Journal of Surgical Dermatology 2021 V6I2 by Journal of Surgical Dermatology

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

Prof. Jacek Cezary Szepietowski Wroclaw Medical University Poland

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

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

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

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

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

Dr. Andrea Sisti University of Siena Italy

Dr. Achih H. Chen Augusta University United States

Dr. Bahman Sotoodian University of Alberta, Edmonton Canada

Dr. Ahmed Hassan El-Sabbagh Mansoura University Hospital Egypt

Dr. Aravazhi Ananda Dorai Tropicana Medical Centre Malaysia

Dr. Aikaterini Tsiogka Paracelsus University Hospital, Salzburg Austria

Dr. Armin Kraus Otto-von-Guericke University Germany

Dr. Ajmal Rashid Combined Military Hospital Sialkot Pakistan

Dr. Artur Diaz-Carandell Hospital Parc Tauli Spain

Volume 6 Issue 2 • 2021

Journal of Surgical Dermatology

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

Volume 6 Issue 2 • 2021

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

Contents EDITORIAL 1

Laser surgery for eyelid margin tumors Adam Kemeny-Beke

RESEARCH HIGHLIGHTS 3

Effective treatment of necrobiosis lipoidica using intense pulsed light therapy

ORIGINAL RESEARCH ARTICLE 5

Floseal® use in dermatologic surgical management of vascular malformations: A novel haemostatic agent in Côte d’Ivoire Komenan Kassi, Vagamon Bamba, Kouame Kanga, Aang Allou, Alexandre Kouassi, Ildevert Patrice Gbery, Sarah Kourouma, Isidore Kouassi, Elidje Joseph Ecra, Mamadou Kaloga, Abdoulaye Sangare, Pauline Yoboue-Yao, Jean-Marie Kanga

The efficacy and safety of a 70% glycolic acid peel with vitamin C for the treatment of acne scars Heng Jun Khee, Liau MeiQi May, Yang Shiyao Sam, Aw Chen Wee Derrick, Ho Sue-Ann

A novel total body digital photography smartphone application designed to detect and monitor skin lesions: A pilot study Nicholas Guido, Erika L. Hagstrom, Erin Ibler, Chantelle Carneiro, Kelsey A. Orrell, Ryan C. Kelm, Alfred W. Rademaker, Dennis P. West, Beatrice Nardone

REVIEW 19

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review Bao Anh Patrick Tran, Tiffany Alexander, Ally-Khan Somani

CASE REPORT 31

Necrobiosis lipoidica treated with intense pulsed light Marisa Gonzaga da Cunha, Flávia Cury Rezende, Ana Lucia Gonzaga da Cunha, Carlos D’Apparecida Santos Machado Filho

Multiple clustered dermatofibroma associated with asymptomatic pericardial cyst Piotr Brzezinski, Viktoryia Kazlouskaya, Cesar Bimbi

Periocular syringomas – Successful treatment with fractional CO2 laser Alberto Goldman, Uwe Wollina

A novel surgical method for total nail ablation: Use of triple flap technique Berna Aksoy

SHORT COMMUNICATION 45

The story behind cryosurgery Sara Mohamed Ibrahim Awad

doi: 10.18282/jsd.v6.i2.143

EDITORIAL

Laser surgery for eyelid margin tumors Adam Kemeny-Beke Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Eyelid margin is one of the most challenging anatomic regions in the human body, and eyelid margin tumors raise special difficulties in the field of periocular surgery based on anatomical, histological and aesthetic points of view. Although manually performed surgical excision is the first line choice to remove eyelid margin tumors, previously, of late, lasers have gained popularity with regards to eyelid tumors and especially eyelid margin tumor extraction. There is scarce data with respect to this topic, and most of them are case reports. Different types of laser apparatus emitting different light beams are available for periorbital laser surgery, i.e. argon laser (Ar, 488–514 nm), erbium:yttrium-aluminiumgarnet laser (Er:YAG, 2790–2940 nm), erbium:yttriumscandium-gallium-garnet laser (Er:YSGG, 2790 nm), and carbon dioxide laser with an infrared source (CO2, 10,600 nm). Due to the introduction of new-generation technical innovations such as pencil-shaped hand pieces or new working modes, nowadays laser therapy is one of the most widespread forms of periocular surgery. There are three basic types of interaction between laser beam and tissue: photocoagulation, photodisruption, and photoablation[1]; the clinically most utilized of these is the last one. In the course of laser surgery, a zone of coagulative necrosis called lateral thermal damage (LTD) abuts the treated area. Given the fact that the extension of LTD plays an outstanding role in the aesthetic result, the presence of possible side effects should diminish. In order to achieve a more precise ablation zone, the laser pulse duration should be decreased to a period shorter than the thermal relaxation time of soft tissues. Although newly improved laser sets have several advantages over classic approaches, periocular laser surgery, especially lid margin laser surgery, is not free of complications. Some special features should be taken into consideration, predominantly anatomical and histological issues, tumor localization, and the proximity of the nasolacrimal drainage system. The main issue concerning every type of surgery is the fact that preoperative diagnosis is the key point, and in cases where this is incorrect, additional treatment will be necessary. Periorbital laser surgery is high-ranked in ophthalmology as it combines the advantages of laser surgery achieved in dermatology and aesthetic surgery. [2-4] There are several

benefits of laser vs. traditional excision including less bleeding, tissue destruction, minimal occurrence of dyschromia, etc. Furthermore, there is no postoperative edema and/or ecchymosis, and there are smaller amounts of granulation tissue and, less frequently, fewer unaesthetic scar formations. The laser sharpens excision, evaporation, and fulguration of tissues, all while maintaining hemostasis. One of the best advantages of laser surgery for eyelid margin tumors is its anatomical aspect; since the laser beam keeps the margins in their anatomical position, entropion or ectropion are not to be reckoned with. Although a more extensive collagen shrinkage can occur due to intense heat compared to manually performed surgical excision, it can be avoided by using appropriate energy fluence[5]. Treatment should be started with low energy and then increased, in order to avoid thermal damage. Several factors may have an impact on the result of eyelid margin laser surgery and some of them may result in side effects Among the most severe adverse events referred to in the literature concerning periocular laser surgery are severe burns, corneal injuries, or even ocular perforation. A 0.3 % rate of corneal trauma after lower eyelid laser blepharoplasty was reported by the ASAPS/ASPRS Laser Task Force Survey Summary [6]. To avoid any corneal damage, stainless steel, or metallic non-refl ctive internal ocular shields are highly recommended in the periorbital areas; by using these materials, no detectable alterations in slit-lamp, pupillary, or funduscopic evaluations after periorbital laser irradiation can be identified. The question of infection could be raised during periocular surgery as, often, an uncovered surface is created during these procedures. Different types of potential infections, i.e., bacterial, viral or fungal can occur in the postoperative period after periocular or eyelid laser surgery. Besides Er:YAG lasers, CO2 lasers have become the current tool for resurfacing and rhytidectomy. Since the aforementioned procedures have been related to increased recovery time mainly in patients with darker skin types, to minimize these imperfections of ablative laser, an ablative fractional photothermolysis laser has been designed, which is able to maintain the favorable clinical efficac of the non-ablative CO2 laser. Hypertrophic or keloid scar formation, erythema, and

Copyright © 2021 Kemeny-Beke A. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Laser surgery for eyelid margin tumors

clinical manifestation of vasodilation have also been reported in the literature as some of the most frequent side effects of periocular laser surgery. Pigmentation disorders can also occur following eyelid laser surgery. Hypopigmentation is more frequent than post-inflammatory hyperpigmentation (PIH) after laser treatment, as deep thermal damage eradicates melanocyte population and may unmask a pre-existing vitiligo. This symptom is called the Koebner phenomenon. Some laser surgeons recommend the use of 5-fluorouracil for advancing wound recovery, but this treatment may increase the risk of post-laser hypopigmentation[7]. To reduce hyper- or hypopigmentation eff cts, the surgeon has to minimize the laser energy output. There is a controversy about wearing occlusive dressing in the postoperative period; some authors recommend its application[2], however, others note that this is a risk factor for post-laser surgery’s bacterial and fungal infection[8]. To summarize the cognition about eyelid laser surgery, it has to be emphasized that many patients, who are afraid of traditional surgical interventions, are less scared of laser surgery, which is safe, simple, fast, and efficient. Laser surgery is a very useful skill not only in periocular surgery but also in eyelid margin surgery. In order to minimize their functional and aesthetic complications, thorough patient selection, careful and meticulous checkup, and adequate surgeon training are absolutely indispensable.

References 1. Thall EH. Principles of lasers. In: Yanoff, Duker JS (editors). Ophthalmology. London: Mosby; 1999. p. 251–256. 2. Yates B, Que SK, D’Souza L, Suchecki J, Finch JJ. Laser treatment of periocular skin conditions. Clin Dermatol. 2015; 33(2): 197–206. 3. Trelles MA, Brychta P, Stanek J, Allones I, Alvarez J, et al. Laser techniques associated with facial aesthetic and reparative surgery. Facial Plast Surg. 2005; 21(2): 83–98. 4. Blanco G, Clavero A, Soparkar CN, Patrinely JR. Periocular laser complications. Semin Plast Surg. 2007; 21(1): 074– 079. doi: 10.1055/s-2007-967752. 5. Fulton JE Jr. Complications of laser resurfacing: Methods of prevention and management. Dermatol Surg 1998; 24(1): 91– 99. doi: 10.1111/j.1524-4725.1998.tb04059.x. 6. Apfelberg DB. Summary of the 1997 ASAPS/ASPRS Laser Task Force Survey on laser resurfacing and laser blepharoplasty. Plast Reconstr Surg 1998; 101(2): 511–518. doi.org/10.1097/00006534-199802000-00043. 7. Park KY, Oh IY, Moon NJ, Seo SJ. Treatment of infraorbital dark circles in atopic dermatitis with a 2790-nm erbium: yttrium scandium gallium garnet laser: A pilot study. J Cosmet Laser Ther 2013; 15(2): 102–106. doi.org/10.3109/14764172. 2012.759236. 8. Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing. An evaluation of 500 patients. Dermatol Surg 1998; 24(3): 315–320. doi: 10.1111/j.1524-4725.1998. tb04161.x.

Keywords: periocular laser surgery; eyelid, margin; complication Citation: Kemeny-Beke A. Laser surgery for eyelid margin tumors. J Surg Dermatol 2021; 6(2): 143. http://dx.doi.org/jsd. v6.i2.143. Received: 10th June 2021; Published Online: 18th June 2021 *Correspondence to: Adam Kemeny–Beke, Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary; kemenyba@med.unideb.hu

doi:10.18282/jsd.v6.i2.143

RESEARCH HIGHLIGHTS Effective treatment of necrobiosis lipoidica using intense pulsed light therapy Low-risk method presents quick turnaround of the degenerative disease, researchers found

patient with chronic degenerative disease of the collagen, after two years of unsuccessful treatment, underwent intense pulsed light (IPL) therapy for 14 months and obtained an excellent result, reported a team of Brazilian dermatologists.

“The successful outcome of this case report suggested that IPL may represent a worthwhile option in the treatment of NL, offering low risks of collateral effects, especially when administered by experienced professionals,” wrote Dr. Marisa Gonzaga da Cunha and her co-authors from São Paulo‟s Faculty of Medicine of ABC and Federal University of São Paulo, Brazil, in a case study published by Journal of Surgical Dermatology (JSD). The patient was afflicted with necrobiosis lipoidica (NL), a disorder of collagen degeneration that typically manifests as one or more tender yellowish-brown patches on the lower legs, usually the shin, developing slowly over several months or even persisting for years. At the center

of the patch is usually a shiny, pale area showing prominent blood vessels; and while NL is usually painless, it could ulcerate upon minor injuries with a risk of secondary bacterial infection and delayed healing. Necrobiosis lipoidica affects people of all races and occurs at any age, but it is three times more common in women than in men, according to the British Association of Dermatologists. The cause of necrobiosis lipoidica has not yet been fully understood by modern science, and it has been surmised that NL may have followed damages to the collagen, or fibers which give the skin its strength, possibly “due to changes in the small blood vessels of the skin,” the association stated. While NL is not contagious or cancerous, “there is a small risk of skin cancer (squamous cell carcinoma) developing in longstanding lesions,” added the British Association of Dermatologists. The condition, when first described by dermatologists in 1920s, was postulated to be in conjunction with diabetes. It was not until in the 1960s when the disease, originally named „dermatitis atrophicans lipoidica diabetic‟ was relabeled as necrobiosis lipoidica, omitting altogether of whether the patient is diabetic or not.

3 doi: 10.18282/jsd.v6.i2.129

RESEARCH HIGHLIGHTS

The link between NL and diabetes has still not been clearly determined yet, and the hypotheses proposed range from an abnormality in glucose transport to the degradation of the collagen. Nevertheless, according to the British Association of Dermatologists, while one in 300 diabetics has NL, “most patients with necrobiosis lipoidica have, or will develop, diabetes.” There have been a number of proposed treatments of NL, “but none is 100% effective,” Dr. da Cunha and co-authors said, adding that the therapies often resulted in varied responses, “typically with flattening of borders and almost always a partial clearing with persistent central atrophy.” On the other hand, the researchers noted that intense pulsed light has already been a staple treatment by dermatologists for conditions such as acne vulgaris, vascular and pigmentary disorders, photo-aged skin and scars. “Its basic principle consists of selective photothermolysis — in other words, light energy is absorbed by a specific target chromophore with energy transfer and heat generation, which promotes its subsequent modification. Wavelength can be established according to the absorption peak dependence of the target chromophore. Pulse duration should last less than the thermal relaxation time, which limits heat diffusion and lesion to nearby structures,” their report stated. With the aid of its cut-off filters, the main advantage of an IPL device is its versatility of wavelengths, fluencies, pulse duration and intervals, which allows for the treatment

of a great variety of lesions, the Brazilian researchers said. “It is possible to adjust them according to the type, depth and size of the lesion as well as the patient‟s skin type so that maximum improvement can be achieved without epidermal loss or collateral effects,” they added. Hence, “[t]aking into consideration the positive results of IPL concerning the stimulation of the neoformation of collagen and its action on blood vessels, its use in the treatment of NL was considered,” said the authors. The female patient in their case study was treated with IPL monthly for a period of 14 months, and rapid improvements in her condition were observed beginning from the second session. After 13 sessions, her skin quality improved significantly, displaying fewer blood vessels and with the edges of the redness of the skin returning to a tone similar the surrounding area, the authors described. The result confirmed the researchers‟ conjecture that IPL promotes tissue remodeling through the formation of new dermal collagen, the increased activity of fibroblasts (which produces collagen), and the decrease in content and rearrangement of the highly elastic elastin fibers. “As IPL stimulates neocollagenesis, it was selected due to its use as a therapeutic attempt, resulting in an excellent response,” they reported.■ Marisa Gonzaga da Cunha, Flávia Cury Rezende, Ana Lucia Gonzaga da Cunha and Carlos D‟Apparecida Santos Machado Filho are co-authors of this featured case report which is published on pages 31–34 in this JSD issue.

4 doi:10.18282/jsd.v6.i2.129

doi: 10.18282/jsd.v6.i2.149

ORIGINAL RESEARCH ARTICLE

Floseal ® use in dermatologic surgical management of vascular malformations: A novel haemostatic agent in Côte d’Ivoire Komenan Kassi1,2, Vagamon Bamba3, Kouame Kanga1,2, Aang Allou2, Alexandre Kouassi1,2, Ildevert Patrice Gbery1,2, Sarah Kourouma1,2, Isidore Kouassi1,2, Elidje Joseph Ecra1,2, Mamadou Kaloga1,2, Abdoulaye Sangare1,2, Pauline Yoboue-Yao1,2, Jean-Marie Kanga1,2 1

Department of Dermatology and Infectious Diseases, Training and Research unit of Medical Sciences, University of Felix Houphouet Boigny, Abidjan, République de Côte d'Ivoire 2

Dermatology Department of Teaching Hospital of Treichville, Abidjan, République de Côte d'Ivoire Dermatology Department of Internal Medicine, University of Bouaké, République de Côte d'Ivoire

Abstract: A vascular malformation is a congenital growth of artery, venous, capillary or lymphatic vessels leading to functional and aesthetic problems. Although surgical maneuvers allow correction of abnormalities, it poses risk of intra and post-operative blood loss. Sealants have been used during surgical procedures to reduce blood loss. A descriptive study was conducted on a new generation Floseal® to demonstrate its effectiveness to reduce intra and post-operative bleeding during vascular malformation corrective surgery. A group of 19 patients presented with vascular malformations and underwent surgical correction associated with Floseal® use. The mean age of our patients’ was 12.3 years (1 to 33 years). The majority of them (57.6%) were aged between 5 to 15 years. The most common vascular malformation treated was hemangioma (45.5%). Majority of these lesions were located on the head (72.7%). Blood transfusion was not accounted for in any of the cases as average blood loss was 18.18 mL (5 to 70 mL). The average length of hospital stay was 2.4 days. Ten patients (90.9%) were discharged in 2 days after drain was removed. Floseal®, a new generation local haemostatic, is easy to use and efficient to achieve haemostasis for treatment of vascular malformation. Haemostasis was achieved in a short time and blood loss was minimal. However, caution should be taken to reduce allergic reactions and potential viral transmissions, and further study should be done to recommend its use. Keywords: vascular malformation; surgery treatment; Floseal® use Citation: Kassi K, Bamba V, Kanga K, Allou A, Kouassi A, et al. Floseal® use in dermatologic surgical management of vascular malformations: A novel haemostatic agent in Côte d’Ivoire. J Surg Dermatol 2021; 6(2): 149; http://dx.doi. org/10.18282/jsd.v6.i2.149. *Correspondence to: Komenan Kassi, Department of Dermatology, Training and Research Unit of the University of Felix Houphouet Boigny of Abidjan, Cote d’ Ivoire; siskakomlo@yahoo.fr, komenan.kassi@univ-fhb.edu.ci Received: 10th January 2021; Accepted: 30th March 2021; Published Online: 29th April 2021

Introduction A vascular malformation is a type of birthmark, or congenital vascular growth, made of arteries, venous, capillaries, or lymphatic vessels; that account for functional and aesthetical problems, because of its progressive nature[1]. The treatment for vascular malformation depends upon the type of malformation. Laser therapy is effective for

capillary malformations, embolization is effective for artery malformations and sclerotherapy is effective for venous malformations. In all vascularmalformations, surgery may be effective alone or in combination with non surgical methods, particularly at instances of incomplete removal. Previous studies state that preoperative embolization, sclerotherapy or laser therapy,can be performed prior to surgery and reconstruction[1,2]. It may be noted that surgery leads frequently to intra or

Copyright © 2021 Kassi K, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Floseal® use in dermatologic surgical management of vascular malformations: A novel haemostatic agent in Côte d’Ivoire

post-operative bleeding that necessitates blood transfusion and prolonged hospital stay,which is also associated with high morbidity and mortality risk. To overcome these complications, some researchers recommend the use of local haemostatic agents composed of thrombin (bovine or human recombinant)[3,4]. In this frame, a new sealant was developed to control a pulsatile and other vascular bleedings. It is a fusion matrix haemostatic sealant that consists of a gelatin matrix mixed with thrombin. this sealant acts with a potential of swelling when in direct contact with blood. This adhesive contact leads to a compression at the bleeding site and achieves haemostasis within 10 min[5]. The aim of this study is to demonstrate the effectiveness and advantages of Floseal ® (human recombinant thrombin) use in vascular malformation surgery to stop bleeding in intra and post-operative period during dermatologic surgery.

Thereafter, Floseal ®was put directly in contact with the bleeding surface through the syringe tip during the procedure. The surface was irrigated and the excess of Floseal®was removed. The reconstruction was conducted and surgical wound was dressed. During follow-up, side effects were assessed and recorded (allergic reactions, viral or bacterial infections, etc.) For data collection, the following parameters: demo graphic, clinical, intra and post-operative blood loss, complications, length of hospital stay, duration of drain removal, need for blood transfusion, and length of follow up was recorded. The blood loss was estimated based on the blood loss from the operation site and the blood collected from the drain.

Materials and methods We conducted a descriptive study conducted over 6 months on patients diagnosed with vascular malformations in the Department of Dermatology, Teaching Hospital of Treichville. All patients diagnosed with vascular malformations were enrolled after obtaining informed oral consent to undergo surgery. Prior to undergoing surgical correction, patients were evaluated with detailed clinical history, physical examination, standard blood testing, biological haemostatic analysis including D-dimer dosage, human genetic analysis for congenital abnormality, and radiologic examination such as: magnetic resonance imaging (MRI), positron emission tomography scan (PET-scan), Echodoppler and arteriography imaging. Patients suspected with allergic reactions to any drugs (particularly bovine collagen component) in the past were excluded from the study. All patients received pre-medication of heparin 3000 to 6000 international units as subcutaneous injection, to prevent coagulation disorders. We used Floseal ® which is a new generation local haemostatic[6]. This sealant contains: •

Human thrombin solution derived from pooled human plasma, with its biological activities of fibrinogen activation

•

Gelatin based matrix from bovine collagen with micro granules. These micro granules represent the mechanical support for the product’s capacity of self-expansion thereby leading to hemostasis.

Floseal® was used in intra operative setting and after excision. The first step was preparation of Floseal®by taking 5000 units of lyophilized human thrombin from a 5mLsyringe while using a 1-mL syringe with 0.8 mL of sterile saline solution. Then, the dispersion needle is assembled with the 1-mL syringe that contains gelatin matrix. Under steady movement (depression and pressure) of the plunger, the thrombin disperses into gelatin within 30 s. The mixture obtained (Figure 1) is used within 2 h.

Figure 1. Floseal®, 5 mL of haemostatic matrix

(Source: Baxter US)

Ethics Statement Oral consent was obtained from all patients to participate in the study. The local dermatological ethical committee has approved this study.

Results A group of 19 patients underwent (Figures 2 and 3) surgical correction for vascular malformations (coupled with Floseal®). Of these, one patient was noted for artery, lymphatic and venous malformation (ALVM) known as Klipple-Trenauney syndrome. The average age of our patients was 12.3 years, ranging from 5 to 29 years old. There were more female patients (ten) than male patients (nine), with a sex ratio of 0.9, and majority of the vascular malformations was located on the head in 57.5% of cases (Table 1). We did not observe any allergic reaction or viral transmission, nor any necessity for blood transfusion in any of these cases. The overall intra and post-operative bleed ranged from 5 to 70 mL, with an average estimated to 18.18 mL. The median length of the post-operative hospital stay was 2.4 days (1 to 7 days). Of all the patients, 18 patients (94.7%) were discharged and drains were removed in this time frame, while clinical state was good, and drains contained less than 20 mL of serum or blood discharge. Only one patient (5.3%) was discharged with his drain because it contained about 90 mL of serum. It was removed

Komenan K, et al.

after one week of follow-up. The average duration of follow-up was 14 days (7 to 45 days).We did not find any sides effects in pre and post-operative period. We found only one post-operative complication as a pyoderma in a patient who presented an enormous lymphatico venous malformation in the arm (the KlippleTrenauney syndrome) that was excised, drained. It healed within two weeks.

Figure 2. Vascular malformations: lymphatic and venous malformation of the hand

Table 1.

Patient’s baseline characteristics

Characteristics

Number (N=19)

Percentage (%)

Sex M 9 47. 4 F 10 52. 6 Age (years) [0–5] 4 21 [5–10] 7 36.8 [10–15] 2 10.5 [15–20] 3 15.8 [20–25] 1 5.3 [25–30] 1 5.3 [30–35] 1 5.3 Type of vascular malformation LM 2 10.5 LVM 3 15.8 VM 5 26.3 ALM 1 5.3 Hemangioma 8 42.1 Location Lower limb 3 15. 8 Forearm 3 15. 8 Arm 2 10. 5 Head (forehead, cheek, nose, 11 57. 9 eyebrow) Abbreviations: VM: venous malformation; LM: lymphatic malformation; LVM: lymphatic and venous malformation; ALVM: artery, lymphatic and venous malformation

Discussion Floseal® is a gelatin matrix combined with thrombin, it has the potential to swell (20% by volume), when in contact with blood. This mechanism allows the product to impart support, (by clot formation due to high concentration of thrombin) to keep the material in place and to provide compression to the bleeding tissue or surface thereby achieving haemostasis within approximately 10 min [5,6]. Floseal® was associated with a significantly higher rate of successful haemostasis and a shorter time to achieve haemostasis (p<0.001 for both) in comparison with the other alternatives when conventional methods failed in cardiovascular surgery[7,8]. In our series, Floseal® use allowed us to achieve a good haemostasis in a short time. This observation could explain the early hospital discharge, i.e. within 2 days and no requirement for blood transfusion. Floseal® use is a simple and short procedure, as it is easily applicable onto the bleeding site or surface. Its use does not need specialized training. Some studies reported that Floseal® is useful in diverse specialties, including spinal, cardiac, renal, liver and spleen surgery, by controlling bleeding within 10min[9– 12]

Figure 3. Venous malformation of the hyper lip: A (before)

and B(after)

doi:10.18282/jsd.v6.i2.149

Moreover, Floseal® can be used in some inaccessible surgical sites, and in some critical patients with severe concomitant diseases or coagulation disorders, to provide

Floseal® use in dermatologic surgical management of vascular malformations: A novel haemostatic agent in Côte d’Ivoire

quick and effective haemostatic control. In our series, we used the new component of Floseal® (human pooled plasma derived thrombin). This was advantageous in reducing the variety of complications related to bovine plasma derived use, ranging from laboratory abnormalities to potentially life threatening bleeding or thrombotic complications[13,14]. However it may be noted that Floseal® use could be limited by its cost. One box of Floseal®costs around 99 US dollarswhich is equal to more than 50,000 West African CFA franc, and proves to be expensive for poor patients without health insurance. This was not an issue in our setting as all patients were covered by health insurance. Alhough human pooled plasma-derived thrombin is less likely to cause allergic reactions when compared to bovine thrombin, it carries the risk of viral transmission like retrovirus, hepatitis viruses and parvovirus as well as prions during blood transfusion[13,15–16]. These possible risks should be balanced against the benefit of Floseal ® generation use, to achieve quick haemostasis in critical peripheral vascular bleeding conditions like artery or artery and venous or artery, venous and lymphatic malformations[17]. Therefore, Floseal® should be used as a local haemostatic agent in dermatologic surgery practice.

Author contributions All authors have contributed equally to the study’s protocol design and writing the manuscript.

Acknowledgments We acknowledge all health care practitioners at the Dermatology Department of the Teaching Hospital of Trechville-Abidjan, République de Côte d’Ivoire, and all members of the Ivorian Society of Dermatology and Venereology

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

References 1. Wassef M, Vanwijck R, Clapuyt P, Boon L, Magalon G. Tumeurs et malformations vasculaires, classification anatomopathologique et imagerie (French) [Vascular tumours and malformations, classification, pathology and imaging]. Ann Chir Plast Esthet 2006; 51(4–5): 263–281. doi: 10.1016/ j.anplas.2006.07.017. 2. Boon LM, Vanwijck R. Traitement médical et chirurgical des malformations veineuses (French) [Medical and surgical treatment of venous malformations]. Ann Chir Plast Esthet 2006; 51(4–5):403–411. doi: 10.1016/j.anplas.2006.07.023. 3. Pace G, Suldutto P, Vicentini C, Miano L. Haemostasis in surgery and our experience in enucleo resection of renal cell carcinoma.World J Surg Oncol 2010; 8: 37. doi: 10.1186/1477-7819-8-37.

4. Achneck HE, Sileshi B, Jamiolkowski RM, Aldala DM, Shapiro ML et al. A comprehensive review of topical haemostatic agents; efficacy and recommendations for use. Ann Surg 2010; 251(2): 217–228. doi: 10.1097/SLA.0b013e3181c3bcca. 5. Reuthebuch O, Lachat ML, Vogt P, Schurr U, Turina M. FloSeal®: Einneuartiges Hämostyptikum in der peripheren Gefäßchirurgie (German) [Floseal®: A new haemostyptic agent in peripheral vascular surgery].VASA 2000; 29(3): 204–206. doi: 10.1024/0301-1526.29.3.204. 6. Spängier HP, Holle J, Braun F. Gewebeklebungmit Fibrin (German) [Tissue adhesion with fibrin. (An experimental study with rat skin grafts)] Wien KlinWochenschr 1973; 85(50): 827–829. 7. Echave M, Oyagüez I, Casado MA. Use of Floseal®, a human gelatine-thrombin matrix sealant, in surgery: A systematic review. BMC Surg 2014; 14: 111. doi: 10.1186/1471-2482-14111. 8. Yao HHI, Hong MKH, Drummond KJ. Haemostasis in neurosurgery: What is the evidence for gelatin-thrombin matrix sealant? J Clin Neurosci 2013; 20(3): 349–356. doi: 10.1016/j.jocn.2012.09.005. 9. Renkens KL, Payner TD, Leipzig TJ, Feuer H, Morone MA, et al. A multicenter, prospective, randomized trial evaluating a new haemostatic agent for spinal surgery. Spine 2001; 26(15): 1645–1650. doi: 10.1097/00007632-200108010-00002. 10. Nasso G, Piancone F, Bonifazi R, Romano V, Visicchio G, et al. Prospective, randomized clinical trial of the Floseal® matrix sealant in cardiac surgery. Ann Thorac Surg 2009; 88(5): 1520–1526. doi: 10.1016/j.athoracsur.2009.07.014. 11. Leixnering M, Reichetseder J, Schultz A, Figl M, Wassermann E, et al. Gelatin thrombin granules for haemostasis in severe traumatic liver and spleen rupture model in swine. J Trauma 2008; 64(2): 456–462. doi: 10.1097/TA.0b013e3180340de1. 12. Law LW, Chor CM, Leung TY. Use of haemostatic gel in postpartum hemorrhage due to placenta previa. Obstet Gynecol 2010; 116(2): 528–530. doi: 10.1097/AOG.0b013e3181e772cf. 13. Lawson JH. The clinical use and immunologic impact of thrombin in surgery. Semin Thromb Hemost 2006; 32(suppl): 98–110. doi: 10.1055/s-2006-939559. 14. The CoStasis Multi-center Collaborative Writing Committee. A novel collagen-base composite offers effective haemostasis for multiple surgical indications: Results of randomized controlled trials. Surgery 2001; 129(4): 445–450. doi: 10.1067/msy.2001.112365. 15. Burnouf T. Modern plasma fractionation.Transfus Med Rev 2007; 21(2): 101–117. doi: 10.1016/j.tmrv.2006.11.001. 16. Eder G, Neuman M, Cerwenka R, Baumgarten K. Preliminary results of a randomized controlled study on the risk of hepatitis transmission of a two-component fibrin sealant (Tissucol/Tisseel). Fibrin Sealant in Operative Med 1986; 51– 59. 17. Weaver FA, Lew W, Granke K, Yonehiro L, Delange B, et al. A comparison of recombinant thrombin to bovine as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures. J Vasc Surg 2008; 47(6): 1266–1273. doi: 10.1016/j.jvs.2008.01.034.

doi: 10.18282/jsd.v6.i2.94

ORIGINAL RESEARCH ARTICLE

The efficacy and safety of a 70% glycolic acid peel with vitamin C for the treatment of acne scars Heng Jun Khee, Liau MeiQi May*, Yang Shiyao Sam, Aw Chen Wee Derrick, Ho Sue-Ann University Dermatology Clinic, National University Hospital (NUH), Singapore

Abstract: Acne scarring is a common complication associated with significant psychological distress. Both glycolic acid (GA) and vitamin C are known to improve the appearance of acne scarring. We performed a review of 13 patients treated with three 70% GA peels with vitamin C at four weeks apart. There was a statistically significant` improvement in acne scarring and post-inflammatory hyperpigmentation from the baseline. Maximal effects were noted four weeks after the third chemical peel. It has an excellent safety profile with no permanent adverse effects noted. A combination of 70% glycolic acid with vitamin C chemical peel is an efficacious, well-tolerated treatment of acne scarring in Asian skin. Keywords: chemical peel; glycolic acid; acne scars Citation: Heng JK, Liau MM, Yang SS, Aw CWD, Ho SA. The efficacy and safety of a 70% glycolic acid peel with vitamin C for the treatment of acne scars. J Surg Dermatol 2021; 6(2): 94; http://dx.doi.org/10.18282/jsd.v6.i2.94. *Correspondence to: Liau MeiQi May, University Dermatology Clinic, National University Hospital (NUH), 5 Lower Kent Ridge Rd, Level 3, Lift Lobby 1, Main Building Level 3, 119074, Singapore; maylmq@gmail.com Received: 5th Febuary 2021; Accepted: 28th April 2021; Published Online: 13th May 2021

Introduction Acne is a common skin disorder which often results in permanent scarring. This can constitute a persisting disfiguring problem and is associated with considerable psychological distress. The development of acne scars is multifactorial, and is associated with the delay in the initiation of acne treatment, the duration of inflammatory response and the enzymatic degradation of collagen fibers. There are two main types of scars: atrophic (net loss of collagen) and hypertrophic (net gain of collagen) scars. Various treatment options are available for acne scarring, which include chemical peels, dermabrasion/ microdermabrasion, laser resurfacing, punch techniques, needling and combined therapies. Chemical peels, also known as chemexfoliation or derma peeling, have been used for many years in the treatment of acne scarring. Often, best results are achieved for superficial macular scars, and the level of improvement is extremely variable in different patient conditions[1]. Glycolic acid (GA), a member of the alpha hydroxy acids (AHA) family, is one of the most commonly used chemical peeling agents. We report our experience in treating acne scars

with a commercial preparation of 70% GA and vitamin C chemical peel (Therapeutic Dermatologic Formula VCi®, Ocean Health, USA).

Materials and methods Methodology We included patients with acne scarring treated with 70% GA peels with vitamin C at the dermatology clinic of National University Hospital (Singapore) between September 2014 and February 2015. All patients above the age of 21 were eligible. The exclusion criteria included the following: patients who had taken oral retinoids, chemical peels or laser ablative procedures in the past six months; were in pregnancy; were breastfeeding; or had active facial dermatitis. All patients who met the inclusion criteria were instructed to stop topical retinoid one week prior to embarking on the priming regime. They received a series of three 70% GA peels with vitamin C, each four weeks apart. The treatment regimen and clinical evaluations are described below.

Copyright © 2021 Heng JK, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The efficacy and safety of a 70% glycolic acid peel with vitamin C for the treatment of acne scars

Treatment regimen Priming All patients were instructed to apply the following in order, twice daily, for 1 month: Cleanser (Therapeutic Dermatologic Formula, AHA facial wash), followed by Toner (Therapeutic Dermatologic Formula, Mild astringent), Control (Therapeutic Dermatologic Formula, AHA Oily & Acne Solution 8), Facial moisturiser (Therapeutic Dermatologic Formula, Ultra-Light Hydrator). Patients were also instructed to apply Sunblock (Therapeutic Dermatologic Formula, PA +++ UVA/UVB, SPF 50+) once daily in the morning. The list of ingredients for each product is listed in Appendix 1.

Peeling Four weeks later, the patient received the first chemical peel. A single pass of 70% GA and vitamin C peel (Therapeutic Dermatologic Formula, VCi® High Potency Peel) was applied for 3–5 min depending on patient’s tolerance. A test spot of the peel was performed to evaluate tolerability prior to performing the full face peel. Spot neutralization (Therapeutic Dermatologic Formula Peel Neutralizer) was performed on areas of erythema, with subsequent full neutralization upon termination of the peel. Vitamin C Serum (Therapeutic Dermatologic Formula, “C”-scape serum) and Sunblock (Therapeutic Dermatologic Formula, PA +++ UVA/UVB, SPF 50+) was applied thereafter.

Post-peel care For the first three days of each peel, patients were instructed to follow the same regime as that listed in “Priming” above, excluding the AHA Oily & Acne Solution 8. Patients were also instructed to use 10% vitamin C serum (Therapeutic Dermatologic Formula, “C”-scape serum) and Quick Recovery Cream (Therapeutic Dermatologic Formula, Quick Recovery Cream) twice daily. From day 4 until the next peel, Quick Recovery Cream was substituted with AHA Oily & Acne Solution 8. Each patient received three 70% GA chemical peels with vitamin C, each four weeks apart (i.e. week 4, 8 and 12).

Clinical evaluation Patients were graded using the ECCA (Echelle d’Evaluation Clinique des Cicatrices d’acné, or Scale for Clinical Eva luation of Acne Scars) scale for acne scarring and post-acne hyperpigmentation index (PAHPI) for the evaluation of post-inflammatory hyperpigmentation[2,3]. The ECCA scale is a semi-quantitative grading system for acne scarring. It is based on summation of individual types of scars and their numerical extent. Scar types deem ed to be more visibly disfiguring were allocated higher weighting factor. The scars, with their corresponding weighting factor in parentheses, are as follows:

1. V-shaped atrophic scars, diameter <2 mm, punctiform (15) 2. U-shaped atrophic scars, diameter of 2–4 mm, sheer edges (20) 3. M-shaped atrophic scars, diameter >4 mm, superficial and irregular surface (25) 4. Superficial elastolysis (30) (This is part of the ECCA official scoring criteria. We based it based on cutaneous findings compatible with solar elastosis, i.e. thickened, yellow, dry and furrowing of skin.) 5. Hypertrophic inflammatory scars, scars of <2 years of age (40) 6. Keloid scars, hypertrophic scars, of >2 years of age (50) Each of the above scars was evaluated with a fourpoint scale, with rating of absent (0), few scars (1), limited number of scars (2) and many scars (3). PAHPI is a validated scoring system evaluating the postinflammatory hyperpigmentation in patients with acne vulgaris. It consists of three characteristics (Table 1): size (S), intensity (I) and number of lesions (N). Digital imaging was performed using Visia® Complexion Analysis. Standardized imaging was captured at each visit at week 0 (baseline), 4, 8, 12 and 16. Ratings on the clinical photographs were done separately by two dermatologists: the managing dermatologist and an independent derma tologist.

Safety assessment score In addition, we monitored five clinical parameters of side effects after administration of each chemical peel: redness, swelling, oozing or crusting, hyperpigmentation and scarring. A 10-point (1–10) visual analogue scale (VAS) for sub jective assessment was also performed at baseline (week 0) and weeks 12 and 16. Table 1.

Scoring the post-acne hyperpigmentation index

Weighted score (S)

Median lesion size (mm)

2 4 6 8

<3 3–6 7–10 >10

Weighted score (I) 3 6 9

Median lesion intensity Slightly darker than surrounding skin Moderately darker than surrounding skin Significantly darker than surrounding skin

Weighted score (N)

No. of lesions

1 2 3 4 5

1–15 16–30 31–45 46–60 >60

Note: Total post-acne hyperpigmentation index = S + I + N; score range: 6–22

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Heng JK, et al.

Results Study population 15 patients (7 males, 8 females) with a mean age of 28.2 years (age range 22–42) were identified during the sixmonth period from September 2014 to February 2015. Their skin types were either Fitzpatrick skin type III or IV. Two patients (13.3%) did not complete the series of peels. One patient withdrew due to mild contact dermatitis to the chemical peel and the other withdrew for personal reasons. A total of 13 patients’ results were analyzed (7 males, 6 females).

Physician scores

Figure 1. ECCA scores pre- and post-treatment

ECCA scoring According to the ECCA scale, a score of 0 indicates no scarring and a score of 540 indicates severe acne scarring. The mean pre-treatment ECCA score was 170.38 (SD = 39.18). The average of both physicians’ ECCA scores are shown below (Table 2). There was a trend towards improvement, with maximal effect noted at week 16, where a total mean score of 115 (SD = 41.37) was achieved (Figure 1, Figure 2a and 2b). The differences in acne scarring scores at week 12 and week 16 compared with pre-treatment scores were assessed using the Wilcoxon signed-rank test. There was a statistically significant reduction in ECCA scores between week 12 and week 0 (mean change = 39.23, P = 0.001), and this improvement was maintained during the review in week 16 (mean change = 55.39, P = 0.001). Table 2.

Average of Physicians’ ECCA scores

Patient Week 0 Week 8 Week 12

Week 16

Percentage improvement

180

135

142.5

117.5

34.70%

200

180

165

17.50%

122.5

26.50%

202.5

160

167.5

17.30%

200

145

172.5

125

37.50%

175

97.5

92.5

47.10%

107.5

110

92.5

30.20%

195

185

165

15.40%

140

82.5

72.5

48.20%

230

207.5

187.5

155

32.60%

112.5

82.5

47.5

57.80%

155

122.5

107.5

48.40%

195

162.5

140

142.5

26.90%

Figure 2a. A 23-year-old patient at: (A) week 0, pre-treatment; and (B) week 16, after three sessions of 70% GA peel with vitamin C

Figure 2b. A 27-year-old patient at: (A) week 0, pre-treatment; and (B) week 16, after three sessions of 70% GA peel with vitamin C

The efficacy and safety of a 70% glycolic acid peel with vitamin C for the treatment of acne scars

PAHPI scoring

Visual analogue scale

A PAHPI score of 6 indicates mild post-acne hyper pigmentation, and a score of 22 indicates severe post-acne hyperpigmentation. The mean pre-treatment PAHPI score was 11.73 (SD = 39.18). The average of both physicians’ PAHPI scores are shown below (Table 3). There was a trend towards improvement, with maximal effect noted at week 16 where a mean score of 7.96 (SD = 2.21) was achieved (Figure 3). The differences in acne scarring scores at week 12 and week 16 compared with pre-treatment scores were assessed using the Wilcoxon signed-rank test. There was a statistically significant reduction in ECCA scores between week 12 and week 0 (mean change = 2.81, P = 0.002), and this improvement was maintained during the review in week 16 (mean change = 3.77, P = 0.002).

The visual analogue scale (VAS) ranged from 1 (no features of acne scars) to 10 (severe acne scarring). 9 out of 13 patients (69.2%) scored an improvement post-peel as compared to pre-peel scores. The mean pre-treatment score was 7.23, with maximal effect noted at week 12 with a mean score of 5.38, which was sustained at week 16 as well. Most of the patients experienced further improvement at week 16, except for two whose scores remained unchanged from week 12. 9 out of 13 patients (69.2%) scored an improvement post-peel as compared to pre-peel scores.

Table 3.

Average of both physicians’ PAHPI scores

Patient Week 0

Week 8

Week 12 Week 16

Percentage improvement

13.5

25.00%

12.5

11.5

23.30%

9.5

36.80%

7.5

10.5

25.00%

11.5

26.70%

6.5

40.90%

7.5

6.5

0.00%

8.5

30.00%

8.5

33.30%

13.5

46.70%

7.5

25.00%

41.70%

7.5

46.40%

Safety assessment The number of patients who experienced side effects postchemical peel are tabulated below (Table 4). All patients experienced erythema and approximately half experienced some degree of swelling post-chemical peel. These resolved completely at week 16. Two patients reported hyper pigmentation at week 8; this had resolved in both patients at week 16. There was no permanent adverse reaction including scarring, oozing or crusting at any time. There was mild hyperpigmentation noted at week 12 in two patients (15%), which fully resolved by week 16. The redness and swelling were transient and resolved within 1–3 days. The 70% GA peel with vitamin C is tolerable and well accepted by our patient population (Table 5).

Discussion Acne scarring is a common acne complication with a high prevalence amongst adolescents and young adults. It is often accompanied by post-inflammatory hyper pigmentation, which are unfortunate consequences asso ciated with psychological distress, depression, poorer Safety assessment of side effects post-chemical peel

Table 4.

Week 4

Week 8

Week 12

Week 16

Redness

Swelling

Oozing/crusting

Hyperpigmentation

Scarring

Table 5. Safety assessment score post-chemical peel, from 1 (absent) to 4(severe) Side effect

Figure 3. PAHPI scores pre- and post-treatment

Mean score (SD) Week 4

Week 12

Week 16

Redness

2.38 (0.51)

2.69 (0.63)

2.46 (0.66)

Swelling

1.69 (0.63)

1.69 (0.48)

1.46 (0.51)

Oozing/crusting

1.00

Hyperpigmentation

1.00

1.15 (0.37)

1.00

Scarring

1.00

doi:10.18282/jsd.v6.i2.94

Heng JK, et al.

academic performance and higher unemployment rates[4]. Furthermore, the appearance of acne scars worsens with normal aging and post-inflammatory hyperpigmentation is longer lasting in patients with darker skin tones, as in our study population. GA is the smallest organic acid amongst the alphahydroxy acids (AHA). It penetrates the epidermis easily, making it the most common AHA used for chemical peeling. It exerts its beneficial effect on skin by moderating keratinization, promoting epidermolysis, dispersing basal layer melanin, and increasing dermal hyaluronic acid and collagen genes expression[5]. The intensity of GA peel is mainly determined by the concentration of the acid and proper neutralization is required to terminate the peel[6]. Vitamin C has also been used to improve acne scarring with its potent natural antioxidant properties and important role in the collagen biosynthetic pathway. Erbağcı and Akçalı compared GA peels versus daily 15% GA cream[7]. The study showed that six consecutive 70% GA peels performed biweekly resulted in significant improvement in atrophic scars scores compared to daily usage of 15% GA cream (54.7% vs. 37.2%, respectively). The study also showed that both high and low potency GAs were superior to placebo. Another study, by Sharad, evaluated the use of 35% GA as an adjuvant to microneedling for acne scars in Indian patients[8]. There was significant mean improvement in acne scars in patients receiving 35% GA plus microneedling compared to the group who only received microneedling (62% vs. 31%, respectively). These studies showed that GA therapy contributed to a significant improvement in acne scarring. We expanded on the works of Erbağcı and Sharad in investigating the effects of 70% GA peels on acne scarring. Our study is one of the few studies which used objective measures such as the ECCA and PAHPI scores, and showed statistically significant improvement in both acne scarring and post-inflammatory hyperpigmentation. Improvements were noticed by week 12, four weeks after the second peel (ECCA mean change: −39.23) and further improvements were observed at week 16, four weeks after the third peel (ECCA mean change: −55.39). Maximal effects for both ECCA and PAHPI scores were seen in week 16. Improvement in ECCA scores was mainly from improvement of atrophic scar scores rather than hypertrophic or keloidal scar scores. This finding is consistent with the mechanism of action of GA in stimulating collagen synthesis[9]. Our study showed good results with high potency glycolic acid with vitamin C. Furthermore, there was an excellent safety profile of the 70% GA peel with vitamin C. Most patients experienced redness or mild swelling which were transient. Post-inflammatory hyperpigmentation occurred in 15% of our patients, which is comparable to Erbağcı’s study, and usually resolved within a few weeks.

Conclusion In conclusion, a combination 70% GA peel with vitamin C is a well-tolerated effective treatment for acne scarring

in Asian skin. Small sample size and lack of a long-term follow up are limitations of our study. Larger studies with a longer period of follow-up will be useful in determining the sustainability effect of this chemical peel.

Acknowledgements The authors thank Ms. Samantha Lee (Senior Manager, Ocean Health Pte. Ltd.), and all NUH dermatology clinic staff.

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

Supplementary information Appendix 1: The ingredients of topical treatments. This supplementary information is available free of charge on JSD’s website at doi: 10.18282/jsd.v6.i2.94.

References 1. Fabbrocini G, Annunziata MC, D’arco V, De Vita V, Lodi G, et al. Acne scars: Pathogenesis, classification and treatment. Dermatology Res Practice 2010; 2010. doi: 10.1155/2010/893 080. 2. Dreno B, Khammari A, Orain N, Noray C, Merial-Kieny C, et al. ECCA grading scale: An original validated acne scar grading scale for clinical practice in dermatology. Derma tology 2006; 214(1): 46–51. doi: 10.1159/000096912. 3. Savory SA, Agim NG, Mao R, Peter S, Wang C, et al. Reliability assessment and validation of the postacne hyper pigmentation index (PAHPI), a new instrument to measure postinflammatory hyperpigmentation from acne vulgaris. J Am Acad Dermatol 2014; 70(1): 108–114. doi: 10.1 016/j.jaad. 2013.09.017. 4. Fried RG, Wechsler A. Psychological problems in the acne patient. Dermatol Ther 2006; 19(4) :237–240. doi: 10.1111/j.15 29-8019.2006.00079.x. 5. Bernstein EF, Lee J, Brown DB, Yu R, Van Scott E. Glycolic acid treatment increases type I collagen mRNA and hyaluronic acid content of human skin. Dermatol Surg 2001; 27(5): 429– 433. doi: 10.1046/j.1524-4725.2001.00234.x. 6. Sharad J. Glycolic acid peel therapy: A current review. Clin Cosmet Investig Dermatol 2013; 2013(6): 281–288. doi: 10.21 47/CCID.S34029. 7. Erbağcı Z, Akçalı C. Biweekly serial glycolic acid peels vs. long–term daily use of topical low–strength glycolic acid in the treatment of atrophic acne scars. Int J Dermatol 2000; 39(10) :789–794. doi: 10.1046/j.1365-4362.2000.00076.x. 8. Sharad J. Combination of microneedling and glycolic acid peels for the treatment of acne scars in dark skin. J Cosmet Dermatol 2011; 10(4): 317–323. doi: 10.1111/j.1473-2165.201 1.00583.x. 9. Kim SJ, Park JH, Kim DH, WON YH, Maibach HI. Increased in vivo collagen synthesis and in vitro cell proliferative effect of glycolic acid. Dermatol Surg 1998; 24(10): 1054–1058. doi: 10.1111/j.1524-4725.1998.tb04074.x.

doi: 10.18282/jsd.v6.i2.177

original research article

A novel total body digital photography smartphone application designed to detect and monitor skin lesions: A pilot study Nicholas Guido1, Erika L. Hagstrom1, Erin Ibler1, Chantelle Carneiro1,2, Kelsey A. Orrell1, Ryan C. Kelm1, Alfred W. Rademaker3,4, Dennis P. West1,4, Beatrice Nardone1* Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 3 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 4 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 1 2

Abstract: Although some smartphone applications are designed for total body photography (TBP), few offer the specificity that enables self- as well as dermatologist-, detection of new lesions, or change in lesion color or in size as little as 1mm, on an ongoing basis. The aim of this study is to assess the sensitivity of a novel TBP application in the detection of changes to color and size of simulated skin lesions. Twenty-five subjects underwent one study visit. After baseline photography, new artificial markings were made or naturally occurring pigmented lesions located in any anatomical region were enhanced/ enlarged, and a second matching set of photographs was then taken. From all 25 subjects, a total of 262 skin markings were evaluable. Of these, 241 (92%) were detected by the app, which resulted in an overall sensitivity of 92%. The high sensitivity establishes the app as capable of providing reliable self-TBP that allows detection and monitoring of new skin lesions or change in both size and color. This method greatly enhances the ability to accomplish ongoing self-monitoring and yet provides quality informing images to the dermatologist to assist in decision-making with the patient. Clinical Trials registration: ClinicalTrials.gov: NCT02740257, https://clinicaltrials.gov/ct2/show/NCT02740257 Keywords: smartphone application; skin self-examination; skin cancer; total body digital photography; skin lesions Citation: Guido N, hagstrom eL, Ibler e, Carneiro C, Orrell KA, et al. A novel total body digital photography smartphone application designed to detect and monitor skin lesions: A pilot study. J surg Dermatol 2021; 6(2): 177; http://dx.doi. org/10.18282/jsd.v6.i2.177. *Correspondence to: Beatrice Nardone, Department of Dermatology, Feinberg School of Medicine, Northwestern University, 676 N S Clair St, Suite 1600, 60611, Chicago, IL; b-nardone@northwestern.edu Received: 27th May 2021; Accepted: 14th Jnly 2021; Published Online: 25th July 2021

Introduction With the emergence of the smartphone and its myriad capabilities less than a decade ago, came the advent of the mobile application market. By 2013, over 200 apps existed that were relevant to dermatology: 18% of these focused on self-surveillance and diagnosis, and 3.5% on teledermatology (TD)[1]. Several of these apps were designed to allow some differentiation between normal nevi and cutaneous melanoma[1], a growing concern in the U.S. as the incidence rate of melanoma increases[2] while the availability of dermatologists continues to decrease[3–5]. Traditionally, TBP is used to globally survey existing lesions and to identify new or changing lesions [6] where

the photographer (physician, nurse, or technician) takes an average of 24 photos (range, 4–50) of the patient in various positions. Close-up photos may be taken for selected lesions, and photos are taken at variable intervals for follow-up[7]. Moreover, TBP has been reported to help detect early melanoma[8] and TBP combined with skin selfexamination (SSE) increases the sensitivity for detecting new or changed nevi from 60% to 72%, with increased specificity from 96% to 98% [9]. Further, patients also are reported to be more compliant with SSE when it is combined with TBP[9]. A limitation of traditional TBP is that it is a timeconsuming, labor-intensive process since patients must be photographed in a variety of positions to capture the

Copyright © 2021 Guido N, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Guido N, et al.

entire body surface. An advantage of TBP is that it has been shown to be capable of detecting new or subtly changing skin lesions independent of an annual full body skin exam, allowing for better melanoma survival rates related to decreased depth of invasion at time of detection [8,10–12]. Limitations with office TBP include the time it takes to train staff, the duration of each photography session beyond normal clinic flow, and the cost of additional photography equipment and/or the photographer[13]. Although currently existing apps allow patients to accomplish TBP from home, there are few specific homebased apps that can detect new lesions or changes to lesions as small as 1mm as well as detect changes in color. The aim of this study is to assess the sensitivity of a new and novel home-based TBP app to detect new lesions and/or changes to lesions.

Materials and methods A convenience sample of 25 subjects participated in the study that was approved by the Northwestern University Institutional Review Board, and all participants provided written informed consent prior to participation. Inclusion criteria were 18–85 years of age and selfreported Fitzpatrick skin type I-IV. Exclusion criteria included history of vitiligo or psoriasis (or any active dermatitic condition on the skin surface in the anatomical region to be studied). The study population underwent one study visit where 2 sets of iPad® photographs were taken by the research team. Each set of images included 3–5 photographs of the relevant anatomic region. After the initial set of photographic images, artificial skin markers were made to either add simulated lesions to the skin of the relevant anatomic region and/or to enhance the subject’s naturally-

occurring skin lesion (by use of a Sharpie™ brush tip permanent marker). The choice of permanent skin marker color was black, brown or red. After skin markings were made to each of the 3 anatomical regions, a comparable second set of photographic images was taken in order to determine if the app reliably detected the new marks and/or changes in size and/or color (Figure1).

SkinIO smartphone application The app used for the study (SkinIO) is designed to be an enhanced full-body skin scanning system that works on mobile devices and tablets to track changes to skin over time with no additional imaging hardware. SkinIO enables smartphone photography of high-risk patients with 13 photographic poses to accomplish TBP using a mobile device. The images are automatically uploaded to a HIPAAcompliant server environment where they can be rapidly processed to detect most any skin "spot" as small as 1mm diameter and of most any color. Dermatologists are enabled to annotate the images and flag specific images for followup at any designated time interval. SkinIO's proprietary image processing algorithm is comprised of several distinct processes that, either in parallel or in series, form the basis for SkinIO's skin lesion detection engine.

Statistical analyses The sensitivity of the app to detect changes in skin marking size and/or color was assessed. Detected new changes were limited by study design to be those placed by use of the variously colored skin markers immediately after the first set of images and immediately before the second set of images. Sensitivity is defined as the rate of app-detected changes compared to the number of artificial skin markings.

Figure 1. Example of 3 out of 12 artificial markings in subject ID SP016: A) Photos taken with the app before adding artificial skin markings. B) Photos taken after adding artificial skin markings (red rectangle). C) Close-up of artificial skin markings: 1. Black (Width=2.2 mm; Height=2.4 mm); 2 red (Width=2.1 mm; Height=2.4 mm); 3 brown (Width 1.7 mm; Height=3.0 mm). All 3 artificial skin markings were correctly detected by the app. doi:10.18282/jsd.v6.i2.177

A novel total body digital photography smartphone application designed to detect and monitor skin lesions: A pilot study

The total number of artificial skin markings made by the researchers versus the total number of skin markings detected by the app informed the determination of app sensitivity.

Results A total of 25 subjects were enrolled and completed the study; 25 (Female= 14/Male= 11; mean age: 28yo; range 22–55yo; race: Asian= 3, White: 18, Unknown/Not reported=4). Of these, 9 subjects were self-reported as Fitzpatrick type II, 12 type III and 4 type IV. Of these 25 subjects, a total of 269 skin lesions and/ or markings were targeted for study and 262 (97%) were evaluable within the image field. Of the 262 evaluable images, the TBP app detected 241, resulting in a sensitivity of 92% (Table 1). Table 1. Number of artificial skin markings for each subject. Subject ID

Skin Skin markings markings evaluable within the image field

SP001

Skin markings detected by TBP app 4

SP002

SP006

SP007

SP008

SP009

SP010

SP011

SP012

SP013

SP014

SP015

SP016

SP017

SP018

SP019

SP020

SP021

SP022

SP023

SP024

SP025

SP026

SP027

SP028

Total

269

262

241

Discussion The observed sensitivity in this study indicates that the app as utilized for TBP is both a reliable and convenient approach to monitor and detect changes to skin markings as small as 1mm in size and color. Use of TBP to monitor patients with atypical/dysplastic nevi has been well underway since the late 1980’s. By 1992, 41% of US residency programs reported use of TBP[14] . In 2000, 62% of dermatologists in academic institutions indicated that they use TBP, and in 2010, this increased to 71% of institutions[15]. Rice and colleagues surveyed 49 US dermatology departments in 2010 and found that 33 (67%) used TBP as a screening method; of those who used TBP, 11 (33%) used digital TBP alone, 11 (33%) used digital with printed images of TBP, and 11 (33%) used printed TBP images alone[13]. Use of TBP images during skin self-examinations (SSEs) has been shown to improve patients’ confidence in performing SSEs[9,16] and to increase patients’ sensitivity for detection of new or changing skin lesions compared to performance of SSE alone, without access to TBP images[9]. In one study, 44% of melanoma lesions were detected in situ with a small thickness in the group with baseline photography [17] . Another study showed that baseline photography aids early detection of melanoma in long-term follow-up of high-risk patients[18]. A 5-year prospective observation study of 311 patients in Australia at “extreme high risk” for melanoma demonstrates the complementary effectiveness of TBP, dermoscopy, and sequential digital dermoscopy imaging in the diagnosis of melanoma[19]. Although there have been recent improvements in the treatment of metastatic melanoma, early detection remains one of the most important strategies to reduce mortality. Evidence supporting this approach includes the recent population-based screening efforts, with initial results suggesting a nearly 50% decrease in melanoma mortality associated with skin cancer screening through total body skin examinations [20] . The fact that most melanomas (~65%) arise de novo, and are not contiguously associated with a melanocytic nevus, underscores the importance of identifying new lesions in addition to changing lesions to maximize sensitivity for melanoma detection[21]. Smartphone applications targeting skin cancer and melanoma, in particular, have often fallen short after undergoing validation studies, and several have been pulled from the market[22–24]. An important issue with apps reliant on automated algorithms has been misdiagnosis of melanoma, and the potential for delay in following up on lesions incorrectly classified as “low risk” [22–24]. Nevertheless, encouraging technological advancements have been made. Applications with mole mapping and photographic imaging have provided dermatologists with visual imagery they can compare over time [25], while smartphone capabilities (cameras, dermoscopy clip-ons, etc.) have provided physicians with the ability to store images and effectively triage referrals [26]. The latter is particularly relevant since poor descriptive terms and lack of imaging from referring primary care doctors has

Guido N, et al.

been reported to lead to delayed follow-up of high risk patients[26]. Teledermatology (TD) has shown promise in this field; it allows digital images with relevant clinical information to be transmitted securely to a consulting dermatologist[27]. One TD app was shown to have 98% sensitivity and 94% specificity with skin lesion interpretation from photos taken by, and submitted by, patients[24]. A recent study evaluated the ability of a mobile smartphone app using novel fractal image analysis to guide diagnosis of pigmented lesions. The app had a sensitivity of 73% and a specificity of 88%, which was comparable to that observed with clinical diagnostic (sensitivity 88%, specificity 97%)[28]. However, like many TD apps, it did not require TBP[24]. Since melanoma can be located in anatomic regions that are difficult to see or reach, patients are more prone to not photograph such lesions[14]. The SkinIO app is designed to provide patients at high risk for skin cancer with an easy-to-use app that will allow them to monitor skin lesions with built-in notification to the dermatologist for prompt attention to detectable changes in lesions or new lesions that may occur at most any anatomic site. Multiple factors have worked against widespread adoption of TBP in the monitoring of patients at high risk for melanoma[24]. Some dermatologists maintain that TBP is not a helpful tool beyond clinical examination alone, given the scarcity of randomized clinical trials that have evaluated TBP[29]. Physicians cite other barriers including the additional time required to perform TBP, difficulties in obtaining reimbursement for TBP, and logistical/ financial constraints, such as the need to obtain software to securely organize and store patient digital images[29]. US dermatology residents have reported little emphasis on learning TBP during training, and as many as 67.4% reportedly prefer additional education[13]. From the patient perspective, TBP is often not covered by third party payors, leading to potentially significant outof-pocket expenses[29]. In some geographic regions, there is simply poor access to imaging centers that provide TBP[29]. In addition to the time required to conduct TBP, poor patient acceptance and medical liability issues have been described as barriers to its use[13]. The app in this study is designed to circumvent some of these barriers by minimizing the physician and staff time devoted to performing TBP. In our experience, smartphone photography of three anatomic regions was accomplished within 10 minutes. The app design avoids the cost of purchasing hardware.

Conclusions Findings from this study inform the feasibility of the app to detect and monitor new skin lesions as well as variation in size and color. Moreover, these findings support further exploration of the SkinIO app to determine its utility with longitudinal monitoring for detection of naturally-occurring changes to naturally occurring lesions, as well as validation of the methodology for improvement in outcome for patients at high risk for skin cancer. The demonstrated high sensitivity doi:10.18282/jsd.v6.i2.177

provided by the app for longitudinal skin lesion monitoring represents a technological advance that clearly warrants further exploration.

Funding Source Northwestern Memorial Foundation

Conflict of interest All the named authors do not have any conflict of interest to disclosure. This study was approved by the Northwestern University Institutional Review Board (IRB).

References 1. Brewer AC, Endly DC, Henley J, Amir M, Sampson BP, et al. Mobile applications in dermatology. JAMA Dermatol 2013; 149(11): 1300–1304. doi: 10.1001/jamadermatol.2013.5517. 2. Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. J Natl Cancer Inst 2015; 107(6): djv048. doi: 10.1093/jnci/djv048. 3. Suneja T, Smith ED, Chen GJ, Zipperstein KJ, Fleischer AB Jr, et al. Waiting times to see a dermatologist are perceived as too long by dermatologists: Implications for the dermatology workforce. Arch Dermatol 2001; 137(10): 1303–1307. doi:10.1001/archderm.137.10.1303. 4. Tsang MW, Resneck JS Jr. Even patients with changing moles face long dermatology appointment wait-times: A study of simulated patient calls to dermatologists. J Am Acad Dermatol 2006; 55(1): 54–58. doi: 10.1016/j.jaad.2006.04.001. 5. Jacobson CC, Resneck JS, Jr., Kimball AB. Generational differences in practice patterns of dermatologists in the United States: Implications for workforce planning. Arch Dermatol 2004; 140(12): 1477–1482. doi: 10.1001/ archderm.140.12.1477. 6. Hibler BP, Qi Q, Rossi AM. Current state of imaging in dermatology. Semin Cutan Med Surg 2016; 35(1): 2–8. doi: 10.12788/j.sder.2016.001. 7. Dengel LT, Petroni GR, Judge J, Chen D, Acton ST, et al. Total body photography for skin cancer screening. Int J Dermatol 2015; 54(11): 1250–1254. doi: 10.1111/ijd.12593. 8. Feit NE, Dusza SW, Marghoob AA. Melanomas detected with the aid of total cutaneous photography. Br J Dermatol 2004; 150(4): 706–714. doi: 10.1111/j.0007-0963.2004.05892.x. 9. Oliveria SA, Chau D, Christos PJ, Charles CA, Mushlin AI, et al. Diagnostic accuracy of patients in performing skin selfexamination and the impact of photography. Arch Dermatol 2004; 140(1): 57–62. doi: 10.1001/archderm.140.1.57. 10. Barnes LM, Nordlund JJ. The natural history of dysplastic nevi. A case history illustrating their evolution. Arch Dermatol 1987; 123(8): 1059–1061. doi:10.1001/ archderm.1987.01660320101021. 11. Halpern AC, Guerry Dt, Elder DE, Trock B, Synnestvedt M, et al. Natural history of dysplastic nevi. J Am Acad Dermatol 1993; 29(1): 51–57. doi: 10.1016/0190-9622(93)70151-I. 12. Rivers JK, Kopf AW, Vinokur AF, Rigel DS, Friedman RJ,et al. Clinical characteristics of malignant melanomas developing in persons with dysplastic nevi. Cancer 1990; 65(5): 1232–1236. 13. Terushkin V, Oliveria SA, Marghoob AA, Halpern AC. Use of and beliefs about total body photography and dermatoscopy among US dermatology training programs: An update. J

A novel total body digital photography smartphone application designed to detect and monitor skin lesions: A pilot study

14. 15.

16.

17.

18.

19.

20.

21.

Am Acad Dermatol 2010; 62(5): 794–803. doi: 10.1016/ j.jaad.2009.09.008. Slue W, Kopf AW, Rivers JK. Total-body photographs of dysplastic nevi. Arch Dermatol 1988; 124(8): 1239–1243. doi:10.1001/archderm.1988.01670080051017. Shriner DL, Wagner RF Jr. Photographic utilization in dermatology clinics in the United States: A survey of university-based dermatology residency programs. J Am Acad Dermatol 1992; 27(4): 565–567. doi: 10.1016/01909622(92)70223-3. Yagerman S, Marghoob A. Melanoma patient self-detection: A review of efficacy of the skin self-examination and patientdirected educational efforts. Expert Rev Anticancer Ther 2013; 13(12): 1423–1431. doi: 10.1586/14737140.2013.856272. Banky JP, Kelly JW, english Dr, Yeatman JM, Dowling JP. Incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma. Arch Dermatol 2005; 141(8): 998–1006. doi: 10.1001/archderm.141.8.998. Wang SQ, Kopf AW, Koenig K, Polsky D, Nudel K,et al. Detection of melanomas in patients followed up with total cutaneous examinations, total cutaneous photography, and dermoscopy. J Am Acad Dermatol 2004; 50(1): 15–20. doi: 10.1016/S0190. Moloney FJ, Guitera P, Coates E, Haass NK, Ho K,et al. Detection of primary melanoma in individuals at extreme high risk: A prospective 5-year follow-up study. JAMA Dermatol 2014; 150(8): 819–827. doi: 10.1001/jamadermatol.2014.514. Katalinic A, Waldmann A, Weinstock MA, Geller AC, Eisemann N, et al. Does skin cancer screening save lives?: An observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 2012; 118(21): 5395–5402. doi: 10.1002/cncr.27566. MacKie RM. Clinical recognition of early invasive malignant

melanoma. BMJ 1990; 301(6759): 1005–1006. 22. Ferrero NA, Morrell DS, Burkhart CN. Skin scan: A demonstration of the need for FDA regulation of medical apps on iPhone. J Am Acad Dermatol 2013; 68(3): 515–516. doi: 10.1016/j.jaad.2012.10.045. 23. Robson Y, Blackford S, Roberts D. Caution in melanoma risk analysis with smartphone application technology. Br J Dermatol 2012; 167(3): 703–704. doi: 10.1111/j.13652133.2012.11046.x. 24. Wolf JA, Ferris LK. Diagnostic inaccuracy of smartphone applications for melanoma detection--reply. JAMA Dermatol 2013; 149(7): 885. doi: 10.1001/jamadermatol.2013.4337. 25. Lee KB, Weinstock MA, Risica PM. Components of a successful intervention for monthly skin self-examination for early detection of melanoma: The "Check It Out" trial. J Am Acad Dermatol 2008; 58(6): 1006–1012. doi: 10.1016/ j.jaad.2008.03.008. 26. Borve A, Dahlen Gyllencreutz J, Terstappen K, Johansson Backman E, Aldenbratt A, et al. Smartphone teledermoscopy referrals: A novel process for improved triage of skin cancer patients. Acta Derm Venereol 2015; 95(2): 186–190. doi: 10.2340/00015555-1906. 27. Whited JD. Teledermatology research review. Int J Dermatol 2006; 45(3): 220–229. doi: 10.1111/j.1365-4632.2004.02427. x. 28. Maier T, Kulichova D, Schotten K, Astrid R, Ruzicka T, et al. Accuracy of a smartphone application using fractal image analysis of pigmented moles compared to clinical diagnosis and histological result. J Eur Acad Dermatol Venereol 2015; 29(4): 663–667. doi: 10.1111/jdv.12648. 29. Marino ML, Carrera C, Marchetti MA, Marghoob AA. Practice gaps in dermatology: Melanocytic lesions and melanoma. Dermatol Clin 2016; 34(3): 353–362. doi: 10.1016/j.det.2016.03.003.

doi: 10.18282/jsd.v6.i2.64

REVIEW

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review Bao Anh Patrick Tran1, Tiffany Alexander2, Ally-Khan Somani3* 1

Department of Dermatology, Howard University Hospital, Washington, D.C., USA

Howard University College of Medicine, Washington, D.C., USA

Department of Dermatology, Indiana University School of Medicine, Indianapolis, USA

Abstract: Basal cell carcinoma (BCC) is the most common type of human malignancy. It is a slow-growing skin cancer with little ability to metastasize, but it is aggressive and can cause local tissue destruction. Descriptions of Basal Cell Nevus Syndrome (BCNS), characterized by a predisposition to the formation of BCC and other neoplasms, and identification of the genetic defect in this syndrome, has led to significant advancement in our understanding of the pathogenesis of BCC. Unregulated expression of target genes in the sonic Hedgehog (SHH) signaling pathway plays a prominent role in the pathogenesis of BCC. An understanding of the signaling components has allowed for the development of pharmacologic agents that inhibit the SHH pathway. The first inhibitor of the SHH pathway approved by the Food and Drug Administration (FDA) for the treatment of BCC is vismodegib. In this review, we will discuss the biochemical pathways involved in BCC as targets of novel pharmacologic therapies. Keywords: basal cell carcinoma; nonmelanoma skin cancer; Hedgehog signaling; vismodegib Citation: Tran BAP, Alexander T, Somani AK. Biochemical pathways and targeted therapies in basal cell carcinoma. J Surg Dermatol 2021; 6(2): 64; http://dx.doi.org/10.18282/jsd.v6.i2.64.

*Correspondence to: Ally-Khan Somani, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA, somania@iupui.edu Received: 18th November 2020; Accepted: 15th Febuary 2021; Published Online: 9th March 2021

Introduction Clinically, the prototypical nodular basal cell carcinoma BCC appears as a single pearly papule with telangiectasia. Histologically, BCC is characterized by a thickened epidermis with invasive buds and lobules of basaloid cells in the dermis with palisading nuclei (Figure 1). Other subtypes of BCC include superficial and morpheaform BCCs, which have different clinical and histological findings. Basal cell carcinoma is the most common type of skin cancer in the world, with an incidence rate greater than 935/100,000 person-year in Southwestern United States, and with the rate increasing at 2% per year[1]. There is significant geographic variability, with

Figure 1. Hematoxylin and eosin stained slide demonstrating the histopathologic features of nodular BCC including invasive lobules of basaloid cells with clefting and palisading nuclei

Copyright © 2021 Tran BAP, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

the highest rates in Australia with an incidence of > 1,000/100,000 person-year compared to the lowest rates seen in parts of Africa with an incidence of < 1/100,000 person-year. Presumably, this is due to differences in skin pigmentation and ultra-violet (UV) light exposure. Indeed, risk factors related to UV and skin type include fair skin, red hair, blue or green eye color, Northern European ancestry, history of blistering sunburns, history of psoralen and UV-A treatment, exposure to arsenic, ionizing radiation, history of solid organ transplant, and certain genodermatoses[2]. BCC is thought to develop as a result of uncontrolled signaling due to mutations in the sonic Hedgehog pathway.

Methods The identification of relevant articles was performed using the databases PubMed, CINAHL, and EMBASE in October 2015. Key search terms included ―basal cell carcinoma,‖ ―vismodegib,‖ and ―hedgehog signaling‖. Language restrictions were not applied. Two reviewers identified potentially relevant studies. Furthermore, the reference sections of review articles were analyzed to harvest further citations.

Results Hedgehog biochemical pathway While important in embryologic development, the Hedgehog (Hh) pathway is considered to be mostly inactive in adults, save for a few important functions such as hair follicle growth[3], regulation of adult stem cells, and tissue maintenance and repair[4]. There are three mammalian homologs of the Hh ligand: Sonic Hedgehog (SHH), Indian Hedgehog, and Desert Hedgehog. Hh predominately functions in the skin but all bind its intended receptors with equal affinity[4]. The Hedgehog pathway is a network of multiple signaling interactions. The components of SHH signaling that serve as current pharmacologic targets are described in brief below: 1. Hedgehog protein has structural homology similar to a carboxypeptidase but instead of demonstrating hydrolytic activity, it has been found to directly bind to Patched (PTCH), a 12-pass transmembrane receptor located on the cell membrane during telophase at the base of primary cilia[5]. Hedgehog protein binds as an extracellular ligand in the ligand-dependent pathway[6]. The Hedgehog pathway uses primary cilium to process its components and amplify the SHH signal[7]. Normally PTCH sits in the cilium, but SHH ligand promotes the exit of PTCH from the cilium[8]. PTCH translocates and internalizes, causing the sterol pumps to be turned off.

Oxysterols subsequently accumulate around a G-protein-coupled receptor known as Smoothened (SMO) and removes the inhibitory effect over SMO[4]. 2. In the absence of SHH, PTCH constitutively inhibits SMO by preventing it from entering the cilium[4] (Figure 2A). This suppresses the initiation of downstream signaling events[4]. PTCH also removes oxysterols that were created by 7-dehydrocholesterol reductase, which inhibits the initiation of SMO pathway[4]. 3. SMO is a 7-pass transmembrane G-protein-coupled receptor. It is a key pharmacologic target in Hedgehog pathway inhibition, and its biochemical structure is characterized when bound to a small molecular SMO inhibitor[9]. When PTCH is no longer in the cilium and inhibition is relieved, SMO and a Glioma-associated oncogene family protein (GLI) enter the cilium[8]. SMO activates GLI, a transcription factor (Figure 2B), by moving to the cell membrane of the cilium and cleaving the GLI family of transcription factors from the Suppressor of fused (SUFU) protein, a negative suppressor which prevents the transcription of GLI1 target genes[4]. 4. GLI binds DNA and activates the transcription of SHH target genes (Figure 2B), which are involved in cell proliferation[10]. GLI is characterized by a nuclear localization signal that targets it to the nucleus, where it binds to GLI promoters via its repeated zinc finger motifs[4,11]. The kinase protein KIF7 positively and negatively regulates the SHH pathway. The promotion of SHH pathway via KIF7 occurs via antagonization of the activity of SUFU and KIF7, and negatively regulates the pathway by inhibiting GLI-dependent transcriptional activation[12]. Activation of the Hedgehog pathway has been extensively studied and three different mechanisms have been proposed: Type I ligand-independent signaling is driven by inactivating mutations of PTCH1 on chromosome 9q (Figure 2C), or activating mutations of SMO (Figure 2D), which leads to constitutive activation of Hedgehog signaling pathway in the absence of the Hedgehog (HH) ligand[13]. Type II ligand-dependent signaling in an autocrine or juxtacrine manner involves the secretion of the HH ligand from the same or neighboring tumor cells which activates the HH pathway. Type III ligand-dependent signaling involves a paracrine manner, in which the HH ligand is secreted from tumor cells. The ligand is received by remote cells in the stroma, which provide signals such as VEGF and IGF back to the tumor[4]. The Type I ligand-independent Hedgehog pathway is the proposed mechanism for the pathogenesis of basal cell carcinoma[4]. The clear role in the pathogenesis of basal cell carcinoma came from the studies of patients with genetic predispositions for developing BCC.

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Figure 2. Simplified Hedgehog signaling pathway demonstrating Hedgehog signaling in physiologic and oncogenic states. (A) In the absence of SHH ligands, PTCH1 is located in the primary cilium and inhibits the activity of SMO. The GLI proteins together with GLI2 and GLI3 are phosphorylated by protein kinases such as PKA. SUFU inhibits GLIs in the cytosol which leads to its proteolytic cleavage to generate the repressor forms GLI2R and GLI3R. (B) In the presence of SHH ligand, PTCH1 exits the primary cilium, and SMO accumulates. The activation of SMO results in the dissociation of the GLI–SUFU complex and the transportation of activated GLI2 and GLI3 proteins to the nucleus. Activated GLI promotes expression of SHH target genes. (C) Loss-of-function mutation of PTCH results in unregulated SMO signaling and promotes tumor formation. (D) Gain-of-function mutation of SMO results in constitutive expression of SHH target genes, promoting tumor formation.

Genodermatoses BCC is a prominent feature of several genetic syndromes (Table 1): 1. Basal Cell Nevus Syndrome (BCNS), also known as Gorlin syndrome, features multiple aggressive basal cell carcinomas, odontogenic cysts, skeletal abnormalities, ectopic calcifications, facial milia, coarse facial features, and palmoplantar pits[14]. It follows an autosomal-dominant inheritance pattern, and is caused by mutations in the Patched (PTCH) tumor suppressor gene on chromosome 9q22.3[15]. Presumably,

a germline PTCH alteration increases the chances of a ―second hit‖ mutation to cause loss of heterozygosity and loss of PTCH function. Without PTCH suppression, SMO has unchecked downstream signaling, which is thought to aid in the development of basal cell carcinoma. 2. Xeroderma pigmentosum (XP) features heightened photosensitivity of the skin resulting in BCC and other skin neoplasms, premature skin aging, ocular manifestations such as photophobia and cataract development, and neurologic manifestations such as microcephaly and sensorineural hearing loss[16]. It is inherited as an autoso-

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Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

Table 1. Syndromes featuring BCC, genetic defect, and mode of inheritance Syndrome

Mutation

Inheritance

Basal Cell Nevus Syndrome

PTCH

Autosomal Dominant

Xeroderma Pigmentosum

Autosomal Recessive

Bazex-Dupré-Christol Syndrome

Unknown

X-linked Dominant

Rombo Syndrome

Unknown

Autosomal Dominant

mal recessive trait and is due to disorders of nucleotide excision repair and replication of damaged DNA caused by mutations in the XP genes[16]. 3. Bazex-Dupré-Christol syndrome features basal cell carcinomas and nevi, follicular atrophoderma, and diffuse congenital hypotrichosis[17]. Its hereditary pattern is X-linked dominant[17]. The genetic defect involved in the pathogenesis of the basal cell neoformations has not yet been defined. 4. Rombo syndrome presents with BCCs, milia, hypotrichosis, vermiculate atrophoderma (―worm-eaten‖ appearance), and peripheral vasodilation with cyanosis[18]. It is inherited in an autosomal dominant fashion. It is distinguished from Bazex syndrome by the skin redness, although its genetic defect is similarly unknown[19]. There are multiple other syndromes that may feature or be associated with the development of basal cell carcinoma. Certainly, areas of future research will include defining the genetic defects in syndromes featuring BCCs.

Molecular pathogenesis In sporadic BCC, the gene-encoding tumor suppressor protein 53 (TP53) has been found to be mutated even in the absence of PTCH1 alteration[20]. TP53 is involved in cell cycle regulation, DNA damage repair, and apoptosis. It is mutated in approximately half of all human malignancies[21]. With regard to the SHH pathway, BCC-like tumors have been induced in a transgenic mouse model with overexpression of SHH[22]. As we have observed in the loss of function of PTCH1 in BCNS, unregulated transcription of SHH target genes promotes BCCs. Downstream of PTCH, activating mutations in SMO have also been found to result in BCC formation (Figure 3)[23]. Finally, GLI overexpression has been shown to induce BCC in a mouse model[24]. SHH signaling does not occur in isolation; cross-talk has been demonstrated with other cell signaling cascades including epidermal growth factor receptor (EGFR), transforming growth factor beta (TGFβ), tumor necrosis factor (TNF), and wingless (Wnt), and these pathways are well summarized in a recent review article[25]. As the mechanisms for these signaling interactions are further elucidated, there may be identification of novel targets for inhibiting the growth and development of ba-

sal cell carcinoma. Interestingly, BCC has a low tendency to metastasize. On the molecular level, the distant spread of a cancer cell is inhibited by metastasis suppressors (MSPs), which are proteins defined by its ability to inhibit a cancer cell’s capacity to metastasize without affecting primary tumor growth[26]. BCC’s low metastatic potential may be due to the maintained expression of MSPs NM23-H1, NDRG1, and E-cadherin[27]. Despite this, metastasis does occur, with an incidence of 0.0028%–0.55%[28]. Unfortunately, metastatic BCC (mBCC) carries a poor prognosis with a median survival of ten months[29]. With the recent advances in systemic therapies targeting components of the SHH pathway, there is hope for improvement of symptoms and survival in mBCC. Treatment of basal cell carcinoma is dependent on the risk of recurrence, which involves clinical features of the tumor, such as anatomic site and borders; patient risk factors, including immunosuppression from solid organ transplant; histopathologic features such as morpheaform or micronodular subtypes; and evidence of perineural invasion[30].Therapies range from topical imiquimod or 5-fluorouracil, photodynamic therapy, radiation, electrodessication and curettage, standard surgical excision with post-operative or intra-operative margin assessment, to Mohs micrographic surgery[31]. While surgery is the mainstay of therapy, targeted inhibitors of hedgehog signaling increase the medical armamentarium in the treatment of advanced and mBCC.

SMO inhibition Cyclopamine was the first pharmacological inhibitor of SHH signaling described and its timeline in the development of SHH inhibitors in humans has been recently reviewed[32]. Briefly, the phenotype of cyclopia, or having one eye, was discovered in lambs whose mothers grazed on corn lilies. The teratogen in this plant was identified and named as cyclopamine. In humans as well, it was realized that cyclopia was caused by defective SHH signaling during embryogenesis. Further studies revealed that cyclopamine binds SMO and inhibits SHH signaling. Small-molecule screens identified other SMO inhibitors with more favorable pharmacology. Cyclopamine has low affinity to the receptors and poor bioavailability[4]. A more soluble and stable derivative—IPI 269609—has been developed[4]. Vismodegib (GDC-0449) is likely the most wellknown SHH pathway inhibitor. In 2009, a phase I clinical trial revealed the clinical promise of this small molecule antagonist of SMO in cases of advanced BCC[33].

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Given its continued success in a phase II trial, the drug was approved by the Food and Drug Administration (FDA) in 2012 for the treatment of locally advanced (laBCC) or mBCC[34,35]. In a recent efficacy and safety outcome update from the ERIVANCE BCC study, in which patients were assessed after an additional 12month follow-up from the primary analysis, the mBCC objective response rate improved from 30.3% to 33.3%[36]. The laBCC objective response rate improved from 42.9% to 47.6%. The median overall survival period for patients with mBCC was 24.1 months but the survival period for laBCC patients was not yet able to be estimated. However, there was an increase in adverse events. The treatment-emergent adverse events (TEAEs) included dysgeusia, muscle cramps, alopecia, weight loss, fatigue, and nausea[36]. Vismodegib has also been studied for use as neoadjuvant chemotherapy 12 months prior to Mohs surgery for BCC lesions. Approximately 42% of patients demonstrated complete histological and clinical clearance, but there was only a 16% histological clearance rate and 36% complete clinical clearance rate 24 weeks post- vismodegib[37]. These studies help to underscore the importance of vismodegib. According to a search in www.clinicaltrials.gov in October 2015, there are 25 ongoing studies on the effects of vismodegib on BCC. The results will hopefully provide further insight into its efficacy. In addition to vismodegib, there are multiple different drugs in development and in clinical trials that inhibit SMO and other components of the SHH pathway. An overview of the SMO inhibitors follows (Figure 3).

SMO inhibitors 1. Saridegib (IPI-926) is a systemic, selective SMO inhibitor that is a derivative of cyclopamine. It is found to have activity in patients with BCC. A phase I trial identified a regimen of 160 mg of saridegib daily in 28day cycles as the recommended dose and schedule for phase II trials[38]. The patients with vismodegib-naive BCCs showed response to the drug but disease progression ultimately developed. There are ongoing clinical trials for saridegib. 2. Sonidegib (LDE225) is a second SMO inhibitor that has been approved by the FDA for laBCC. The BOLT phase II clinical trial showed a 47% objective response rate in patients taking 200 mg for laBCC and a 35% response rate in patients taking 800 mg for laBCC[39]. The drug has not proven to be very useful for mBCC. The response rate for patients taking the 200 mg mBCC arm was 15%, whereas those taking the 800 mg arm had a 17% response rate. Essentially all patients in both arms encountered side effects but the 200 mg arm

had lower adverse events, a lower discontinuation rate, and longer duration of treatment; therefore, it was more favorable. In the 12-month follow-up, the 200 mg arm patients had a 58% response rate as opposed to the 800 mg arm patients who had a 44% response rate[40]. At the 12th month mark, approximately 78% of patients discontinued treatment, mostly due to adverse events. Currently, there are three active clinical trials evaluating the efficacy of sonidegib and BCC. 3. CUR61414 is another SMO inhibitor that has been studied in a topical formulation that showed promise in pre-clinical studies in SHH signaling blockade in mice, but had no clinical activity in human BCC during a phase I clinical trial[41]. Lauressergues et al. found CUR61414 to be a low potency inhibitor compared to other SMO antagonists[42]. 4. BMS-833923 (XL-139) is a SMO inhibitor that decreases GLI and PTCH mRNA expression and reduces cell viability[43]. It has also been shown to have strong receptor-ligand interaction and binding affinity against SMO receptor[44]. It showed a clinical partial response in a patient with BCNS in a phase I trial, but was complicated by pancreatitis[45]. Currently, there is a phase I study of BMS-833923 in subjects with advanced or metastatic BCC and in two patients with BCNS. 5. MK4101 is a SMO inhibitor which has been used in preclinical studies in lung cancer cell lines that have been reported to have increased SHH signaling[46]. 6. PF-04449913 is a targeted SMO inhibitor that underwent a phase I clinical trial in patients with advanced solid tumors, which resulted in no partial or complete responses; however, some patients had prolonged stable disease[47]. It has been studied in the use of hematopoietic malignancies and has shown to inhibit hematopoietic precursor cells in Drosophila and to modulate self-renewal signatures and cell cycle progression[48,49]. There are many clinical trials that are evaluating the use of PF-04449913 in hematologic malignancies. 7. LEQ506 is a second-generation targeted inhibitor of SMO currently in a phase I clinical trial for advanced solid tumors including BCC[50,51]. 8. TAK-441 is a SMO inhibitor found to have in vitro activity against a mutant form of SMO that is vismodegib-resistant[52]. A phase I dose-escalation trial of TAK441 in patients with advanced solid tumors concluded that TAK-441 had a maximum tolerated dose of 1600 mg/day. Out of 34 patients, one BCC patient showed partial response and seven patients with various tumors showed stable disease progression[53]. There is currently a clinical trial evaluating TAK-441 in adult patients with advanced non-hematologic malignancies.

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Figure 3. Hedgehog signaling pathway demonstrating pharmacologic inhibitors of the signaling cascade and its molecular targets

9. SANTs1-4 are four pre-clinical small molecule inhibitors of SMO that are structurally distinct from cyclopamine and were identified in cell-based assays[54]. 10. Itraconazole is an antifungal agent found to inhibit SHH signaling during a screen of drugs that have been previously tested in humans[55]. It decreases cell proliferation, GLI1 mRNA, and tumor size[55]. It has also been shown to have activity against mutant SMO resistant to vismodegib[56]. In a clinical trial, itraconazole showed a 23% reduction in BCC size, a 45% reduction in neoplastic proliferation, and a 65% reduction in SHH pathway activity[57]. The combination of itraconazole and arsenic trioxide (ATO) antagonizes the SHH pathway at sites that are distinct from SMO inhibitors. In five patients with relapsing mBCC after SMO inhibitor treatment, three showed stable disease progression after undergoing three treatment cycles of the combination. The remaining patients discontinued treatment. However, the combination therapy demonstrated reduced GLI mRNA by 75% from baseline[58]. There are currently five clinical trials that are testing itraconazole specifically in patients with BCC, including one with a combination treatment of arsenic trioxide and itraconazole. 11. Taladegib (LY2940680) is a SMO inhibitor that binds to the extracellular end of the transmembranehelix bundle of SMO and inhibits SMO mutants that are vismodegib-resistant[9,59]. There are eight active studies on taladegib.

12. Vitamin D3 is thought to directly bind to SMO to inhibit the SHH pathway[60]. A phase II study of the combination of topical diclofenac 3% and calcitriol of 3 μg/g on superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC) has just been completed. The post-treatment expression levels of antiapoptosis (B-cell lymphoma Bcl-2) immunohistochemical and proliferation (Ki-67) markers were measured. Combination therapy showed a significant decrease in Ki-67, and complete histologic tumor regression was seen in 43.8% of those with sBCC. However, there were no significant changes in patients with nBCC[61].

SHH ligand inhibitors 1. Robotnikinin is a small molecule which binds the extracellular SHH protein that inhibits PTCH[62]. While of interest on a mechanistic level, it seems that blocking this interaction will not be clinically relevant, given that the mutations in BCC tend to occur downstream of this signaling step. 2. Hedgehog-interacting protein (Hhip) sequesters the extracellular SHH ligand and is part of a negative feedback mechanism during embryologic development [63]. For the reasons stated above, it may not be an important pharmacologic inhibitor of the SHH pathway. 3. 5E1 is a monoclonal antibody to SHH that blocks SHH binding to PTCH[64]. It has been shown to reduce tumor stroma in pancreatic cancer xenografts[65].

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However, there are currently no clinical trials to evaluate its efficacy in humans.

GLI inhibition 1. Arsenic trioxide is an FDA-approved drug for the treatment of acute promyelocytic leukemia, but it directly inhibits GLI in the SHH pathway[66]. It inhibits GLI2 ciliary accumulation and promotes its degradation. Since ATO and itraconazole act at sites different from SMO inhibitors, the combination has proven useful for treatment in those that are resistant to vismodegib[56]. As stated previously, there is currently a study underway that analyzes the effectiveness of ATO and itraconazole. Also, a study has just been completed by Stanford University in which arsenic alone was used to treat BCC. The results are not yet published[67]. 2. Imiquimod is currently approved for use as a topical treatment for superficial BCC on the trunk and extremities[68]. It has been shown to directly decrease SHH signaling by decreasing GLI activity[69]. In a three-year follow-up for a randomized controlled trial of photodynamic therapy vs. imiquimod vs. fluorouracil for the treatment of superficial basal cell carcinoma, imiquimod was shown to have the highest probability of tumor-free survival (79.7%) at three years post-treatment[70]. There are multiple clinical trials analyzing the efficacy of imiquimod as treatment of BCC. 3. GANT61 is a GLI inhibitor that has been shown to reduce GLI expression in a rhabdomyosarcoma model[71]. However, more recently, a study demonstrated in vitro that GLI expression was not significantly decreased by the treatment with GANT61 in the leukemia cell lines but GANT61 inhibited proliferation of the cell lines and the viability of the cells[72]. 4. GANT58 is a GLI inhibitor that has been shown to reduce GLI expression and tumor cell viability in an acute T-cell lymphoma model[73].

Discussion The Hedgehog pathway serves as a key role in the treatments used for multiple malignancies. However, the components of the Sonic Hedgehog pathway have successfully been pharmacologic targets in the treatment of BCC. The inhibition of the SHH ligand leads to unregulated PTCH. PTCH can then continue to inhibit SMO and thus cause downregulation of the transcription factor GLI. Drugs that act as SMO inhibitors are the most numerous and have proven to be vital for BCC therapy. Vismodegib has shown a 48% and 33% response rate in laBCC and mBCC, respectively. 200 mg of

sonidegib had a 43% and 15% response rate in laBCC and mBCC, and 38% and 17% response rate for 800 mg of sonidegib in laBCC and mBCC, respectively[74]. Although the drugs effectively inhibit SMO, there are concerns about SMO mutations and vismodegib resistance. Resistance to vismodegib after an initial successful treatment has developed predominately through SMO (D473H and G497W) mutations as well as PTCH, SHH, and GLI[8,75-77]. SMO D473H is a result of aspartic acid mutating to tyrosine at position 473 whereas G497W is a mutation of glycine to tryptophan[76]. Upregulation of the IGF-1R/PI3K pathway has also been demonstrated in resistant tumor samples, as well as disruption of ligand responsiveness and autoinhibition[77,78]. Mutations in SMO and concurrent copy number mutations in SUFU and GLI are in many cases of the relapsed tumors. In untreated Gorlin syndrome, the SMO mutations were absent; in 15% of sporadic BCCs, they were present[78,79]. Shimizu has found that TAK-441 is able to potently inhibit the SMO- D473H mutation because the dissociation rate of TAK- 441 was much smaller than that of vismodegib or cyclopamine[80]. An open-label study analyzed sonidegib in nine patients with laBCC who were resistant to vismodegib treatment. The results showed that only three patients had stable disease and five patients had disease progression[81]. However, patients with mBCC will have a higher likelihood of acquired resistance with a rate as high as 21% [75]. Although many of the SHH therapies used for BCC were successful, most patients experienced adverse effects and some discontinued the treatment as a result. The most common treatment-emergent adverse events (TEAEs) included dysgeusia, muscle cramps, alopecia, weight loss, fatigue, and nausea[36]. Given that SHH plays a role in hair follicle development, it is understandable that the blockade of this pathway results in alopecia. An interim analysis of a large clinical trial on the safety and efficacy of vismodegib (STEVIE) reported that 36% of their participants discontinued the drug due to adverse events[82]. However, 67% showed partial or complete response. The side effects are difficult to avoid since they exhibit the ―class effect‖. They are directly caused by Hedgehog pathway inhibition and are thus ―on-target‖[83]. Notably, vismodegib was also shown to reduce tumor burden in patients with BCNS, although the side effects resulted in a high rate of discontinuation of therapy[84]. Sofen et al. put patients on two courses of vismodegib for eight weeks, each with a four-week break in-between, but this did not improve the adverse events[37]. Vismodegib was found to be teratogenic in rats at doses that were 20% of the recommended dosage[4]. It caused absent or fused digits, craniofacial anomalies,

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and an open perineum. It is a pregnancy Category D drug[4]. Side effects from systemic SHH inhibition may in fact elucidate other functions of SHH signaling in adults that are yet to be discovered[32]. The next steps for further developing SHH medications include finding long term treatment options, circumventing side effects, providing tailor-made therapy for the patient, and reducing the financial toxicity of treatment. Some patients may not fit neatly into the locally advanced or metastatic BCC categories while others may be perfect candidates but are not willing to tolerate the side effects. Treatments should target individuals based on a multitude of factors that not only include the molecular mechanisms of cancer etiology and progression, but incorporate additional aspects such as tumor resistance, adverse events, and patient adherence. Another consideration is the economic burden of new medications. A one-month supply of once-daily capsules of vismodegib from Genentech is USD7,500. If the expected length of treatment is 10 months, the total cost could be upwards of USD75,000. By the year 2022, the sales predictions in Europe are projected to peak at USD533 million[85]. Although vismodegib has proven to be successful so far, the financial burden should be taken into account.

was done by BAP Tran and AK Somani.

Acknowledgements We would like to thank the investigators of hedgehog and other molecular pathways whose research we could not cite primarily due to reference restraints.

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

References 1.

Conclusion In summary, basal cell carcinoma is an important clinical entity. Its molecular pathogenesis is driven by excessive signaling through the Hedgehog pathway. Advances in our understanding of hedgehog and other cell signaling cascades have resulted in the development of novel drugs in the treatment of human malignancy. There are certain frontiers that need to be pushed to develop newer therapies for BCC. Discovering alternative SHH targets can help avoid adverse events and SMO resistance. More clinical trials on the efficacy of cheaper drugs such as itraconazole can guide us toward alleviating an economic burden. For now, vismodegib is the mainstay of medical treatment, but further elucidation of these biochemical pathways will undoubtedly lead to increasing medical management of advanced and mBCC.

Author contributions BAP Tran and AK Somani were involved in the overall study concept and design. Acquisition, analysis, and interpretation of data were performed by BAP Tran and T Alexander. BAP Tran and T Alexander also drafted the manuscript. Critical revision of the manuscript’s content

Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol 2012; 166(5): 1069–1080. doi: 10.1111/j.1365-2133.2012.10830.x. Correia de Sá TR, Silva R, Lopes JM. Basal cell carcinoma of the skin (part 1): Epidemiology, pathology and genetic syndromes. Future Oncol 2015; 11(22): 3011–3021. doi: 10.2217/fon.15.246. Wang LC, Liu ZY, Gambardella L, Delacour A, Shapiro R, et al. Conditional disruption of Hedgehog signaling pathway defines its critical role in hair development and regeneration. J Invest Dermatol 2000; 114(5): 901–908. doi: 10.1046/j.1523-1747.2000.00951.x. Abidi A. Hedgehog signaling pathway: A novel target for cancer therapy: Vismodegib, a promising therapeutic option in treatment of basal cell carcinomas. Indian J Pharmacol 2014; 46(1): 3–12. doi: 10.4103/0253-7613.12 4884. Ruch JM, Kim EJ. Hedgehog signaling pathway and cancer therapeutics: progress to date. Drugs 2013; 73(7): 613–623. doi: 10.1007/s40265-013-0045-z. Fuse N, Maiti T, Wang B, Porter JA, Hall TMT, et al. Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched. Proc Natl Acad Sci U S A 1999; 96(20): 10992–10999. doi: 10.1073/pnas.96.20.10992. Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011; 27: 513–537. doi: 10.1146/annurev-cellbio-092910-154048. Atwood SX, Whitson RJ, Oro AE. Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 2014; 4(7): a013581. doi: 10.1101/cs hperspect.a013581. Wang C, Wu H, Katritch V, Han GW, Huang XP, et al. Structure of the human smoothened receptor bound to an

26 doi:10.18282/jsd.v6.i2.64

Tran BAP, et al.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

antitumour agent. Nature 2013; 497(7449): 338–343. doi: 10.1038/nature12167. Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 2014; 141(18): 3445–3457. doi: 10.1242/dev.083691. Hatayama M, Aruga J. Gli protein nuclear localization signal. In: Litwack G, (editor). Hedgehog signaling: Volume 88 of vitamins and hormones. US: Academic Press; 2012. p. 73 –89. doi: 10.1016/B978-0-12-394 622-5.00004-3. Liem KF Jr, He M, Ocbina PJR, Anderson KV. Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic Hedgehog signaling. Proc Natl Acad Sci U S A 2009; 106(32): 13377–13382. doi: 10.1073/pnas.090 6944106. Proctor AE, Thompson LA, O’Bryant CL. Vismodegib: An inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma. Ann Pharmacother 2014; 48(1): 99–106. doi: 10.1177/1060028013506696. Evans DG, Farndon PA. Nevoid basal cell carcinoma syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, et al., (editors). GeneReviews. Seattle, WA: University of Washington; 1993–2016. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85(6): 841–851. doi: 10.1016/S009 2-8674(00)81268-4. DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest Dermatol 2012; 132(3 Pt 2): 785–796. doi: 10.1038/jid.2011.426. Vabres P, Lacombe D, Rabinowitz LG, Aubert G, Anderson CE, et al. The gene for Bazex-Dupré-Christol syndrome maps to chromosome Xq. J Invest Dermatol 1995; 105(1): 87–91. doi: 10.1111/1523-1747.ep12313359. Michaëlsson G, Olsson E, Westermark P. The Rombo syndrome: A familial disorder with vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, basal cell carcinomas and peripheral vasodilation with cyanosis. Acta Derm Venereol 1981; 61(6): 497–503. Parren LJMT, Frank J. Hereditary tumour syndromes featuring basal cell carcinomas. Br J Dermatol 2011; 165(1): 30–34. doi: 10.1111/j.1365-2133.2011.10334.x. Reifenberger J, Wolter M, Knobbe CB, Köhler B, Schönicke A, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005; 152(1): 43–51. doi: 10.1111/j.1365-2133.2005.06353.x. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, et al. Mutational landscape and significance across 12 jor cancer types. Nature 2013; 502(7471): 333–339. doi:

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

10.1038/nature12634. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr, et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1997; 276(5313): 817–821. doi: 10.1126/science.276.5313.817. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998; 391(6662): 90–92. doi: 10.1038/34 201. Nilsson M, Undèn AB, Krause D, Malmqwist U, Raza K, et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA 2000; 97(7): 3438–3443. doi: 10. 1073/pnas.97.7.3438. Athar M, Li C, Kim AL, Spiegelman VS, Bickers DR. Sonic Hedgehog signaling in basal cell nevus syndrome. Cancer Res 2014; 74(18): 4967–4975. doi: 10.1158/0008-5472.CAN-14-1666. Cook LM, Hurst DR, Welch DR. Metastasis suppressors and the tumor microenvironment. Semin Cancer Biol 2011; 21(2): 113–122. doi: 10.1016/j.semcancer.2010.12. 005. Bozdogan O, Yulug IG, Vargel I, Cavusoglu T, Karabulut AA, et al. Differential expression patterns of metastasis suppressor proteins in basal cell carcinoma. Int J Dermatol 2015; 54(8): 905–915. doi: 10.1111/ijd.12581. von Domarus H, Stevens PJ. Metastatic basal cell carcinoma: Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol 1984; 10(6): 1043–1060. doi: 10.1016/S0190-9622(84)80334-5. Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell carcinoma: A summary of published cases from 1981 through 2011. JAMA Dermatol 2013; 149(5): 615–616. doi: 10.1001/jamadermatol.2013.3064. National Comprehensive Cancer Network. Basal cell skin cancer (Version 1.2015) [Internet]. Fort Washington, PA: National Comprehensive Cancer Network; 2016 [cited 2014 Dec 11]. Available from: http:// www.nccn .org/professionals/physician_gls/pdf/nmsc.pdf. Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus. J Am Acad Dermatol 2007; 56(1): 125–143. doi: 10.1016/j.jaad.2006.06.006. Wong SY, Dlugosz AA. Basal cell carcinoma, Hedgehog signaling, and targeted therapeutics: The long and winding road. J Invest Dermatol 2014; 134(e1): E18–E22. doi: 10.1038/skinbio.2014.4. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, et al. Inhibition of the Hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009;

27 doi:10.18282/jsd.v6.i2.64

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

34.

35.

36.

37.

38.

39.

40.

41.

42.

361(12): 1164–1172. doi: 10.1056/NEJMoa0905360. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366(23): 2171–2179. doi: 10.1056/NEJMoa1113713. Axelson M, Liu K, Jiang X, He K, Wang J, et al. U.S. Food and Drug Administration approval: Vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res 2013; 19(9): 2289–2293. doi: 10.1158/1078-0432.CCR-12-1956. Sekulic A, Migden MR, Lewis K, Hainsworth JD, Solomon JA, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol 2015; 72(6): 1021–1026.e8. doi: 10.1016/ j.jaad.201 5.03.021. Sofen H, Gross KG, Goldberg LH, Sharata H, Hamilton TK, et al. A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol 2015; 73(1): 99–105.e1. doi: 10.1016/j.jaad.2015.03.013. Jimeno A, Weiss GJ, Miller WH Jr, Gettinger S, Eigl BJC, et al. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res 2013; 19(10): 2766–2774. doi: 10.1158/1078-04 32.CCR-12-3654. Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015; 16(6): 716–728. doi: 10.1016/S1470-2045(15)70100-2. Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol 2016; 75(1): 113–25.e5. doi: 10.1016/j.jaad. 2016.02.1 226. Tang T, Tang JY, Li D, Reich M, Callahan CA, et al. Targeting superficial or nodular basal cell carcinoma with topically formulated small molecule inhibitor of smoothened. Clin Cancer Res 2011; 17(10): 3378–3387. doi: 10.1158/1078-0432.CCR-10-3370. Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, et al. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect 2016; 4(2): e00214. doi: 10.1002/prp2.214.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

Riedlinger D, Bahra M, Boas-Knoop S, Lippert S, Bradtmöller M, et al. Hedgehog pathway as a potential treatment target in human cholangiocarcinoma. J Hepato-Biliary-Pancreat Sci 2014; 21(8): 607–615. doi: 10.1002/jhbp.107. Akare UR, Bandaru S, Shaheen U, Singh PK, Tiwari G, et al. Molecular docking approaches in identification of High affinity inhibitors of human SMO receptor. Bioinformation 2014; 10(12): 737–742. doi: 10.6026/ 97320630010737. Siu LL, Papadopoulos K, Alberts SR, Kirchoff-Ross R, Vakkalagadda B, et al. A first-in-human, phase I study of an oral Hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors. J Clin Oncol 2010; 28: 15s (suppl; abstr 2501). Galimberti F, Busch AM, Chinyengetere F, Ma T, Sekula D, et al. Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. Int J Oncol 2012; 41(5): 1751–1761. doi: 10.3892/ijo.2012.1599. Wagner AJ, Messersmith WA, Shaik MN, Li S, Zheng X, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015; 21(5): 1044–1051. doi: 10.1158/1078-0432.CCR-14-1116. Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, et al. Small-molecule hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci 2016. doi: 10.1111/cas.13019. Giordani G, Barraco M, Giangrande A, Martinelli G, Guadagnuolo V, et al. The human Smoothened inhibitor PF-04449913 induces exit from quiescence and loss of multipotent drosophila hematopoietic progenitor cells. Oncotarget 2016; 7(34): 55313–55327. doi: 10.18632/oncotarget.10879. Peukert S, He F, Dai M, Zhang R, Sun Y, et al. Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened. ChemMedChem 2013; 8(8): 1261–1265. doi: 10.1002/cmdc.201300217. Novartis Pharmaceuticals. A dose finding and safety study of oral LEQ506 in patients with advanced solid tumors. [Internet]. Switzerland: Novartis Pharmaceuticals; 2016 [updated 2016 Oct 7; cited 2014 Dec 14]. Available from: https://clinicaltrials.gov/ct2/show/NCT01106508. Ishii T, Shimizu Y, Nakashima K, Kondo S, Ogawa K, et al. Inhibition mechanism exploration of investigational drug TAK-441 as inhibitor against vismodegib-resistant Smoothened mutant. Eur J Pharmacol 2014;723: 305–313.

28 doi:10.18282/jsd.v6.i2.64

Tran BAP, et al.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

doi: 10.1016/j.ejphar.2013.11.014. Goldman J, Gail Eckhardt S, Borad MJ, Curtis KK, Hidalgo M, et al. Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. Clin Cancer Res 2015; 21(5): 1002–1009. doi: 10.1158/1078-0432.CCR-14-1234. Chen JK, Taipale J, Young KE, Maiti T, Beachy PA. Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A 2002; 99(22): 14071–14076. doi: 10.1073/pnas.182542899. Kim J, Tang JY, Gong R, Kim J, Lee JJ, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 2010; 17(4): 388–399. doi: 10.1016/j.ccr.2010.02.027. Kim J, Aftab BT, Tang JY, Kim D, Lee AH, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013; 23(1): 23–34. doi: 10.1016/j.ccr.2012.11.017. Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin O n c o l 2 0 1 4 ; 3 2 ( 8 ) : 7 4 5 – 7 5 1 . d o i : 1 0 . 1 2 00/JC O.2013.49.9525. Ally MS, Ransohoff K, Sarin K, Atwood SX, Rezaee M, et al. Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory ic basal cell carcinoma. JAMA Dermatol 2016; 152(4): 452–456. doi: 10.1001/jamadermatol.2015.5473. Bender MH, Hipskind PA, Capen AR, Cockman M, Credille KM, et al. Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated Hedgehog signaling. Cancer Res 2011; 71(8 Supplement): 2819–2819. doi: 10.1158/1538-7445.AM2011-2819. DeBerardinis AM, Banerjee U, Miller M, Lemieux S, Hadden MK. Probing the structural requirements for vitamin D3 inhibition of the Hedgehog signaling pathway. Bioorg Med Chem Lett 2012; 22(14): 4859–4863. doi: 10.1016/j.bmcl.2012.05.037. Brinkhuizen T, Frencken KJA, Nelemans PJ, Hoff MLS, Kelleners-Smeets NWJ, et al. The effect of topical diclofenac 3% and calcitriol 3 μg/g on superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC): A phase II, randomized controlled trial. J Am Acad Dermatol 2016; 75(1): 126–134. doi: 10.1016/j.jaad .2016.01.050. Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 2009; 5(3):

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

154–156. doi: 10.1038/nchembio.142. Kwong L, Bijlsma MF, Roelink H. Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling. Nat Commun 2014; 5: 4849. doi: 10.1038/ncomms5849. Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, et al. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J Biol Chem 2010; 285(34): 26570–26580. doi: 10.1074/jbc.M110.112284. Chang Q, Foltz WD, Chaudary N, Hill RP, Hedley DW. Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during Hedgehog pathway inhibition. Int J Cancer 2013; 133(1): 225–234. doi: 10.1002/ijc.28006. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A 2010; 107(30): 13432–13437. doi: 10.1073/pnas.1006822107. Tang JY. Arsenic trioxide in treating patients with basal cell carcinoma [Internet]. Stanford, California: Stanford University; 2016 [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01791894. Sapijaszko MJA. Imiquimod 5% cream (Aldara) in the treatment of basal cell carcinoma. Skin Ther Lett 2005; 10(6): 2–5. Wolff F, Loipetzberger A, Gruber W, Esterbauer H, Aberger F, et al. Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation. Oncogene 2013; 32(50): 5574–5581. doi: 10.1038/onc.2013.343. Roozeboom MH, Arits AHMM, Mosterd K, Sommer A, Essers BAB, et al. Three-year follow-up results of photodynamic therapy vs. imiquimod vs. fluorouracil for treatment of superficial basal cell carcinoma: A single-blind, noninferiority, randomized controlled trial. J Invest Dermatol 2016; 136(8): 1568–1574. doi: 10.1016/j.jid.2016.03.043. Srivastava RK, Kaylani SZ, Edrees N, Li C, Talwelkar SS, et al. GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis. Oncotarget 2014; 5(23): 12151–12165. doi: 10.18632/oncotarget.2569. Arnhold V, Boos J, Lanvers-Kaminsky C. Targeting Hedgehog signaling pathway in pediatric tumors: In vitro evaluation of SMO and GLI inhibitors. Cancer Chemother Pharmacol 2016; 77(3): 495–505. doi: 10.1007/s00 280-016-2962-5. Hou X, Chen X, Zhang P, Fan Y, Ma A, et al. Inhibition of Hedgehog signaling by GANT58 induces apoptosis and shows synergistic antitumor activity with AKT

29 doi:10.18282/jsd.v6.i2.64

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

74.

75.

76.

77.

78.

79.

inhibitor in acute T cell leukemia cells. Biochimie 2014; 101: 50–59. doi: 10.1016/j.biochi.2013.12.019. Silapunt S, Chen L, Migden MR. Hedgehog pathway inhibition in advanced basal cell carcinoma: Latest evidence and clinical usefulness. Ther Adv Med Oncol 2016; 8(5): 375–382. doi: 10.1177/1758834016653605. Chang ALS, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol 2012; 148(11): 1324–1325. doi: 10.1001/archdermatol.2012.2354. Pricl S, Cortelazzi B, Dal Col V, Marson D, Laurini E, et al. Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Mol Oncol 2015; 9(2): 389–397. doi: 10.1016/j.molonc.20 14.09.003. Cowey CL. Targeted therapy for advanced basal-cell carcinoma: Vismodegib and beyond. Dermatol Ther 2013; 3(1): 17–31. doi: 10.1007/s13555-013-00 19-9. Atwood SX, Sarin KY, Whitson RJ, Li JR, Kim G, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell 2015; 27(3): 342–353. doi: 10.1016/j.ccell.2015.02.002. Sharpe HJ, Pau G, Dijkgraaf GJ, Basset-Seguin N, Modrusan Z, et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell 2015; 27(3): 327–341. doi: 10.1016/j.ccell.2015.02.001.

80.

81.

82.

83.

84.

85.

Shimizu Y, Ishii T, Ogawa K, Sasaki S, Matsui H, et al. Biochemical characterization of smoothened receptor antagonists by binding kinetics against drug-resistant mutant. Eur J Pharmacol 2015; 764: 220–227. doi: 10.1016/j.ejphar.2015.05.062. Danial C, Sarin KY, Oro AE, Chang ALS. An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib. Clin Cancer Res 2016; 22(6): 1325–1329. doi: 10.1158/1078-0432.CCR-15-1588. Basset-Seguin N, Hauschild A, Grob J-J, Kunstfeld R, Dréno B, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): A pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015; 16(6): 729–736. doi: 10.1016/S1470-20 45(15)70198-1. Khoo ABS, Ali FR, Lear JT. Defining locally advanced basal cell carcinoma and integrating smoothened inhibitors into clinical practice. Curr Opin Oncol 2016; 28(2): 180–184. doi: 10.1097/CCO.0000000000000259. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366(23): 2180–2188. doi: 10.1056/NEJMoa11 13538. Fellner C. Vismodegib (erivedge) for advanced basal cell carcinoma. P T 2012; 37(12): 670–682.

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CASE REPORT

Necrobiosis lipoidica treated with intense pulsed light Marisa Gonzaga da Cunha1*, Flávia Cury Rezende1, Ana Lucia Gonzaga da Cunha2, Carlos D’Apparecida Santos Machado Filho1 1

Faculty of Medicine of ABC, Santo André, São Paulo, Brazil

Federal University of São Paulo, São Paulo, Brazil

Abstract: Necrobiosis Lipoidica (NL) is a chronic degenerative disease of the collagen with higher incidence on the anterior part of lower extremities, especially the tibial area. There were a number of proposed treatments, but none is 100% effective. We present a case of a fifty-year-old female patient with a suspected diagnosis of necrobiosis lipoidica, confirmed by histopathological examination. After two years of treatment with topical corticosteroids and weekly applications of Psoralen and ultraviolet A radiation (PUVA), there were no signs of improvement and we decided to perform a treatment with intense pulsed light therapy. Over a period of 14 months, a total of 13 sessions were carried out and a satisfactory treatment result was obtained. Keywords: Necrobiosis lipoidica; treatment; intense pulsed light Citation: da Cunha MG, Rezende FC, da Cunha ALG, Machado Filho CDAS. Necrobiosis lipoidica treated with intense pulsed light. J Surg Dermatol 2021; 6(2): 65; http://dx.doi.org/10.18282/jsd.v6.i2.65.

*Correspondence to: Marisa Gonzaga da Cunha, Faculdade de Medicina do ABC, Santo André, SP, Brazil; dramarisagonz aga@yahoo.com.br Received: 6th December 2020; Accepted: 24th Febuary 2021; Published Online: 21st April 2021

Introduction Necrobiosis Lipoidica (NL) is a chronic degenerative disease of the collagen with higher incidence on the anterior part of lower extremities, especially the tibial area. However, it occasionally occurs on other sites of the trunk, arms and face as well[1]. It mainly affects young women, although the literature has described some cases in children[2]. NL presents as one or more unilateral or bilateral inflammatory plaques with erythematous border and shiny atrophic center, which attributes to its characteristic yellowish color that allows the visualization of blood vessels and subcutaneous fat. The plaques slowly extend over the years and painful ulcerations occur in 15% of the cases. The disease is frequently associated with diabetes mellitus; 65% of the patients with NL have diabetes mellitus and a significant rate of individuals present

abnormal results in glucose tolerance tests. Nevertheless, the etiopathogenic relation between NL and diabetes mellitus has not been clearly determined yet, and several hypotheses have been proposed: an abnormality in glucose transport by fibroblasts, abnormalities in the synthesis and degradation of collagen, and vascular occlusion caused by platelet aggregation alterations due to microangiopathy or by immune complex deposition. Histological findings show that NL is essentially a granulomatous inflammatory disease whose first manifestations occur as vasculitis of small vessels, evolving into granulomatous vasculitis of medium vessels with degeneration of collagen fibers. It involves the dermis and the hypodermis in a septal panniculitis pattern. The lymphocytic component of the dermal infiltrate is predominantly composed of T-cells, in particular the T-helper cells. In many cases, studies with direct immunofluorescence show immunoglobulin deposits, especially of IgM, and complement in vessel walls.

Copyright © 2021 da Cunha MG, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribu-tionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Necrobiosis lipoidica treated with intense pulsed light

The proposed treatments include the following: potent topical corticosteroid therapy with tacrolimus and tretinoin; intralesional corticosteroid therapy; and therapy with systemic drugs such as aspirin and dipyridamole, ticlopidine, pentoxifylline, nicotinamide, chloroquine, corticosteroids, cyclosporine and mycophenolate mofetil. Moreover, physical treatments with surgery, artificial skin grafts, PUVA, laser and hyperbaric oxygen are widely used therapies. However, there is no treatment that is 100% effective for most cases of NL. The literature lacks more detailed studies with sufficient number of patients that demonstrate the effectiveness of the therapies mentioned above. Studies using any of these therapies show variable responses, typically with flattening of borders and almost always a partial clearing with persistent central atrophy.

Case report We present a case of a 50-year-old female patient with a diabetic history of 23 years who in the past five years had started developing a progressive enlargement of plaques with erythematous border and yellowish atrophic center on the bilateral anterior tibial area, which allowed the visualization of blood vessels (Figure 1A and 1B). She was treated with topical corticosteroids and weekly applications of PUVA over a period of two years without signs of improvement.

Figure 1B. Left leg before the treatment

Since there was unresponsiveness to the established treatments, the patient was treated monthly with intense pulsed light therapy. For a period of 14 months, a total of 13 treatment sessions were performed with an Intense Pulsed Light device (Active Optical System, Israel). This device is based on Geometrical Energy Management (GEM-IPL) technology, which utilizes a range of wavelengths from 420 nm to 1100 nm, pulse duration of 10 milliseconds (single-pulse mode), energy ranging from 10 to 20 sec/cm2, output power levels ranging from 0 to 12, and air cooling system with pointer of 1.5x5 cm. A combination of wavelengths for oxyhemoglobin (vascular) and for collagen stimulation (rejuvenation) was chosen, with the application of 2 pulses of each (pulse duration of 8 milliseconds) and the program set to 8. The patient noticed improvement in her condition from the second session onwards. We decided not to do a biopsy of the lesion after treatment due to the diabetic patient fearing a new scar, and also due to satisfactory clinical improvement with no gain or change in medical management.

Results Figure 1A. Right leg before the treatment: Plaques with erythematous border and yellowish atrophic center on the bilateral anterior tibial area with the visualization of blood vessels. Skin atrophy can be observed in detail.

After thirteen sessions an improvement in skin quality was observed, showing less vessels and the erythematous edges returned to normal, similar to the surrounding skin area (Figure 2A and 2B)

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da Cunha MG, et al.

Figure 2A. Right leg after treatment: Improvement in skin atrophy can be observed in detail. The central erythematous lesion is the biopsy site, hence, the diagnosis could be confirmed.

Figure 2B. Left leg after the treatment: Improvement in skin texture can be observed and the erythematous skin color has disappeared

Discussion The Intense Pulsed Light (IPL) device, with a xenon lamp, emits incoherent polychromatic light of broad

spectrum with wavelengths between 390 and 1200 nm at varied intervals and pulse durations. Its basic principle consists of selective photothermolysis—in other words, light energy is absorbed by a specific target chromophore with energy transfer and heat generation, which promotes its subsequent modification. Wavelength can be established according to the absorption peak dependence of the target chromophore. Pulse duration should last less than the thermal relaxation time, which limits heat diffusion and lesion to nearby structures[3,4]. With the aid of cut-off filters, the main advantage of this device is its versatility in promoting a wide range of wavelengths, fluencies, pulse duration and intervals, which allows for the treatment of a great variety of lesions. It is possible to adjust them according to the type, depth and size of the lesion as well as the patient’s skin type so that maximum improvement can be achieved without epidermal loss or collateral effects[5]. IPL has been used in the treatment of many dermatologic conditions such as acne vulgaris, vascular and pigmentary disorders, photo-aged skin and scars[3,4]. The wavelength for the oxyhemoglobin absorption occurs between the yellow and green light portion of the spectrum, peaking at 418 nm, 542 nm and 577 nm. Collagen absorption peaks in the visible light range, close to the infrared spectra[3]. Regarding facial rejuvenation, IPL has been used as a non-ablative resurfacing technique, which targets the dermis without affecting the epidermis. Although the exact mechanism is not completely known, tissue remodeling occurs through the formation of new dermal collagen (types I and III), the increased activity of fibroblasts and the decrease in content and rearrangement of elastin fibers with a resulting clinical improvement[4]. A study with fibroblast cultures showed that IPL did not cause structural changes in fibroblasts; there was, however, a proliferation of fibroblasts, an increase of mRNA expression for procollagen types I and III and the consequent increase of procollagen I and III secretion rate and neocollagenesis[5]. Today, IPL is also implemented in the treatment of a series of vascular alterations, targeting the oxyhemoglobin chromophore which is abundant in blood vessels[3]. When activated, it causes the photocoagulation of vascular endothelium, leading to fibrosis and obliteration of blood vessels, thus ensuring improvement of the clinical condition[4] without regulatory effects on vascular endothelial growth factors (VEGF)[5]. We decided to use intense pulsed light as the patient had already tried all the recommended treatments, which

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Necrobiosis lipoidica treated with intense pulsed light

had resulted in zero recovery rates. As IPL stimulates neocollagenesis, it was selected due to its use as a therapeutic attempt, resulting in an excellent response.

Conclusion Taking into consideration the positive results of IPL concerning the stimulation of the neoformation of collagen and its action on blood vessels, its use in the treatment of NL was considered. The successful outcome (Figures 1B and 2B) of this case report suggested that IPL may represent a worthwhile option in the treatment of NL, offering low risks of collateral effects, especially when administered by experienced professionals[4].

References 1. Rupley KA, Riahi RR, Hooper DO. Granuloma annulare and necrobiosis lipoidica with sequential occurrence in a

patient: Report and review of literature. Dermatol Pract Concept 2015; 5(1): 29–34. doi: 10.5826/dpc.0501a03. 2. Ianoşi SL, Tutunaru C, Georgescu CV, Ianoşi NG, Georgescu DM, et al. Specific features of a rare form of disseminated necrobiosis lipoidica granuloma annulare type: A case report. Rom J Morphol Embryol 2014; 51(4): 1455–1461. 3. Sarkar A, Dewangan YK, Bain J, Rakshit P, Dhruw K, et al. Effect of intense pulsed light on immature burn scars: A clinical study. Indian J Plast Surg 2014; 47(3): 381– 385. 4. Piccolo D, Marcantonio DD, Crisman G, Cannarozzo G, Sannino M, et al. Unconventional Use of Intense Pulsed Light. Biomed Res Int 2014; 2014: 618206. doi: 10.1155/2014/618206. 5. Wu D, Zhou B, Xu Y, Yin Z, Luo D. Impact of intense pulsed light irradiation on cultured primary fibroblasts and a vascular endothelial cell line. Exp Ther Med 2012; 4(4): 669–67. doi: 10.3892/etm.2012.664.

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CASE REPORT

Multiple clustered dermatofibroma associated with asymptomatic pericardial cyst Piotr Brzezinski1, Viktoryia Kazlouskaya2, Cesar Bimbi3* 1 2 3

6th Military Support Unit, Ustka, Department of Dermatology, os. Ledowo 1N, Ustka, Poland SUNY Downstate, Department of Dermatology, Brooklyn, New York, USA Institute of Dermatology Centro Historico, Dermatology, Porto Alegre, Brazil

Abstract: Multiple clustered dermatofibroma (MCDF) is an unusual variant of dermatofibroma (DF) presentation, localized on one segment of the body. Multiple dermatofibroma is a term for when there are more than 15 dermatofibromas, which in itself is already a rare condition. The dermatofibromas usually appear in younger adults and are predominantly located on lower parts of the body. No associations, except one case with pulmonary hypertension, were described in patients with MCDF. Herein we present another case of this rare complaint in a 58 year old female with clustered lesions on the thigh. Pericardial cyst was identified in our patient during routine chest X-ray and the patient is asymptomatic. MCDFs do not usually require treatment unless requested by the patient for cosmetic reason. This variant of MCDF, which is neither congenital nor eruptive, is extraordinarily rare, with only 13 cases reported. Further reports may identify possible associations of MCDF. Keywords: dermatofibroma; histiocytomas; pericardial cyst Citation: Brzezinski P, Kazlouskaya V, Bimbi C. Multiple clustered dermatofibroma associated with asymptomatic pericardial cyst. J Surg Dermatol 2021; 6(2): 156; http://dx.doi/10.18282/jsd.v6.i2.156. *Correspondence to: Cesar Bimbi, Institute of Dermatology Centro Historico, Dermatology, Porto Alegre, Brazil; cbimbi@ terra.com.br Received: 7th April 2021; Accepted: 4th May 2021; Published Online: 22nd May 2021

Introduction Dermatofibroma (DF) is a common benign fibrohistiocytic proliferation. While it is frequently seen in the routine practice of a dermatologist, it is sometimes difficult to establish a diagnosis without a skin biopsy, due to its multiple clinical and histopathological variations. Unusual clinical forms of DF include giant, atrophic, DF with satellite, polypoid, and subcutaneous. Multiple DFs are rare, eruptive and congenital forms are described. When DFs are grouped in one body segment, terms multiple clustered dermatofibroma (MCDF) or agminated DF are used. It is a rare condition and it is usually not associated with any systemic abnormalities. Correct diagnosis may prevent unnecessary tests and treatments.

Case report A 58 year-old, otherwise healthy woman, was referred with a history of slightly pruritic reddish-brown papules and nodules grouped on the left buttock. She recalled that the first lesion appeared when she was 15 years old, with new lesions gradually appearing near the others. No history of

trauma or insect bites was reported, with the lesions ceasing to grow by the fourth decade. Physical examination showed dark brown firm lesions, 4 to 10-mm in diameter, concentrated on the left buttock (Figures 1 and 2). There was no regional lymphadenopathy. Attempts to squeeze the lesions with the fingers lead to retraction beneath skin and a dimple forms (dimple sign), indicating tethering of the skin to the underlying fibrous tissue. Two skin biopsies were taken and revealed poorly circumscribed spindle cell proliferation with underlying epidermal hyperplasia and rete ridges pigmentation (Figure 3). Thickened bundles of collagen were present at the periphery of the lesions (Figure 4). Based on clinical and histopathological presentation, the diagnosis of MCDF was established. The patient reported that she had a routine chest X-ray done several months ago and a possible cardiac mass was identified. Computer tomography was performed and was consistent with pericardial cyst 2.2 × 3.48 cm in size. Patient is asymptomatic and continues to follow up with a cardiologist for the annual examination.

Copyright © 2021 Brzezinski P, et. al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Multiple clustered dermatofibroma associated with asymptomatic pericardial cyst

Figure 1. Multiple clustered lesions on the left thigh

Figure 2. Closer look at the pigmented lesions on the left thigh

Discussion Dermatofibromas are ordinary harmless papules or nodules of little more than cosmetic significance and typically present solitary or in a very few numbers on the anterior surface of the lower legs in middle-aged women[1]. Instead of being benign tumours, they probably represent a pattern of fibrous reaction to trauma, virus, or insect bite [2] . Multiple dermatofibroma is a term when more than 15 dermatofibromas appear and it is a rare condition. The first clinical variant of multiple form of DF is when “eruptive-mode” lesions are presented throughout the body at which time they can be associated with some illnesses, especially dermatomyositis [3] , immunossupressive therapy[4] HIV infection[5] or antiretroviral therapy[6]. Congenital multiple clustered dermatofibroma is a second form of presentation of multiple DF and is differentiated by the pediatric-age onset[7,8]. Multiple clustered dermatofibroma (MCDF) is a third and distinct entity which usually appears during the first or second decade of life. This variant of MCDF which is neither congenital nor eruptive is extraordinarily rare, with only 13 cases reported. The clinical characteristics

Figure 3. Biopsy of the thigh lesion. Fibrohistiocytic proliferation with epidermal hyperplasia and pigmented rete ridges. [Hematoxylin and Eosin (H&E) staining, X50]

Figure 4. Higher magnification revealing pigmented rete rigdes, epidermal hyperplasia, fibrohistiocytic proliferation, widened vessels and thickened collagen bundles. (H&E staining, X200)

of this case shows all the features common to all cases of this variant form of DF previously reported, these being, occurrence in healthy individual in the second decade, slowly progressive evolution increasing over many years[9,10] and DF typical lesions. The location on the left buttock is also quite typical, and 2 biopsies on different places were consistent with dermatofibroma[11,12]. In our case the patient was asymptomatic, with pericardial cyst accidentally identified. Pericardial cysts are very rare and represent congenital defect of mesenchymal lacunae to form pericardial sac. While mostly asymptomatic, they may cause dyspnea and cough and may require surgical excision. The association with MCDF may be casual but is reported here for further studies. The prognosis of MCDF is benign and the appearance is the only concern. Lesions usually tend to stop enlarging over decades and some improvement in the appearance of the lesions may be observed. Surgical modalities may be an option, but secondary scarring is of concern. Patients should be reassured that no further work up is needed. Patient refused further treatment, when reassured that the condition is benign. Our case also adds one more report of MCDF to the known literature also favoring the recognition

Brzezinski P, et al.

of this variant, hence avoiding unnecessary and stressful investigations.

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

References 1. Bhabha FK, Magee J, Ng SY, Grills CE, Su J, et al. Multiple clustered dermatofibroma presenting in a segmental distribution. Australas J Dermatol 2016; 57(1): e20–e22. doi: 10.1111/ajd.12257 2. Evans J, Mattacks CA, Clarke T, Pond CM. Dermatofibromas and arthropod bites: Is there any evidence to link the two? Lancet 1989; 334(8653): 36–37. doi: 10.1016/S01406736(89)90267-5. 3. H u a n g P Y, C h u C Y, H s i a o C H . M u l t i p l e e r u p t i v e dermatofibromas in a patient with dermatomyositis taking prednisolone and methotrexate. J Am Acad Dermatol 2007; 57(5): 81–84. doi: 10.1016/j.jaad.2006.05.070 4. Gualandri L, Betti R, Cerri A, Pazzini C, Crosti C. Eruptive dermatofibromas and immunosuppression. Eur J Dermatol 1999; 9(1): 45–47. 5. Ammirati CT, Mann C, Hornstra IK. Multiple eruptive dermatofibromas in three men with HIV infection. Dermatology 1997; 195(4): 344–348. 6. Bachmeyer C, Cordier F, Blum L, Cazier A, Vérola O, et

doi:10.18282/jsd.v6.i2.156

10.

11.

12.

al. Multiple eruptive dermatofibromas after highly active antiretroviral therapy. Br J Dermatol. 2000; 143(6): 1336– 1337. doi: 10.1046/j.1365-2133.2000.03924.x. Pinto-Almeida T, Caetano M, Alves R, Selores M. Congenital multiple clustered dermatofibroma and multiple eruptive dermatofibromas-Unusual presentations of a common entity. An Bras Dermatol 2013; 88(6 Suppl 1): 63–66. doi: 10.1590/ abd1806-4841.20132647. Finch J, Berke A, McCusker M, Chang MW. Congenital multiple clustered dermatofibroma in a 12-year-old girl. Pediatr Dermatol 2014; 31(1): 105–106. doi: 10.1111/j.15251470.2011.01681.x. Gershtenson PC, Krunic AL, Chen HM. Multiple clustered dermatofibroma: Case report and review of the literature. J Cutan Pathol 2010; 37(9): e42–e45. doi: 10.1111/j.16000560.2009.01325.x. Berbis P, Benderitter T, Perier C, Frey J, Privat Y. Multiple clustered dermatofibromas. Evolution over 20 years. Dermatologica 1988; 177(3): 185–188. doi: 10.1159/00 0248540. Shaheen B, Saldanha G, Calonje E, Johnston GA. Multiple clustered dermatofibromas (fibrous histiocytomas): An atypical clinical variant of dermatofibroma. Clin Exp Dermatol 2014; 39(1): 88–90. doi: 10.1111/ced.12200. S o o n S L , H o w a r d A K , Wa s h i n g t o n C V. M u l t i p l e , clustered dermatofibroma: A rare clinical variant of dermatofibroma. J Cutan Med Surg 2003; 7(6): 455–457. doi: 10.1177/120347540300700604.

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CASE REPORT

Periocular syringomas – Successful treatment with fractional CO2 laser Alberto Goldman1, Uwe Wollina2* 1

Clinica Goldman, Porto Alegre/ RS, Brazil

Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany

Abstract: Syringoma is a benign tumor of eccrine origin which arises from eccrine ducts. Syringomas are most commonly found on the eyelids in middle-aged women. Traditional treatments include surgical excision, curettage, peelings, dermabrasion and laser. We report on the successful use of fractional laser on periocular syringomas. A 53-year-old female patient with multiple periorbital syringomas underwent three sessions of fractional carbon dioxide (CO2) laser. Settings of 20 watts of power, 600 μm of spacing, 800 μs of dwell, time stack 2 (Smartxide DOT, DEKA, Florence, Italy) were used. The sessions were performed monthly. Significant improvement of the esthetic appearance was observed after three sessions. There was a decrease of visible syringomas associated with an evident improvement of the skin texture, skin quality and flaccidity. No side effects were observed. We suggested continuing the treatment but the patient was satisfied with the current aspect and result. In conclusion, fractional CO2 laser represents an effective treatment option for the treatment of periorbital syringomas. Keywords: syringoma; treatment; esthetics; fractional CO2 laser Citation: Goldman A and Wollina U. Periocular syringomas – Successful treatment with fractional CO2 laser. J Surg Dermatol 2021; 6(2): 145; http://dx.doi.org/10.18282/jsd.v6.i2.145.

*Correspondence to: Uwe Wollina, Department of Dermatology and Allergology, Academic Teaching Hospital DresdenFriedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany; wollina-uw@khdf.de Received: 14th March 2021; Accepted: 17th May 2021; Published Online: 4th June 2021

Introduction Syringoma is a benign adnexal tumor with eccrine differentiation that affects 0.6% of the general population with an age-peak in the second and third decade of life. Different clinical subtypes have been described, e.g. localized or generalized, sporadic, familiar and associated with Down’s syndrome. Eruptive syringoma is a rare generalized subtype that has occasionally been reported as a possible paraneoplastic disease. The most common type, however, is the sporadic localized one. The majority of these tumors arise in the head and neck region, and genital manifestation is rare[1-4]. In contrast to periocular syringomas, which are mostly asymptomatic, genital tumors may be associated with pruritus and pain[5]. Histologically, syringomas are symmetrical, well-circ-

mscribed cysts and cords or strands localized in the upper dermis, without any connection to the epidermis. The proliferations have been coined comma- or tadpole-shaped, lined by single or double layers of cuboidal epithelial cells. Immunohistological investigations suggest an eccrine duct origin[6]. The solid strands seem to originate from the outer cells of the lower epidermal duct or the transitional portion between the intraepidermal duct and dermal duct in the normal eccrine gland[7].

Case report A 53-year-old female patient presented with multiple 1 to 3 mm large, skin-colored or slightly yellowish, periocular syringomas (Figure 1A). The patient provided written consent to publish the figures in this manuscript.

Copyright © 2021 Goldman A and Wollina U. This is an Open Access article distributed under the terms of the Creative Commons Attribu-tionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Goldman A and Wollina U

For at least 10 years she experienced these lesions, which slowly progressed. Before treatment, the diagnosis had been confirmed elsewhere with an ablative CO2 laser. However, the outcome after 13 sessions was poor. Therefore, this patient was referred to another type of therapy. Two years ago, she had an upper and lower blepharoplasty. There was an improvement in the skin and fat bags, but no change in the skin quality or in the syringomas. Ten years ago, she had a cardiac valve surgery. Therefore, she took 100 mg of acetylsalicylic acid per day. There was no family history of syringomas. The patient was treated with three sessions of fractional CO2 laser using the following parameters: 20 watts of power, 600 μm of spacing, 800 μs of dwell, time stack 2 (Smartxide DOT, DEKA, Florence, Italy). The sessions were performed monthly. Topical prilocaine-lidocaine ointment was used for anesthesia. In the beginning of the session, single shots were placed on the tiny tumors followed by complete treatment of the periorbital area using the scanner. Significant improvement of the esthetic appearance was observed after three sessions. There was a decrease of visible syringomas associated with an evident improvement of the skin texture, skin quality and flaccidity (Figure 1B). No side effects were observed. We suggested that she continue with the treatment, but the patient was satisfied with the outcome. There was no relapse during the next 12 months after the last laser session.

Discussion Periocular syringomas are often asymptomatic but may compromise the facial esthetic appearance. Therefore, patients ask for safe and effective treatment. Ablative non-fractional lasers have been used in the past with

B Figure 1. A 53-year-old female patient with multiple recalcitrant periocular syringomas on photoaged skin. (A) Before treatment with fractional CO2 laser. (B) Outcome after three sessions of fractional CO2 laser with marked reduction of syringoma count and significant improvement of periocular esthetics

mixed results (Table 1). Wollina previously treated 24 patients with eyelid syringomas with an erbium-doped yttrium-aluminium-garnet (Er:YAG) laser. Between one and three sessions were necessary to remove more than 80% of these tiny eccrine tumors. However, relapse occurring during the hot summer has occasionally been noted. There was no comparable rejuvenating effect as seen in the present case[8]. Fractional CO2 laser combines fractional photothermolysis and the formation of coagulation zones with an ablative 10,600-nm wavelength, which allows for the effective treatment of photoaging, rhytides, and scars. Compared to classical CO2 laser, recovery periods are significantly shorter and the risk of scar formation by the treatment is minimized[9]. The depth of tissue ablation is dependent on the power, fluence, spot size and density used. The dermal remodeling involves the expression of heat-shock proteins[10,11]. Several aspects of aging skin can be improved such as dyschromia, skin texture, and fine lines[12]. For the present patient, who had been treated with ablative CO2 laser with only slight changes, we decided to switch to the advanced technology of fractional CO 2 laser. The treatment was very successful, not only in diminishing the syringoma count, but in the rejuvenation of the whole periocular area. Further studies are needed for verification.

Conclusion Syringomas are eccrine benign tumors of skin occurring

39 doi:10.18282/jsd.v6.i2.145

Periocular syringomas – Successful treatment with fractional CO2 laser

Table 1. Treatment outcome in syringomas in studies with more than 20 patients Treatment

Patients

Erb:YAG laser

CO2 laser + BoTN*

CO2 laser

Fractional CO2 laser

Outcome >80% improvement after 1 to 3 sessions >75% improvement in 88% after 4 sessions 87.5% of >60% improvement (CO2 + BoTN) 70.5% (CO2 alone) >75% improvement in 24.1% after 2 sessions >75% improvement in 8.6% after 2 sessions

Reference Wollina, 2016[8] Kitano, 2016[13] Seo et al., 2016[14] Lee et al., 2015[15] Cho et al., 2011[16]

BoTN – Botulinum toxin

most frequently in the head and neck area. As suggested by our own experience, fractional CO2 laser may be an effective and safe tool to improve facial appearance for the treatment of multiple periocular syringomas that poorly respond to ablative CO2 laser. We recommend a combination of pinhole shots for syringomas, with scanner-assisted laser treatment of the whole affected area to optimize outcome.

Author contributions A Goldman and U Wollina prepared the manuscript and evaluated the outcome after treatment. First consultation and laser treatment were done by A Goldman. Both authors have read and approved the final version of the manuscript.

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

References 1.

Lee JH, Chang JY, Lee KH. Syringoma: A clinicopathologic and immunohistologic study and results of treatment. Yonsei Med J 2007; 48(1): 35–40. doi: 10.33 49/ymj.2007.48.1.35. Ghanadan A, Khosravi M. Cutaneous syringoma: A clinicopathologic study of 34 new cases and review of the literature. Indian J Dermatol 2013; 58(4): 326. doi: 10.4103/0019-5154.113956. Turan E, Yurt N, Yeşilova Y, Tanrıkulu O. A rare association in Down syndrome: Milialike idiopathic calcinosis cutis and palpebral syringoma. Cutis 2016; 98(6): E22–E23. Incel Uysal P, Yalcin B, Ozhamam E, Bozdogan O. Coexistence of adult onset eruptive syringoma and bilateral

10.

11.

12.

renal cell carcinoma: A case report. Am J Dermatopathol 2017; 39(1): 56–58. doi: 10.1097/DAD.0000000000 000592. Kavala M, Can B, Zindanci I, Kocatürk E, Türkoğlu Z, et al. Vulvar pruritus caused by syringoma of the vulva. Int J Dermatol 2008; 47(8): 831–832. doi: 10.11 11/j.1365-4632.2008.03664.x. Wollina U, Schaarschmidt H, Rülke D. Sweat gland tumors of skin—Immunohistochemistry with common antibodies in the paraffin section. Int J Oncol 1992; 1(4): 395–402. doi: 10.3892/ijo.1.4.395. Kim BC, Park EJ, Kwon IH, Cho HJ, Park HR, et al. An immunohistochemical study of the origin of the solid strand in syringoma, using carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin 5. Int J Dermatol 2012; 51(7): 817–822. doi: 10.1111/j.13 65-4632.2011.05069.x. Wollina U. Erbium-YAG laser therapy—Analysis of more than 1,200 treatments. J Glob Dermatol 2016; 3(2): 268–272. doi: 10.15761/GOD.1000171. Hunzeker CM, Weiss ET, Geronemus RG. Fractionated CO2 laser resurfacing: Our experience with more than 2000 treatments. Aesthet Surg J 2009; 29(4): 317–322. doi: 10.1016/j.asj.2009.05.004. Grunewald S, Bodendorf M, Illes M, Kendler M, Simon JC, et al. In vivo wound healing and dermal matrix remodelling in response to fractional CO2 laser intervention: Clinicopathological correlation in non-facial skin. Int J Hyperthermia 2011; 27(8): 811–818. doi: 10.3109/02 656736.2011.595380. Skovbølling Haak C, Illes M, Paasch U, Hædersdal M. Histological evaluation of vertical laser channels from ablative fractional resurfacing: An ex vivo pig skin model. Lasers Med Sci 2011; 26(4): 465–471. doi: 10.10 07/s10103-010-0829-2. Tierney EP, Hanke CW, Petersen J. Ablative fractionated CO2 laser treatment of photoaging: A clinical and histo-

40 doi:10.18282/jsd.v6.i2.145

Goldman A and Wollina U

13.

14.

logic study. Dermatol Surg 2012; 38(11): 1777–1789. doi: 10.1111/j.1524-4725.2012.02572.x. Kitano Y. Erbium YAG laser treatment of periorbital syringomas by using the multiple ovoid-shape ablation method. J Cosmet Laser Ther 2016; 18(5): 280–285. doi: 10.3109/14764172.2016.1157361. Seo HM, Choi JY, Min J, Kim WS. Carbon dioxide laser combined with botulinum toxin A for patients with periorbital syringomas. J Cosmet Laser Ther 2016; 18(3): 149–153. doi: 10.3109/14764172.2015.1052517.

15.

16.

Lee SJ, Goo B, Choi MJ, Oh SH, Chung WS, et al. Treatment of periorbital syringoma by the pinhole method using a carbon dioxide laser in 29 Asian patients. J Cosmet Laser Ther 2015; 17(5): 273–276. doi: 10.3109/14764172.2015.1027224. Cho SB, Kim HJ, Noh S, Lee SJ, Kim YK, et al. Treatment of syringoma using an ablative 10,600-nm carbon dioxide fractional laser: A prospective analysis of 35 patients. Dermatol Surg 2011; 37(4): 433–438. doi: 10.1111/j.1524-4725.2011.01915.x.

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doi: 10.18282/jsd.v6.i2.167

CASE REPORT

A novel surgical method for total nail ablation: Use of triple flap technique Berna Aksoy1,2* 1 2

Bahcesehir University, Faculty of Medicine, Dermatology Department, Istanbul, Turkey VM Medicalpark Hospital, Dermatology Clinic, Kocaeli, Turkey

Abstract: Total nail ablation for the treatment of onychodystrophies can be performed by using chemicals, surgical resection or laser ablation of nail matrix. A female patient with bilateral severe onychodystrophy as a result of inadvertent previous nail surgeries was treated surgically. Proximal complete nail matrix resection and distal 10 mm wide transverse strip partial nail bed resection were performed. A 5 mm wide transverse strip of nail bed was left intact proximally. Proximal nail matrix defect was closed by using the skin of proximal nail fold. The distal nail bed defect was reconstructed by using triple flap technique which was composed of a main central advancement flap containing ventral toe skin and two side flaps containing nail fold skin. The patient healed without any problem and her nail problem was treated successfully. The cosmetic appearance of her first toes was acceptable. Surgical nail ablation followed by volar skin coverage of dorsal surface of the distal phalanx bone by using triple flap technique is an effective surgical treatment method for the correction of advanced nail plate deformities requiring total nail ablation. Keywords: ablation; dystrophy; flap; nail; onychodystrophy; surgery; treatment Citation: Aksoy B. A novel surgical method for total nail ablation: Use of triple flap technique. J Surg Dermatol 2021; 6(2): 167; http://dx.doi.org/10.18282/jsd.v6.i2.167. *Correspondence to: Berna Aksoy, VM Medicalpark Hastanesi, Ovacik mah, D-100 Karayolu Ustu, No: 36, Basiskele, Kocaeli, Turkey; bmaksoy@mynet.com, bernaaaksoy@gmail.com Received: 8th April 2021; Accepted: 1st July 2021; Published Online: 7th July 2021

Introduction When a nail becomes severely deformed permanent to tal ablation of the nail is the best choice of treatment[1]. Here we describe a case with severe bilateral great toe ony chodystrophy treated by total surgical nail matrix excision followed by plantar skin coverage of dorsal aspect of distal part of great toe by using a novel flap technique for provid ing protection in the absence of a nail plate.

Surgical technique and case report A 25 years old female patient with bilateral severe ony chodystrophy characterized by nail plate thickening and deformation resulting from inadvertent previous nail surgeries visited to our clinic (Figure 1). During the treatment of the patient, the principles of 1975 Declaration of Helsinki were followed. Surgical intervention was performed under local digital bloc anesthesia and Salem’s digital tourniquet. Proximal complete nail matrix resection including the underside of the proximal nail fold was performed following total nail plate avulsion. To prevent

postoperative nail spike formation, nail matrix horns were ablated by using electrocautery after total surgical resection of nail matrix was completed. Approximately 8–9 mm wide transverse strip distal nail bed resection was performed to replace thin and fragile soft tissue of nail bed with thick and strong tissue of plantar skin. A 5 mm wide strip of nail bed was left intact proximally between two resection sites for cosmetic reasons (Figure 2A). Proximal nail matrix defect was closed by using the skin of proximal nail fold. The distal nail bed defect was reconstructed by using triple flap technique which was composed of a main central advancement flap containing ventral great toe skin and two side flaps containing nail fold skin of both sides of distal great toe (Figure 2B). The side flaps containing nail fold skin bilaterally were raised to obtain maximum dorsal mobilization of the central advancement flap containing plantar skin of distal part of great toe. Each one of these side flaps was shortened 2 mm from distal edge of the flap for better coaptation following dorsal transfer of central advancement flap. All the flaps were sutured in their final places after removal of tourniquet and control of bleeding. Operation is completed with wound dressing with slight

Copyright © 2021 Aksoy B. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Aksoy B

pressure. The patient was restricted for 14 days and normal activity was allowed after suture removal following this period. The patient healed without any problem and her nail problem was treated successfully. The cosmetic appearance of her first toes was acceptable 8 months after operation (Figure 3). There was no regrowth of nail plates bilaterally. Effective and stable soft tissue coverage of dorsal surface of distal phalanx bone was provided by the thick plantar skin transferred dorsally by using the triple advancement flap method.

Figure 1. Preoperative picture of severe bilateral nail plate dystro

phy involving great toe (A) left, (B) right.

(A)

(B)

Figure 2. (A) Appearance after proximal and distal nail bed

resections. (B) Appearance after reconstruction with triple volar flap.

Figure 3. Late postoperative picture of the right and left great toes

doi:10.18282/jsd.v6.i2.167

Discussion Total permanent nail ablation for the treatment of severe nail dystrophies involving the nail plate can be performed by total surgical nail matrix excision and total ablation of nail matrix with electrocautery, chemicals or laser[1–3]. Clinical results of phenol cauterization of nail matrix compares favorably with surgical ablation [1,2]. Phenol cauterization results in fewer nail spicule formation and less postoperative pain[1,2]. However, addition of bilateral nail matrix horn ablation by using electrocautery will decrease the risk of postoperative spicule formation greatly following surgical total nail matrix excision. Significant cardiotoxicity of phenol due to systemic absorption from dermal ap plication site is a problem especially when patients have cardiac disorders [4]. Ten percent sodium hydroxide can also be used to perform total nail matrix destruction to avoid systemic toxic effects of phenol use[3]. Chemonecro sis of the surrounding tissues is a potential problem with both phenol and sodium hydroxide nail matrix ablation. Thus, chemical cauterization of the whole nail matrix with significant damage to surrounding soft tissues causes damage to thin soft tissue layer which covers the dorsal surface of the distal phalanx bone. Therefore, scarred nail bed area following recovery from chemical injury will lead to less stable soft tissue coverage for underlying bone. Total chemical nail matrix ablation method also leaves nail bed area unprotected because protective function of nail plate is lost. Total nail matrix ablation by using electrocautery and lasers also leave dorsal part of distal great toe unprotected because nail plate will never grow again in the absence of nail matrix[2,3]. Surgical resection of nail matrix for total permanent nail ablation may be used for the treatment of difficult nail plate deformities[5]. We used modification of the Zadic technique which is an effective method for total surgical matricectomy[3]. Effective execution of surgical total nail matrix excision combined with electrosurgical ablation of nail matrix horns bilaterally results in total nail ablation and postoperative nail spike formation is unlikely. Since protective function of nail plate is lost following total nail matrix resection the nail bed area and underlying distal phalanx bone is open to injury. This problem was overcome by replacing thin and fragile nail bed tissue with thick and durable plantar skin through the use of triple flap technique in our case. Triple flap technique is an extension of lateral foldplasty technique that was described previously and used to treat ingrown toe nails[6]. Distal nail bed defect associated with resection of subungual exostosis and overlying callus was reconstructed successfully by using a modification of this triple flap technique[7]. Pincer nail deformity can be successfully treated by a similar modification of this triple flap technique[8]. Radical nail matrix resection or the Syme procedure involves the radical en bloc resection of the entire nail complex[3]. The plantar faciocuteneous flap formed from amputation of the distal half of the terminal phalanx bone is sutured dorsally over the soft tissue defect created

A novel surgical method for total nail ablation: Use of triple flap technique

from the excision of the nail matrix complex for primary wound closure. This surgical method is associated with a success rate of almost 100% despite the poor cosmetic and functional outcome[3]. This method must be reserved for patients with recurrent nail plate deformities that are refractory to repeated treatments of total nail matricectomy.

Conclusion Surgical nail ablation followed by plantar skin coverage of dorsal surface of the distal phalanx bone by using triple flap technique is an effective surgical treatment method for the correction of advanced nail plate deformities requiring total nail ablation with a low recurrence rate. Effective and stable soft tissue coverage of dorsal part of distal great toe is provided by this treatment method which replaces thin nail bed tissue with thick plantar skin of the first toe. Cosmetic appearance is satisfactory as a 5 mm strip of nail bed tissue is left in place. To the best of our knowledge, there is no other surgical technique described for the compensation of loss of protective function of a nail plate following total nail matrix destruction.

Author contributions Study concept and design: BA, HMA; Acquisition of data: BA, HMA; Analysis and interpretation: BA, HMA; Study supervision: HMA.

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

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

study was poster-presented at the 25th EADV Congress, 28 September – 2 October, 2016, Vienna, Austria and at the 6th National Dermatologic Surgery Days, 17 – 20 November, 2016, Ankara, Turkey.

References 1. Becerro de Bengoa Vallejo R, Losa Iglesias ME, Alou Cervera L, Sevillano Fernández D, Prieto Prieto J. Total nail ablation for onychodystrophy with optimized gauze-phenol application. J Eur Acad Dermatol Venereol 2010; 24(8): 936–42. doi: 10.1111/j.14683083.2010.03569.x. 2. Andrew T, Wallace WA. Nail bed ablation – Excise or cauterise? A controlled study. Br Med J 1979; 1(6177): 1539. doi: 10.1136/bmj.1.6177.1539. 3. Ceilley RI, Collison DW. Matricectomy. J Dermatol Surg Oncol 1992; 18: 728–34. doi: 10.1111/j.15244725.1992.tb02007.x. 4. Li Z, Zhang H, Li SH, Byard RW. Fatal phenol toxicity following attempted tattoo removal. J Forensic Sci 2016; 61(4): 1143–5. doi: 10.1111/1556-4029.13106. 5. Johnson DB Jr, Ceilley RI. A revised technique for ablation of the matrix of a nail. J Dermatol Surg Oncol 1979; 5(8): 642–3. doi: 10.1111/j.1524-4725.1979. tb00738.x. 6. Aksoy B, Aksoy HM, Civas E, Oc B, Atakan N. Lateral foldplasty with or without partial matricectomy for the management of ingrown toenails. Dermatol Surg 2009; 35(3): 462–468. doi: 10.1111/j.1524-4725.2009.01067.x. 7. Aksoy HM, Aksoy B, Balcı M, Üstün H. Onychoclavus due to subungual exostosis: Reconstruction of the resulting defect by triple volar advancement flap: Surgical technique. Turk Klin Tip Etigi Hukuku Tarihi 2011; 31(2): 496–499. doi: 10.5336/medsci.2010-19078. 8. Aksoy B, Aksoy HM. Novel surgical method for pincer nail treatment: Partial matricectomy and triple flap technique. Dermatol Surg 2017; 43(11): 1397–1399. doi: 10.1097/DSS.0000000000001094.

doi: 10.18282/jsd.v6.i2.123

SHORT COMMUNICATION

The story behind cryosurgery Sara Mohamed Ibrahim Awad Dermatology department, Assiut University Hospital, Assiut University, Assiut, Egypt

Keywords: cryosurgery; history; cryogens Citation: Awad SMI. The story behind cryosurgery. J Surg Dematol 2021; (6)2: 123; http://dx.doi.org/10.18282/jsd.v6. i2.123. Correspondence to: Sara Mohamed Ibrahim Awad, Assiut University Hospital, Egypt; saramawad@gmail.com Received: 22nd January 2021; Accepted: 3rd April 2021; Published Online: 26th April 2021

Introduction Cryosurgery is used to describe the controlled destruction of tissue by freezing. Today, cryosurgery is widely practiced in medicine, so it would be interesting to know how the story of cryosurgery began. Here are some short stories behind the discovery and evolution of cryosurgery.

The earliest therapeutic uses of cold The first use of cold as a means of physical treatment dates back to the age of the ancient Egyptians, as described by an Egyptian papyrus document. As early as 2500 B.C., the ancient Egyptians identified the analgesic and anti-inflammatory effects of cold. They noted that cold application soothes sites of trauma, minimizes pain and reduces inflammation. Later, Hippocrates (460–370 B.C.), an ancient Greek physician commonly referred to as the father of medicine, found that local cold exposure has the ability to reduce swelling, bleeding and pain. Also, tissue cooling by surface application of snow and ice was used to produce anesthesia before the amputation of soldiers in Napoleon’s Grand Army[1].

Modern cryosurgery begins The “modern” cryosurgery is relatively of young age and its birth is closely intertwined with developments in low temperature physics, engineering, and instrumentation. It is only during the last few centuries that cold treatment has evolved from generalized application to specific, focal destruction of tissue in today’s cryosurgery. English physician James Arnott, “the father of modern cryosurgery”, was the first person to use extreme cold locally for the destruction of tissue. He used a mixture of salt and crushed ice for the palliation of tumors, with resultant reduction of pain and local hemorrhage. Arnott won the prize medal at the Great Exhibition of London of

1851 for his cold equipment that allowed reducing tissue temperature to ₋20 ºC[2,3].

End of the 19th century: The race for liquefied gases begins In the late 1800s, along with tremendous scientific advances, there was an interest in liquefying gases. Oxygen was first liquefied in small quantities in 1877. Over the next few years, all of the so-called “permanent gases” (oxygen, nitrogen and hydrogen) were liquefied. In 1895–1896, commercial liquefaction of air was established by Carl Von Linde. The term “cryogen” came into use during those years[4].

The day liquid air became available to physi cians Campbell White in 1899 was the first one to use liquefied gas in medicine. He used liquid air (₋195 °C) for the treatment of diverse skin diseases. White used a glass flask that acted as a liquid air sprayer, which became the first handheld cryosurgery device. In 1907, Whitehouse used sprayed liquid air to treat a wide variety of skin conditions that ranged from epitheliomas to lupus erythematosus to vascular nevi[5].

Liquid oxygen quits the race Because of its similar properties to liquid air, liquid oxygen (₋182.9 °C) was used as a cryogenic agent in a similar way as liquid air, particularly during the 1920s and 1930s. However, liquid oxygen soon became obsolete as a cryogenic agent because of safety considerations related to fire[6].

Carbon dioxide snow gains interest In parallel to the investigation on the medical use of liquid air (1907), the use of carbon dioxide snow (₋78.5 °C) was

Copyright © 2021 Awad SMI. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The story behind cryosurgery

favored by William A. Pusey[7]. After 1910, liquid air was seldom used, and solid CO 2 became the most popular cryogenic agent because it was cheaper and more readily available than liquid air. The carbon dioxide was held in liquefied state by pressure (about 800 psi). When released into air, the decrease in pressure causes freezing and formation of a white snow that was then compressed into various shapes suitable for different treatments. John F. Hall-Edwards first described his carbon dioxide collector and compressor in 1911[4].

Liquid nitrogen comes ahead

Liquid nitrogen (₋196 °C) became commercially available and was introduced into clinical practice in 1950 by Herman V. Allington, who described the technique of using cotton swabs dipped in liquid nitrogen for the treatment of a variety of non-neoplastic skin diseases[8].

Application and storage of refrigerants Generally, refrigerants were applied either by direct painting onto the skin or by means of a dipped cotton wool applicator into liquid air. However, the depth of freezing achieved was inadequate for the treatment of tumors. In 1907, Whitehouse designed a spray bottle of liquid air which provided much lower minimum temperatures[5]. The physical chemist James Dewar solved the problems of transportation and storage of liquid gas. He invented a flask with two silvered walls separated by an evacuated air chamber, thus insulating the inside from the outside of the flask. Even today the containers used to keep liquid nitrogen have much of the same design and are still called “Dewar flasks”. Through the collaboration between a physician, Irving Cooper, and an engineer, Arnold Lee, the first cryosurgical probe was built in 1961, which became the prototype for the subsequent liquid nitrogen cryosurgical probe. In 1963, Cooper described the use of liquid nitrogen probe for brain surgery. This new piece of equipment opened up the way for many new inventions in the area of cryosurgery[9].

Handheld cryosurgical apparatus A more widespread use of cryosurgery in medical practice came with the design of handheld devices that can be easily used in the physician’s office. Various cryosurgical apparatuses were developed using liquid nitrogen, nitrous oxide, carbon dioxide and other cryogens. In 1965, Dr. Douglas Torre developed a liquid nitrogen spray device that could also be equipped with cryoprobe tips of different sizes and shapes[10,11]. Finally, in 1967, Dr. Setrag Zacarian designed a handheld cryosurgical device using liquid nitrogen. Zacarian brought the term “cryosurgery” into use for the first time. A series of different designs followed, which gave rise to several models of handheld cryosurgical units[12,13].

Cryosurgical equipment and techniques now adays Liquid nitrogen (₋196 °C) is the most popular cryogen

in current use; it is the coldest and can destroy a large volume of tissue required for treatment of malignant lesions. Handheld devices using liquid nitrogen are the most commonly used units nowadays. Basically, they are small containers with storage capacity of 250–500 mL, most commonly used as a spray, and less often as a closed system with cryoprobes of different sizes and shapes (contact therapy)[13,14]. A unique technique, “intralesional cryosurgery”, was later introduced in 1993 by Egyptian dermatologist Dr. Ahmed Hani Weshahy, who used needles called “Weshahy cryoneedles” to deeply freeze lesion irrespective of lesion volume, while cells at the surface, particularly melanocytes, are much less affected, hence minimizing surface reactions[15].

The story of cryosurgery has never reached an end After nearly two centuries, cryosurgery is gaining more interest in several fields of medicine, including dermatology. Over the years, cryosurgery has become a well-established treatment modality for a wide variety of benign skin lesions and is also highly effective treatment for premalignant lesions as well as for selected cases of malignant skin lesions. Dermatologic Cryosurgery has become widely applicable and has now reached a unique status, with new indications and novel uses still being described.

Conflict of interest

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

References

1. Larrey DJ. Mémoires de chirurgie militaire, et campagnes (French) [Surgical memoirs of the campaigns of Russia, Germany, and France]. Philadelphia: Carey & Lea, 1832. p. 1812–1817. 2. Arnott J. Practical illustrations of the remedial efficacy of a very low or anaesthetic temperature.—I. In cancer. Lancet 1850; 56(1409): 257–259. doi: 10.1016/S0140-6736(02)898 74-9. 3. Bird H, Arnott J. A pioneer in refrigeration. Anaesthesia 1949; 4(1): 10–17. doi: 10.1111/j.1365-2044.1949.tb05803.x. 4. Hall-Edwards JF. Carbon dioxide snow: Its therapeutic uses. London: Simpkin, Marshall, Hamilton, Kent; 1913. p. 10–11. 5. Whitehouse H. Liquid air in dermatology; its indications and limitations. JAMA 1907; 49(5): 371–377. doi: 10.1001/jama. 1907.25320050009002a. 6. Irvine HG, Turnacliff DD. Liquid oxygen in dermatology. Arch Derm Syphilol 1929; 19(2): 270–280. doi: 10.1001/ archderm.1929.02380200098007. 7. Pusey WA. The use of carbon dioxide snow in the treatment of nevi and other lesions of the skin. A preliminary report. JAMA 1907; 49(16): 1354–1356. doi: 10.1001/jama.1907. 25320160 032001h. 8. Allington HV. Liquid nitrogen in the treatment of skin diseases. Calif Med 1950; 72:153–155. 9. Cooper IS, Lee AS. Cryostatic congelation: A system for producing a limited controlled region of cooling or freezing of biological tissues. J Nerv Ment Dis 1961; 133(3): 259–263.

doi:10.18282/jsd.v6.i2.123

Awad SMI

doi: 10.1097/00005053-196109000-00013. 10. Torre D. Alternate cryogens for cryosurgery. J Dermatol Surg 1975; 1(2): 56–58. doi: 10.1111/j.1524-4725.1975.tb00073.x. 11. Torre D. Cutaneous cryosurgery. N Y State J Med 1970; 70(20): 2551–2554. 12. Zacarian SA. Cryosurgery in dermatologic disorders and in the treatment of skin cancer. J Cryosurg 1968; 1: 70–75. 13. Zacarian SA. Cryosurgery of skin cancer and cryogenic

techniques in dermatology. Springfield, Illinois: Charles C. Thomas; 1969. p. 71. 14. Zacarian SA. Cryosurgical advances in dermatology and tumors of the head and neck. Springfield, Illinois: Charles C. Thomas; 1973. p. 55–73. 15. Weshahy AH. Intralesional cryosurgery. A new technique using cryoneedles. J Dermatol Surg Oncol 1993; 19(2): 123– 126. doi: 10.1111/j.1524-4725.1993.tb03440.x.

Journal of Surgical Dermatology

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

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

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

Journal of Surgical Dermatology 2021 V6I2

Articles inside

A novel surgical method for total nail ablation: Use of triple flap technique

Multiple clustered dermatofibroma associated with asymptomatic pericardial cyst

Periocular syringomas – Successful treatment with fractional CO2 laser

The story behind cryosurgery

Necrobiosis lipoidica treated with intense pulsed light