Efficacy of Different Modes of Fractional CO 2 Laser in the Treatment of Primary Cutaneous Amyloidosis: A Randomized Clinical Trial

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1 Lasers in Surgery and Medicine 47: (2015) Efficacy of Different Modes of Fractional CO 2 Laser in the Treatment of Primary Cutaneous Amyloidosis: A Randomized Clinical Trial Samia M. Esmat, MD, 1 Marwa M. Fawzi, MD, 1 Heba I. Gawdat, MD, Heba S. Ali, 1 and Safinaz S. Sayed, MD 2 1 Department of Dermatology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt 2 Department of Histology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt Background: Primary cutaneous amyloidosis (PCA) comprises three main forms: macular, lichen, and nodular amyloidosis. The current available treatments are quite disappointing. Objectives: Assess and compare the clinical and histological changes induced by different modes of Fractional CO 2 laser in treatment of PCA. Patients and Methods: Twenty five patients with PCA (16 macular and 9 lichen amyloidosis) were treated by fractional CO 2 using; superficial ablation (area A) and deep rejuvenation (area B). Each patient received 4 sessions with 4 weeks intervals. Skin biopsies were obtained from all patients at baseline and one month after the last session. Patients were assessed clinically and histologically (Congo red staining, polarized light). Patients were followed-up for 3 months after treatment. Results: Both modes yielded significant reduction of pigmentation, thickness, itching, and amyloid deposits (P-value < 0.001). However, the percentage of reduction of pigmentation was significantly higher in area A (Pvalue ¼ 0.003). Pain was significantly higher in area B. Significant reduction in dermal amyloid deposits denotes their trans-epidermal elimination induced by fractional photothermolysis. Conclusion: Both superficial and deep modes of fractional CO 2 laser showed comparable efficacy in treatment of PCA. Superficial mode being better tolerated by patients, is recommended as a valid therapeutic option. Lasers Surg. Med. 47: , ß 2015 Wiley Periodicals, Inc. Key words: Primary cutaneous amyloidosis; Fractional CO 2 ; Superficial ablation; Deep rejuvenation amyloidosis is characterized by closely set, discrete, severely itchy brown-red papules that are commonly located on the legs (shins). While, macular amyloidosis is characterized by pruritic macules that show a reticulated or rippled pattern of pigmentation, with the upper back being a commonly affected site [3]. The exact etiology of PCA is not yet fully understood. Genetic predisposition, Epstein-Barr virus and environmental factors have all been proposed as possible etiologic factors [2]. Amyloid is thought to be derived from keratinocytes through filamentous degeneration and hence is termed amyloid K, and is deposited mainly in the papillary dermis [4]. Despite the presence of various therapeutic modalities for PCA, none is considered curative or satisfactory [5]. Among these modalities are: potent topical corticosteroids (under occlusion) [5], topical calcineurin inhibitors [6], topical dimethyl sulfoxide (DMSO) [7], PUVA [8], UVB phototherapy [5], systemic retinoids [9], low-dose cyclophosphamide [10], and cyclosporine [11]. In addition, there are physical therapeutic options for PCA such as: electrodessication [12], dermabrasion [6], pulsed dye laser [13], and frequency-doubled Q-switched Nd: YAG laser [14]. They comprise the removal of the epidermis and part of the papillary dermis as well as some of the amyloid deposits, thereby allowing re-epithelialization to occur from adnexal structures. Recently, fractional ablative 2,940 nm Erbium: YAG laser was tried for the treatment of lichen amyloidosis and showed considerable efficacy. The authors suggested trans-epidermal elimination as a probable mechanism of action [15]. The lack of an optimal therapy for PCA among the currently available treatment options, prompted us to INTRODUCTION Amyloidosis refers to extracellular proteinaceous deposits. These deposits can be either localized to a single body site or systemic, involving multiple organs, and tissues [1]. In primary localized cutaneous amyloidosis (PCA), deposits are limited to the skin. PCA is classified into three main forms; macular, lichen, and nodular amyloidosis [2]. Lichen and macular amyloidosis are best considered as different manifestations of the same disease. Lichen Funding sources: None. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Correspondence to: Heba Ismail Gawdat, MD, Department of Dermatology, Kasr Al Ainy Hospital, Cairo University, 59 Street 104, Maadi Gardens, Zip code: 11431, Cairo, Egypt. heba.gawdat@yahoo.com Accepted 25 March 2015 Published online 6 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /lsm ß 2015 Wiley Periodicals, Inc.

2 FRACTIONAL CO 2 AND PRIMARY CUTANEOUS AMYLOIDOSIS 389 conduct the current study to assess and compare the clinical and histological changes induced by two modes of fractional CO 2 laser in the treatment of PCA and to shed the light on the possible mechanism of action. PATIENTS AND METHODS This prospective randomized comparative single blinded clincal trial included twenty five adult patients (17 females and 8 males) aged (mean ) with PCA. Sixteen patients had macular and nine hadchen amyloidosis. The study was approved by the Dermatology Research Ethical Committee (REC), Faculty of Medicine, Cairo University. Informed written consents were obtained from all patients before conducting the study. Patients on topical (one month) or systemic treatment (three months) prior to the study, pregnant, or lactating females, patients with history of hypertrophic scars, keloids, systemic retinoid therapy within the last six months as well as those with coagulation disorders were all excluded. All patients were subjected to the following: full detailed history (age, sex, onset, course, disease duration, associated disorders, history of medications, etc), dermatological examination of PCA lesions as regards their type, site, and extent. In addition, a 3 mm punch biopsy was retrieved from PCA lesions of all recruited patients at baseline as well as two more biopsies (one biopsy from each treated area) one month after the last treatment session. Treatment Protocol Each patient underwent a split-lesion therapy where PCA lesions were divided into two equal areas that were randomly assigned (using envelope concealment method) by a fixed investigator to treatment by either superficial ablation mode (area A) (Fractional CO 2 laser parameters: power 15 watts, spacing 500 mm, dwell time 500 ms, stacking 1, depth of penetration: 90 mm, percent of coverage: 13.3%) or deep ablative rejuvenation mode (area B) (Fractional CO 2 laser parameters: power 25 watts, spacing 900 mm, dwell time 800 ms, stacking 3, depth of penetration: 180 mm, percent of coverage: 6.2%), (Smartxide DOT, Advanced CO 2 Fractional technology, DEKA, Italy). Topical anesthetic cream (5% lidocaine and prilocaine) was applied under occlusion to the areas to be treated 60 minutes before laser session. Each patient received 4 sessions with 4 weeks intervals. All patients were instructed to apply topical antibiotic ointment and to avoid friction of the treated areas to allow proper wound healing. Patient Assessment Baseline assessment. All recruited patients were assessed by two blinded investigators at baseline using the following grading systems; (a) Degree of pigmentation of the lesions: Grade 1 ¼ mild, Grade 2 ¼ moderate, and Grade 3 ¼ marked, (b) Pattern of pigmentation: Grade 0 ¼ absence of rippling and Grade 1 ¼ presence of rippling, (c) Thickness of the lesions: macular amyloidosis (Grade 0 ¼ absence of lichenification, Grade 1 ¼ presence of lichenification), and lichen amyloidosis (Grade 1 ¼ mildly papular, Grade 2 ¼ moderately papular, Grade 3 ¼ markedly papular), (d) Itching was assessed on a scale from 0 to 10 (0 ¼ no itching and 10 ¼ severe itching). Final assessment (three months after the last session). All patients were assessed three months after the last laser session. The degree of improvement in the grading system of each of the previously mentioned parameters was evaluated using the following scoring systems; (a) Degree of reduction of pigmentation: Score 0 ¼ no improvement, Score 1¼ mild improvement, Score 2 ¼ moderate improvement, Score 3 ¼ marked improvement, and Score 4¼ complete clearance, (b) Degree of reduction in thickness: Score 0 ¼ <25% reduction, Score 1 ¼ (25 50%) reduction, Score 2 ¼ (51 75%) reduction, and Score 3 ¼ (>75%) reduction. Patients were evaluated at each session and three months after the last session for the occurrence of complications such as; dyspigmentation (hyper/hypopigmentation), scarring, infection, and pixilation. Pain (during and following sessions) was evaluated on a scale from 0 (absent) to 10 (severe). Recurrence was reported as well, during the follow-up period (three months after the last session). All patients were photographed at baseline and three months after the last session using a digital camera (Sony Cyber-shot digital still camera, DSC-N1, 10 megapixel Sony Corp, Tokyo, Japan). Evaluation of comparative photographs was done by two blinded investigators. Histological Assessment. Three punch biopsies (3 mm) were retrieved from PCA lesions of all recruited patients at baseline (one biopsy) and one month after the last laser session (two biopsies). The specimens were fixed in formaline saline 10% and processed to obtain paraffin blocks. Five to six paraffin sections were cut and stained by Hematoxylin and Eosin (H & E) and Congo red, followed by polarized light for detection of apple-green birefringence of amyloid deposits. All stained specimens were evaluated histologically to detect the following: the amount of amyloid present, the depth of amyloid deposits in the dermis, the amount of melanin present, thickness of the epidermis, and depth of the rete ridges. Tracing of amyloid material. Three patients volunteered for two additional biopsies (one from each treated area) at days 2, 4 and 6, respectively, following the first laser session. This was done in an attempt to follow the course of amyloid deposits after laser treatment, for demonstration of the presumed mechanism of action of Fractional CO 2 laser. Morphometric study. Congo red stained sections of studied patients were subjected for image analysis before and after treatment. Image analysis was done Using Leica Qwin 500 LTD software image analysis computer system (Cambridge, England) present in the Histology department, Faculty of Medicine, Cairo University. This included measuring: (a) mean area percent of amyloid deposits within the dermis, (b) mean area percent of melanin

3 390 ESMAT ET AL. pigment within the epidermis- This was done at a magnification of 400 in 5 non-overlapping fields for every specimen in a field area mm 2 -, (c) epidermal height, and (d) depth of the rete ridges, in which ten readings were measured by micrometer for every specimen at a magnification of 100. Results obtained from image analyzer were subjected to statistical analysis. Patient Satisfaction. Patient satisfaction was evaluated using the following scoring system: Score 0¼ no satisfaction, Score 1¼ poor satisfaction (<25%), Score 2 ¼ mild satisfaction (25 50%), Score 3 ¼ moderate satisfaction (51 75%), and Score 4 ¼ marked satisfaction (>75%). Statistical Methods Data was analyzed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL). Numerical data were expressed as mean and standard deviation or median and range as appropriate. Qualitative data were expressed as frequency and percentage. For not normally distributed quantitative data, comparison between two groups was done using Mann-Whitney test (non-parametric t-test). Wilcoxon-signed ranks test (non-parametric paired t-test) was used to compare two consecutive measures of not normally distributed numerical variables. A P-value < 0.05 was considered significant. RESULTS The current study included 25 patients with PCA (17 females [68%] and 8 males [32%]) whose ages ranged between 23 and 50 years (mean ). The recruited patients comprised 16 cases of macular (64%) and 9 cases of lichen amyloidosis (36%) with a total of 50 PCA lesions. The most commonly affected site was the upper back (n ¼ 13, 52%), followed by the lower limbs (n ¼ 11, 44%) where 8 out of 11 patients had bilateral lesions (72.7%), and only one patient had lesions on both arms (4%). The mean disease duration was years. Physician Assessment Both therapeutic modes (area A: superficial ablation mode, area B: deep ablative rejuvenation mode) yielded significant reduction of pigmentation in all treated PCA lesions (P-value < 0.001) (Fig. 1). However, the percentage of reduction of pigmentation was significantly higher in area A (20% of lesions showed complete clearance ¼ score 4, Fig. 1. A: Clinical appearance of macular amyloidosis in the back of a male patient at baseline, B: Three months after the last laser session (using superficial ablation mode) showing excellent clinical improvement, C: Clinical appearance of lichen amyloidosis in the shin of tibia of another male patient at baseline, and D: Three months after the last laser session (using deep ablative rejuvenation mode) showing excellent clinical improvement.

4 FRACTIONAL CO 2 AND PRIMARY CUTANEOUS AMYLOIDOSIS % showed marked improvement¼ score 3, 12% showed moderate improvement¼score 2 and 4% showed mild improvement¼score 1) compared to area B (40% of lesions showed marked improvement¼ score 3, 28% showed moderate improvement¼score 2, and 16% showed mild improvement¼score 1) (P-value ¼ 0.003). Both areas (A and B) showed significant reduction of rippling (P-value < 0.001). In addition, 10 out of 16 patients with macular amyloidosis were free of lichenification after treatment by either parameter, and 9 patients with lichen amyloidosis showed significant reduction in their lesions thickness (P-value ¼ 0.006) (Table 1). There was significant reduction in itching after treatment by both therapeutic modes compared to baseline values [median itching pre-treatment was 7 (range ¼ 3 10), while after treatment the median itching was 2 (range ¼ 0 6) (P-value < 0.001). There was significant positive correlation between itching on one hand and both lichenification and thickness of papular lesions on the other hand before and after treatment (in both areas A,B) (r ¼ 0.641, P-value ¼ 0.008). In addition, there was significant positive correlation between the degree of improvement in itching and pigmentation reduction in both areas A and B (r ¼ 0.415, P-value ¼ and r ¼ 0.456, P-value ¼ 0.022, respectively). Histological Assessment At baseline. Histological examination of skin sections stained with Congo red revealed accumulation of amyloid deposits within the papillary dermis- which showed apple green birefringence under polarized light- associated with increased epidermal thickness and deepened rete ridges. This was associated with numerous dilated blood vessels (Fig. 2A and B). One month after the last laser session. Significant reduction of amyloid deposits which ranged from complete absence in some areas to detectable residue in others, was demonstrated in both areas A and B (P-value < 0.001) (Fig. 2C and D). Residual amyloid deposits were seen close to the dermoepidermal junction. Positive Congo red staining was detected within the epidermis in the additional biopsies taken-from the three volunteered patients- at days 2, 4 and 6 after the first laser session (Fig. 3A, B and C). There were no significant differences between both treated areas as well as the day of biopsy retrieval. Although, there was significant reduction in epidermal thickness only in area A (P-value ¼ 0.032), yet the depth of rete ridges was significantly reduced in both areas A and B (P-value ¼ 0.002). There was no significant reduction of melanin in both treated areas (Table 2). Clinico-pathological assessment demonstrated significant positive correlation between the degree of improvement in itching and epidermal thickness reduction in both areas A and B (r ¼ 0.473, P-value ¼ and r ¼ 0.558, P-value ¼ 0.004, respectively). Patient satisfaction. Patients satisfaction was higher in PCA lesions treated by superficial ablation mode (area A) in comparison to those treated by deep rejuvenation mode (area B), but the difference was not statistically significant (P-value ¼ 0.073). Fourteen patients (56%) reported marked satisfaction (Score 4¼ >75%), eight patients (32%) reported mild satisfaction (Score 2¼25 50%), and 3 patients (12%) reported poor satisfaction (Score 1¼ <25%). There was significant relation between Patients satisfaction score and the degree of pigmentation reduction after treatment by the superficial ablation mode only (areas A) (P-value ¼ 0.01). On the other hand, there was a significant relation between Patients satisfaction and the degree of itching reduction after treatment by both therapeutic modes (Pvalue ¼ 0.03). Histologically, there was a significant relation between patients satisfaction score and the degree of epidermal thickness reduction in both areas A and B (P-value ¼ 0.01, 0.02, respectively). TABLE 1. The Degree of Reduction in Pigmentation, Rippling and Thickness of Pca Lesions Fractional CO 2 Superficial Ablation Mode (area A) treated lesions Fractional CO 2 Deep Rejuvenation Mode (area B) treated lesions Clinical Parameters Pigmentation (Percentage of reduction) Presence of Rippling (Grade 1) (N, %) Thickness of LA lesions Pre Post P-value Pre Post P-value 3 (2 4) 1 (0 3) < (2 4) 2 (0 3) <0.001 (66.7%) (50.0%) N ¼ 24 (96%) N ¼ 6 (24%) <0.001 N ¼ 24(96%) N ¼ 7 (28%) < (1 3) 0 (0 1) (1 3) 0 (0 1) Grading systems: (a) Degree of pigmentation of the lesions: Grade 1 ¼ mild, Grade 2 ¼ moderate, and Grade 3 ¼ marked, (b) Pattern of pigmentation: Grade 0 ¼ absence of rippling and Grade 1 ¼ presence of rippling, (c) Thickness of the lesions: lichen amyloidosis (LA) (Grade 1 ¼ mildly papular, Grade 2 ¼ moderately papular, Grade 3 ¼ markedly papular). Scoring systems: (a) Degree of reduction of pigmentation: Score 0 ¼ no improvement, Score 1 ¼ mild improvement, Score 2 ¼ moderate improvement, Score 3 ¼ marked improvement and Score 4 ¼ complete clearance, (b) Degree of reduction in thickness: Score 0 ¼ <25% reduction, Score 1 ¼ (25 50%) reduction, Score 2 ¼ (51 75%) reduction, and Score 3 ¼ (>75%) reduction.

5 392 ESMAT ET AL. Fig. 2. A: Photomicrograph of a section in the skin of the a patient before treatment showing the amyloid deposits in the papillary layer of the dermis (arrows) close to a dilated blood vessel (B.V) (Congo red 200), B: Apple green birefringence of amyloid deposits under polarized light, C: Photomicrograph of a section in the skin of the same patient after treatment by deep ablative rejuvenation mode showing minimal residue of amyloid deposit (arrow) within the dermis, markedly decreased depth of rete ridges (wavy arrow) (Congo red 200), and D: Photomicrograph of a section in the skin of the same patient after treatment by superficial ablation mode showing minimal residue of amyloid deposit within the dermis and markedly decreased depth of rete ridges (wavy arrow) (Congo red 200). Complications. Two patients experienced post-inflammatory hyperpigmentation (PIH), one showed PIH in area B, while the other showed PIH in both treated areas A and B. PIH resolved in both patients after the follow-up period (3 months after the last laser session) by the aid of topical bleaching and corticosteroid creams. In addition, two more patients showed pixilation following the third laser session, in area B (Fig. 4A and B). Pain was significantly higher in area B (mean: ) compared to area A (mean: ) (P-value ¼ 0.02). Otherwise, none of the patients suffered from other complications. Follow-up. There was no recurrence of pigmentation, lichenification, or itching in both treated areas- in all patients- during the 3 months follow-up period. DISCUSSION The present study sheds light on the potential efficacy of fractional CO 2 laser for the treatment of PCA with regard to clinical appearance, histological pattern, and itching. Fractional CO 2 was applied in two modes; superficial ablation mode (area A) and deep ablative rejuvenation mode (area B). Clinical evaluation revealed significant reduction in pigmentation, thickness, and itching scores after treatment by both therapeutic modes, with area A showing more significant reduction in pigmentation only. This could be attributed to the higher density of MTZs in area A (spacing 500 mm) that might have contributed to more elimination of amyloid deposits and significant reduction of epidermal thickness, thus, leading to significantly better improvement of pigmentation. Recently, very good response- with almost no side effects- of a lichen amyloidosis patient was demonstrated following 6 sessions of fractional ablative erbium YAG laser (2940 nm), with spot size 9 9 mm and fluence 1400 mj. Six to eight stackings were given at each spot with 3 weeks interval [15]. Moreover, Norisugi et al., 2014, demonstrated the efficacy of CO 2 surgical laser in the treatment of two patients with lichen amyloidosis with regard to flattening of the papules and improvement of itching. Both patients were treated twice a month using the following parameters: W with 0.12-second pulse duration, second rest duration and a 5 mm spot size. No complications were reported [16]. The concept of a laser-dependent transport system capable of eliminating dermal material was first introduced by Hantash et al., 2006 [17]. Previous studies demonstrated the presence of necrotic debris (both dermal and epidermal) within microthermal zones (MTZs) termed microscopic epidermal necrotic debris (MENDs) [18]. The observed significant reduction in amyloid deposits-in the current study- is most probably due to their trans-epidermal elimination with MENDs through MTZs induced by fractional photothermolysis.

6 FRACTIONAL CO 2 AND PRIMARY CUTANEOUS AMYLOIDOSIS 393 Fig. 3. A: Photomicrograph of a section in the skin of a patient after treatment by superficial ablation mode showing positive staining for Congo red (arrows) within the epidermis (on day 2 after first laser session), B: Photomicrograph of a section in the skin of another patient after treatment by deep ablative rejuvenation mode showing positive staining for Congo red (arrows) within the epidermis (on day 4 after first laser session), there is no significant difference between both modes, C: Photomicrograph of a section in the skin of a third patient after treatment by superficial ablation mode showing minimal amyloid residues encroaching the dermo-epidermal junction (on day 6 after first laser session) (Congo red X 200). In accordance, the observed reduction of amyloid deposits in the papillary dermis after treatment was associated with residual amyloid deposits at the dermoepidermal junction. In addition, positive Congo red staining was noticed in the epidermis of sections retrieved at days 2, 4 and 6 following the first laser session. Moreover, correction of the process of keratinization induced by fractional ablative laser leading to further enhancement of amyloid elimination was previously mentioned [19]. TABLE 2. The Degree of Reduction in Amyloid, Melanin, Epidermal Thickness, and Depth of Rete Ridges in Pca Lesions Histopathological Parameters Fractional CO 2 Superficial Ablation Mode (area A) treated lesions Fractional CO 2 Deep Rejuvenation Mode (area B) treated lesions Pre Post P-value Pre Post P-value Amyloid Melanin Epidermal Thickness in mm Depth of Rete Ridges in mm ( ) 3.91 ( ) ( ) ( ) 6.43 ( ) < ( ) 3.74 ( ) ( ) ( ) ( ) ( ) ( ) 7.78 ( ) 3.86 ( ) ( ) ( ) <

7 394 ESMAT ET AL. Fig. 4. A: Clinical appearance of a female patient having post-inflammatory hyperpigmentation after treatment by deep ablative rejuvenation mode, B: Clinical appearance of another female patient having pixilation after treatment by deep ablative rejuvenation mode. The significant improvement in lichenification and flattening of papular lesions could be attributed to the significant reduction in both epidermal thickness and the depth of rete ridges in post-treatment sections. These histological changes are consistent with the rejuvenating nature of fractional CO 2 laser [19,20]. In the same context, improvement in amyloidosis associated itching correlated positively with decrease in epidermal thickness suggesting that cutaneous texture improvement along with the decrease in amyloid deposits might be responsible for symptomatic post-treatment relief of itching. Post-inflammatory hyperpigmentation (PIH) occurred in two patients, where one patient developed PIH in both treated areas (A, B) and the other developed PIH only in area B. Also, two more patients showed pixilation (minute depressions at the site of MTZs) in area B, which persisted during the follow-up period (3 months). In addition, all patients reported significantly higher pain score in area B compared to area A. None of the previously mentioned complications necessitated stoppage of treatment. No recurrence of pigmentation, itching or lichenification within the follow-up period (three months) was reported in any of the recruited patients. The relatively short follow-up period does not clearly elucidate the actual recurrence rate. Hence, longer follow-up periods are recommended to detect the optimum number of therapeutic sessions and the proper spacing between them. Patient satisfaction was relatively higher for area A compared to area B, yet the difference was not significant. Marked satisfaction was reported in 56% of patients, while 32% reported mild satisfaction. Patient satisfaction was positively correlated with lower pigmentation and itching scores. In conclusion, PCA lesions are effectively treated by fractional ablative CO 2 Laser with significant clinical improvement of pigmentation, as well as, itching. This clinical improvement is associated with significant reduction of dermal amyloid deposits. Appearance of amyloid deposits in the epidermis suggests their trans-epidermal elimination. Both superficial and deep ablative modes showed comparable results. The superficial ablative mode being better tolerated by patientswith more significant reduction in pigmentation and epidermal thickness- is recommended as a useful therapeutic tool for PCA. REFERENCES 1. Maize J, Maize J Jr, Metcalf J. Metabolic Diseases of the Skin. In: Elder, David E, Elenitsas R, Johnson, Bernett L, editors. Lever s Histopathology of the Skin. 9 th ed. Philadelphia: Lippincott Williams and Wilkins; pp Black MM, Upjohn E, Albert S. Amyloidosis. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. Missouri: Mosby Elsevier Publishing; pp Vijaya B, Dalal BS, Sunila, Manjunath GV. Primary cutaneous amyloidosis: a clinic-pathological study with emphasis on polarized microscopy. Indian J Pathol Microbiol 2012;55: Black MM, Wilson-Jones E. and Macular amyloidosis: a study of 21 cases with special reference to the role of the epidermis in its histogenesis. Br J Dermatol. 1971;84(3): Bandhlish A, Aggarwal A, Koranne RV. A Clinico-Epidemiological Study of Macular Amyloidosis from North India. Indian J Dermatol. 2012;57(4): Wong CK Amyloid Treatment. Clin Dermatol. 1990;8(2): Krishna A, Nath B, Dhir GG, Kumari R, Budhiraja V, Singh K. Study on epidemiology of cutaneous amyloidosis in Northern India and effectiveness of dimethyl sulphoxide in cutaneous amyloidosis. Indian J Dermatol online. 2012;3- (3): Jin AG, Por A, Wee LK, Kai CK, Leok GC. Comparative study of phototherapy (UVB) Vs photochemotherapy (PUVA) Vs topical steroids in the treatment of primary cutaneous lichen amyloidosis. Photodermatol Photoimmunol Photomed. 2001;17(1): Hernandez-Nunez A, Dauden E, Moreno de Vega MJ, Fraga J, Aragues M, Garcia-Diez A. Widespread biphasic amyloidosis: response to acitretin. Clin Exp Dermatol. 2001;26- (3): Das J, Gogoi RK. and Treatment of primary localized cutaneous amyloidosis with cyclophosphamide. Indian J Dermatol Venereol Leprol. 2003;69(2): Behr FD, Levine N, Bangert J. Lichen amyloidosis associated with atopic dermatitis: clinical resolution with cyclosporine. Arch Dermatol. 2001;137(5):

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