28]. A more recently published case series investigating the role of CO2 laser therapy for the treatment of cutaneous sarcoidosis reported three patients with biopsy-confirmed cutaneous disease limited to the nose who underwent treatment with a CO2 laser (ESC/Sharplan 40C) utilizing a 6 mm spot size at 18 W in ‗paint mode‘ under local anesthetic[29]. There was no mention of pulse duration or cooling. Additionally, the epidermis in patient 1 and patient 3 was ablated for cosmetic reasons using a subsequent resurfacing pass with the CO 2 laser with a 6-mm spot size at 14 W in ‗feather mode‘[29]. Residual lesional tissues at the wound base was present in patient 1 and patient 3 and were injected intralesionally with triamcinolone acetonide (TAC) 5 mg/mL in an attempt to prevent recurrence. Patient 1, a 55-year-old Indian woman with a 4-year history of biopsy-confirmed nasal lupus pernio maintained results 6 years after treatment with the desired contour and only subtle hypopigmentation observed over the treated area[29]. Patient 2, a 57-year-old white male with a two-year history of biopsy-confirmed cutaneous sarcoidosis was treated for a nodule on the nasal bridge. The new nasal contour remained stable when last examined 14 months after treatment[29]. There was an 8 mm pale, pink, slightly atrophic scar visible at treatment site. Patient 3, a 58year-old Afro-Caribbean woman with a 10-year history of biopsy-confirmed sarcoidosis was treated for nasal lesions of lupus pernio. She obtained good cosmetic result with CO2 laser remodeling and maintained this for more than nine months[29]. Combination lasers for treatment of cutaneous sarcoidosis Combination therapies can be utilized to improve treatment efficacy and/or cosmesis, particularly when attempting to simultaneously treat various cutaneous topographic features such as erythema, telangiectasias, nodules and hypertrophy. This can be particularly beneficial when treating conditions that have both epidermal and dermal components in disease pathology. In a recently published case, a 54-year-old Caucasian woman with a 9-year history of biopsy-proven cutaneous sarcoidosis defined clinically by papular, erythematous to violaceous plaques on the elbows, knees, and dorsum of the nose underwent treatment with an intense pulsed light system (Photoderm-Vasculight) utilizing a 590 nm cutoff-filter in combination with 1064 nm Nd:YAG laser utilizing a double pulse (T1: 2.8ms, T2: 2.8ms, no mention of spot size) at 37 J/cm2 delivered with 20 ms delay between pulses[30]. No cooling or anesthesia was used. The sessions were conducted over a two year period but there was no specific mention of the interval duration between treatments. In each session, the energy was slightly increased up to a fluence of 45 J/cm2[30]. After the final treatment, the patient exhibited near-complete resolution of her lupus pernio with excellent cosmetic outcome without any treatment-associated side effects[30]. The patient remained asymptomatic without recurrence at the two-year follow-up without any further treatment. A more recently published paper reported a case of lupus pernio refractory to topical, oral and intralesional corticosteroids as well as oral hydroxychloroquine and allopurinol treated with combination PDL and non-ablative fractional CO2 laser[31]. No specific patient demographics or past medical history were reported. The patient was treated using a combined laser therapy with PDL and non-ablative fractional resurfacing. PDL was utilized at 595 nm performed first in single pulses using a 7 mm spot size with approximately 10% overlap, 0.45 ms pulse duration, and 8 J/cm2 fluence[31]. Anesthesia was 30% lidocaine ointment under plastic wrap occluded for 90 min before the procedure, and there was no mention of cooling. Immediately after PDL laser treatment, non-ablative CO2 fractional resurfacing was performed with the Fraxel Dual laser 1550 nm at 70 mJ, treatment level 6, with 8 passes[31]. There was no mention of spot size, pulse duration or cooling. Ice packs were applied for 10 min after the procedure[31]. Prophylactic hydroquinone 4% cream was applied twice daily for two weeks prior to the procedure and one week after the pro- 8 doi: 10.18282/jsd.v1.i1.20 Laser therapy for cutaneous sarcoidosis: A review cedure for the prevention of dyschromias. The authors reported significant cosmetic improvement after the first procedure, which became more apparent in the following months. Improvement was maintained for 6 months of follow-up[31]. There was no mention of any reported side effects such as atrophy, hyper- or hypopigmentation, scarring or return of pernio. Table 1 illustrates a comprehensive technical case summary of laser therapy for the treatment of cutaneous sarcoid. Table 1. Comprehensive technical case summary of laser therapy for the treatment of cutaneous sarcoid Author Demographics Number of Wavelength treatments Spot Size Pulse Duration Goodman et al.[18] PDL One pass, two sessions 585 nm 5 mm Biopsyproven lupus pernio PDL 6 sessions 585 nm 63-year-old white female Biopsyconfirmed cutaneous sarcoidosis PDL None reported Holzmann et al.[21] 10-year-old white male Biopsyconfirmed scar sarcoid PDL Ekback et al.[23] 57-year-old white woman 17-year history of biopsyconfirmed cutaneous sarcoid Nd: YAG Diagnosis Laser 39-year-old white female 5 year hx of stable, diffuse, violaceous erythema with scattered granulomatous papules limited to the nose Cliff et al.[17] 62-year-old white female Roos et al.[20] Fluence Cooling and Anesthesia 0.46 ms 5–8 J/cm2 None reported 75% improvement over baseli ne None reported Great improvements were seen for 6–10 months after treatment 5 mm none reported 6.6 J/cm2 None reported "Dramatic cosmetic improvement" None reported A repeat biopsy from the nose taken from an area that demonstrated cosmetic improvement after laser treatment showed a paucity in vascularity within the superficial dermis compared to the initial biopsy but a persistence of noncaseating epitheliod granulomas within the deep dermis 585 nm 12 mm 0.5 ms 6 J/cm2 None reported Complete resolution of nodules Subtle persistent erythema Free of nodular lesions 13 months after systemic corticosteroids were discontinued Three sessions 595 nm 7 mm 0.5 ms 7.7 J/cm2 Cold air cooling, no local or systemic anesthesia Complete clearance after third treatment Mild to moderate purpura, minimal crusting No evidence of lesion recurrence at one-year follow-up Two sessions 532 nm None reported 50 ms 12–16 J/cm2 None reported Near complete resolution None reported Follow-ups for three years demonstrated no sign of relapse Results Side Effects Follow-up (To be continued on the next page) 9 doi: 10.18282/jsd.v1.i1.20 Soleymani T and Abrouk M (Continued) Author Wavelength Spot Size Pulse Duration Two sessions 10600 nm 6 mm None reported 18 W Local anesthetic, no cooling reported Desired outcome achieved Subtle hypopigpopigmentatio n 6 years after treatment, desired outcome was maintained CO2 One session 10600 nm 6 mm None reported 18 W Local anesthetic, no cooling reported Desired outcome achieved 8 mm pale, pink, slightly atrophic scar visible at treatment site 14 months after treatment, outcome remained stable 10-year history of biopsyconfirmed sarcoidosis CO2 Two sessions 10600 nm 6 mm None reported 18 W Local anesthetic, no cooling reported Good cosmetic result None reported Results maintained for more than 9 months None reported PDL One session 595 nm 7 mm 0.45 ms 8 J/cm2 None reported Improvement maintained at 6-month follow-up Fraxel 1 session with 8 passes immediately following PDL 1550 nm None reported None reported 70 mJ IPL None reported 590 nm None reported None reported None reported 1064 nm None reported Demographics Diagnosis Laser 55-year-old Indian woman 4-year history of biopsy-confirme d nasal lupus pernio CO2 57-year-old white male Two-year history of biopsy-confirme d cutaneous sarcoidosis 58-year-old Afro-Carribean woman None reported O'Donoghue et al.[29] Number of treatments Fluence Emer et al.[31] 54-year-old white woman Rosende et al.[30] Young et al.[28] 9-year history of biopsy-proven cutaneous sarcoidosis Nd:YA G Cooling and Anesthesia Results Anesthesia Improvewas 30% ment noted lidocaine after the ointment first under plastic procedure wrap occluded for 90 min before the procedure. There was no mention of cooling. Ice packs were applied 10 min after procedure Side Effects Follow-up None reported After final treatment there was near complete resolution with excellent cosmetic outcome None reported Asymptomatic without recurrence at 2-year follow-up Double 37 J/cm2 pulse T1: 2.8 ms T2: 2.8 ms 20 ms delay between pulses 37-year-old Afro-Caribbean woman 20-year history of biopsyconfirmed nasal lupus pernio CO2 Numerous passes, one session 10600 nm None reported None reported 20–25W Local anesthetic, no cooling reported "Excellent cosmetic outcome" None reported Improvement maintained at 7-year follow-up 52-year-old Afro-Caribbean woman Unclear duration of biopsy-confirme d nasal lupus pernio CO2 Numerous passes, one session 10600 nm 4 mm, 6 mm 0.2 s 18–19 J/cm2 Local anesthetic, no cooling reported "Excellent cosmetic outcome" None reported Results maintained at 32-month follow-up, follow-up still ongoing. 10 doi: 10.18282/jsd.v1.i1.20 Laser therapy for cutaneous sarcoidosis: A review Conclusion References In conclusion, laser therapy, particularly PDL, appears to be an effective, safe and generally well-tolerated modality for the treatment of cutaneous sarcoidosis. Less is known about the efficacy and tolerability of ablative laser therapy for the treatment of cutaneous sarcoidosis, though the limited data appears promising as well. It is important to note that although these outcomes show potential, the data is limited, hence requiring further investigation with a greater number of patients. While these laser treatments provide an excellent option for cutaneous sarcoidosis, potential complications should be considered. The most common immediate side effects of PDL are erythema and mild edema, and long term complications consist mainly of hyper- or hypopigmentation and atrophic scarring, though these are often transient. For ablative lasers such as CO2 and Er:YAG, common immediate side effects include oozing, bleeding and crusting while long term side effects consist of hyper- or hypopigmentation, scarring and secondary bacterial or fungal infection. In our analysis of the literatures, the vast majority of complications after laser therapy were minimal, consisting primarily of mild pigmentary changes. Also, it is important to note that although the vast majority of literatures indicate an improvement of cutaneous disease after laser treatment, a few reports have described a new development or worsening of cutaneous sarcoidosis after laser treatment [32,33]. Given that the guidelines for the treatment of cutaneous sarcoidosis remain undefined as no high-powered randomized controlled trials have been conducted to establish them (as is the case with conditions such as psoriasis, for example), dermatologists are left to utilized their expert judgement to tailor individual treatment based on disease severity, related comorbidities, and possible adverse outcomes. In our opinion, laser therapy for the treatment of cutaneous sarcoidosis appears to be an effective, safe and generally well-tolerated treatment modality and should be considered for patients with localized cutaneous disease that is refractory to conventional treatments. However, expert discretion should be utilized. Additional randomized controlled studies are needed to further investigate the utility and efficacy of laser therapy in the treatment of cutaneous sarcoidosis. 1. Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: A comprehensive review and update for the dermatologist: Part I. Cutaneous disease. J Am Acad Dermatol 2012; 66(5): 699.e1–699.e18; quiz 717–718. doi: 10.1016/j.jaad. 2011.11.965. Brownell I, Ramirez-Valle F, Sanchez M, Prystowsky S. 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Arch Dermatol 2001; 137(4): 507–508. 12 doi: 10.18282/jsd.v1.i1.20 doi: 10.18282/jsd.v1.i1.7 CASE REPORT Recurrent verrucous carcinoma of the foot: A case report Jayabal Pandiaraja*, Selvaraju Uthayam SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India Abstract: Verrucous carcinoma is an uncommon, locally invasive and slow growing squamous cell carcinoma of the skin and mucous membrane. The proposed causative agent for verrucous carcinoma is human papillomavirus (HPV). It has low metastatic potential compared to squamous cell carcinoma. This is a report of a 75-year-old male admitted with history of growth over the forefoot. Histopathological examinations confirmed verrucous carcinoma and the patient underwent forefoot amputation with 2 cm clear surgical margin. During the 4th month of follow-up, the patient developed a lesion at the post-operative site which was proven as a recurrence. Even though it carried low metastatic potential, it needed repeated resection or amputation because of high local recurrence. Keywords: Forefoot; recurrences; amputation Citation: Pandiaraja J and Uthayam S. Recurrent verrucous carcinoma of the foot: A case report. J Surg Dermatol 2016; 1(1): 13–15; http://dx.doi.org/10.18282/jsd.v1.i1.7. *Correspondence to: Jayabal Pandiaraja, 26/1, Kaveri Street, Rajaji Nagar, Villivakkam, Chennai, Tamil Nadu, India, dr.pandiaraja@ gmail.com Received: 22nd November 2015; Accepted: 14th January 2016; Published Online: 16th March 2016 Introduction Verrucous carcinoma is an uncommon, low grade squamous cell carcinoma affecting the skin and mucous membrane[1]. The reported incidence of verrucous carcinoma varies, mostly affecting males in their fifties. Among the numerous proposed causes for verrucous carcinoma, the most prominent is the human papillomavirus (HPV). Verrucous carcinoma has a favorable prognosis because of its low risk of distant metastasis. There are multiple variants of verrucous cell carcinoma. It can occur in the oropharynx, perianal region and lower limb, including the foot[2]. Case report A 74-year-old male was admitted with complaints of growth over the plantar aspect of the left foot for 5 months. The patient had a history of occasional bleeding in the growth for 5 months. There was no history of loss of appetite and weight loss. The patient was a non-alco- holic and non-smoker with no previous history of papilloma or wart excision. Local examination showed proliferative growth of 3 × 2 cm in the plantar aspect of the left foot, in between the great toe and the third toe. Palpation growth was hard in consistency and tenderness was present (Figure 1). Lymph node examination showed no inguinal lymphadenopathy. An edge biopsy from the ulcer showed squamous cells with papillary projections. The supporting stoma was non-reactive with the appearance of benign keratinocytes (Figure 2). High quality magnetic resonance imaging (MRI) showed a lesion of 3 × 2 cm located on the plantar aspect of the left foot with deep tissue involvement without bony invasion. Pre-operative diagnosis was made as verrucous carcinoma with deep tissue involvement and the patient underwent forefoot amputation with 2 cm clear margin. Histopathology of resected specimen confirmed verrucous carcinoma with clear margin. During the fourth month of follow-up, patient developed proliferative lesion on the forefoot amputation site (Figure 3). Biopsy from the lesion showed recurrent Copyright © 2016 Pandiaraja J and Uthayam S. 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. 13 Recurrent verrucous carcinoma of the foot: A case report verrucous carcinoma. Patient underwent below knee amputation because of the recurrence. Figure 1. Proliferative growth of 3 × 2 cm in the plantar aspect of the left foot, in between the great toe and the third toe Figure 2. An edge biopsy from the ulcer showed squamous cells with papillary projections. The stoma is mostly non-reactive with benign keratinocytes (H and E, ×400) Discussion Verrucous carcinoma usually appears as a raised, white cauliflower-like mass. It usually occurs in the oral cavity and genital region. When lesion occurs on the foot, it mostly occurs in the forefoot[3]. As the tumor grows, it invades locally and involves the plantar fascia or the destruction of the metatarsal bones[4]. DNA of HPV serotypes 6, 11, 16 and 18 have been identified in verrucous carcinoma specimens[5]. Histopathology shows squamous cells with papillary projections. The stoma is usually non-reactive. Keratin pearls are uncommon in verrucous carcinoma compared to squamous cell carcinoma[2]. Sometimes it may show infiltration of inflammatory cells[6]. Multiple deep biopsies are mandatory for proper diagnosis because superficial biopsy could produce false negative results. There are numerous differential diagnoses for verrucous carcinoma including both benign and malignant conditions. It is mandatory to differentiate other differential diagnoses because treatment differs for each diagnosis[6]. The lower limb is a rare site for cancerous lesions. It is very difficult to differentiate between benign and malignant lesions when it occurs in the lower limb. Preoperative imaging is mandatory in order to decide the extension of resection or amputation because verrucous carcinoma has high propensity for recurrence. For soft tissue invasion of the foot, MRI is the best investigative method. However, in suspected bony invasion or high risk cases, computed tomography (CT) scores better compared to MRI[7]. The accepted treatment for verrucous carcinoma is local excision with clear margin. It is very difficult to determine the exact macroscopic margin during surgery because of the destruction of adjacent tissues by the growth[8]. Amputations are only indicated when there is extensive deep tissue involvement, aggressive invasive disease, limb with compromised blood supply, massive wound defect, secondary wound infections, and tumor recurrences secondary to incomplete excision[9,10]. Electrodessication, cryotherapy and laser ablation mostly cause recurrences. Conclusion Figure 3. During follow-up, patient developed proliferative lesion on the forefoot amputation site Verrucous carcinoma is an uncommon, highly invasive and slow growing squamous cell carcinoma. Even though it rarely metastasizes, it has high local recurrence. Patients may require amputation because of the local recurrence. Amputations are more likely to be preferred when there is soft tissue or bone involvement. This case 14 doi: 10.18282/jsd.v1.i1.7 Pandiaraja J and Uthayam S report highlights an important feature of verrucous carcinoma–that local recurrence can occur in verrucous carcinoma when there is soft tissue involved even with amputation. 6. Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. 7. References 1. 2. 3. 4. 5. Hassona Y, Scully C. Verrucous tongue lesion. N Engl J Med 2015; 372(21): 2049. doi: 10.1056/NEJMicm1408030. Alkan A, Bulut E, Gunhan O, Ozden B. Oral verrucous carcinoma: A study of 12 cases. Eur J Dent 2010; 4(2): 202 –207. Lesic A, Nikolic M, Sopta J, Starcevic B, Bumbasirevic M, et al. Verrucous carcinoma of the foot: A case report. J Orthop Surg (Hong Kong) 2008; 16(2): 251–253. Pempinello C, Bova A, Pempinello R, Luise R, Iannaci G. Verrucous carcinoma of the foot with bone invasion: A case report. Case Rep Oncol Med 2013; 2013: e135307. doi: 10.1155/2013/135307. Samman M, Sethi N. Oral verrucous pre-malignant lesions 8. 9. 10. and HPV. Clin Otolaryngol 2015; 40(3): 292–293. doi: 10.1111/coa.12374. Santoro A, Pannone G, Contaldo M, Sanguedolce F, Esposito V, et al. A troubling diagnosis of verrucous squamous cell carcinoma (“the bad kind” of keratosis) and the need of clinical and pathological correlations: A review of the literature with a case report. J Skin Cancer 2010; 2011: e370605. doi: 10.1155/2011/370605. García-Gavín J, González-Vilas D, Rodríguez-Pazos L, Sánchez-Aguilar D, Toribio J. Verrucous carcinoma of the foot affecting the bone: Utility of the computed tomography scanner. Dermatol Online J 2010; 16(2): 8. Miller SB, Brandes BA, Mahmarian RR, Durham JR. Verrucous carcinoma of the foot: A review and report of two cases. J Foot Ankle Surg 2001; 40(4): 225–231. doi: 10.1016/S1067-2516(01)80022-3. Suen K, Wijeratne S, Patrikios J. An unusual case of bilateral verrucous carcinoma of the foot (epithelioma cuniculatum). J Surg Case Rep 2012; 2012(12): 1–3. doi: 10.1093/ jscr/rjs020. Yoshitatsu S, Takagi T, Ohata C, Kozuka T. Plantar verrucous carcinoma: Report of a case treated with Boyd amputation followed by reconstruction with a free forearm flap. J Dermatol 2001; 28(4): 226–230. doi: 10.1111/j.1346- 8138.2 001.tb00122.x. 15 doi: 10.18282/jsd.v1.i1.7 doi: 10.18282/jsd.v1.i1.13 CASE REPORT Trichofolliculoma of the nasal vestibule Tan Shi Nee1*, Mazita Ami2, Mohamad Razif Mohamad Yunus3, Primuharsa Putra Sabir Husin Athar2 Department of Otorhinolaryngology – Head & Neck Surgery, School of Medicine, KPJ Healthcare University College, Negeri Sembilan, Malaysia Ear, Nose & Throat – Head & Neck Consultant Clinic, KPJ Klang Specialist Hospital/ KPJ Healthcare University College, Negeri Sembilan, Malaysia 3 Department of Otorhinolaryngology – Head & Neck Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia 1 2 Abstract: The presence of a nasal vestibule mass can be challenging in obtaining diagnosis and treatment due to the features of nasal vestibule. There are various types of diseases that can involve the nasal vestibule. Here, we presented the case of a patient with swelling of the right nasal vestibule and was incidentally diagnosed histopathologically as trichofolliculoma, a rare skin lesion. We discussed the characteristics of trichofolliculoma disease and presented a diagnosis, necessary treatment of this case and related literature review. Keywords: Nasal; vestibule; trichofolliculoma; skin Citation: Tan SN, Ami M, Mohamad Yunus MR, Sabir Husin Athar PP. Trichofolliculoma of the nasal vestibule. J Surg Dermatol 2016; 1(1): 16–17; http://dx.doi.org/10.18282/jsd.v1.i1.13. *Correspondence to: Tan Shi Nee, Department of Otorhinolarygology – Head & Neck Surgery, School of Medicine, KPJ Healthcare University College, Lot PT 17010, Persiaran Seriemas, Kota Seriemas, 71800, Nilai, Negeri Sembilan, Malaysia, [email protected]. Received: 1st December 2015; Accepted: 15th February 2016; Published Online: 16th March 2016 Introduction Materials and methods The anterior part of nasal cavity is the nasal vestibule. It is lined by keratinized squamous epithelium and has components such as sebaceous and sweat glands[1]. There are various forms of pathologic lesions that may be benign, malignant or caused by infectious diseases that can occur in the vestibule due to histological differences. Trichofolliculoma arising from hair follicles is a rare, benign skin lesion and was described initially by Miescher in 1944[2]. It is a hamartomatous lesion of hair follicle origin which differentiates between a trichoepithelioma and a hair follicle nevus[3]. This condition may often be misdiagnosed as a sebaceous cyst, basal cell carcinoma or nevus. We presented the case of a patient with mass on the right nasal ala. A 66-year-old male was presented to our ear, nose and throat clinic. Patient complained of right nasal vestibule mass for the past three months. He had no underlying medical illnesses. Clinical examinations showed the presence of right nasal ala swelling. The mass had gradually increased in size over a few years. Diagnostic nasal endoscopic examination did not reveal any abnormality and patient’s family history did not reveal any similar condition. No other similar lesion was seen in other parts of his body. Results An excisional biopsy was performed under general anaesthesia. The lesion was excised in a full thickness Copyright © 2016 Tan SN, 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. 16 Trichofolliculoma of the nasal vestibule manner with an elliptical incision and narrow margins of the normal tissue. The mass was 2 × 2 cm, excised from the right nasal ala, and the stump was cauterized with bipolar electrocautery. Patient was then discharged with oral analgesics. Histopathological sections showed an early cystic cavity lined by stratified squamous epithelium which was in continuity with the overlying epidermis. A network of hair follicles arose from this cystic area within the dermis. There were also many smaller, separate secondary follicles seen within the dermis. There was no evidence of dysplasia or malignancy. The feature was compatible with trichofolliculoma (Figure 1). No recurrence of the disease was noted during the 12-month follow-up period after excision. occasionally develop in the vulva[5,6]. Usually, the lesion will be a single, flesh-colored and firm nodule or papule on the face with the presence of hair emerging from the central pit. The presence of dilated follicles and stratified squamous epithelia with lesions containing hairs are seen via microscopy. Treatment is by surgical excision and usually the prognosis is excellent with no recurrence[7]. Conclusion Trichofolliculoma is a rare skin follicle lesion, uncommonly found in the external nasal region. It has excellent prognosis. Most treatments are surgical excisions and are usually directed towards cosmetic improvement. Conflict of Interest All authors have no conflict of interest. The clinical pictures of our patient reported in this case report were unfortunately unavailable due to the retrospective nature of the case. References 1. 2. 3. Figure 1. Histopathological section showing a network of hair follicles arising from the cystic area within the dermis 4. 5. Discussion Trichofolliculoma is a rare hamartomatous skin lesion which is commonly seen in adults[3]. It is also known as a benign adnexal tumour of hair follicle origin[3]. The aetiological genesis of this skin lesion is unknown, but it was believed to be due to the differentiation of the pluripotent skin cells towards hair follicles[4]. It is rarely associated with gender and race predilection[3]. Trichofolliculoma can be seen in the head and neck regions, particularly the face. It is also seen in eyelids and may 6. 7. Kim SJ, Byun SW, Lee SS. Various tumors in the nasal vestibule. Int J Clin Exp Pathol 2013; 6(12): 2713–2718. Miescher G. Trichofolliculoma. Dermatologica 1944; 89: 193–194. Park SY, Han WJ, Kim KJ, Noh KK. A case of trichofolliculoma in the nasal vestibule. Korean J Otolaryngol-Head Neck Surg 2007; 50(3): 265–267. Gokalp H, Gurer MA, Alan S. Trichofolliculoma: A rare variant of hair follicle hamartoma. Dermatol Online J 2013; 19(8): 19264. Chang JK, Lee DC, Chang MH. A solitary fibrofolliculoma in the eyelid. Korean J Ophthalmol 2007; 21(3): 169–171. doi: 10.3341/kjo.2007.21.3.169. Peterdy GA, Huettner PC, Rajaram V, Lind AC. Trichofolliculoma of the vulva associated with vulvar intraepithelial neoplasia: Report of three cases and review of the literature. Int J Gynecol Pathol 2002; 21(3): 224–230. doi: 10.1097/00004347-200207000-00004. Choi CM, Lew BL, Sim WY. Multiple trichofolliculomas on unusual sites: A case report and review of the literature. Int J Dermatol 2013; 52(1): 87–89. doi: 10.1111/ j.13654632.2011.05120.x. 17 doi: 10.18282/jsd.v1.i1.13 doi: 10.18282/jsd.v1.i1.16 CASE REPORT Paramedian forehead flap for nasal tip reconstruction after Mohs surgery Felipe Bochnia Cerci Hospital Santa Casa de Curitiba, Department of Dermatology, Curitiba, Paraná, Brazil Abstract: The paramedian forehead flap is a great option for restoring complex nasal defects. Its main indications are large and deep wounds located on the distal third of the nose (tip and ala). For full-thickness defects, the paramedian forehead flap may be used alone or in combination with other methods. We presented a patient with a nodular basal cell carcinoma on the nasal tip and collumela treated by Mohs micrographic surgery and repaired with a paramedian forehead flap. Prior to reconstruction, it is essential that surgical margins are completely evaluated and free of tumor. For optimal paramedian forehead flap results, adequate surgical planning and meticulous technique are imperative. Keywords: Mohs surgery; surgical flaps; nose neoplasms Citation: Cerci FB. Paramedian forehead flap for nasal tip reconstruction after Mohs surgery. J Surg Dermatol 2016; 1(1): 18–21; http://dx.doi.org/10.18282/jsd.v1.i1.16. *Correspondence to: Felipe Bochnia Cerci, Hospital Santa Casa de Curitiba, Department of Dermatology, Curitiba, Paraná, 80010030, Brazil, [email protected]. Received: 18th December 2015; Accepted: 11th February 2016; Published Online: 16th March 2016 Introduction The paramedian forehead flap (PFF) is a distinctive flap for the restoration of complex nasal defects. Its main indications are large and deep wounds located on the distal third of the nose (tip and ala), including full-thickness defects[1,2]. The PFF can uniquely restore contour, texture and projection of the nasal tip and convexity of the ala, especially when combined with cartilage grafting. The disadvantages of this flap are the requirement of a multi-stage procedure and the forehead donor site scar, which is usually inconspicuous[1,3]. Prior to reconstruction, surgical margins should be completely evaluated by Mohs micrographic surgery (if available) since a recurrence beneath a PFF would be catastrophic. Case report A 77-year-old woman presented to the Department of Dermatology with a 1.6 cm erythematous nodule involving the nasal tip and collumela. A biopsy was performed and revealed a nodular basal cell carcinoma. The patient was submitted to Mohs micrographic surgery under local anesthesia (bupivacaine and lidocaine). After two stages, clear margins were achieved. The resulting defect measured 2.0 × 1.8 cm and affected the nasal tip and collumela (Figure 1). Parts of the lower lateral cartilages were removed. Due to the significant loss of volume of the nasal tip (Figure 2), a PFF was chosen to restore it. The main steps of the PFF are described below. For a more detailed description, several references are available[1-3]. Initially, in order to restore nasal tip projection and for better flap support, a cartilage graft was harvested from the right auricular concha through a posterior incision and sutured with 4.0 vicryl on the nasal tip (Figure 3). After cartilage grafting, the PFF was designed based on the left supratrochlear artery demarcated on the supraorbital rim 1.5 cm lateral to the facial midline (Figure 4). The pedicle was designed with a 1.2 cm width. With a suture foil, a defect template was created and demarcated on the forehead, connected to the pedicle (Figure 4). The flap was then incised, elevated and sutured into the defect using 4.0 monocryl (subcutaneous/dermis) and 5.0 Copyright © 2016 Cerci FB. 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. 18 Paramedian forehead flap for nasal tip reconstruction after Mohs surgery nylon (dermis/epidermis). The forehead was closed primarily in three layers using 4.0 vicryl (galea/muscle/ subcutaneous), 4.0 monocryl (subcutaneous/dermis) and 5.0 nylon (dermis/epidermis) (Figure 5). After 4 weeks, the second stage was performed; (Figures 6 and 7) and consisted of pedicle division and thinning of the proximal portion of the flap after delicate elevation. 5 weeks post-operation, the patient had an optimal result with nasal contour restoration and functional preservation (Figure 8). Figure 1. Surgical defect involving the nasal tip and collumela Figure 2. Important loss of volume of the nasal tip. Parts of the lower lateral cartilages were removed Figure 3. A) Conchal cartilage graft harvested through a posterior incision; B) Cartilage graft sutured on the nasal tip Figure 4. Paramedian forehead flap demarcated on the forehead. Pedicle based on the left suprathroclear artery Figure 5. A) Flap incised; B) Flap sutured into place 19 doi: 10.18282/jsd.v1.i1.16 Cerci FB Figure 6. 4 weeks after the first stage Figure 7. A) and B) Supratrochlear artery can be visualized after pedicle division (arrows) Figure 8. 5 weeks post-operatively. A) Oblique view; B) Frontal view (scar on the right forehead is from a different surgery); C) Lateral view. Note the adequate restoration of volume and projection of the nasal tip Discussion The nasal tip is a common location for the occurrence of non-melanoma skin cancer and frequently presents challenging surgical defects. When wounds are extensive, deep, and/or involve missing cartilage or mucosal lining, no other repair can approach the consistency and predictability of the PFF[1]. For full-thickness defects, reconstruction should be performed in three layers: mucosal repair, cartilage grafting and soft tissue restoration. The subunit principle is an essential concept in nasal reconstruction. When a defect involves more than 50% of a subunit, one should consider excising the residual skin and resurfacing the entire subunit to achieve optimal aesthetic outcome[4]. In the present case, cosmesis could have been further optimized by trimming the defect and recreating the supratip cosmetic junction. The PFF can provide soft tissue covering but not structural support. Nasal lining and structural cartilage are infrastructures that must be either intact, supplemented and/or restored prior to the PFF[4]. Several options are available to restore small mucosal defects (<1 cm) including a turnover hinge flap, turndown of a forehead flap extension, a full-thickness skin graft (FTSG), and bipedicle vestibular skin advancement flap. Larger 20 doi: 10.18282/jsd.v1.i1.16 Paramedian forehead flap for nasal tip reconstruction after Mohs surgery lining restoration may require a turnover forehead flap, FTSG vascularized by an overlying PFF, or intranasal lining flaps (septal mucoperichondrial hinge flap, composite septal chondromucosal pivotal flap)[5,6]. Except for intranasal mucosal flaps, the other options mentioned may be successfully executed under local anesthesia[1]. Cartilage grafts may be divided into two groups: structural (native cartilage present but require additional support) or restorative (replacing what was removed) [1]. Structural functions of the cartilage include: preventing tissue contraction and distortion; bracing heavy flap tissue; maintaining airway patency and augmenting the internal nasal valve; and achieving contour support (i.e., nasal tip graft for better projection)[2]. Donor sites for cartilage grafts may include the antihelix/scaphoid fossa and the conchal bowl[7]. Antihelical cartilage is ideal for long, straight and flexible segments, whereas conchal cartilage is ideal for grafts that demand more curvature, substance and rigidity. Conchal grafts work better to avoid nasal valve or lobule collapse, and for collumela and tip projection. Antihelical cartilage is better suited to avoid alar rim contraction[7-9]. The pedicle side is an important consideration when designing the PFF. Traditionally, the pedicle has been designed contralateral to the defect to minimize its torsion. However, a narrow pedicle (1 to 1.5 cm) allows an ipsilateral design without concerns of significant torsion[3]. For defects located on the midline of the nose such as in the present case, either side of the pedicle is adequate. The flap should be elevated at three different planes. At the superior margin, it should be elevated in the superficial subcutaneous and gradually deepened into the deep subcutaneous and subgaleal plane as the dissection approaches the base of the pedicle in the eyebrow. At the inferior margin (at least 3 cm above the orbital rim), undermining must be subgaleal to avoid transection of the supratrochlear artery. The forehead is approximated as much as possible without tension. However, when significant tension is noted, the remaining wound should heal by second intention[1,2]. The use of skin grafts for the remaining donor site closure can result in a large “patchy scar”. In the present case, due to the relative small size of the defect, the donor area could be entirely closed. The safety of performing the PFF in an outpatient setting has been well documented, with low complication rates when performed with adequate technique[10]. Potential complications of the PFF include bleeding, pain, poor scarring, infection, dehiscence, distortion of free margins and flap necrosis. Conclusion The PFF is a valuable flap in the repair of nasal tip defects following Mohs micrographic surgery. Cartilage grafting should be considered for better flap support, to maintain nasal valve patency and to preserve nasal valve function. If greater than 50% of a nasal subunit has been excised, one should consider resecting the residual subunit for better aesthetic outcome. Good surgical planning and meticulous technique are imperative for optimal results. Conflict of interest The author declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Cerci FB, Nguyen TH. Paramedian forehead flap for complex nasal defects following Mohs micrographic surgery. Surg Cosmet Dermatol 2014; 6(1): 17–24. Nguyen TH. Staged interpolation flaps. In: Roher TE, Cook JL, Nguyen TH, Mellete Jr, JR, (editors). Flaps and grafts in dermatologic surgery. New York: Elsevier; 2007. p. 91–105. Jellinek NJ, Nguyen TH, Albertini JG. Paramedian forehead flap: Advances, procedural nuances, and variations in technique. Dermatol Surg 2014; 40 (Suppl 9): S30–S42. doi: 10.1097/DSS.0000000000000112. Burget GC, Menick FJ. The subunit principle in nasal reconstruction. Plast Reconstr Surg 1985; 76(2): 239–247. doi: 10.1097/00006534-198508000-00010. Boyd CM, Baker SR, Fader DJ, Wang TS, Johnson TM. The forehead flap for nasal reconstruction. Arch Dermatol 2000; 136(11): 1365–1370. doi: 10.1001/archderm.136.11.1365. Baker S. Internal lining. In: Baker S, Naficy S, (editors). Principles of nasal reconstruction. St. Louis: Mosby; 2002. p. 31–46. Byrd DR, Otley CC, Nguyen TH. Alar batten cartilage grafting in nasal reconstruction: functional and cosmetic results. J Am Acad Dermatol 2000; 43(5 Pt 1): 833–836. doi: 10.1067/mjd.2000.107740. Ratner D, Skouge JW. Surgical pearl: The use of free cartilage grafts in nasal alar reconstruction. J Am Acad Dermatol 1997; 36(4): 622–624. doi: 10.1016/S0190-9622(97) 70253-6. Cerci FB. Auricular cartilage graft for nasal reconstruction after Mohs micrographic surgery. Surg Cosmet Dermatol 2015; 7(2): 109–115. doi: 10.5935/scd1984-8773.201572649. Newlove T, Cook J. Safety of staged interpolation flaps after Mohs micrographic surgery in an outpatient setting: a single-center experience. Dermatol Surg 2013; 39(11): 1671–1682. doi: 10.1111/dsu.12338. 21 doi: 10.18282/jsd.v1.i1.16 doi: 10.18282/jsd.v1.i1.36 CASE REPORT Severe local skin reaction after the application of ingenol mebutate gel treated by photodynamic therapy: A case report Luca Negosanti1*, Rossella Sgarzani1, Matteo Santoli2, Massimino Negosanti3, Nicoletta Banzola3, Francesca Negosanti4 1 Division of Plastic Surgery, S.Orsola-Malpighi University Hospital, Bologna, Italy Division of Plastic Surgery, Bellaria Hospital, Bologna, Italy 3 Division of Dermatology, S.Orsola-Malpighi University Hospital, Bologna, Italy 2 4 Division of Dermatology, Centro Dermatologico Srl, Bologna, Italy Abstract: Ingenol mebutate (IM) was recently introduced for the treatment of actinic keratosis (AK). It is considered a safe and effective treatment in spite of local reactions frequently reported. These reactions may consist of erythema, flaking, crusting, swelling, vesicles and erosions, and would usually spontaneously recede within 20–30 days. We reported a case of a patient affected by multiple actinic keratosis of the scalp treated with IM. The patient reported a severe reaction that was not solved in two months. We decided to treat the reaction with photodynamic therapy and aminolevulinic acid. This treatment was demonstrated to be effective in solving this severe side effect. Keywords: Actinic keratosis; ingenol mebutate; photodynamic therapy Citation: Negosanti L, Sgarzani R, Santoli M, Negosanti M, Banzola N, et al. Severe local skin reaction after the application of Ingenol Mebutate gel treated by photodynamic therapy: A case report. J Surg Dermatol 2016; 1(1): 22–24; http://dx.doi.org/10.18282/jsd.v1.i1.36. *Correspondence to: Luca Negosanti, Centro Dermatologico Srl, Via Mazzini 2/2, 40138, Bologna, Italy, luca.negosanti81@gmail. com. Received: 15th January 2016; Accepted: 17th February 2016; Published Online: 16th March 2016 Introduction Ingenol mebutate (IM) was recently introduced for the treatment of actinic keratosis (AK). It consists of self-administered therapy by applying IM on the affected skin surface with multiple AK for two consecutive days (trunk and extremities) or three days (scalp and face). It is considered a safe and effective treatment in spite of local reactions frequently reported[1]. These reactions may consist of erythema, flaking, crusting, swelling, vesicles and erosions, and would usually spontaneously recede within 20–30 days[2]. In our experience, we observed a severe local reaction that did not demonstrate any signs of healing after 50 days of treatment. This reaction was successfully treated using photodynamic therapy (PDT) with aminolevulinic acid (ALA)[3]. Case report A 62-year-old male patient presented with multiple AK of the scalp (Figure 1). We decided to apply 150 µg/g of IM for three consecutive days on a surface area of 25 cm2 in order to treat the entire surface in a single stage. The patient was adequately informed about the nature of treatment, the possible side effects and the expected results. A control was planned one week after the first day of therapy. Local application of antibiotic and steroids (Gentamicin and Betamethasone) was prescribed for 10 days. Copyright © 2016 Negosanti L 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. 22 Severe local skin reaction after the application of ingenol mebutate gel treated by photodynamic therapy: A case report days after the first session, we observed complete resolution of the inflammatory reaction with some residual AK. The reaction receded progressively and the PDT treatment was therefore repeated one month after the previous session. 30 days after the second session, we obobserved low signs of inflammation and no residual AK (Figure 3). Figure 1. Patient presented with multiple AK of the scalp After 7 days, the patient presented a local reaction characterized by multiple crusts with modest swelling. We previously observed this reaction in other patients, so we decided to continue the local therapy and planned controls every week. The reaction increased in intensity progressively and presented no signs of resolution. After two months the patient presented severe crust reaction all over the scalp (Figure 2). We decided to perform a surgical toilet of the crust and observed the severe swelling underneath it. The skin presented an intense inflammatory reaction and granulation tissue. No biopsy was performed. In order to solve this situation, we applied ALA 20% all over the scalp and after two hours, PDT was administered for 12 min. PDT was set with a wavelength of 633 + 6 nm, an intensity of 105 mW/cm2 and a dose of 126 J/cm2. 30 Figure 2. A local reaction at two months after IM application Figure 3. Results 30 days after the first treatment session of ALA-PDT Conclusion IM is recently introduced as therapy for AK. Over the past few years, we treated 36 patients affected by multiple AK with IM. Our population consisted of 28 males and 8 females with a mean age of 69 years old (range 61–77). The interested treatment sites were trunk and extremities in 24 cases, and face and scalp in 12 cases. We applied IM 500 µg/g for two consecutive days on a surface area of 25 cm2 on trunk or extremities and IM 150 µg/g for three consecutive days on a surface area of 25 cm2 on the face and scalp. We observed the reported local reactions with complete healing in a mean time of 27 days (range 18–36). In just one case, we observed a severe local reaction that did not demonstrate any signs of healing after 50 days of treatment. This reaction was successfully treated using PDT with ALA[3]. This type of treatment association was described by Berman et al., but not for the treatment of severe local reaction after IM application[4]. In the presented case, we observed a severe local reaction characterized by inflammation, swelling and crusts all over the treated area that did not recede within 60 days. The clinical aspect of the reaction was similar to a hypertrophic AK associated with an infective affection. Considering the well-known utility of ALA-PDT in the 23 doi: 10.18282/jsd.v1.i1.36 Negosanti L, et al. treatment of both AK and infective diseases, we applied it on the patient’s skin in order to solve the severe local reaction[5]. We observed a complete resolution just after two sessions of PDT. Such intense and lasting reaction after IM application has never been reported in any literature. ALA-PDT was demonstrated to be effective in solving this severe side effect. The main reason can be linked to the efficacy of ALA-PDT both on neoplastic and infective diseases of the skin. Conflict of interest 2. 3. 4. The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References 1. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366: 1010–1019. doi: 10.1056/NEJMoa1111170. 5. Longo C, Neri L, Argenziano G, Calvieri S, CalzavaraPinton PG, et al. Management of local skin reactions after the application of ingenol mebutate gel for the treatment of actinic keratosis: Four illustrative cases. J Eur Acad Dermatol Venereol 2014; 30(2): 320–321. doi:10.1111/jdv. 12714. Negosanti L, Pinto V, Sgarzani R, Negosanti F, Zannetti G, et al. Photodynamic therapy with topical aminolevulinic acid. World J Dermatol 2014; 3(2): 6–14. doi: 10.5314/ wjd.v3.i2.6. Berman B, Nestor MS, Newburger J, Park H, Swenson N. Treatment of facial actinic keratoses with aminolevulinic acid photodynamic therapy (ALA-PDT) or ingenol mebutate 0.015% gel with and without prior treatment with ALA-PDT. J Drugs Dermatol 2014; 13(11): 1353–1356. Pariser DM, Eichenfield LF, Bukhalo M, Waterman G, Jarratt M, et al. Photodynamic therapy with 80 mg/g methyl aminolaevulinate for severe facial acne vulgaris: A randomised vehicle-controlled study. Br J Dermatol 2015. doi: 10.1111/bjd.14345. 24 doi: 10.18282/jsd.v1.i1.36 doi: 10.18282/jsd.v1.i1.34 CASE REPORT Giant seborrheic keratosis of the face – An unusual presentation Koh Khai Luen1*, Rashid Shawaltul Akhma2, Wan Sulaiman Wan Azman1 1 Reconstructive Sciences Department, Hospital Universiti Sains Malaysia, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia 2 Department of Plastic and Reconstructive Surgery, Hospital Raja Perempuan Zainab II, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia Abstract: Seborrheic keratosis is the most common benign epidermal lesion in the world, especially among the elderly. Its inherent benign nature has precluded the need to remove it for medical reasons. Most of the concerns presented to dermatologists or plastic surgeons are of cosmetic reasons, besides some unusual appearances that necessitate cutaneous malignancy evaluation. Unusually large sizes of seborrheic keratosis are rarely reported, and its clinical significance is largely unknown. It has been proven by recent molecular studies that seborrheic keratosis is true neoplasia rather than a mere epidermal hyperplasia, and various authors have reported several cases of concomitant malignancy arising from seborrheic keratosis. Plastic surgeon expertise is often required when faced with an extensive lesion, requiring reconstructive procedures to preserve good aesthetic and functional outcomes. The purpose of this review is to report a case of an unusually large seborrheic keratosis on the face, highlighting its clinical relevance and surgical management. Keywords: face; giant seborrheic keratosis; surgical management Citation: Koh KL, Akhma RS, Wan Azman WS. Giant seborrheic keratosis of the face – An unusual presentation. J Dermatol 2016; 1(1): 25–28; http://dx.doi.org/10.18282/jsd.v1.i1.34. *Correspondence to: Koh Khai Luen, Reconstructive Sciences Unit, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia, [email protected]. Received: 13th January 2016; Accepted: 11th February 2016; Published Online: 21st April 2016 Introduction Seborrheic keratosis is one of the most common benign epidermal cutaneous lesions encountered by dermatologists and plastic surgeons in their daily practice[1,2]. However, given its benign nature, removal for medical reasons are unnecessary unless a histological confirmation of the clinical diagnosis is required, or the lesion has become traumatised and symptomatic. The most common concern for patients is often on the cosmetic outcome, especially when the lesion is on the face. Some unusual appearances of the lesions, such as gradual increase in size and pigmentation, may also serve as a concern for patients to present themselves to dermatologists for cutaneous malignancy evaluation[2]. Seborrheic keratosis was first described in 1869 by Neuman as ‘senile warts’ since it commonly affected the elderly population, with a verrucous-like ‘stuck on’ appearance[3]. Bathelemy was the first to coin the term ‘seborrheic warts’ in 1896[3]. It can occur anywhere on the body, but more commonly on sun-exposed areas of the face, trunk and extremities except the palm and sole. Historically, the lesions were merely thought to be epidermal hyperplasia until the advancement in molecular study emerged. A clonality analysis had shown that the majority of lesions are monoclonal tumours and have true autonomous growth, but without chromosomal instability. The growth of the epidermal cells are arrested at the G1 phase, hence maintaining its biologically benign nature[1]. Various authors had reported a concomi- Copyright © 2016 Koh KL, 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. 25 Giant seborrheic keratosis of the face – an unusual presentation tant occurrence of malignant growth associated with seborrheic keratosis, although without strong association of it[4-9]. Unusually large-sized seborrheic keratoses are rarely reported, and their clinical significance is largely unknown. The majority of lesions occur in multiplicity with sizes less than 3 cm, and they can usually be removed with non-surgical options[1]. Baer emphasised that the lesions can become very large and he published a case of giant seborrheic keratosis with the size of 5.5 × 3.5 cm at the inguinal region[3]. Other authors had described the rarity of this tumour at the perigenital area with the largest dimension of 15 × 10 cm, warranting excision and reconstruction[10]. The aim of this review was to report an unusually large, seborrheic keratosis on the face, by highlighting its clinical relevance and surgical management. were no recurrences (Figure 1F). The patient has opted for conservative management of other lesions. (a) A (b) B (c) C (d) D (e) E (f) F Materials and methods The patient was a 75-year-old male with no known medical illnesses who had a large, painless, pedunculated lesion on the right side of his face for the past 30 years. In addition, there were similar multiple, yet smaller swellings around the face, scalp and neck. The patient came to seek treatment due to the growing mass pulling down on the upper right eyelid, and it has affected his vision on the right lateral gaze (Figure 1A, 1B). There was no significant history of bleeding from the mass, nor any infestation or infection. The history of skin exposure to sunlight was elicited. Clinically, there was a 20 × 15 cm oval-shaped pedunculated lesion, which appeared with an uneven surface and verrucous-like at the right temple, pulling down the right lateral upper eyelid. It was firm in consistency, mobile and with a well-demarcated stalk at the base (Figure 1C). There were also multiple, various-sized flat lesions stuck on the forehead, scalp and cheek. There were no clinically palpable neck nodes. The visual field at the right lateral gaze was reduced. Results A clinical diagnosis of giant seborrheic keratosis was made and a surgical excision was performed. The defected area was closed with a simple advancement flap from the surrounding skin laxity (Figure 1D). Figure 1E depicts gross appearance of the lesion. Histopathological examination (HPE) showed hyperkeratotic subtype of seborrheic keratosis without cellular atypia. After a 6-month follow-up, the scar was inconspicuous with an improvement in the function of the right eyelid, and there Figure 1. (A, B) Preoperative photo showed extension of the lesion and distortion of the right upper eyelid due to the gravitational effect of the mass (C) Intraoperatively, the tumour was pedunculated with stalk arising from the right temple region (D) Incision made along the base of the lesion leaving a defect size of 5 x 6 cm (E) Gross appearance of the lesion (F) Postoperative photo after 6 months showed inconspicuous scar and normal right upper eyelid Discussion Seborrheic keratosis is readily diagnosed clinically, especially among the elderly, with its classical appearance. However, not all verrucous lesions are seborrheic keratosis[11]. Clinical dilemma arises in flat-like lesions which have a smooth surface and pigmentation, or unusually large lesions mimicking malignant growth, especially at sun-exposed areas. Lesions need to be differentiated from other cutaneous malignancy. Thomas et al. reported a case of clinically typical seborrheic keratosis, but histologically proven to be malignant melanoma[12], while Tsai et al. reported a case of sebaceous carcinoma, which was found to be contagious with seborrheic keratosis of 26 doi: 10.18282/jsd.v1.i1.34 Koh KL, et al. the abdomen[8]. All suspicious lesions with diagnostic dilemmas or atypical presentations always require surgical excision and histological confirmation. Despite the benign nature of seborrheic keratosis, various authors have reported the concomitant cases of malignant skin tumours associated within these lesions[5,7,12-14]. This may represent a probability of tumour collision rather than malignant transformation of the seborrheic keratosis; however, it cannot be excluded entirely. Bowen’s disease is the most common neoplasm (7%) followed by basal cell carcinoma (4%), and up to 10% of excised lesions have a certain degree of atypia[6]. Lim, in 2006, retrospectively reviewed 639 consecutive histologically diagnosed seborrheic keratosis and found that 44 cases (7%) have associated lesions which were malignant lesions, with 4 cases arising from seborrheic keratosis[15]. This study was quickly followed by Vun et al. where they published their review of 813 cases of seborrheic keratosis, in which 45 cases were associated with non-melanoma cancer which were mainly basal cell carcinoma[16]. Both studies concluded that the predominant site for such malignant findings were on the face, especially at the temple region, but did not specifically mention the characteristics on seborrheic lesions that were associated with malignancy. Hence, it should be emphasised that seborrheic keratosis at sun-exposed areas is at a higher risk of concomitant malignancy, and histopathological diagnosis is warranted despite its benign nature. In our case, the lesion arose from the right temple region but lacked typical malignant changes besides its unusual size. Seborrheic keratosis is also associated with other clinically important variants: namely stucco keratosis, dermatosis papulose nigra and Leser Trélat syndrome[17]. Leser Trélat syndrome warrants special consideration as it is a paraneoplastic syndrome with abrupt eruptions of numerous seborrheic keratosis[18]. It is often associated with internal malignancy such as adenocarcinoma. Molecular study has shown an association of PIK3CA gene mutation involved in the pathogenesis of seborrheic keratosis. This gene poses oncogenic properties in a number of malignant tumours such as the colon, breast and bladder cancers. Hence, seborrheic keratosis may serve as cutaneous markers for internal malignancy especially in unusual presentations, and is also considered as a bad prognostic factor by several authors. In our case, there was no relevant history in regard to malignancy. Nonsurgical methods such as cryosurgery is commonly performed by dermatologists[2]. However, in some cases with large lesions or lesions affecting special areas such as the eyelids, conservative surgical excision and reconstruction are preferred to preserve the functional unit. Invariably, a plastic surgeon’s expertise would be needed. As described in the case report, surgical excision was performed with an advancement of the surrounding skin to achieve tension free primary closure without distorting the surrounding structure. This technique utilised the laxity of the elderly’s skin surrounding the temple region without distorting the eyelid function. Other methods of reconstruction include skin grafting, but with poor cosmetic outcome or local pivotal flap, using cervico-facial rotational advancement flap in younger patients with less tissue laxity[19]. Conclusion Seborrheic keratosis can manifest in an unusual way, and histopathological analysis is warranted to look for concomitant malignancy. Surgical excision with reconstruction is a preferred method at specialised areas in order to preserve aesthetic and functional outcomes. Conflict of interest The author declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References 1. 2. 3. 4. 5. 6. 7. Hafner C, Vogt T. Seborrheic keratosis. J Dtsch Dermatol Ges 2008; 6(8): 664–677. doi: 10.1111/j.1610-0387.2008. 06788.x. Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, et al. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119–1125. Baer RL. Giant pedunculated seborrheic keratosis. Arch Dermatol 1979; 115(5): 627. doi: 10.1001/archderm.1979. 04010050057023. Beheshti A, Hajmanoochehri F. Seborrheic keratosis with Bowenoid transformation. Comp Clin Path 2015; 24(3): 703–704. doi: 10.1007/s00580-014-2042-3. Boyd AS, Su PF, Shyr Y, Tang YW. Squamous cell carcinomas in situ arising in seborrheic keratoses: An association with concomitant immunosuppression? Int J Dermatol 2014; 53(11): 1346–1350. doi: 10.1111/ijd.12086. Gaffney DC, Muir JB, De'Ambrosis B. Malignant change in seborrhoeic keratoses in a region with high solar ultraviolet levels. Australas J Dermatol 2014; 55(2): 142–144. doi: 10.1111/ajd.12035. Terada T. Pigmented Bowen disease arising in pigmented reticulated seborrheic keratosis. Int J Clin Oncol 2010; 27 doi: 10.18282/jsd.v1.i1.34 Giant seborrheic keratosis of the face – an unusual presentation 8. 9. 10. 11. 12. 13. 15(6): 608–610. doi: 10.1007/s10147-010-0086-1. Tsai TM, Wu YH, Yang KC, Yang CY, Tsai TH, et al. Sebaceous carcinoma associated with seborrheic keratosis. J Cutan Med Surg 2010; 14(5): 240–244. doi: 10.2310/7750. 2010.09059. Rajabi P, Adibi N, Nematollahi P, Heidarpour M, Eftekhari M, et al. Bowenoid transformation in seborrheic keratosis: A retrospective analysis of 429 patients. J Res Med Sci 2012; 17(3): 217–221. Bandyopadhyay D, Saha A, Mishra V. Giant perigenital seborrheic keratosis. Indian Dermatol Online J 2015; 6(1): 39–41. doi: 10.4103/2229-5178.148939. Longo C, Moscarella E, Piana S, Lallas A, Carrera C, et al. Not all lesions with a verrucous surface are seborrheic keratoses. J Am Acad Dermatol 2014; 70(6): e121–e123. doi: 10.1016/j.jaad.2013.10.042. Thomas I, Kihiczak NI, Rothenberg J, Ahmed S, Schwartz RA. Melanoma within the seborrheic keratosis. Dermatol Surg 2004; 30(4): 559–561. doi: 10.1111/j.1524-4725.2004. 30178.x. Birnie AJ, Varma S. A dermatoscopically diagnosed collision tumour: Malignant melanoma arising within a sebor- 14. 15. 16. 17. 18. 19. rhoeic keratosis. Clin Exp Dermatol 2008; 33(4): 512–513. doi: 10.1111/j.1365-2230.2008.02715.x. Salerni G, Alonso C, Gorosito M, Fernández-Bussy R. Seborrheic keratosis-like melanoma. J Am Acad Dermatol 2015; 72(1 Supp1): S53–S55. doi: 10.1016/j.jaad.2014. 07. 009. Lim C. Seborrhoeic keratoses with associated lesions: A retrospective analysis of 85 lesions. Australas J Dermatol 2006; 47(2): 109–113. doi:10.1111/j.1440-0960.2006.00258.x. Vun Y, De'Ambrosis B, Spelman L, Muir JB, Yong‐ Gee S, et al. Seborrhoeic keratosis and malignancy: Collision tumour or malignant transformation? 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Philadelphia: Elsevier Health Sciences; 2014. 28 doi: 10.18282/jsd.v1.i1.34 doi: 10.18282/jsd.v1.i1.6 ORIGINAL RESEARCH ARTICLE Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique Laila M Mohammad1, Lamia H Elgarhy1*, Dina G Saad2, Walid A Mostafa3 1 Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta, Egypt 2 Department of Dermatology and Venereology, El-Menshawy General Hospital, Tanta, Egypt 3 Plastic Surgery Unit, Faculty of Medicine, Tanta University, Tanta, Egypt Abstract: There are different modalities for management of atrophic acne scars which include lasers. Ablative fractional CO2 laser was developed to address the shortcomings of traditional ablative lasers, with superior results to non-ablative fractional lasers. Autologous fat transfer has been utilized for nearly a decade in tissue augmentation and reconstruction. Present studies were designed to compare ablative fractional CO2 laser treatment with scar subcision and autologous fat transfer in the treatment of atrophic acne scars. 20 patients with atrophic acne scars were recruited: 10 patients were treated by three sessions of ablative fractional CO2 laser therapy, and 10 patients treated by subcision and autologous fat transfer. All patients were followed up for three months, and were assessed by digital photograph before and after treatment through the application of Goodman and Baron quantitative and qualitative grading systems, in addition to reports by three physicians committees and reports of patients’ satisfaction. Analysis of both groups showed significant improvements in all types of atrophic acne scars. The mean percentage of total quantitative improvement was more significant in the case of autologous fat transfer with regard to ice-pick and total number of scars. Therefore, scar subcision with autologous fat transfer proved to be as effective as, or even more effective than, ablative fractional CO2 laser in the treatment of atrophic acne scars with regard to the total number of scars as well as ice-pick type. Keywords: Acne scars; laser; fat transfer Citation: Mohammad LM, Elgarhy LH, Saad DG, Mostafa WA. Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique. J Surg Dermatol 2016; 1(1): 29–36; http://dx.doi.org/10.18282/jsd.v1.i1.6. *Correspondence to: Lamia H Elgarhy, Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, 31111, Tanta, Egypt, [email protected]. Received: 19th November 2015; Accepted: 2nd February 2016; Published Online: 12th April 2016 Introduction Acne scars in teenage and early adult years are common cosmetic concern. The scars are the result of compromised collagen production during natural wound healing process, resulting in topographical depressions. The desire to prevent scarring is often a reason for treating ac- ne[1]. Atrophic acne scars were classified as rolling, ice-pick or boxcar. Rolling scars appear like hills or valleys without sharp borders, while ice-pick scars appear as rounded deep depressions culminating in a pinpoint base. On the other hand, boxcar scars are larger in size with sharply defined edge[2]. Different treatment modalities have been used to ameliorate atrophic scars with varying Copyright © 2016 Mohammad LM, 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. 29 Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique degrees of success. These include chemical peels[3], subcision[4], surgical excision[5], punch grafting[5], dermabrasion[6], ablative and non-ablative laser resurfacing[7], as well as tissue augmentation with a variety of fillers [8]. Fractional ablative lasers deliver microscopic columns of energy which vaporize myriads of tiny holes covering different percentage of skin depending on the case to be treated. The majority of the epidermis is left intact, thus allowing these microscopic lesions to heal very quickly and limit complications. This modality is currently used for treatment of acne scarring, photoaging and skin laxity, among other indications. In contrast, traditional ablative laser resurfacing (with an ultra-pulsed CO2 or Er:YAG laser) ablates 100% of the epidermal surface, which is associated with prolonged healing and an increased risk of scarring and infection. In addition, the fractional approach allows much deeper treatment (up to 1,500 µm) because of the extremely small beam diameter (100–300 µm)[9,10]. This is dramatically different from traditional ablative procedures that ablate the entire surface to approximately 300–350 µm. Few complications have been reported with fractional ablative resurfacing[11]. Subcision, also called “subdermal/incisionless undermining”, is indicated for the same type of scars that might be improved with fillers or its appearance is improved with manual stretching of the skin during examination[12]. It appears to work by breaking up the attachments of these scars under the skin and releasing the surface from deeper structures[13]. Autologous fat transfer has enjoyed a renaissance in the last several years. As for other surgical approaches, renewed interest has evolved from refined techniques, enhanced instruments and knowledge gleaned by new research[14,15]. The understanding of fat physiology, stem cells and metabolism has benefited with an appreciation of longevity that is possible with fat transfer[16]. Materials and methods This study was performed on 20 acne scar patients recruited from the Outpatient Clinic of Dermatology and Venereology Department, Tanta University Hospital, from April 2012 to October 2013. Inclusion criteria were males and females older than 18 years of age with atrophic acne scars. Patients younger than 18 years of age and patients with retinoid use in the past 6 months, systemic disease (diabetes or hypertension), collagen disease, malignancy, photosensitivity, and keloidal tendencies were excluded from the study. After obtaining informed consent, the patients studied were subjected to detailed history taking, thorough general and dermatological examination, and assessment of acne scar severity before and after treatment through the application of Goodman and Baron quantitative and qualitative grading systems[17,18] in addition to assessment by three physicians committees and reports of patients’ satisfaction. The improvement was graded as 0% to 25% (mild), 25% to 50% (moderate), 50% to 75% (marked) and 75% to 100% (excellent). All patients were photographed before and three months after the treatment. 10 patients (group A) were treated by autologous fat transfer and 10 patients (group B) were treated by three sessions of F-CO2 laser. Group A (Subcision and autologous fat transfer) 10 patients were subjected to subcision and fat grafting. The procedure was done under local anesthesia at Tanta University Plastic Surgery Unit under complete aseptic precautions. The fat was harvested using tumescent anesthesia (20 ml of 2% lidocaine + 50 ml saline + 0.25 mg 1/200,000 adrenaline) that was injected at the lower hemi-abdominal iliac crest region using 20 ml syringes. Approximately 10 min were allowed to pass for the adrenaline to be effective. A 0.5 cm stab incision was made at the donor site to introduce a 3 mm liposuction cannula connected to a 60 ml syringe with screw lock. The fat was aspirated by steady to-and-fro movements in subcutaneous tissues until the desired amount was aspirated. The syringe of aspirated fat was held with its nozzle downwards for 15 min so that the solution was settled by gravity and supernatant fat layer was separated, and then the remaining fluids were discarded. The aspirated fat was then placed on a sterile piece of gauze to be filtered and concentrated by gentle shaking. The fat was then placed in 3 ml syringes. Infraorbital nerve block was done using 1 ml (2% lidocaine and 1/200,000 adrenaline) through buccal mucosa to provide anesthesia without causing tissue distortion. A successful infraorbital nerve block provides anesthesia to the area between the lower eyelid and the upper lip. This was helped by applying local anesthetic cream (Emla) on the involved area 20 min before the procedure. Fan-shaped subcision of the scars was done using 18-Gauge needle, creating tracts for fat placement in subdermal regions. The fat was placed using the 3-mm syringes during cannula retraction in its bed created by the subcision tracts. Molding was done against the zygoma and maxilla. 30 doi: 10.18282/jsd.v1.i1.6 Mohammad LM, et al. testing of proportions or Z test. Correlation between variables was evaluated using Pearson’s correlation coefficient. Significance was adopted at p < 0.05 for interpretation of results of significance test. Group B (F-CO2 laser) Each patient attended three sessions of fractional ablative CO2 laser system MX7000 scanner type, manufactured by Daeshin Enterprise Co. Ltd (Seoul, Korea), spaced 4 weeks apart. Each session was performed with a single pass at the following parameters: power 12 mJ, scan scale 15 × 15 mm, depth level 2 μm, density level 3 MTZ/cm3, repeat time off and mode selection microxel scanner. Results There was no significant difference between both groups regarding age, sex and duration of the disease. Qualitative grading system of acne scars before and after treatment of the patients studied with different types of acne scars showed significant improvement in both groups. Comparison between the two groups before treatment showed no significant difference (p = 0.361). Comparison between the two groups after treatment showed no significant difference (p = 0.06) (Table 1). Quantitative assessment of acne scars in group A showed statistically significant improvement in ice-pick (p = 0.0001*), rolling (p = 0.004*), boxcar scars (p = 0.0001*) and the total number of scars (p = 0.0001*) (Figures 1a–2b). Similarly, group B showed statistically significant improvement in ice-pick (p = 0.001*), rolling (p = 0.002*), boxcar scars (p = 0.004*) and the total number of scars (p = 0.0001*) (Figures 3a-4b). Relations between total quantitative assessment scores of the Statistical analysis The collected data were organized, tabulated and statistically analyzed using SPSS software version 13. For qualitative data, comparison between two groups and more was done using chi-square test (2). For comparison between means of two groups, parametric analysis (t-test) and non-parametric analysis (Z value of MannWhitney U test) were used. For comparison between means of the same group before and after treatment, parametric analysis (paired t-test) and non-parametric analysis (Z value of Wilcoxon Signed Ranks test) were used. Comparison was done between percent of change after treatment and pre-treatment of the two groups using Table 1. Qualitative grading system of Goodman and Baron for acne scars before and after treatment by scar subcision and autologous fat transfer versus Fractional CO2 laser Group A (N = 10) Before 2 Group B (N = 10) After Before After Before After 0 0.833 3.529 7 70.0 0.361 0.060 30.0 3 30.0 70.0 0 0 N % N % N % N % Grade 1 0 0 0 0 0 0 0 Grade 2 0 0 10 100 0 0 Grade 3 5 50.0 0 0 3 Grade 4 5 50.0 0 0 7 p 2 20.00 0.0001* p 14.00 0.001* p < 0.05 is considered statistically significant Figure 1 . (A) Right side of the face of female patient with mixed atrophic acne scars; (B) The same patient three months after scar subcision with autologous fat 31 doi: 10.18282/jsd.v1.i1.6 Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique Figure 2. (A) Left side of the face of male patient with mixed atrophic acne scars; (B) The same patient three months after scar subcision with autologous fat transfer Figure 3. (A) Right side of the face of female patient with mixed atrophic acne scars; (B) The same patient three months after the last session of fractional ablative CO 2 laser acne scar patients studied (treated by subcision with autologous fat transfer versus fractional ablative CO 2 laser), their ages and duration of disease showed no significant difference. Comparison between both groups showed statistically significant improvement in group A compared to group B in ice-pick scars (p = 0.028*) and boxcar scars (p = 0.002*), but not in rolling scars (p = 0.421) and the total number of the scars (p = 0.278) (Table 2). The mean percentage of improvement in after-treatment compared to before-treatment scores of quantitative assessment showed that the number of ice-pick scars decreased after treatment with scar subcision and autologous fat transfer by 59.85% and decreased after F-CO2 laser by 39.76%, with significant difference between both groups (p = 0.011*). The total number of scars decreased after treatment with autologous fat transfer by 57.78% and decreased after fractional CO2 laser by 41.97%, with significant difference between both groups (p = 0.020*). Mean percentage of improvement of rolling and boxcar scars decreased after treatment with autologous fat transfer by 58.31% and 46.37%, respectively, and decreased after fractional CO2 laser by 42.21% and 42.28%, respectively. There were no significant difference between both groups regarding rolling and boxcar scars (p = 0.251 and p = 0.713, respectively) (Table 3). No significant difference was found between patients’ and physicians committees’ opinions on the improvement of different types of acne scars in the patients studied (p = 0.656 and p = 0.371, respectively) (Table 4). Group A patients tolerated their procedure well. Mild oedema was temporary and faded within one week. Pain was relieved by analgesics and the patients were able to attend their daily routines. Group B patients tolerated their procedure well. However, they were not able to attend their daily duties as all of them were advised to avoid the sun for 5–7 days after the session and all patients experienced grainy crusts that resolved after a maximum of 5 days, which increased the downtime post session. Discussion Figure 4. (A) Left side of the face of patient with mixed atrophic acne scars; (B) The same patient three months after the last session of fractional ablative CO2 laser Facial scarring has always been a challenge to treat. There are different modalities for the management of these scars including various types of resurfacing which have the disadvantages of either being too mild and ineffective or being too aggressive and complicated[19]. Autologous fat transfer has enjoyed a renaissance in the last several years. In particular, the micro droplet approach offers the surgeon an opportunity to address superficial 32 doi: 10.18282/jsd.v1.i1.6 Mohammad LM, et al. Table 2. Quantitative acne scars assessment scores of Goodman and Baron before and after treatment by subcision with autologous fat transfer versus fractional ablative CO2 laser Group A (N = 10) Scar type Group B (N = 10) Before After 20–94 0.529 2.395 87.50 ± 31.99 52.40 ± 24.04 0.603 0.028* 85.00 54.00 Before After Before After Range 70–100 17–45 45–158 Mean ± SD 81.80 ± 11.67 32.80 ± 9.61 Median 80.50 34.00 Ice-pick Paired t-test P 14.819 0.0001* 4.650 0.001* Range 6–45 2–14 1–24 0–12 1.064 0.805 Mean ± SD 18.50 ± 15.73 7.10 ± 4.91 9.40 ± 6.38 4.60 ± 3.31 0.288 0.421 Median 9.00 5.00 8.00 4.50 Rolling Z value▪▪ P 2.873 0.004* 4.474 0.002* Range 12–27 6–15 1–17 0–11 5.397 3.615 Mean ± SD 20.70 ± 5.25 10.60 ± 4.09 7.70 ± 5.52 4.40 ± 3.56 0.0001* 0.002* Median 21.50 11.00 8.00 Boxcar Paired t-test P 3.00 5.779 0.0001* 3.851 0.004* Range 96–172 36–74 55–167 23–107 1.232 1.119 Mean ± SD 121.00 ± 28.41 50.50 ± 13.75 104.60 ± 31.05 61.10 ± 26.61 0.234 0.278 Median 115.00 47.50 107.50 62.50 Total scars number Paired t-test P 10.936 0.0001* 5.905 0.0001* p < 0.05 is considered statistically significant Table 3. Mean percentage of change in after-treatment compared to before-treatment scores of quantitative assessment of ice-pick, rolling, boxcar and total number of scars treated by subcision with autologous fat transfer versus fractional ablative CO 2 laser Quantitative assessment of acne scars Mean percent of change in after-treatment compared to before-treatment scores among the patients studied with acne scars (N = 20) Z-test p Group A (N = 10) Group B (N = 10) Range Mean ± SD Range Mean ± SD ●Ice-pick assessment 77.33%–48.57% 59.87 ± 10.88 71.83%–18.57% 39.76 ± 19.45 2.854 0.011* ● Rolling assessment 68.89%–44.44% 58.31 ± 10.65 100%–60.00% 42.21 ± 41.62 1.185 0.251 ● Boxcar assessment 73.91%–30.00% 46.73 ± 19.51 100%–0.00% 42.28 ± 32.23 0.373 0.713 Total number of scars 67.59%–45.83% 57.78±9.02 71.59%–20.15% 41.97 ± 17.42 2.548 0.020* p < 0.05 is considered statistically significant 33 doi: 10.18282/jsd.v1.i1.6 Fractional ablative CO2 laser treatment versus scar subcision and autologous fat transfer in the treatment of atrophic acne scars: New technique Table 4. Physicians committees’ opinions versus patients’ opinions regarding improvement of acne scars of the patients studied treated by subcision with autologous fat transfer versus fractional ablative CO 2 laser Opinions about improvement of acne scars of patients studied with different types of acne scars (N = 20) Group A (N = 10) Degree of improvement of acne scars Physicians committee 2 Group B (N = 10) Patients opinions p Physicians committee Patients opinions N % N % N % N % Physicians committee Patients opinions Mild (0–<25%) 0 0 0 0 0 0 0 0 1.986 0.843 Moderate (25%–<50%) 3 30.0 2 20.0 5 50.0 3 30.0 0.371 0.656 Marked (50%–<75%) 5 50.0 3 30.0 2 20.0 4 40.0 Excellent (75%–100%) 2 20.0 5 50.0 3 30.0 3 30.0 2 p 5.56 0.062 1.17 0.558 p < 0.05 is considered statistically significant skin problems such as acne scars and relatively shallow rhytids[20]. Ablative fractional CO2 laser has been developed to address the shortcomings of traditional ablative lasers and non-ablative fractional resurfacing (NAFR) treatments. With the ability to achieve deep dermal ablation and coagulation, clinical results superior to nonablative fractional lasers could be obtained[21, 22]. Analysis of current research up to recent dates showed that this study was the first to perform subcision for atrophic facial acne scars with fat injection directly under the scars to act as filler and a source of stem cells at the same time. This showed significant improvement in acne scars, ice-pick type in particular, which were evaluated three month after the procedure. This differs from results of Azzam et al. which showed no improvement of ice-pick scars after the fat grafting and they recommended punch excision or chemical reconstruction techniques to treat ice-pick scars[23]. This can be attributed to their different technique in which autologous fat transfer was done through 0.5 cm stab incision pre-auricular in the hair line or in an already existing scar for cheek augmentation, followed by a fan-shaped subscision of atrophic acne scars. Rohrich et al. also considered that fat transfer alone was not generally effective for individual bound down ice-pick scars[24]. On the other hand, Goodman et al. observed that once the scar is freed, fat may be satisfactorily injected[13]. Moreover, Donofrio focused on lipocyte stem cells rather than mature adipocytes as the driving force in long term clinical benefit for post-radiation depressed scars[25]. He stated that adipose tissue contains a clonogenic pool of stromal cells having the same functional and immunophenotypic properties of bone marrow mesenchymal stem cells. The longevity of fat transplants has been extensively studied although consistent results in the literature vary[26,27]. Theories include replacement fibrosis, neovascularization of transplanted fat, and differentiation of lipocyte stem cells into mature adipocytes[14,28,29]. Duration has not been specifically studied in acne scars. However, one study of depressed post-surgical scars in 30 patients utilizing a subcision technique followed by autologous fat grafting through 4 mm cannula, revealed 27 patients with very good results at three years. Two patients required additional treatment at 6 months due to partial recurrence[30]. Adipose-derived stem cells (ADSCs) are considered a powerful source of skin regeneration because of their capability to provide cellular elements and cytokines. It seems that autologous ADSCs have great promise for applications in wound healing and scar remodeling[6]. Stem cell therapy can improve the quality of the skin, reduce the formation of scars and re-establish the normal function of the skin and its appendages[31]. In the present study, it was found that three sessions of ablative fractional CO2 laser showed significant qualitative and quantitative improvement of atrophic acne scars, which was consistent with previous reports of Chapas et al.[32], Manuskiatti et al.[33] and Cho et al.[34]. However, 34 doi: 10.18282/jsd.v1.i1.6 Mohammad LM, et al. Azzam et al. reported that patients with boxcar scars showed no improvement using (15 mJ) power by fractional CO2 laser with appearance of pixilated pattern and acne activation in some cases[24]. This can be attributed to different power used in current work (12 mJ). On comparing the results of both groups, both methods were equally effective in improving atrophic acne scars quality and quantity. The mean percentage of scar improvement between before- and after-treatment quantitative assessments showed that autologous fat transfer is more effective in improving ice-pick scars and there were no significant differences in the total number of scars from fractional CO2 laser for rolling and boxcar scars. Previous histologic and immunohistologic studies demonstrated a large difference in results between fat grafting and fractional ablative CO2 laser for the treatment of acne scars, and favored fat grafting[35]. Histologic and immunohistologic experimental study compared biopsies taken from nude mice before and after fat graft, and showed an increased density of extracellular matrix surrounding the fatty tissue and between the fatty tissue and the dermis[32]. In another study on mice, skin changes with fat grafting were investigated in skin biopsies eight weeks after the graft, which revealed that fat graft caused increased collagen fibers neosynthesis at the recipient site and thickened the dermis. Regarding skin color and scar quality, marked improvement could be seen after fat graft [36]. The current study concluded that a single session of acne scar subcision with autologous fat transfer proved to be as effective as or even more effective than three sessions of ablative fractional CO2 laser one month apart, with regard to the total number of scars, in the treatment of atrophic acne scars as well as ice-pick type – which is considered in general the most difficult type in its treatment – with minimal downtime and almost no complications when done in the proper setting, technique and patient selection, and is also considered as a non-expensive technique which can be done with a few equipment. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Ethics Statement This research was approved by the research ethics committee of Tanta Faculty of Medicine (approval code 1700 /03 /13). 13. 14. Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. 15. Goodman GJ. Post acne scarring: A review. J Cosmet Laser Ther 2003; 5(2): 77–95. doi: 10.1080/14764170310001258. Alam M, Dover JS. Treatment of acne scarring. Skin Therapy Lett 2006; 11(10): 7–9. Landau M. Chemical peels. Clin Dermatol 2008; 26(2): 200–208. doi: 10.1016/j.clindermatol.2007.09.012. Goodman GJ. Commentary: Subcision versus 100% trichloroacetic acid in the treatment of rolling acne scars. Dermatol Surg 2011; 37(5): 634–636. doi: 10.1111/j.15244725.2011.01955.x. Kadunc BV, de Almeida ART. Surgical treatment of facial acne scars based on morphologic classification: A Brazilian experience. 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Facial Plast Surg Clin North Am 2008; 16(4): 451–458. doi: 10.1016/j.fsc. 2008.09.001. 36 doi: 10.18282/jsd.v1.i1.6 doi: 10.18282/jsd.v1.i1.15 ORIGINAL RESEARCH ARTICLE Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation Sara Majewski1, Chantelle Carneiro1, Erin Ibler1, Peter Boor1, Gary Tran1, Mary C Martini1,2, Salvatore Di Loro3, Alfred W Rademaker2,4, Dennis P West1,2, Beatrice Nardone1* 1 2 3 4 Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL Department of Information Technology, Telecom Italia Group, Rome, Italy Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL Abstract: Clinical assessment of skin photosensitivity is subjectively determined by erythema and tanning responses to sunlight recalled by the subject, alternatively known as Fitzpatrick Skin Phototype (SPT). Responses may be unreliable due to recall bias, subjective bias by clinicians and subjects, and lack of cultural sensitivity of the questions. Analysis of red-green-blue (RGB) color spacing of digital images may provide an objective determination of SPT. This paper presents the studies to assess the melanin index (MI), as determined by RGB images obtained by both standard digital camera as well as by videodermoscope, and to correlate the MI with SPT based upon subjects’ verbal responses to standardized questions administered by a dermatologist. A sample of subjects representing all SPTs I–VI was selected. Both the digital camera and videodermoscope were calibrated at standard illumination, light source and white balance. Images of constitutive skin of the upper ventral arm were taken of each subject using both instruments. The studies showed that 58 subjects (20 M, 38 F) were enrolled in the study (mean age: 47 years; range: 20–89), stratified to skin phototype I–VI. MI obtained by using both digital camera and videodermoscope increased significantly as the SPT increased (p = 0.004 and p < 0.0001, respectively) and positively correlated with dermatologist-assessed SPT (Spearman correlation, r = 0.48 and r = 0.84, respectively). Digital imaging can quantify melanin content in order to quantitatively approximate skin pigmentation in all skin phototypes including Type VI skin. This methodology holds promise as a simple, non-invasive, rapid and objective approach to reliably determine skin phototype and, with further investigation, may prove to be both practical and useful in the prediction of skin cancer risk. Keywords: Melanin Index; Fitzpatrick Skin Phototype; digital imaging Citation: Majewski S, Carneiro C, Ibler E, Boor P, Tran G, et al. Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation. J Surg Dermatol 2016; 1(1): 37–42; http://dx.doi.org /10.18282/jsd. v1.i1.15. *Correspondence to: Beatrice Nardone, Department of Dermatology, Northwestern University, 676 N. St. Clair Suite 1600, Chicago, IL 60611, USA, [email protected]. Received: 11th December 2015; Accepted: 3rd February 2016; Published Online: 14th April 2016 Copyright © 2016 Majewski 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. 37 Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation Introduction Materials and methods For several decades, clinical assessment of photosensitivity has been based on the SPT[1]. As originally designed, the standardized questions about the ease of burning and tanning reactions to the first sun exposure in the summer were administered by trained personnel, especially those in dermatology, and the clinicians determined the SPTbased on the patient’s responses[1]. Over the years, the standardized questions were used in written surveys. By relying on patient's memory of sun burning and tanning, recall bias may be introduced. Furthermore, clinicians have evolved to visually assess the SPT without asking the patient to recall their skin reaction to ultraviolet light (UVL). Subjective assessment of SPT by clinicians was heavily influenced by patients’ hair and eye color [2]. Since SPT was correlated with susceptibility to developing skin cancer, errors in determining the subject’s SPT contribute to misunderstanding of their susceptibility to skin cancer and need for sun protection. Various in vitro and in vivo methods to quantify skin pigmentation have been proposed and evaluated to avoid subjective bias in SPT but none have successfully differentiated all 6 phototypes[2]. Over the last decade, non-invasive instrumentation has been utilized to assess pigmentation in vivo including spectrophotometry[3], colorimetry[4], skin color scale chart [5], fiber optic sensor[6] and digital imaging with RGB color space analysis [7,8]. While several studies reported the use of colorimetry[4,9] and spectrophotometry[10] to assess SPT, Pershing et al. used spectrophotometry to objectively determine all six SPTs using only constitutive skin color independent of UVL-induced erythema[2]. The “gold standard” method of assessing skin pigmentation is spectrophotometry; however, it is difficult to perform spectrophotometry under clinical conditions. Although skin pigmentation is not the only factor that plays a role in protection against sunburn[11], it remains an important risk factor for skin cancer development. It has been reported that the low incidence of cutaneous malignancies in darker skinned groups is primarily a result of photoprotection contributed by increased epidermal melanin, which provides an inherent sun protection factor (SPF) of up to 13.4 in African American individuals[12]. Thus, a clinically feasible and objective assessment of skin pigmentation remains an unmet need[4]. The aim of this study was to assess SPT utilizing MI as determined by RGB images obtained both by digital camera and high resolution, high magnification videodermoscope. This single-center observational study assessed MI obtained from RGB digital images in adult male and female subjects with Fitzpatrick Skin Phototypes I–VI[13]. A sample of subjects, representing all SPTs and attended Northwestern University’s Department of Dermatology, participated in the study. The sample consisted of subjects attending our large urban academic center (Chicago) during study enrollment. However, data on previous lifestyle and/or prior living in other geographic regions of the US and/or the world are unknown, and are therefore a limitation to this study and to the utility of SPT designations in general. The study was approved by the Northwestern University Institutional Review Board, and all participants provided written informed consent prior to participation. Exclusion criteria were history of vitiligo, use of self-tanning products or tanning accelerators in the 6 weeks prior to enrollment, and recent history of prolonged sun exposure or indoor tanning. Inclusion criteria were being between age 18 to 70, and able to read in English. A dermatologist administered the following questions: a) If after several months of not being in the sun, you stayed outdoors for about one hour at noon for the first time in the summer without sunscreen, what would happen to your skin?–Always sunburn, usually burn, burn minimally, burn rarely, or never sunburn; b) Over the next 7 days, would you develop a tan? –Never tan, tan lightly, tan moderately, or tan deeply. SPTs are assigned based upon the subjects’ responses (Table 1). Subjects also self-reported age, gender, and ethnic background by completing an anonymous written survey. Table 1. Fitzpatrick Skin Phototype Scale[1] Fitzpatrick Skin Phototype Skin Reactions to Sunlight during the First Summer Exposure I (N = 10) Always burns, never tan (painful burn at 24 h and no tan at 7 days) II (N = 13) Burn easy, then develop light tan (painful burn at 24 h and a light tan at 7 days) III (N = 8) Burn moderately, then develop light tan (slightly tender burn at 24 h and moderate tan at 7 days) IV (N = 10) Burn minimally/rarely, then develop moderate tan (no burn at 24 h and a good tan at 7 days) V (N = 10) No burns, always develops dark tan VI (N = 7) No burns, no noticeable change in appearance Assessment of Melanin Index Two digital systems were used to capture images for 38 doi: 10.18282/jsd.v1.i1.15 Majewski S, et al. analysis: a high resolution digital camera (Nikon D80®, Nikon Inc., USA) and a videodermoscopy system (Kit EasyScan Pico, Business Enterprise, Trapani, Italy). In order to minimize measurement bias and to ensure standardization of all parameters (distance, focus, source light and white balance), digital camera images were taken with a fixed light source at the same distance for all subjects. The camera was placed in manual mode, and white balance was established for each subject using Standard Kodak Color Palette. The videodermoscope utilized a fixed light intensity, fixed white balance, as well as fixed brightness and contrast to avoid re-calibration before each subject. Prior to videodermoscopy, antiseptic gel was applied to ensure smooth contact with the skin and to minimize stratum corneum light scattering. Images of the upper ventral arm (constitutive skin), 5 cm above the head of the humerus, were taken. These measurements were assessed for validity against the SPT determined by the dermatologist without adjustment for hair, eye color and presence of freckles. Images taken with both instruments were stored electronically and processed by ImageJ software[14]. To obtain mean MI values, the formula (1) was used to measure melanin based on reflectance values of the red channel in the RGB image. This formula is equivalent to that used for narrow band spectrophotometers[8,15]. (1) Ar,g,b= 100×Log10 (1/Rr,g,b); where A, according to the model of Dawson et al.[16], is the absorbance of the skin and R is the reflectance. If it is assumed that MI can be obtained from the absorbance of the red channel (Ar), then: (2) MI=Ar=100×Log10 (1/Rr). Reflectance of the skin is obtained from the ratio between the mean brightness value of the region of interest (ROI) and the white standard in the same ROI, hence: (3) Rr= Sr/Wr The final formula becomes: (4) MI= 100×Log10(1/Sr/Wr) = 100×(Log101–Log10Sr/ Wr) = 100× (–Log10Sr/Wr). In order to satisfy the final formula above and to make automated measurements, two of the authors (Di Loro S and Nardone B) created an ImageJ Java plugin where S is the mean brightness of skin in ROI and W is the known (previously measured) mean white brightness in the color palette in the same ROI. using a Spearman correlation coefficient. A p value <0.05 was considered statistically significant. Statistical analysis Discussion Median MI obtained using both digital camera and videodermoscope were compared across SPT categories using the Kruskal-Wallis test. MI was also correlated with SPT This study demonstrated that MI as determined from RGB images, in concert with high resolution digital photography or high resolution videodermoscopy, is an objective Results 58 subjects (20 male, 38 female) were enrolled in the study (mean age: 47 years; range: 20–89 years), with skin types I–VI (I = 10; II = 13; III = 8; IV = 10; V = 10; VI = 7), and various races (36 White, 19 Black, 3 Asian). MI obtained by both digital camera and videodermoscope increased significantly as the SPT increased (Kruskas-Wallis test, p = 0.0044 and p < 0.0001, respectively). The MI obtained by the videodermoscope demonstrated a progressive gradient from Fitzpatrick skin type I through VI (Table 2). Of note, MI obtained by the digital camera showed an overlap among FSTs III and IV. MI did not correlate with the gender or age of the subject. Also, a statistically positive correlation with the assessed Fitzpatrick SPT was found for both digital camera and videodermoscope (Spearman correlation, r = 0.48 and p = 0.0001, r = 0.84 and p < 0.0001, respectively). Patient self-reported burn susceptibility significantly decreased as MI obtained by videodermoscope increased (Kruskal-Wallis test, p < 0.0001). No statistical difference was found between MI obtained by videodermoscope and self-reported ability to tan (Kruskal-Wallis test, p = 0.21). Table 2. Melanin Index obtained from the digital camera and videodermoscope Fitzpatrick Skin Phototype* Digital Camera1 Videodermoscope2 MI Median (1st, 3rd quartile) MI Median (1st, 3rd quartile) 8.80 (6.20, 11.00) 1.85 (0.80, 2.30) II (N = 13) 9.20 (6.40, 11.00) 2.50 (1.80, 3.60) III (N = 8) 10.55 (6.90, 12.85) 3.15 (1.70, 4.25) IV (N = 10) 10.95 (7.70, 13.00) V (N = 10) 12.20 (7.20, 14.50) VI (N = 7) 14.70 (14.20, 20.10) Kruskal-Wallis test p = 0.0044 6.30 (3.00, 12.80) 33.35 (15.00, 38.00) 41.20 (27.30, 45.50) p < 0.0001 I (N = 10) * Determined by dermatologist’s (JKR) assessment 1 Positive Correlation with SPT for Digital Camera (r = 0.48, p = 0.0001) 2 Positive Correlation with SPT for Videodermoscope (r = 0.84, p < 0.0001) Abbreviations: MI = Melanin Index 39 doi: 10.18282/amor.v1.i2.86 Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation measure of skin pigmentation among all skin types. Moreover, the positive correlation with Fitzpatrick SPT suggests that this method for objective determination of MI provides a quantifiable assessment that may be useful to predict skin cancer risk in people of all skin types. Over the last three decades, the Fitzpatrick SPT evolved from its original purpose of determining the amount of ultraviolet light (UVL) for treatment of New England psoriasis patients to become an assessment tool for skin cancer risk[17-19]. As part of this evolution, the original 4 skin types (I–IV), which assessed sun reactivity with standardized questions about the ease of sun burning and tanning reactions to the first exposure in the summer, were modified by adding SPT V and VI to include those with brown and black skin[1]. Our research demonstrated that the modifications to include people with skin of color were neither culturally sensitive nor accurate, as people of color were unable to respond to the questions of sunburn and tanning[20-22]. People with deep pigmentation of the skin did not report turning red or pink but rather experienced “irritation” after sun exposure[20-22]. Another limitation of the six Roman numeral Fitzpatrick SPT integers was the reliance upon a history of sunburn after the first exposure of summer. For those who reside in regions that have sun exposure all year (e.g. Arizona, Florida, California), the sunburning and tanning questions after the first exposure of summer was irrelevant. Lastly, in the 1990s, people began to apply sunscreens to prevent sunburns; thus, those with sun-sensitive skin may never have experienced sunburn and thus were unable to answer the question about ease of burning. The heterogeneity of those with multi-ethnic backgrounds makes it difficult to assess susceptibility to skin cancer on the basis of skin color, which is predominantly determined by pigments such as hemoglobin, melanin, bilirubin and carotene[23,24,4]. There has been a tendency to group people of similar ethnic group into a single category of SPT, which introduces potential bias into the subjective assessment of SPT by investigators[25-27]. The limitations of Fitzpatrick SPT, especially in people with darker skin[28,29], include recall bias, subjective bias by clinicians and subjects, lack of cultural sensitivity of the questions, and adherence to sun protection recommendations, resulting in children not having experienced prior sunburns. Although skin pigmentation is not the only factor that plays a role in protection against sunburn[11], it remains an important risk factor for skin cancer development. It has been reported that the low incidence of cutaneous malignancies in darker skinned groups is primarily a result of photoprotection provided by increased epidermal melanin, which provides an inherent sun pro- tection factor (SPF) of up to 13.4 in African American individuals[12]. Nonetheless, the Fitzpatrick SPTs are traditionally associated with skin cancer risk as follows: I, II - high risk; III, IV-moderate risk; and V, VI-very low risk of skin cancer development. To date, reflectance methods such as spectrophotometry are considered the “gold standard” to determine melanin and hemoglobin content in the skin. Even if such instrumentation resulted in relatively non-confounded measures of melanin content, these instruments are expensive and require highly trained users, frequent calibration, as well as standard ambient room temperatures[30,2]. Such features make it clinically difficult to conduct melanin measurements, especially in pediatrics where prediction of those at risk may enhance sun protection[31]. Our findings are in part consistent with a recent study where a strong correlation between MI and individual typology angle (ITA) values were found, suggesting that either of these methods can be used to assess skin pigmentation depending on the relevance of the measurement outcome of the intended study. Determining skin type is necessary for understanding personal risk of sunburn and, by extension, personal risk of skin cancer [32]. Videodermoscopy is widely applicable, non-invasive, portable and relatively inexpensive. Since dermoscopy is familiar to clinicians, novel technology utilizing videodermascope that allows assessment of SPT is likely to be readily adaptable to practice. While it is difficult to achieve standardization for distance, brightness and identical pose with a digital camera, imaging with videodermoscopy involves a non-invasive, easy-to-use, portable device that provides a high resolution digital image with rapid and easy calibration essential to ensuring color reproducibility. Videodermoscope also provides objective and reproducible measurements to determine MI and to efficiently predict skin response to sunlight. Importantly, under clinical conditions, MI measurements are actually more consistent with a videodermoscope than with a digital camera. Conclusion Although these findings warrant further investigation in a larger and more racially diverse subject population in order to validate this methodology, the data suggest that quantification of pigmentation in a digital image holds promise as a simple, non-invasive, practical and objective approach to more reliably document skin phototypes, particularly for those who are at high risk of developing skin cancer. Software and hardware, with standardization, may undergo development and be adaptable for quanti- 40 doi: 10.18282/jsd.v1.i1.15 Majewski S, et al. fication of change in pigment associated with biological processes such as stimulation of melanogenesis by hormones and UVL. 9. Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References 1. 2. 3. 4. 5. 6. 7. 8. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. 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JAMA Dermatol 2015; 151(8): 902–903. doi: 10.1001/jamadermatol.2015. 0351. 42 doi: 10.18282/jsd.v1.i1.15 doi: 10.18282/jsd.v1.i1.42 ORIGINAL RESEARCH ARTICLE Important aspects of Demodex diagnostics Alexey Kubanov A1, Gallyamova Yulia2, Anzhela Grevtseva2* 1 State Scientific Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation, Moscow, Russia 2 Russian Medical Academy of Postgraduate Education, Ministry of Healthcare of the Russian Federation, Moscow, Russia Abstract: The article presented our reviews on methodological advances in the diagnosis of demodecosis via our own research on demodecosis diagnosis efficiency with the aid of fluorescence lifetime measurement using confocal laser scanning microscopy. Under our supervision, there were 60 patients with acne and rosacea complicated with demodecosis, 60 patients with acne and rosacea without demodecosis, and 30 healthy volunteers. All patients underwent skin scraping and epilation of eyebrows and/or eyelashes, and the examination of skin morphology was conducted using confocal laser scanning microscopy. The research has shown the advantages of in vivo confocal laser scanning microscopy over the conventional microscope. Keywords: Demodex; demodecosis; Demodex mites; confocal laser scanning microscopy; acne; rosacea Citation: Kubanov A, Gallyamova Y, Grevtseva A. Important aspects of Demodex diagnostics. J Surg Dermatol 2016; 1(1): 43–51; http://dx.doi.org/10.18282/jsd.v1.i1.42. *Correspondence to: Anzhela Grevtseva, Russian Medical Academy of Postgraduate Education, Ministry of Healthcare of the Russian Federation, Barrikadnaya Str., 2/1, Moscow, 123995, Russia, [email protected]. Received: 1st February 2016; Accepted: 15th February 2016; Published Online: 20th April 2016 Introduction Demodecosis is a skin disease caused by a group of parasitic and opportunistic mites from the group of acariasis known as Demodicidae (Demodex folliculorum longus and Demodex folliculorum brevis). The mites with the size of 0.2–0.5 mm live in sebaceous and meibomian glands, which are in the hair follicles of humans and mammals. According to various sources, the incidence of demodecosis is from 2% to 5% and is ranked at the seventh place in terms of frequency among skin diseases. In terms of the structure of acneiform dermatoses, 10.5% are classified as demodecosis. Despite the fact that mites on human skin are part of skin microflora, they do not cause any clinical symptoms and complaints in the vast majority of people; however, they maintain the acuity of the inflammatory process in dermatoses such as acne, rosacea, seborrheic dermatitis and perioral dermatitis, which may also cause distinct diseases[1]. In the presence of Demodex, clinical mani- festation may acquire a more pronounced characterization with the prevalence of papulopustules elements, diffusive erythema, formative stages of granulomas, nodular elements and macro-abscesses[1]. In 1903, Stcherbatchoff N found mites in ciliary follicles of eyelids of a person, in which, these mites play a vital role in the development of blepharitis and blepharoconjunctivitis, as cited by Whiting DA[2]. Interestingly, different types of mites cause different clinical manisfestations, which presumably are connected to the size of the mites themselves. Detection of both Demodex folliculorum longus and Demodex folliculorum brevis often observed erythema and desquamation of epithelium, and symmetric papulopustules elements, respectively[3]. Long-term chronic demodecosis is characterized by skin thickening, a feeling of constriction, decreased elasticity and softness, and presence of serous or saniopurulent crusts[4]. According to the International Classification of Diseases, 10th Revision, demodecosis can be attributed under code B88.0, i.e., in the subgroup of “other acariasis” Copyright © 2016 Kubanov A, 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. 43 Important aspects of Demodex diagnostics including demodecosis acarodermatitis, which is a type of dermatitis caused by Dermanyssus gallinae, etc. By all means, the diagnosis of demodecosis is possible only after the establishment of laboratory diagnostics which find mites of the genus Demodex. The most common method of laboratory diagnostics is based on the preparation of acarogram by counting larvae, nymphs, eggs and mites in adult stage. The criterion of mites activity is that the number of mites must be more than 5, with larvae or eggs on 1 cm2 of the infected area. In the diagnosis of demodecosis of the eyelashes, the detection of a mite on 2–4 eyelashes is considered as normal. In order to evaluate the effectiveness of the therapy, repeated acarogram is carried out for the purpose of counting the number of mites and determining their activity. The activity of mite infestation can be measured through changes in the number of mites per 1 cm2 of the infected area. It is known that the course of treatment of demodecosis can move into the untreated zones via acaricide means. In such cases, more often than not, the mites are located at the edge of the scalp[4]. Technically, the procedure of mite detection is quite simple. Demodex is possibly detected by scraping during the extraction of ducts’ contents of sebaceous glands, or by removing the eyelashes and/or eyebrows without damaging the hair follicles. Skin scraping is conducted by means of disposable scalpel at places where the greatest congestion of Demodex reside (forehead, wings of nose, and chin). The tested material is placed on a glass slide with a 10% alkaline solution (KOH), covered with a glass slide and examined under the microscope at low magnification. The advantage of this method is its ability to analyze large affected areas, as well as removing mites not only from the surface of the skin but also directly from the sebaceous glands. However, there is a problem: it is not always possible to detect mites deeper in the sebaceous glands. Another disadvantage is the epithelium trauma, which is associated with the relative painfulness of the procedure and the discomfort in patients after epilation[4]. It should be noted that information on scraping method is less abundant, and negative analysis result of laboratory research does not prove the absence of mite infestations[5]. There are other ways of detecting mites, such as carrying out surface biopsy (“scotch tape test”)[5,6]. A drop of cyanoacrylate adhesive (BF-6, sulfacrylate) is placed on an oil-free cover glass, and then pasted onto the affected surface for 1 min. After its removal from the affected surface, the alkaline solution is applied, covered with a glass slide and examined under the microscope at low magnification. The modification of the procedure is in the use of scotch tape, with the size of 1 cm2, adhered onto the cover glass on the alkaline solution after its removal. Upon removing the cover glass or adhesive tape, the surface layer of the epidermis and the contents of sebaceous glands with the existing mites remain on the surface. The advantage of the method is its ease of use, but skin epithelium trauma, difficulty in obtaining material from the nose wings, and incomplete sterility of the obtained samples are clear disadvantages[4]. A more difficult method of demodecosis diagnosis is carrying out a skin biopsy with subsequent histology of the received samples. For this purpose, a small skin area is obtained either by puncture (punch) or excisional (scalpel) method, fixed within a day in 10% neutral formalin solution, compacted with paraffin and stained with hematoxylin-eosin. Histological study provides many advantages; in particular, it is possible to fully see the sebaceous glands and surrounding areas. The main disadvantages of this method include skin trauma with the formation of scar and the inability to examine a large area of the skin[4]. As a diagnostic tool to identify Demodex, Segal R et al. proposed the use of dermatoscope. The dermoscopy method allows the visualization of mites on skin surface and enlarged skin vessels. However, in this case, there is less information as it is impossible to detect the mites at in-situ localization in the sebaceous glands and in the presence of nodular elements, as well as in macro-abscesses[7]. Despite the fact that the “gold standard” for the pathomorphological evaluation of normal and affected skin in dermatology is still a biopsy followed by histological study, there is always a demand in the applied medicine field for informative, high-tech and non-invasive diagnostic methods, which include confocal laser scanning microscopy[8]. Marvin Minski in 1957 patented “scanning microscope with two-stage focus” (termed “confocal”, based on having the same foci). In common fluorescence microscope, the mercury or xenon lamp is used as the light source for fluorescence emission; however, in modern confocal microscope, it uses laser. The laser in confocal microscopy was used by P. Davidovich for the first time in 1969. As a source of light in modern confocal microscopes, laser is used for a more accurate work of the optical system of the microscope due to reduced number of reflections in the images, thus providing better focus of the beam of light. A focused laser beam illuminates a certain point of the skin[9]. Due to the specific arrangement of the microscope, the back focus of the condenser –where “confocal” aperture of photo-detector is established–coincides with the front focus of lens and thus obtains images from a very thin layer of an object coined as “optical sections”. The work of confocal microscope 44 doi: 10.18282/jsd.v1.i1.42 Kubanov A, et al. is based mainly on the ability of various structures of the skin to refract the laser light to obtain images of the epidermis and dermis layers[10], and to evaluate the state of the vessels of the skin and dermal fibers[11]. In vivo confocal laser scanning microscopy is a new method of studying skin structure through micrograph images that are in the form of white, grey and black shades. Micrograph images of melanocytes and keratinocytes look bright and white, respectively, whereas air and serous fluid look black[12]. Confocal laser scanning microscopy allows the determination of skin thickness and the visualization of different layers of the skin. Thus, the method provides additional information concerning composition and structure of the skin[13]. In ophthalmology, it is possible to visualize changes in meibomian glands in the form of extension or obstruction, the presence of inflammatory infiltrates and the detection of Demodex mites[14]. The method of confocal laser scanning microscopy can be compared to histological research of the skin with the advantage that this research is carried out non-invasively[10]. According to various sources, the sensitivity of the method is 83%–91%, while the specificity is 95%–99%[15-17]. The use of confocal laser scanning microscopy in vivo in dermatology is considered one of the most prospective methods today, in spite of the fact that it has several disadvantages (obtaining relatively superficial images up to 200 microns which limits the possibility of research of deeper skin layers, absence of the possibility of obtaining vertical images, high cost of the equipment and its operation and, consequently, the inaccessibility to a larger number of dermatologists)[11,18]. In comparison to conventional light microscopy, the advantages of confocal laser scanning microscopy method are, for instance, due to its high-contrast images with high resolution, three-dimensional reconstruction, and digital data processing[12,17]. One of the advantages of this method is its ability to detect and quantify Demodex folliculorum on the face of patients with rosacea and acne by counting the mites and follicles per unit area. Sattler EC et al. examined the skin of patients with rosacea and described the presence of Demodex in the form of round or long cone-shaped structures[19]. Kojima T et al. demonstrated the use of confocal laser scanning microscopy for the diagnosis of eye affected with Demodex[20]. The authors were able to detect mites in the terminal of eyelash bulbs, causing inflammatory infiltrates around the meibomian glands and conjunctiva. Thus, confocal laser scanning microscopy is considered as a non-invasive and rapid method for detecting mites of the genus Demodex based on scientific findings in literatures[21]. Considering the relevance of this subject as discussed above, we have conducted an examination on healthy volunteers and patients suffering with acne and rosacea through confocal laser scanning microscopy in vivo means. The aim of the research is to assess the impact of Demodex via clinical manifestation of acne and rosacea, and to compare the efficiency of demodecosis diagnosis in patients with acne and rosacea by various methods. Materials and methods Under our supervision, there were 60 patients suffering from acne and rosacea complicated with demodecosis (group I), 60 patients suffering from acne and rosacea without demodecosis (group II) and 30 healthy volunteers (group III). Diagnosis of acne and rosacea was established based on clinical manifestation of the diseases. Statistical analysis was performed using SPSS 21 software package. The relationship between categorical indicators was established with the use of Fisher's exact test. Fisher's exact test is a test reflecting statistical significance, used in the analysis of categorical data when sample sizes are small. In order to assess the significance differences in the size of the follicles, both the one-way analysis of variance (ANOVA test) and paired comparisons analysis was used. In order to assess the degree of acne’s severity, the classification of the American Academy of Dermatology was followed as below: I degree–the presence of comedones (opened and closed) and up to 10 papules; II degree–comedones, papules, up to 5 pustules; III degree–comedones, papulopustules rash, up to 5 nodules; IV degree–pronounced inflammatory reaction in the deeper layer of the dermis, with the formation of multiple painful nodules and cysts. The symptoms of rosacea’s severity were assessed through its clinical and morphological classifications: erythematous; papular; pustules; infiltrative-productive. All respondents were examined for the presence of Demodex by scraping the contents of sebaceous glands, epilation of eyebrows and eyelashes. Using confocal laser scanning microscope VivaScope 1500® (Lucid Inc., Rochester, NY), the research was conducted at three points of interest (both cheeks and forehead). Distribution of the groups in terms of age, gender and diagnosis are presented in Table 1 44 men and 106 45 doi: 10.18282/jsd.v1.i1.42 Important aspects of Demodex diagnostics women, with the mean age of 29.6 ± 10.3 years old, participated in the study. Criteria of patients’ inclusion in group I and II are: patients had been diagnosed with acne and rosacea existence, age 18 years and above, and gave informed consent before their participation in the study. Exclusion criteria from the study were namely the existence of concurrent somatic diseases of a heavy current or neoplastic character, alcohol or drug addiction, patient’s lack of desire to continue with the study, occurrence of allergic reactions, development of significant side effects during treatment, and pregnancy and lactation. Criteria for inclusion in group III: age 18 years and above, with absence of any skin and somatic diseases of a heavy current or neoplastic character. Table 1. Distribution of groups by age, gender and diagnosis Group I Group II Group III Total 33.7 ± 13.0 28.3 ± 12.0 26.9 ± 6.03 29.6 ± 10.3 male 24 (40%) 14 (23%) 6 (20%) 44 female 36 (60%) 46 (77%) 24 (80%) 106 acne 40 (67%) 34 (57%) - 74 rosacea 20 (33%) 26 (43%) - 46 60 (100%) 60 (100%) 30 (100%) 150 Age (years) Gender Diagnosis Total The presence of mites was confirmed by scraping the contents of sebaceous glands, epilation of eyebrows and eyelashes. Scraping was conducted using a sterile lancet at places with greatest congestion of sebaceous glands, which are located on the face – forehead, nose, chin and cheeks. The received material was placed on a glass slide, with a drop of 10% KOH solution (potassium hydroxide) applied onto it and then viewed under a microscope. The number of mites per 1 cm2 were counted. The diagnosis of demodecosis was considered valid if the contamination of mites on the skin was more than 5 mites on 1 cm2, or if there are more than 4 mites on the eyelashes. During microscopy evaluation, mites from the genus Demodex, i.e., Demodex folliculorum longus and Demodex folliculorum brevis, were found. A research using confocal laser scanning microscope VivaScope 1500® (Lucid Inc., Rochester, NY) was carried out at three points (both cheeks and forehead) in two operating modes of a microscope, i.e., VivaBlock and VivaStack. The patients’ skin was visualized in the form of 5 × 5 mm size, with laser power of 21.7 mW. By means of confocal microscopy, quantification of mites in the follicles was carried out, during which, the average size of follicles and Demodex mites were determined in depth. For statistical analysis, the Fischer’s exact test and the one-way ANOVA test were used. Results Clinical characteristics of patients are presented in Table 2 and Table 3. As can be seen in both tables, Demodex was detected more frequently in patients with rosacea than in patients with acne. During analysis, it was found that patients with demodecosis (group I) were dominated with heavier clinical forms of acne and rosacea. This group was marked with III and IV degrees of acne, with papular and pustules forms of rosacea in most cases, and with two patients diagnosed with infiltrative-productive form of rosacea. On the other hand, in group II the superficial forms of the disease revealed I and II degrees of acne with the existence of erythematous form of rosacea. It gives the grounds to assume that the existence of demodecosis complicates the course of acne and rosacea, thereby promoting the development of inflammatory elements. The prevalence of severe forms of acne and rosacea in patients with concomitant diagnosis of demodecosis confirms the need for microscopic diagnosis of Demodex in patients with acne and rosacea. Table 2. Distribution of patients with acne depending on the presence of mites and disease severity Disease severity (degree) I II III IV Total yes no Frequency 6 2 8 % severity 75.0% 25.0% 100.0% % complication 17.6% 5.0% 10.8% Frequency 17 4 21 % severity 81.0% 19.0% 100.0% % complication 50.0% 10.0% 28.4% Frequency 11 22 33 % severity 33.3% 66.7% 100.0% % complication 32.4% 55.0% 44.6% Frequency 0 12 12 % severity 0.0% 100.0% 100.0% % complication 0.0% 30.0% 16.2% 34 40 74 Frequency Total Presence of Demodex mites % severity 45.9% 54.1% 100.0% % complication 100.0% 100.0% 100.0% As can be seen in Table 2, Demodex is detected in patients with acne who had more severe forms of the disease in most cases (the significance difference of Fisher's 46 doi: 10.18282/jsd.v1.i1.42 Kubanov A, et al. Table 3. Distribution of patients with rosacea depending on the presence of mites and disease severity Presence of Demodex mites Type of disease no 18 4 22 81.8% 18.2% 100.0% 69.2% 20.0% 47.8% Frequency 6 10 16 % severity 37.5% 62.5% 100.0% % complication 23.1% 50.0% 34.8% Frequency 2 4 6 % severity 33.3% 66.7% 100.0% % complication 7.7% 20.0% 13.0% Frequency 0 2 2 % severity 0.0% 100.0% 100.0% % complication 0.0% 10.0% 4.3% Frequency 26 20 46 % severity 56.5% 43.5% 100.0% % complication 100.0% 100.0% 100.0% Frequency % complication Papules Pustules Infiltrativeproductive Total Total yes Erythematous% severity telangiectatic exact test was p = 0.001). Depending on the types ofrosacea, the incidence of mites of the genus Demodex is statistically significant. As shown in Table 3, mites were detected in severe forms of rosacea: papular, pustules and infiltrative-productive (the significance difference of Fisher's exact test was p = 0.004). In determining the species of Demodex, it was revealed that patients with acne bore different species of Demodex which can also be in the combination of two types of mites. In over half of the cases (N = 33; 82.5%) Demodex folliculorum longus was identified, 10% (N = 4) had Demodex folliculorum brevis while both species of mites were found in 7.5% (N = 3) (Table 4). In most cases, patients with rosacea revealed the existence of Demodex folliculorum longus (N = 14; 70%) (Table 5). In situations where more severe forms of acne were found, the presence of Demodex folliculorum longus was often detected significantly (the significance of Fisher's exact test was p = 0.004). As can be seen in Table 5, the mite species were significantly dependent on the clinical form of the disease, which had not been revealed previously (the significance difference of Fisher's exact test was p = 0.354). However, by analyzing the data in Table 4 and Table 5, it is apparent that the mites Demodex fol liculorum longus were more often detected in patients Table 4. Species of Demodex mites in patients with acne depending on the severity of the disease (group I) Demodex species Disease severity (degree) I II III IV Total Demodex folliculo- Demodex folliculorum rum brevis longus Demodex folliculorum longus + Demodex folliculorum brevis Total Frequency 1 0 1 2 % severity 50.0% 0.0% 50.0% 100.0% % species 25.0% 0.0% 33.3% 5.0% Frequency 2 1 1 4 % severity 50.0% 25.0% 25.0% 100.0% % species 50.0% 3.0% 33.3% 10.0% Frequency 1 20 1 22 % severity 4.5% 90.9% 4.5% 100.0% % species 25.0% 60.6% 33.3% 55.0% Frequency 0 12 0 12 % severity 0.0% 100.0% 0.0% 100.0% % species 0.0% 36.4% 0.0% 30.0% Frequency 4 33 3 40 % severity 10.0% 82.5% 7.5% 100.0% % species 100.0% 100.0% 100.0% 100.0% 47 doi: 10.18282/jsd.v1.i1.42 Important aspects of Demodex diagnostics Table 5. Species of Demodex mites in patients with rosacea depending on the clinical form (group I) Demodex species Demodex folliculorum brevis Demodex folliculorum longus Demodex folliculorum longus + Demodex folliculorum brevis Total Frequency 2 1 1 4 % severity 50.0% 25.0% 25.0% 100.0% % species 50.0% 7.1% 50.0% 20.0% Frequency 2 7 1 10 % severity 20.0% 70.0% 10.0% 100.0% % species 50.0% 50.0% 50.0% 50.0% Clinical form of the disease Erythematous form Papules form Pustules form Infiltrativeproductive form Total Frequency 0 4 0 4 % severity 0.0% 100.0% 0.0% 100.0% % species 0.0% 28.6% 0.0% 20.0% Frequency 0 2 0 2 % severity 0.0% 100.0% 0.0% 100.0% % species 0.0% 14.3% 0.0% 10.0% Frequency 4 14 2 20 % severity 20.0% 70.0% 10.0% 100.0% % species 100.0% 100.0% 100.0% 100.0% with acne of III and IV degrees and with papular and pustules forms of rosacea. Therefore, we can assume that it is Demodex folliculorum longus that provokes more severe clinical forms of acne. In order to assess the reliability of the method using confocal microscopy, the survey was conducted in all three groups. The obtained data are presented in Table 6 and shows not only high information content of the method, but also its superiority over the microscopic diagnosis. As can be seen in the table, the mites were found in all patients with demodecosis using the confocal laser scanning microscopy. Demodex was defined as rounded or long cone-shaped formations in hair follicle orifices and sebaceous glands (Figure 1). During the inspection on patients from group III, the mites were successfully identified in 10 patients (13%), Figure 1. Images obtained using confocal laser scanning microscope VivaScope 1500 ® (Lucid Inc., Rochester, NY). Hair follicles and sebaceous glands with the presence (left) and absence (right) of Demodex mites 48 doi: 10.18282/jsd.v1.i1.42 Kubanov A, et al. Table 6. Identification of Demodex mites with different diagnostic methods Identification of Demodex folliculorum Demodex folliculorum longus detected Group I (number of patients; %) Group II (number of patients; %) Group III (number of patients; %) − − − − 47 (62%) 8 Total (number of patients; %) 47 (62%) 8 Demodex folliculorum brevis detected (10.5%) Two types of mites detected (6.5%) Detected with confocal laser scanning microscope 60 10 6 76 (79%) (13%) (8%) (100%) 60 10 6 76 (79%) (13%) (8%) (100%) Total (10.5%) 5 − of whom the method of scraping has shown negative result (Table 6). The study from healthy volunteers of group III found Demodex mites in follicles of 6 people (8%) by using the method of confocal laser scanning microscopy. These data confirmed the assumptions of numerous authors that mites can be saprophytes[4]. Thus, the study proves to be a highly informative method, as it allows the discovery of mites especially in depths inaccessible for scarification. By using confocal laser scanning microscope to scan different layers of the skin, we established an average detection depth of mites which equals to approximately 46.63 microns, and corresponds to the level of the granular layer of the epidermis. This method allowed the calculation of the average number of Demodex in the follicle (N = 3.37) and the average size of Demodex 5 − (6.5%) (which is equal to 0.024 microns). Interesting data were obtained at the size measurement of follicle orifices. It was established that the sizes of follicle orifices in all three groups were authentically different (Table 7 and Table 8). The differences in sizes of hair follicle orifices and excretory ducts of sebaceous glands in group I were found to be statistically significant, exceeding the sizes in groups II and III. When comparing the sizes of hair follicle orifices and excretory ducts of sebaceous glands of groups II and III, the differences were not statistically significant. The largest size of the orifices was found in patients with demodecosis. This fact makes it possible to assume that a large pore size is a favorable condition for infestation of the mites. Table 7. Sizes of hair follicle orifices in the studied groups Sizes of hair follicular orifices and excretory ducts of sebaceous glands (Мean ± sd) Group I 0.125 ± 25 × 0.123 ± 35 Group II Group III 0.89 ± 32 × 0.095 ± 31 0.065 ± 23 × 0.072 ± 29 Table 8. Size differences of hair follicle orifices and excretory ducts of sebaceous glands among groups Size differences of hair follicle orifices and excretory ducts of sebaceous glands Group I and II Group I and III Group II and III 0.012 × 0.017 0.007 × 0.009 0.11 × 0.29 Discussion The study demonstrated that demodecosis is often diagnosed in patients with severe clinical forms of acne and rosacea. This fact suggests that the mites complicate the course of the diseases, and thus promoting the development of inflammatory elements. This once again confirms that in order to achieve effective treatment on these dermatoses, there is a need for diagnostic advancement for Demodex mites. 49 doi: 10.18282/jsd.v1.i1.42 Important aspects of Demodex diagnostics In the analysis, the mites’ species were found to be significantly dependent on the clinical form of the disease; however, the Demodex folliculorum longus mites were more often detected in patients with acne of III and IV degrees and with papular and pustular rosacea. Thus, we can assume that Demodex folliculorum longus provokes more severe clinical forms of acne. The obtained data proved to have high informational content of confocal microscopy in view of its diagnostic advantages on demodecosis and its superiority over light microscope. Confocal laser scanning microscope makes it possible to visualize mites that are both found in the deeper layers of the skin and inaccessible to scarification. This method has a high potential to be a diagnostic means for demodecosis, which makes it possible to scan various layers of the skin that allows the determination of the depth of mite detection (≈46.63 microns), number of mites and also their size. The lack of epithelium trauma and painful procedures are other additional advantages of this method. 5. 6. 7. 8. 9. 10. Conclusion Thus, as a result of research on patients with acne, rosacea and healthy volunteers, we established high informational content of confocal laser scanning microscopy in the diagnosis of demodecosis and its advantages over the usual light microscope. 11. Conflict of interest 12. The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. 13. References 1. 2. 3. 4. Chen W, Plewig G. Human demodecosis: Revisit and a proposed classification. Br J Dermatol 2014; 170(6): 1219– 1225. doi: 10.1111/bjd.12850. Whiting DA. 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Noninvasive in vivo detection and quantification of Demodex mites by confocal laser scanning microscopy. 20. 21. Br J Dermatol 2012; 167(5): 1042–1047. doi: 10.1111/ j.1365-2133.2012.11096.x. Kojima T, Ishida R, Sato EA, Kawakita T, Ibrahim OMA, et al. In vivo evaluation of ocular demodecosis using laser scanning confocal microscopy. Invest Ophthalmol Vis Sci 2011; 52(1): 565–569. doi: 10.1167/iovs.10-5477. Erdemir AT, Gurel MS, Koku Aksu AE, Bilgin Karahalli F, Incel P, et al. Reflectance confocal microscopy vs. standardized skin surface biopsy for measuring the density of Demodex mites. Skin Res Technol 2014; 20(4): 435–439. doi: 10.1111/srt.12137. 51 doi: 10.18282/jsd.v1.i1.42 Author Guidelines Cover Letter The cover letter is necessary for each submission. The cover letter should be uploaded as a separate file in Step 4 during the submission. 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