Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events

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1 Tattoo and Body Art Original Paper Received: January 27, 2016 Accepted after revision: September 27, 2016 Published online: December 15, 2016 Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events Jørgen Serup a Mitra Sepehri b Katrina Hutton Carlsen a a Tattoo Clinic at the Department of Dermatology and b Wound Healing Centre, Bispebjerg University Hospital, Copenhagen, Denmark Keywords Tattoo Complication Allergy Infection Sarcoidosis Pigments Ink Health problems Diagnosis Classification Abstract Background/Aims: Tattooing is a global trend. Clinical knowledge of complications is based on case reports collected over a century. Larger cohorts reflecting complications associated with contemporary trends are lacking. Methods: The study was a retrospective review of a consecutive cohort of patients with tattoo complications diagnosed in the Tattoo Clinic of Bispebjerg University Hospital in Copenhagen, Denmark, from 2008 to 2015, based on patient history and systematic clinical examination. Results: A total of 493 tattoo complications in 405 patients were studied. Overall, 184 (37%) presented allergic reactions with plaque elevation in 32.2%, excessive hyperkeratosis in 3.7%, and ulceration in 1.4%, predominantly observed in red tattoos and nuances of red; 66 (13%) presented papulo-nodular reactions, mainly observed in black tattoos (considered non-allergic) and due to pigment agglomeration; 53 (11%) had bacterial infections; 46 (9%) were psycho-social complications; 144 (30%) belonged to several specific diagnostic entities, including photosensitivity, pain syndrome, and lymphopathy. We found no cases of cutaneous or other malignancies. Sarcoi dosis was primarily seen in black tattoos and was a common associated disease, found in 23 reactions (5%), compared to the background population. Conclusion: The study introduces a new concept of classification of tattoo complications based on simple tools such as patient history and objective findings supplemented with histology. The study reflects complications originating from presently used tattoo inks, often with organic pigments. The introduced classification has been submitted to the World Health Organisation (WHO) as a proposal to the 11th revision of the International Classification of Diseases S. Karger AG, Basel Introduction Dermatology must at any time provide specialist treatment of skin diseases in the spirit of the ever-changing spectrum of diseases in the society. Today, this includes tattoos, as some 100 million Europeans have tattoos, and this is paralleled by an increasing incidence of acute and chronic tattoo complications. Tattoo complication is a karger@karger.com S. Karger AG, Basel /16/ $39.50/0 Mitra Sepehri, MD Wound Healing Centre Bispebjerg University Hospital, Bispebjerg Bakke 23 DK 2400 Copenhagen NV (Denmark) hotmail.com

2 Tattoo Clinic raw data collection Consecutive patient intake Patient history (405 with systematic records) Clinical examination (493 tattoo reactions) Biopsy, clinically indicated (259 biopsies) Retrospective assessment of tattoo reactions Theoretical construct of new diagnostic entities Fig. 1. Study flowchart. Stratification into main diagnosis (level A) and secondary diagnosis (level B) follows the general principles of the WHO Diagnostic Classification System. Application of new diagnostic system to clinical raw data Stratification into level A and B diagnosis Level A, main diagnosis (total 493 reactions) representing the main problem or main findings Level B, secondary diagnosis (total 231 reactions) representing subgroups, associated manifestations or problems, events, or special disease mechanisms Final clinical diagnosis Material by diagnostic groups 1. Infection (A = 59, B = 5) 2. Inflammation (A = 277, B = 55) 3. Psycho-social (A = 46, B = 6) 4. Miscellaneous (A = 82, B = 33) 5. Technique and treatment hazards (A = 29, B = 132) very complex issue and has already been introduced as a subspecialty in dermatology [1 5]. The classification includes infectious, non-infectious, acute, and chronic complications. Chronic tattoo reactions are associated with significant itch and discomfort and reduced quality of life of a severity comparable to other pruritic dermatoses [6]. The international tattoo industry and manufacturing of tattoo ink products undergo constant changes. During the past decennia, inorganic tattoo pigments have been widely replaced by more colourful organic pigments. Older case reports exemplified by reports of allergy to cinnabar containing mercury and yellow pigment containing cadmium are, therefore, of historical interest today [7]. The Tattoo Clinic at the Department of Dermatology at Bispebjerg University Hospital, Copenhagen, Denmark, was established in 2008 and aimed to offer the growing number of sufferers with tattoo complications specialised examination and treatment substantiated by research. It is, therefore, well positioned to provide a significant and representative cohort of patients who have undergone a standardised work-up. Hitherto, there has been no recognised diagnostic classification of tattoo complications. The main goal of this study was to propose a new clinical classification of tattoo complications. Wenzel et al. [8] surveyed the literature from 1991 to 2011 on adverse reactions. Coloured tattoos presented more complications (83.3%) than black tattoos (12.5%), and infections also remained a problem. Reports were hampered by the difficulty of diagnosing allergy and the difficulty in the interpretation of granulomatous and sarcoid granuloma reactions. In the survey, granulomatous, lichenoid, and hypersensitivity reactions due to allergy were classified together due to lack of clarity of the reports. In , Klügl et al. [9] evaluated self-reported health problems with tattooed skin in the public domain. The evaluation was based on 3,411 reports in an internetbased study in German-speaking countries. The study did not separate mild complaints and medical complications. However, a broad range of skin problems (67.5%) and systemic reactions (6.6%) were identified, with 6% having persistent problems. Coloured tattoos, in practice dominated by red and large tattoos, carried higher risk. To the best of our knowledge, more recent original li terature on tattoo complications only includes 2 syste matic studies of series of patients diagnosed at clinics of dermatology. In 2007, Kazandjieva and Tsankov [10] (So- Tattoos and Clinical Complications 669

3 Table 1. Clinical classification of 493 tattoo reactions Level A Level B Infections A: 59 (12%), B: 5 (2%) Virus Local 6 (1.2%) 0 (0%) Bacteria Local 16 (3.2%) 1 (0.4%) Regional 33 (6.7%) 2 (0.9%) Systemic 4 (0.8%) 2 (0.9%) Inflammation, non-infectious A: 277 (56%) B: 55 (24%) Allergic Plaque elevation 159 (32.2%) 1 (0.4%) Ulceration 7 (1.4%) 0 (0%) Excessive hyperkeratosis 18 (3.7%) 0 (0%) Non-allergic Papulo-nodular 66 (13%) 3 (1.3%) Other chronic 1 (0.2%) 0 (0%) Toxic early reaction 0 (0%) 0 (0%) Urticaria Light induced 13 (2.6%) 43 (18.6%) Not light induced 13 (2.6%) 8 (3.5%) Psycho-social A: 46 (9%) B: 6 (3%) Exit programme Gang rehabilitation 30 (6.1%) 1 (0.4%) Non- exit Medical, X-ray mark 1 (0.2%) 0 (0%) Non-medical, regret 15 (3.0%) 5 (2.2%) Miscellaneous A: 82 (17%) B: 33 (14%) Local Pimples 3 (0.6%) 7 (3.0%) Malignant tumour 0 (0%) 0 (0%) Benign tumour/keratoacanthoma 3 (0.6%) 0 (0%) Irritation 3 (0.6%) 0 (0%) Keloid 1 (0.2%) 0 (0%) Vaseline reaction 0 (0%) 1 (0.4%) Regional Neurosensitive 11 (2.2%) 2 (0.9%) Lymphoedema 1 (0.2%) 0 (0%) Pigment diffusion 6 (1.2%) 6 (2.6%) Systemic Latex allergy 1 (0.2%) 0 (0%) Vasculitis 0 (0%) 1 (0.4%) Sarcoidosis 23 (4.7%) 3 (1.3%) Allergic skin reaction, rash 9 (1.8%) 1 (0.4%) Associated other skin diseases 6 (1.2%) 3 (1.3%) Systemic, other 1 (0.2%) 0 (0%) Other Cosmetic 3 (0.6%) 8 (3.5%) Traumatic 2 (0.4%) 1 (0.4%) Henna 9 (1.8%) 0 (0%) fia, Bulgaria) screened 234 dermatological patients who happened to have tattoos and found 5 (2.1%) with complications (infections, allergy, and granulomatous inflammation). In 2012, Wollina [11] (Dresden, Germany) reported a retrospective series of 7 patients with severe tattoo complications collected from 2001 to Cases included infections with MRSA and atypical mycobacteria, severe allergy in red tattoos (with 1 case with ulceration), and a case of granulomatous and sarcoid reactions by histopathology. Both reports were hampered by either lack of detail or uncertainty about the final diagnoses as well as missing reference to some established nosographic or nosological entity. There is a lack of knowledge concerning the injected dose as well as the precise composition of inks that, besides the colourful pigment, also contain impurities and contaminants [3, 12, 13]. This is a barrier in the diagnosis and clarification of tattoo complications and their cause. Uncertainty also includes microbial contaminants, which were found in many tattoo ink products labelled sterile [14 16]. Tattooed individuals are at any time under potential risk of bacterial and viral infections, allergies, and other kinds of inflammatory and toxic events manifested locally or systemically. Patients and Methods Level A Level B Technique and treatment hazards A: 29 (5.9%) B: 132 (57%) By tattooing Pigment overload 9 (1.8%) 43 (18.6%) Infected ink 0 (0%) 19 (8.2%) Other source of infection 0 (0%) 14 (6%) Needle trauma 8 (1.6%) 23 (10%) By treatment Laser 7 (1.4%) 11 (2.2%) Lactid acid 2 (0.4%) 0 (0%) Surgical excision, scar 0 (0%) 1 (0.4%) Scar, other 3 (0.6%) 8 (3.5%) Water tattooing 0 (0%) 9 (3.9%) Self-treatment 0 (0%) 4 (1.7%) Primary, level A (n = 493) and secondary, level B (n = 231) diagnoses by number. For further details, see the supplementary materials (for all online suppl. material, see (Fig. 1, Table 1). 670 Serup/Sepehri/Hutton Carlsen

4 19% 8% 30% 37% Allergic reaction Non-allergic reaction Bacterial infection Systemic reaction Other 44% 19% Pigment overload Light-induced urticaria Needle trauma Infected ink Other 11% 14% 8% 10% Fig. 2. Diagram of commonly observed primary clinical diagnoses, level A ( n = 493). Fig. 3. Diagram of commonly observed secondary clinical diagnoses, level B ( n = 231). Results The 405 patients included consecutively in the study presented in total 493 tattoo complications ranging from 1 to 5 complications in a patient; 226 females (56%) presented 273 complications and 179 males (44%) presented 220 complications. The average age was 33 years (8 75 years) at the first visit. Clinical Diagnostic System We registered 493 level A diagnoses and 231 level B diagnoses (see Table 1, Figs. 2, 3). Level A Diagnoses are presented in Table 1 and Figure 2. Allergic reaction was the largest group followed by non-allergic reactions (papulo-nodular reactions), infections, and miscellaneous systemic reactions. Level B Diagnoses are presented in Table 1 and Figure 3. In 43 reactions (19%) pigment overload (excessive pigment installed by tattooing) was noted. This was strongly associated with black tattoos and observed in 41 reactions (95%). In 43 reactions (19%) light-induced urticaria was observed. In 23 cases (10%) needle trauma resulted in reactions. In 19 reactions (8%) bacterial infections were indicated to have been caused by infected ink (infection started in 1 specific colour or in a shadowed tattoo made with manually diluted ink). Diagnostic Groups Detailed results of the study are presented in Table 1. The most important and clinically relevant subgroups will be described in the following text. Infections Bacterial infection was common with 53 infections (11%) noted in this material; 3.2% were local, 6.7% regional, and 0.8% systemic. Inflammatory Reactions (Non-Infectious) Allergic reaction was the dominating category, manifested as 3 distinct patterns: plaque elevation, ulcero-necrotic, and excessive hyperkeratotic pattern (see Table 1). Plaque elevation or plaque-like patterns (allergic) were found in 32.2%. Consistent thickening and elevation of the entire tattoo at any site of the tattoo where the problem colour was inserted are seen in Figure 4 a and b. Scaling was variable. Ulcero-necrotic pattern (severe allergic), necrosis, and ulceration were observed in 1.4% of reactions. The reaction affected any site of the tattoo where a particular colour was injected. Excessive hyperkeratotic pattern (allergic, with a special epidermal response) was observed in 3.7% (see Fig. 4 c). It had basic features of plaque elevation; however, lesions were dominated by massive hyperkeratosis and cornification of the surface with an extraordinary epidermal response of proliferation elicited by the underlying inflammation. The surface might be flat, furrowed, whitish, and occasionally with local ulceration due to epidermal necrosis. Notches, ducts, cysts, and epidermoid Tattoos and Clinical Complications 671

5 a b c Fig. 4. a Plaque elevation: uniform elevation with scaling in any part of the tattoo coloured bright red, contrasting no reaction in other colours. b Plaque elevation: uniform swelling in any red part of the tattoo without scaling, contrasting no reaction in black parts. c Excessive hyperkeratosis: major thickening in any part of the red tattoo due to dermal inflammation and an excessive hyperkeratotic response with epidermal hyperplasia, furrowing, and adherent scaling. Note deep notches, spontaneously or along a line of the motif tattooed black. inclusions deeper in tissues may develop. The pathologist may occasionally interpret histology as pseudoepitheliomatous hyperplasia. Allergic Cross-Reactions Of 184 allergic reactions, cross-reactions were observed in 22 trigger tattoos (12%) with 23 responder tattoos, i.e. a new tattoo with allergic reaction (the trigger) that challenged and provoked an allergic reaction in 1 or more older tattoos (the responder), the responder hitherto tolerated. The responder was located in a different anatomical site and often performed by another tattooist supposedly with different ink, albeit the visual colour was the same. Non-Allergic Reactions A papulo-nodular pattern (non-allergic) was seen in 66 of 493 reactions (13%). Variable distribution of pa pules or nodules or both were seen in the tattoo (Fig. 5a c). Elements were more dense and larger in diameter in deeply coloured parts of the tattoo and possibly overdosed with pigment (pigment overload) in 38 of 66 reactions (58%). Large agglomerates of pigments can occasionally be seen directly by the naked eye in a raw punch biopsy. Other parts of the same tattoo containing the same colour and made with the same tattoo ink product dosed more sparsely, however, may appear completely normal. Subject to individual predisposition, papules and nodules may have the histology of plain inflammation and foreign body reaction, granulomatous inflammation, or sarcoid granuloma. Reactions may possibly be an isolated local manifestation of sarcoidosis exclusively in the tattoo or part of widespread sarcoidosis even involving the lungs and other organs. Urticaria Reactions Light-induced urticaria represented inflammatory reactions of tattoos after exposure to sun. Reactions were mostly acute and of short duration but occasionally polymorphous and protracted, lasting days. It was noteworthy that in the total material and as a secondary diagnosis at level B, 43 (19%) had light-induced urticarial reactions locally in the tattoo ( Fig. 3 ). In total, combining levels A and B diagnoses, as many as 56 reactions (11%) provoked by light were reported. Not light-induced urticaria with generalised affection of the skin was seen in 26 (5%), with 13 (50%) of these 672 Serup/Sepehri/Hutton Carlsen

6 a b Fig. 5. a Papulo-nodular reaction: small papules with tiny scales developed in lines where the concentration of tattoo pricks is larger, while isolated pricks show no reaction. b Papulo-nodular reaction: larger papules concentrated in lines and in the legs of the tattooed insect (with face of a lady), where the tattooist wishes the black colour to be more intense, thus requiring an additional amount of ink in the skin. c Papulo-nodular reaction with nodules concentrated in black lines. Histology showed sarcoid granuloma. The patient had cutaneous sarcoidosis. Additionally, a traumatic scar showed sarcoidosis. c manifesting as classical chronic urticaria without light as an aggravating factor. It appeared as wheal and flare reactions in the tattoo or in the entire skin occurring after tattooing or following exposure to mechanical trauma or intake of alcohol. Psycho-Social Complications Psycho-social complications among gang members included in a re-socialisation programme, Exit, were seen in 30 (6%). Most of these patients were treated with Q-switched YAG lasers. Miscellaneous Reactions Local Reactions Benign tumours were noted in only 3 cases (0.6%): 2 cases of keratoacanthoma and 1 case of fibroma with hyperkeratosis. The cases were confirmed by or consistent with the pathologist s evaluation, and tumours resolved spontaneously without surgical intervention. No primary malignant tumours in tattooed skin were observed in the 493 tattoo reactions in 405 patients. Regional Reactions Neurosensitive complications with discomfort and invalidating pain, contrasting little or no inflammation of the tattoo by histology, were reported by 11 patients (2.2%). Lymphoedema (local and regional) was only seen in 1 case. One patient was observed with chronic lymphadenopathy allocated to allergy also involving pigment deposited in the regional node as the primary diagnosis. A number of patients reported swollen lymph nodes some weeks after tattooing, with spontaneous regression. Pigment diffusion or tattoo blow out into the neighbouring skin or underlying structures occurring over time, with visible migration of pigment outside the tattoo, was observed in 6 cases, sometimes influenced by gravity. Systemic Reactions Sarcoidosis was a very common association and seen in 23 of 40 tattoos (57.5%). Tattoos and Clinical Complications 673

7 Table 2. Tattoo colour and primary diagnoses, level A Clinical diagnoses Red Red nuances Violet, purple Black Blue, green, turquoise White Yellow Brown Multicolour Cosmetic, Henna Total traumatic, grey (n = 493) Allergic, local (37%) Non-allergic (14%) Bacteria (11%) Systemic (8%) Exit (6%) Urticaria (5%) Regional (4%) By tattooing (3%) Non-Exit (3%) Other (3%) By treatment (2%) Local (2%) Virus (1%) This table refers to Table 1, the 13 main diagnostic groups. Allergic Skin Reaction, Rash. Rash was seen in 9 of 40 (23%) with general skin reactions, i.e. severe allergic reactions or rash in patients with known nickel allergy and challenge of the allergy by tattooing supposedly due to nickel contamination of the tattoo ink. One case, primarily sensitised to parabens by tattooing, developed severe generalised dermatitis requiring hospitalisation. Associated other skin diseases were observed in only 6 reactions (atopic dermatitis, contact dermatitis, psoriasis, and nodular prurigo). Psoriasis was exceptional and only observed directly in the newly tattooed skin. Technique and Treatment Hazards By Tattooing In total, technique hazards were seen in 116 of 493 tattoos (24%): pigment overload in 52 tattoos (10.5%), infected ink in 19 (8.2%), other source of infection in 14 (6%), and needle trauma in 31 (6.3%). By Treatment In total, treatment hazards were seen in 45 of 493 tattoos (9%). Of these, 18 presented complications related to laser removal with infection, delayed healing, hypertrophic scar formation, keloid, chronic inflammation, and photosensitivity (every case associated with inefficient treatment outcome with incomplete removal); 2 patients attempted tattoo removal by lactic acid injection resulting in severe scar formation; 1 person had a disfiguring scar following surgical excision of a tattoo; and 11 showed abnormal scar formation (hypertrophic scar in the tattoo). In 9 reactions, tattooing with water had been attempted by the tattooist to remove tattoo pigment (in all cases unsuccessfully and followed by mild scarring). In 4 cases, persons had performed self-treatment and attempted to remove the tattoo with sandpaper, by shave excision using a scalpel, or by punching with needles. Colour of Tattoo with Complication The main diagnoses related to tattoo colour are shown in Table 2 and Figure 6. Allergic reactions were observed in 157 of 184 (85%) of red tattoos and in nuances of red. Non-allergic reactions were observed in black tattoos in 59 of 67 (88%), while bacterial infections were colour independent ( Table 2 ). The majority of symptoms and clinical manifestations were triggered by tattoos with colours in the red spectrum (40%) and by black tattoos (35%); 13% of the complications occurred in multi-coloured tattoos (see Fig. 6 ). Histology A total of 259 punch biopsies evaluated routinely by pathologists at the Department of Pathology, Bispebjerg University Hospital, showed the following: inflammation only 179 (69%), granulomatous inflammation 32 (12%), sarcoid granuloma 21 (8%), pseudolymphoma 8 (3%), interface dermatitis 8 (3%), fibrosis 6 (2%), ulce r- ation 6 (2%), and pseudoepitheliomatous hyperplasia/ excessive hyperkeratosis 4 (2%) (see Table 3 ). In many instances, punch biopsy according to the pathologist s detailed report showed an overlap of different histopath- 674 Serup/Sepehri/Hutton Carlsen

8 2% 2% 13% 0.2% 2% 1% 40% 5% 35% Red = red and red nuances Other = cosmetic (black, brown, red) Red Black Blue, green, turquoise White Yellow Brown Multicolour Henna Other Table 3. Biopsy diagnosis of tattoo complications by histopatho logy Histopathology Total Colour of tattoo black red other Inflammation 179 (69) 35 (20) 91 (51) 53 (29) Granulomatous inflammation 32 (12) 14 (44) 10 (31) 8 (25) Sarcoid granuloma 21 (8) 15 (71) 2 (10) 4 (19) Pseudolymphoma 8 (3) 0 6 (75) 2 (25) Interface dermatitis 8 (3) 0 5 (63) 3 (37) Fibrosis/scar 6 (2) 1 (17) 2 (33) 3 (50) Ulceration 6 (2) 1 (17) 2 (33) 3 (50) Pseudoepitheliomatous hyperplasia/ excessive hyperkeratosis 4 (2) 0 3 (75) 1 (25) Follicular reaction 4 (2) 2 (50) 2 (50) 0 Epidermoid cyst/fistule 3 (1) 0 2 (67) 1 (33) Keratoacanthoma 2 (0.7) 0 2 (100) 0 Verruca vulgaris 2 (0.7) 2 (100) 0 0 Other (fibroma, dermatitis, rash, etc.) 7 (3) 4 (57) 0 3 (43) Normal 9 (3) 4 (44) 1 (12) 4 (44) Fig. 6. Problem colours of tattoos, level A diagnoses ( n = 493). Data are given as n (%). Some patients had more than 1 diagnosis by histopathology (n = 291) in 259 biopsies. ological patterns in the very same sample, thus with a mix of patterns. Supplementary Data The following data is provided as online supplementary data: tattoo by type (online suppl. Table 4), anatomical sites (online suppl. Table 5), symptoms according to patient s history (online suppl. Table 6), debut of symptoms after tattooing (online suppl. Table 7), known skin diseases and predispositions (online suppl. Table 8), and known allergies (online suppl. Table 9). Discussion The tattoo trend is paralleled by many complications. Health systems need to adapt to the global challenge of tattoo complications and provide competent treatment opportunities for sufferers. There is a strong need for prevention; however, research is lagging behind. Guarantee of safe inks, which may seem simple, is beyond reach due to lack of knowledge. Prevention is a difficult task because tattooing has long historical roots and is based on cultures spontaneous wishes and feelings, and people s assumption of ownership of their own skin as being a human right. Multiple approaches building on pragmatism and realistic instruments are needed and outlined in the strategy recently introduced as Integrated Prevention of Tattoo Complications [17]. Improvement of medical services and diagnostic methods are part of the strategy. This study of 493 consecutive tattoo complications in 405 patients collected in a dermatology clinic specialised in tattoo complications illustrated that there are many diagnostic entities in the evaluation of adverse tattoo reactions to establishing a specific diagnosis. The clinical patterns of tattoo complications deve loped in this study have been submitted to the World Health Organisation (WHO) as a proposal to the 11th revision of the International Classification of Diseases (ICD-11) under the International Classification of Skin Diseases. The main diagnostic groups are commented on following the same structure as that used in Patients and Methods, Results, and as shown in Table 1. It is known that bacterial infection is a common complication in tattooing. The tattooing process can, in a worst-case scenario, lead to life-threatening infections, which usually develop within a week after the tattoo procedure [18, 19]. Our material was likely to underestimate this complication since many patients with infections were treated in the primary sector and severe infections as medical casualties. Chronic inflammatory reactions were very common. Allergic reactions were associated with 184 complications (37%) (see Fig. 2 ) predominantly associated with red pigment (85%) (see Table 2 ). Allergic reaction manifested as Tattoos and Clinical Complications 675

9 plaque elevation was the dominant entity among allergic reaction patterns. It has been suggested that patch or intradermal testing before or after tattooing could clarify or predict allergic complications [20]. This has no rationale since the allergen is likely to be a hapten formed in the skin with a long and unknown latency [21]. Non-allergic chronic reactions were dominated by papulo-nodular reactions, and the association between black pigments was very strong. We suspect that these reactions are essentially foreign body reactions explained by the special tendency of carbon black nanoparticles to aggregate and agglomerate, thus over time forming large clusters of black pigment in the outer dermis, reaching a size when a foreign body tissue response may be induced depending on individual predisposition [22]. Urticaria reactions locally in tattoos were more frequently seen as light-induced reactions compared to reactions not light induced, which were quite uncommon. Tattoos, light, complaints, and complications constitute an unspecified number of facets. In the general population of people with tattoos, as many as 1 in 5 report sensitivity of their tattoo to sunlight, and photosensitivity ranks as the most frequent complaint [23, 24]. In our material of tattoo complications, photosensitivity with some immediate swelling of tattoos occurred in a significant number of cases. Red colours were more frequently associated with light-induced reactivity, indicating that azo chemicals and their photochemical split products may play a role in photosensitivity reactions. Widespread urticaria and type 1 allergy induced by tattooing and also affecting non-tattooed skin has previously only been poorly described. Most cases with widespread urticaria in our material lasted several months. Widespread urticaria was not provoked by light and possibly due to allergy to some soluble ingredient(s) of tattoo inks or to some chemical contaminant or pigment metabolite. Psycho-social complication was a significant group; 30 patients (6.1%) were referred to the clinic due to gang rehabilitation, hereby named Exits. This number was likely to be underestimated. Psycho-social complication and simple tattoo regrets are not uncommon, but being a public clinic we do not treat this category. Miscellaneous complication was a large group including many distinct diagnostic groups and many different disease mechanisms, each of high specificity. The group is commented on below. The absence of skin cancers originating in tattoos is in accordance with a recent review of the literature concluding malignant tumours in tattoos to be rarely observed and coincidental [25]. Keratoacanthoma are a paradox and a dilemma for the clinician, being clinically benign with spontaneous healing despite malignant histology, which often mimics squamous cell carcinoma [26]. Medical consensus concludes that tattoos do not produce cancers either in the skin or in the regional lymph nodes despite the presence of pigment in nodes. This was recently supported in a study on black tattoos and photocarcinogenicity in mice, which even indicated that light absorption in black tattoo pigment may delay the deve lopment of sun-induced skin cancer [27]. Neurosensitive reactions were a new observation. A few cases labelled complex regional pain syndrome and brachial plexopathy with muscle atrophy have been reported in the literature [28, 29]. Tattoos associated with severe pain were colour independent, located in various body sites, and not limited to sites considered especially sensible. It may be hypothesised that metabolites of some tattoo pigments may be neuro-stimulators of C-fibres and elicit pain and itch. Inflammatory tattoo reactions generally result in surprisingly prominent itch and pain, and metabolism in the skin with the formation of neuromodulators from pigment raw materials may be common and not limited to distinct pain conditions and syndromes [6]. Pain can propagate and become regional or segmental following dermatomes and can be invalidating and a pain syndrome. Lymphedema was only observed in 1 case thought to be the result of a block of the local lymphatic system by clusters of pigment comparable to the African disease known as podoconiosis [30]. The lymphatic system was also involved with marked swelling and necrosis of regional lymph nodes in a case of severe allergic reaction of a red tattoo, with deposits of red tattoo pigment in the regional node subject to a parallel allergic reaction. Pigment diffusion or tattoo blow out with tattoo pigment stain of the surrounding skin but no lymphedema was observed and can be disfiguring in cosmetic tattoos. The association of tattoo and sarcoidosis is known, as is the association of sarcoidosis and other skin affections (sarcoid granuloma of the skin, scars, erythema nodosum, etc.; see extensive review by Kluger [31] ). Sarcoid reaction in a tattoo might be an isolated local manifestation of sarcoidosis and exclusively in the tattoo or part of widespread sarcoidosis even involving the lungs and ot h- er organs. Details on the association between tattoos and sarcoidosis will be published in a separate publication. Other associated skin diseases (e.g. psoriasis and atopic dermatitis) were uncommon and thus did not represent a major risk in relation to tattooing. The prevalence of any previously known skin diseases was comparable to 676 Serup/Sepehri/Hutton Carlsen

10 the prevalence of the diseases in the general population with the exception of sarcoidosis, which was found in 2% (see online suppl. Table 7). We found no association with lichen planus. Technique and treatment hazard was a prominent group, with 24% and 9%, respectively (see Table 1 ). Laser removal is a powerful photochemical procedure and is thus of special concern from the perspective of inducing major complications and allergy during or after laser removal. Indeed, acute allergic reactions including anaphylactic reaction as well as delayed flare up of allergic reactions of the treated tattoos have been reported during or shortly after laser removal of tattoos [32 34]. The use of laser equipment by an inexperienced layperson (cosmetologist, tattooist, or private person) can result in numerous complications [35]. Treating doctors and tattooists should constantly develop their knowledge and skills. Lactic acid, water tattooing, and self-treatment to remove tattoos can also cause serious hazards and complications, as observed in our study. Tattoo pigments represent different chemicals, and thus the colours of tattoos are expected to be linked to specific clinical complications. Allergic reactions were predominant in red tattoos and in nuances of red, papulo-nodular reactions were observed in black tattoos, and bacterial infections appeared colour independent. The study confirmed that histopathology was useful for a description of the degree and level of inflammation in the dermis, the location and clustering of pigment, and the diagnosis of sarcoid granuloma (see Table 3 ). Also, in accordance with the medical literature, the study confirmed that the traditional histopathological patterns often overlap and provide little help in discriminating different clinical entities, with sarcoid granuloma and sarcoidosis being the exception [31, 36 39]. There is no histopathological hallmark of allergy. As discussed, pigment agglomeration and foreign body reaction were considered important in reactions of black tattoos, confirmed by histology with pigment bodies and associated inflammation, which may be granulomatous. Foreign body reaction delineated in the pathologist s textual description of a sample was, nevertheless, often not readable from the pathologist s conclusive diagnosis, which respects the many uncertainties and lack of diagnostic standard of this variable disease. Histology, typically with lymphocytic infiltration, failed to produce any support in the important discrimination of allergic reactions in red tattoos and non-allergic reactions in black tattoos. In the present study, only 8 biopsies (3%) with interface dermatitis were observed, contrasting with our previous finding (78%) in a pivotal study of interface dermatitis as a marker of allergy of red tattoos [40]. However, interface dermatitis can easily be overlooked in routine histopathology of tattoo reactions focused at traditional patterns of reactions. It should be emphasised that a punch biopsy may not be representative of the entire tattoo reaction. Nevertheless, histopathology remains a very useful and indispensable supplementary tool. Acknowledgements This study was funded by Bispebjerg University Hospital, Denmark. We would like to thank Dr. Regitze Henrik-Nielsen and Dr. Vera Skødt, specialists in dermato-histopathology at the Department of Pathology, Bispebjerg University Hospital, who evaluated all skin biopsies. The Health Foundation and King Christian IX and Queen Louise s Anniversary Fund are acknowledged for funding parts of the study not covered by Bispebjerg University Hospital, Denmark. Statement of Ethics The Tattoo Clinic at Bispebjerg University Hospital works under the ethical approval number (H-A ) issued by the Regional Ethics Committee and under the ethical standards of the Hospital regarding any aspect of patient care. The Helsinki declaration II was followed. Disclosure Statement The authors have no conflicting interests to declare. References 1 Serup J, Kluger N, Bäumler W: Tattooed skin and health; in Current Problems in Dermatology. Basel, Karger, 2015, vol De Cuyper C, Pérez-Cotapos M-L (eds): Dermatologic Complications with Body Art, Tattoos, Piercings and Permanent Make-Up. Heidelberg, Springer, Laux P, Tralau T, Tentschert J, et al: A medical-toxicological view of tattooing. Lancet 2016; 387: Kluger N: Cutaneous complications related to permanent decorative tattooing. Expert Rev Clin Immunol 2010; 6: Simunovic C, Shinohara MM: Complications of decorative tattoos: recognition and management. Am J Clin Dermatol 2014; 15: Hutton Carlsen K, Serup J: Patients with tattoo reactions have reduced quality of life and suffer from itch: Dermatology Life Quality Index and Itch Severity Score measurements. Skin Res Technol 2015; 21: Tattoos and Clinical Complications 677

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