International Journal of Academic Medicine

REVIEW ARTICLE
Year
: 2019  |  Volume : 5  |  Issue : 1  |  Page : 19--50

Tattoo-associated complications and related topics: A comprehensive review


Jameson M Petrochko1, Andrew C Krakowski2, Colin Donnelly3, John B Wilson3, Jennifer Bruno Irick3, Stanislaw P Stawicki4,  
1 Temple/St. Luke's School of Medicine, St. Luke's University Health Network, University Hospital, Bethlehem, USA
2 Department of Dermatology, St. Luke's University Health Network – Anderson Campus, Easton Pennsylvania, USA
3 Department of Emergency Medicine, St. Luke's University Health Network – Anderson Campus, Easton Pennsylvania, USA
4 Department of Research and Innovation, St. Luke's University Health Network, University Hospital, Bethlehem, USA

Correspondence Address:
Dr. Stanislaw P Stawicki
Department of Research and Innovation, St. Luke's University Health Network, University Hospital, Bethlehem, Easton Pennsylvania
USA

Abstract

As tattoos become more common, it is likely that practitioners will encounter adverse tattoo reactions with increasing frequency. While some tattoo-related complications (TRCs) may be nonspecific and challenging to diagnose, others present overtly and can be identified quickly by a well-informed practitioner. TRCs occur at both of these extremes, highlighting the need for better awareness and knowledge sharing regarding this heterogeneous group of morbidities. This review is a result of a compilation of the best available clinical evidence across various groupings of TRCs. The authors' intent was to provide the reader with a comprehensive overview of the topic while creating a rich repository of referenced knowledge for future investigations. From the standpoint of frontline health-care providers, effective recognition and management of TRCs require an open-mind, high degree of clinical suspicion, and nonjudgmental approach to a mainstream phenomenon that is still considered by many to be a taboo. The following core competencies are addressed in this article: Medical knowledge, Patient care, and Systems-based practice.



How to cite this article:
Petrochko JM, Krakowski AC, Donnelly C, Wilson JB, Irick JB, Stawicki SP. Tattoo-associated complications and related topics: A comprehensive review.Int J Acad Med 2019;5:19-50


How to cite this URL:
Petrochko JM, Krakowski AC, Donnelly C, Wilson JB, Irick JB, Stawicki SP. Tattoo-associated complications and related topics: A comprehensive review. Int J Acad Med [serial online] 2019 [cited 2019 Dec 11 ];5:19-50
Available from: http://www.ijam-web.org/text.asp?2019/5/1/19/256793


Full Text



 Introduction



A tattoo can be defined as the intentional insertion of pigment into one's dermis using a punctate instrument.[1] In addition to serving a broad range of decorative functions, tattooing (e.g., the procedure of tattoo placement) also includes permanent makeup and reconstructive dermatological/surgical applications.[2],[3],[4] Whenever foreign material is inserted into the body, there exists an opportunity for complications, including trauma related to implantation, infection, the body's reaction to the pigment, and many other possible sequelae.[4],[5],[6]

As tattoos become more prevalent,[6],[7] the number of tattoo-related complications (TRCs) is also likely to grow. Unfortunately, patients may avoid bringing up issues related to their tattoos for fear of being stigmatized. We set out to perform a comprehensive review of TRCs with two main objectives. The primary goal is to give health-care providers an appreciation for the wide variety of morbidities that may arise from tattoos in their patients and to enhance physicians' understanding of these complications so that they may provide better clinical care. Our secondary goal is to increase awareness of TRCs and to encourage physicians to inquire about tattoos in a non-judgmental fashion so that they may more effectively care for patients with TRCs.

 Literature Review Methodology



To optimize content for the current manuscript, we performed a comprehensive literature search utilizing PubMed and Google™ Scholar. Out of approximately 19,550 candidate manuscripts, we distilled more than 400 sources for this definitive review. This includes both primary and secondary publications (e.g., those referenced by articles from our primary literature search). Finally, the authors also searched various websites and discussion boards dedicated to tattoos and related topics.

 Overview of Specific Tattoo-Related Complications



In the subsequent sections, we will outline a broad range of TRCs, ranging from allergic reactions to the tattoo ink material itself to magnetic resonance imaging (MRI)-associated burns. The focus of each specific TRC section is to provide the reader with a clinically relevant overview as well as a rich repository of referenced knowledge, specifically intended to help facilitate future research in this area of inquiry.

 Anaphylactic Reaction to Tattoo Ink



Anaphylaxis has been reported following tattoo placement and is a serious but uncommon TRC.[8],[9] Reported symptoms include generalized pallor, hives, abdominal pain, and shortness of breath approximately 6–12 h after ink exposure (or re-exposure).[8],[9] In one case, the patient underwent application of new color ink to an existing dark ink tattoo, with an approximate 30-day period between the two exposures.[8] Moreover, the patient had a multicolored tattoo placed 6 years before the described episode of anaphylaxis without adverse reaction; approximately 6 months after her first bout of anaphylaxis, the patient had more color added to the tattoo and experienced a second, similar but more rapid anaphylactic reaction.[8] In another case, the patient presented to the emergency department (ED) with redness and swelling of the left (tattooed) arm, lips, and left cheek, approximately 6 h after, he had a black and white tattoo placed on his left forearm to cover up a tattoo he had received at least 30 years prior.[9]

The pathophysiological mechanism is thought to be a type 1 hypersensitivity, with reported positive reaction to several tattoo inks.[8] Patients may have had prior tattoos without adverse reactions, suggesting sensitization to the antigens. The reason the patients did not experience an ongoing reaction is not clear, and it is unlikely that a tolerance was acquired, as one patient had a similar reaction when another tattoo was applied 6 months later.[8] The sequestration of tattoo pigment in dermal fibroblasts may play a role in preventing an ongoing reaction.[10] Of note, it is important to recognize that various tattoo pigments contain different elements and chemical compounds, often in different proportions.[11] Commonly used tattoo pigments are listed in [Table 1].{Table 1}

All three anaphylactic episodes outlined above (two in the first patient[8] and one in the second patient[9]) were considered to be life-threatening TRCs and were treated successfully with combinations of H1 antagonists, glucocorticoids, lorazepam, and droperidol. Follow-up information was not given in either case report, so it is unclear if the tattoos caused further symptoms. As laser removal of tattoo ink has itself been associated with several cases of hypersensitivity reactions,[12],[13],[14],[15] surgical excision could be considered in this particular clinical scenario. Reactions to laser tattoo removal (LTR) are discussed in another section of this review.

Within the general context of this section, other types of more localized reactions include documented cutaneous responses to pigment materials such as henna.[16] Used mainly in the placement of temporary tattoos, this type of pigment can result in reactions of noticeable severity, not infrequently with a slight temporal delay.[17],[18] An example of a severe localized cutaneous reaction to traditional henna can be seen in [Figure 1].{Figure 1}

 Uveitis With Inflammation of Nonocular Tattoos (Without Signs of Systemic Sarcoidosis)



There are reports of unilateral or bilateral uveitis that occurs with simultaneous tattoo inflammation, and this is likely an underreported phenomenon.[19] Tattoo reactions can occur with uveitis in the setting of systemic sarcoidosis;[20] however, such cases are excluded from this section. Ocular complaints include pain[19],[21] and vision problems,[21],[22] and tattoo symptoms include pruritus,[23] redness,[23] and swelling.[19],[21] Some instances were severe enough to threaten vision.[19] Cases have occurred related to tattoos anywhere on the body,[19] with variable temporal relationship, from immediate posttattoo period[22] to years later.[21],[23] Most of the tattoo reactions were granulomatous (when biopsied),[19],[21],[24],[25] while most of the uveitides were nongranulomatous.[19] There is a confirmed case of nongranulomatous uveitis presenting with granulomatous tattoo inflammation.[19] A case of posterior uveitis with retinal vasculitis and cystoid macular edema was temporally attributed to tattoo placement in one case, but the evidence is largely circumstantial.[26]

Of importance, cases in this section occur without signs or symptoms of systemic sarcoidosis.[19],[21],[22],[23],[24],[25] The mechanism for simultaneous uveitis and tattoo inflammation is not known, although hypotheses include subclinical sarcoid[25] (e.g., ocular inflammation alongside tattoo inflammation in the presence of systemic sarcoid has also occurred[20],[27]) or a special granulomatous hypersensitivity to cobalt.[23],[24] However, this phenomenon has been observed in nonblue tattoo ink[19],[25] (cobalt is traditionally used as a blue pigment). Screening patients presenting with uveitis for tattoo-related symptoms is a quick and inexpensive way to identify this phenomenon,[22] and systemic sarcoidosis should be considered when this phenomenon is observed. Excision has been shown to result in resolution of the uveitis.[19],[21] If the tattoo is too large to remove, oral prednisone and immunosuppression have been shown to be efficacious in treating ocular inflammation, often with a simultaneous resolution of tattoo-related symptoms.[19]

 Complications of Ocular Tattoos



Cosmetic applications of the so-called “ocular tattoos” (OT) are relatively new and are sometimes referred to as “corneal” or “conjunctival” tattoos.[28] The goal of the procedure is to inject ink just beneath the conjunctiva at several sites without penetrating the sclera.[29] The ink then diffuses to uniformly alter the pigmentation of the sclera, without corneal involvement [Figure 2]a and [Figure 2]b.[30] Several cases of complications arising from OT were found in the medical literature.[28],[30],[31],[32],[33] Two cases presented with ocular inflammation and globe penetration,[31],[33] two with ocular inflammation without globe penetration,[30],[32] and two involved painless nodules that did not affect visual acuity.[28],[30] Cases were reported within several weeks of OT placement.{Figure 2}

Clinical management of inflammation and globe penetration comprises surgery to remove the injected dye, with concurrent control of the inflammatory response.[31],[33] Increased intraocular pressure may be present, with the potential for long-term sequelae including decreased visual acuity.[31] Patients with inflammation and no globe penetration were treated with steroids, antibiotics, and tropicamide and recovered well.[30],[32] One patient with painless nodules was diagnosed with episcleritis and treated with prednisone and moxifloxacin,[30] and another was monitored without active treatment, with no sequelae during 6-month follow-up.[28] Although the eye is a relatively uncommon site for tattoo placement, associated TRCs can be vision-threatening.[33]

 Complications Specific to Laser Tattoo Removal



The number of LTRs is increasing as the incidence of tattooing increases. Complications can include local pruritus,[34],[35] local urticaria,[36] generalized urticaria,[35] generalized eczema,[15] systemic allergic response,[13] inflammation of tattoos distant from the one being removed,[12],[37] lymphadenopathy with or without upper respiratory and constitutional symptoms,[14] an anaphylaxis-like systemic reaction with lack of peripheral eosinophilia,[12] fungal infection,[38] and darkening of the tattoo.[39],[40] Complications that are specifically thought to be due to suboptimal laser technique or aftercare include blistering, hypertrophic scarring, hypopigmentation, hyperpigmentation or depigmentation, keloid formation, and persistent erythema.[41],[42] Although not an adverse effect per se, treatment of nontattoo-pigmented lesions with a laser may confound the clinical examination and thus delay diagnosis (and treatment) of melanoma.[43]

Lasers are useful tools for removing tattoos, although different types of lasers have advantages and disadvantages. For example, CO2 lasers nonselectively ablate the skin and work well for many colors of tattoos, although frequently result in hypopigmented scarring.[44] On the other hand, Neodymium:yttrium aluminum garnet lasers, for example, work via selective photothermolysis of certain colors of tattoos and cause less damage to tissue but also do not always work for all colors. Proposed mechanisms for LTR-related inflammatory symptoms include release of tattoo pigment that was sequestered in fibroblasts, mast cells, and macrophages (and subsequent immune system exposure);[36] systemic distribution of released pigment particles;[15] and alteration of pigments to create new antigens.[36] Cases in which a distant tattoo develops symptoms[12],[37] support the first and second mechanisms, as mast cell lysis can cause systemic symptoms without singling out the distant tattoo, and sensitization of the immune system to neoantigens should not result in inflammation of a distant tattoo that does not contain these neoantigens. Finally, alexandrite laser[39] as well as Q-switched ruby,[40] Q-switched Nd:YAG,[40] and pulsed green dye[40] laser treatments have caused darkening of areolar tattoos. The mechanism is thought to involve iron dioxide[39],[40] and possibly titanium dioxide.[39]

Management of LTR reactions varies according to clinical presentation/extent of the problem. In mild cases limited to isolated lymphadenopathy, no specific treatment may be needed.[14] For more severe reactions, 3 days of prophylaxis with prednisone, cetirizine, and ranitidine has effectively prevented a local urticarial/erythematous reaction in at least one patient, although the cutaneous reactions resolved spontaneously shortly after the first two laser treatments, for which prophylaxis was not given.[36] A patient with evidence of a mild systemic inflammatory response did well following a 3-day course of oral prednisone but experienced a rebound anaphylaxis-like reaction that required treatment with epinephrine and intravenous (IV) corticosteroids in the ED.[12] Intralesional triamcinolone, topical clobetasol propionate, and oral diphenhydramine are usually sufficient to effectively manage nongeneralized pruritic reactions that extend beyond the tattoo.[34] Bullae resulting from LTR usually resolve after drainage.[41] To minimize the risk of complications, the laser as well as the spot size, fluence, and pulse duration should be selected based on the color of the tattoo pigment and the patient's skin.[6]

 Tattoo Complications Following Laser Hair Removal



Tattoo reactions to laser hair removal (LHR) over the site of the tattoo have been reported.[45],[46] Specific reported complications included keloid formation[45] and local burns.[46] The previous history of keloid formation was thought to be an important factor in new keloid formation.[45] Mechanistically, LHR is based on selective photothermolysis.[45],[46] The process is selective in that the laser only heats a target that absorbs light at a specific wavelength.[46] The melanin in the hair shaft allows the hair shaft to be targeted while sparing the surrounding tissue.[45],[46] However, if a tattoo pigment is present, the dye may compete for absorption of the light, heat up, and cause the skin to burn.[45] Fading of the tattoo after LHR procedure may occur.[45]

Management of the reported keloid comprised intralesional triamcinolone acetonide injections, resulting in improvement.[45] It was noted that post-LHR burns might result in an atrophic scar 6 months after the procedure.[46] To prevent the above occurrences, the best approach is avoidance of LHR over a tattoo.[45]

 Pseudolymphoma



Pseudolymphomas are uncommon benign lymphoproliferative disorders that mimic lymphomas histologically and clinically and have been reported in association with tattoos.[47],[48] Clinical presentation may include asymptomatic erythema,[49],[50] asymptomatic nodules or plaques,[51],[52],[53],[54],[55] pruritic erythema,[56] erythematous papules,[57] pruritic nodules or polypoid lesions,[58],[59],[60],[61],[62] pruritic plaques,[47],[63] indurated swelling,[64],[65] or photosensitivity.[50],[66] An example of a tattoo-associated pseudolymphoma is shown in [Figure 3]. Chronic presentation several decades following tattoo placement has been described, with localized pruritus and nodularity after infrared radiation exposure.[67] In another case, a light-induced reaction was noted involving yellow areas of a tattoo near a biopsy-confirmed pseudolymphoma.[55] At least one case of malignant transformation to lymphoma has been reported,[68] although the lesions were not restricted to the tattoo.{Figure 3}

Given the nonspecific clinical findings, biopsy is required in this uncommon setting. Microscopically, pseudolymphoma displays a dense lymphocytic infiltrate that may easily be confused with malignant lymphoma.[62] Although differentiation of pseudolymphoma from lymphoma can be difficult, evidence of polyclonality via immunohistochemistry or polymerase chain reaction (PCR) suggests the former.[63],[69] The etiology of pseudolymphoma occurring in a tattoo is not completely known, although it is likely not completely attributable to mercury, as pseudolymphomas have been reported in colors other than red (the usual tattoo ink color that may contain mercury).[49],[51],[54],[56],[66] Various treatment options have been attempted for tattoo-associated pseudolymphomas, with full excision being the recommended treatment.[66] Laser removal has been shown to be effective,[28],[67] although adverse effects of LTR are possible.[12],[13],[14],[15]

 Tattoo-Related Granulomatous Reactions



Granulomas can be defined as “relatively discrete collections of histiocytes or epithelioid histiocytes with variable numbers of admixed multinucleate giant cells of varying types and other inflammatory cells.”[70] Granulomatous tattoo reactions (GTRs) can be difficult to diagnose because the differential diagnosis is long, and many of the diagnoses have overlapping clinical and histologic findings. The patient may present with a variety of nonspecific signs/symptoms [Table 2] after a variable amount of time.[71] This often necessitates a biopsy for a definitive diagnosis. Top diagnoses include foreign body granulomatous reaction, allergic/hypersensitivity granulomatous reaction, sarcoidosis, granuloma annulare (GA), necrobiosis lipoidica (NL), and infection.{Table 2}

Granulomas caused by sarcoidosis, foreign body granulomas, and allergic/hypersensitivity granulomas can be challenging to distinguish. It is difficult to histologically differentiate a foreign body granuloma from a granuloma of sarcoidosis,[25],[85],[93],[102],[109],[115],[116] especially because there is some degree of overlap[117],[118],[119],[120] and foreign bodies are expected to be present in tattoos.[3] It is similarly difficult to differentiate a granuloma caused by sarcoidosis from an allergic/hypersensitivity granuloma[115],[121] with low reliability of patch testing.[85],[121] Diagnosis of sarcoidosis can also include extracutaneous findings and should not be made based solely on a single granulomatous lesion on biopsy, such as that of a tattoo.[103],[109],[122] A clear chest X-ray does not rule out sarcoidosis, and angiotensin-converting enzyme levels are not sufficiently accurate.[123],[124]

The all-encompassing term “cutaneous sarcoidosis” represents a heterogeneous group of conditions. Consequently, the reader should be aware of the vastness of this important topic and should consider our subsequent discussions within the appropriate clinical context relevant to this review.[70],[81],[88],[96],[118],[125],[126]

 Sarcoid-Like Granulomatous Disease of Unknown Significance



Cases of GTRs may occur without clear evidence of systemic sarcoidosis, either because the workup was negative or not performed.[3],[71],[72],[73],[74],[76],[77],[78],[80],[85],[86],[89],[90],[91],[92],[95],[97],[101],[108],[111],[112],[115] [Table 3] lists some of the terms related to GTRs, as reported in the literature.{Table 3}

The diagnosis of GTR will generally be made after a biopsy is performed of the involved cutaneous area. As previously outlined, GTRs should raise suspicion of underlying systemic sarcoidosis[71],[127] or an infectious etiology,[70] and these entities, as well as GA and NL, should be considered before a tattoo reaction is diagnosed as a “sarcoid-like granulomatous disease of unknown significance.”[25],[85],[93],[95],[105],[109],[115],[116],[117],[118],[119],[120] Hypothesized mechanisms of granuloma formation are not fully understood, and include altered immune response, retention of a foreign substance, altered neural signaling, or a combination thereof.[128] Interestingly, tattooing with red poster paint comprising monoazopigments in a Danish prison reliably caused pruritic lesions whose histology was compatible with sarcoidosis.[86] Long-term follow-up would be necessary to determine if the cases of GTRs that occur without signs or symptoms of systemic sarcoidosis are truly independent of systemic sarcoidosis, or merely the initial overt manifestation of otherwise subclinical systemic sarcoidosis.[85],[102]

A variety of treatments have been tried in the setting of GTR [Table 4], with varying degrees of success. LTR may cause a significant reaction,[12],[13],[14],[15] especially in a patient demonstrating a previous negative reaction to tattoo pigment.[3] Of note, spontaneous resolution following punch biopsy has been observed.[95],[108]{Table 4}

 Sarcoidosis Associated With Tattoo Placement



According to the American Thoracic Society and European Respiratory Society, “Sarcoidosis is a systemic granulomatous disease that primarily affects the lung and lymphatic systems of the body.”[124],[132],[133],[134] Cutaneous manifestations of systemic sarcoidosis are common, affecting approximately 15%–25% of all sarcoidosis patients and having a variety of presentations.[124],[132],[133],[134] The most common presentations of sarcoidosis involving tattoos include nodules, plaques, papules, or infiltrates that were sometimes scaly but usually not painful.[102] Tattoo sarcoidosis does not appear to be an all-or-nothing phenomenon, as there have been cases, in which all tattoos[82] or only certain colors of a tattoo[27],[84],[87],[98],[114],[135] were affected. Tattoo granuloma may or may not be the only cutaneous sign of sarcoidosis,[20],[82],[87],[104],[107],[109],[136] as there may be extracutaneous or constitutional symptoms as well.[20],[27],[82],[83],[84],[94],[102],[107],[109],[132],[136],[137] The time between tattooing and clinical presentation is highly variable, with some authors reporting a range of 1–10 years,[94] while others describing lag times as long as 30–40 years.[103],[104]

The mechanism of sarcoidosis is unknown, but there are many hypotheses about why it may manifest in the setting of tattoos.[20],[94],[98],[103] One is that foreign bodies such as tattoo ink may serve as inciting factors for granuloma formation.[82],[98],[107],[109],[103] Sarcoidosis manifesting within a tattoo may also represent “scar sarcoidosis,”[20],[98] which tends to occur at sites of old injury (e.g., surgical scars or tattoos).[134],[135] The so-called Koebner response (e.g., the appearance of skin lesions within lines of trauma) is yet another possibility.[20],[98]

There is no formal therapeutic recommendation for this phenomenon, and various treatment regimens have been described.[75],[83],[94],[102],[103],[104],[105],[106],[107],[109],[113],[136],[138] Systemic corticosteroid treatment has demonstrated effectiveness in nearly 79% of patients and failed in only 7% of cases.[75],[83],[94],[102],[103],[104],[105],[106],[107],[109],[113],[136],[138] Interestingly, simultaneous spontaneous resolution of the tattoo lesions and the pulmonary radiographical findings have been observed.[105]

 Granuloma Annulare



GA occurring at the site of tattoos is well described,[78],[129],[131],[139],[140] in addition to cutaneous reactions that are considered to be GA-like.[141],[142],[143],[144] Symptomatically, GA tattoo reactions are similar to the aforementioned GTRs[129],[141],[142] but are histologically distinct (e.g., the presence of necrobiotic reaction).[70],[129],[131],[141] In general, GA lesions may have the tendency to bleed.[131],[140] Although the exact mechanism underlying GA is unknown, these lesions can be triggered by a variety of events including insect bites, trauma, warts, conditions (e.g., diabetes, human immunodeficiency virus [HIV], etc.), and medications,[70] in addition to tattoos. Although the main trigger for GA is thought to be trauma,[143] the prevailing theory for the mechanism of GA formation in tattoos is a delayed hypersensitivity involving the pigment or another chemical in the ink.[129],[131],[139],[140],[141],[142] Sparing of certain ink colors supports this theory.[143]

Treatment modalities include butyrate hydrocortisone cream (transient relief but relapse after treatment disruption),[129] clobetasol dipropionate (unknown effect and patient lost to follow-up),[128] clobetasol propionate (some improvement),[131] intralesional Kenalog and topical steroids (unsuccessful),[140] and resection (successful with no recurrence or scar complication).[140] Additional workup to rule out sarcoidosis and fungal or mycobacterial causes should be undertaken.[144]

 Necrobiosis Lipoidica



NL is a noninfectious palisading granulomatous disease that manifests clinically as atrophic yellowish plaques with erythematous edges and can progress to sclerosis and ulceration.[145] NL has been reported in the setting of tattoo,[81],[145],[146] including a case that the authors refer to as an “NL-like tattoo reaction.”[81] The other case presented as more classic NL, with atrophic yellowish patches[146] or plaques[145] and erythema. Delayed onset after tattoo can range from several weeks to 3.5 years, with possible predisposition for women in the third decade of life.[81],[145],[146] The etiology of NL is not known, although it is more common in patients with diabetes.[145] The association between the tattoo and NL may be hypersensitivity or related to Koebnerization, with the former being favored.[81] In terms of management, various strategies have been described, from antibiotics to surgical excision[81] and the intralesional application of triamcinolone acetonide and topical betamethasone valerate.[145],[146]

 Uncategorized Necrotizing Granulomatous Reactions



There have been several reported cases of necrotizing granulomatous reactions that did not fit neatly into any other category.[88],[96],[147] These presented with scaly plaques/crusts,[147] or painful, ulcerated lesions[88],[96] at the site of the tattoos. One patient's reaction occurred only on the red tattoo areas on the arm and leg within a year of tattoo placement.[147] Another occurred on the eyelids nearly 10 years after cosmetic tattoo placement[96] and was refractory to multiple therapies, while the third occurred on the wrist after an unknown amount of time.[88] Proposed etiologic factors have varied from “reaction to red ink”[147] to “allergic granulomatous reaction to blepharopigmentation,”[96] to a reaction associated with the use of undiluted phosphorescent pigment not intended for use in humans as tattoo ink.[88],[96],[147],[148] Reported treatment approaches include excision,[147] triamcinolone acetonide injections,[96] a combination of both of these modalities.[88]

 Infectious Granulomas in the Setting of Tattoo Placement



When inoculated into the skin with a needle, mycobacteria species can infect tattoos and cause granulomatous reactions. The presentation varies but often takes the form of an erythematous, pruritic, popular, or pustular rash over a recent tattoo[149],[150] with or without constitutional symptoms.[151],[152],[153],[154],[155],[156],[157],[158],[159],[160],[161],[162] Asymptomatic presentations have also been described.[155],[160] Diagnosis is usually made on biopsy and may be delayed due to the ambiguity of these lesions.[149],[153],[154],[155],[157],[158],[159],[160],[163],[164] As mycobacterial infections can present without granulomas or acid-fast bacilli on histology,[153],[154],[165] it is important to perform testing for mycobacteria specifically, with DNA sequencing being the most sensitive testing method.[153],[155],[166] High clinical suspicion combined with epidemiological evidence is needed to make a diagnosis.[160] The source of infection varies, but the main reservoir of nontuberculosis mycobacteria (NTM) is considered to be tap water.[154] This may explain the association between black[156] or gray tattoos[151],[152],[153],[154],[155],[157],[158],[165] and mycobacterial outbreaks, as black ink is often diluted with tap water.[153],[154],[155],[156],[157],[158],[165],[167]

Mycobacterium chelonae appears to be the most common NTM tattoo infection, with nearly 100 cases reported in the literature.[150],[151],[153],[154],[155],[156],[157],[158],[165],[167],[168],[169],[170]M. chelonae has also been implicated in “outbreaks” of tattoo infections[153],[154],[155],[156],[157],[158],[165],[167] and has been found in contaminated tattoo inks, likely related to impure water supply.[153] Kennedy et al. described successful treatment of M. chelonae with empiric macrolides.[153] Other strategies, such as “watch and wait”[157],[165] or clarithromycin monotherapy,[165] have also been successful.[151],[154],[156],[167],[169]

Other nonlepromatous, NTM infections described in association with tattoos include M. abscessus,[168],[171],[172],[173],[174],[175]Mycobacterium fortuitum,[159],[163]Mycobacterium immunogenum,[164]Mycobacterium haemophilum,[160],[166],[176] and Mycobacterium franklinii.[177] In some cases, the exact species of mycobacteria could not be determined.[178],[179],[180],[181] Reported antibiotic regimens have varied; typically, empiric treatment is initiated and then modified based on specific susceptibility data. Permanent makeup tattoos tended to present with lymphadenopathy,[176],[178] and in one outbreak, abscesses and fistulae.[176] Most patients with abscesses and/or fistulae underwent surgical intervention, with good clinical and cosmetic results.

 Tuberculosis Tattoo Infection



Mycobacterium tuberculosis tattoo infection (MTTI) is an uncommon occurrence, with cases reported as far back as 1895.[182] The presentation is nonspecific like the aforementioned NTM infections, with ulceration,[182] plaques,[183] and/or pustules.[184] There may be no constitutional symptoms or a personal or family history of M. tuberculosis infection (MTI). Lymphadenopathy can occur with MTI.[184],[185]

Cases of MTTI were reported at the turn of the 20th century[184] and were attributed to a patient with advanced pulmonary tuberculosis (TB) who tattooed others using ink he made from his saliva and India ink.[182] Another case presented with papules involving areas of a tattoo that had been touched-up about 22 months prior.[183] A significant proportion of contemporary published cases of MTTI occurred in India, where TB is endemic and tattoo artists occasionally use saliva to moisten the pigment/needle during the procedure and use the same needles for multiple clients.[186],[187],[188] In 1985, a case occurred in the United States, where the prison inmate placing the tattoo had sputum culture-confirmed active pulmonary MTI, so a similar route of transmission is suggested but not confirmed.[185] Finally, one case reported in Singapore involved a commercial tattoo parlor, with unknown route of infection.[189]

The epidemiology of MTTI differs from other NTM tattoo infections in that the reservoir of M. tuberculosis is humans, not tap water or the environment. The primary route of tattoo inoculation is thought to be saliva.[184],[185],[187],[188] Transmission through soil that is sometimes applied to the tattoo after its placement (for presumed antiseptic properties) has also been proposed as a source for TB, although this seems less likely than person-to-person transmission.[190] Several approaches to MTTI management have been described, including X-ray therapy,[183] rifampicin, isoniazid ethambutol, and pyrazinamide.[186],[187] Other authors generically mention good response to “standard antitubercular treatment.”[188]

 Lepromatous Tattoo Infection



Tattoo-related leprosy (TRL) has been reported as early as 1939[191] and usually presents with some combination of a hypopigmented/discolored[192],[193],[194] or erythematous[87],[194],[195],[196],[197] lesion involving the tattoo, hypoesthesia/anesthesia over the lesion,[192],[193],[195],[196],[197] nearby neuropathy (sensory/motor/paresthesia),[87],[193] and thickening of a nearby nerve.[191],[193],[194],[195],[196],[197] Time from tattooing to onset of symptoms can range from 5 months[197] to >50 years.[195] Most described cases are paucibacillary, while a few are multibacillary.[191] Lepromin reactions are often positive.[193],[195] Pathology showed granulomas with or without caseation/necrosis.[87],[192],[193],[195] Acid-fast bacilli are usually seen.[87],[191],[192],[193],[195],[196],[197]Mycobacterium leprae DNA can be detected on a diagnostic biopsy.[87] Upgrading reactions have been noted;[195],[197] one patient presented initially with an upgrading reaction[195] while another experienced upgrading after starting leprosy therapy.[197] In one case, leprosy manifested on a previously asymptomatic tattoo that had been placed 2 years prior when the patient was treated for MTI.[87] It was theorized that this was a HIV-negative immune reconstitution syndrome that occurs upon initiation of TB treatment. The prevailing theory of transmission in TRL is direct inoculation by unsterile needles, similar to the method of transmission for cutaneous TB tattoo infection. Many cases occurred in India, where needle sterilization is sometimes lacking. Successful treatments include dapsone/rifampicin,[191],[196] dapsone/rifampicin/clofazimine for multibacillary leprosy and one upgrading reaction,[191],[195] and dapsone/rifampicin/prednisone for other upgrading reaction.[197] Clofazimine/minocycline/ofloxacin with prednisolone for accompanying ulnar neuropathy was also reported.[87]

 Neoplasms in the Setting of Tattoo



The key question surrounding tattoos and neoplasms of the skin revolves around potential causality. There are insufficient data to evaluate the frequency of neoplasms on tattoos, so causality (or lack thereof) is inferred via biologic plausibility and the occurrence of unique presentations that are extraordinarily unlikely to occur by chance. Theorized mechanisms by which tattoos could contribute to neoplasm initiation/propagation include trauma via needle puncture,[94],[132],[198],[199],[200],[201],[202],[203],[204],[205],[206],[207],[208],[209] injection of carcinogenic chemicals,[132],[202],[205],[206],[208],[210],[211] altered absorption of UV rays,[203],[209] and a chronic local inflammatory state.[94],[110],[198],[200],[202],[205],[211],[212],[213],[214],[215] Although there is no proof for any particular type of neoplasm, causality seems more likely in some variants than others. Here, we will discuss the best available knowledge regarding tattoo association with neoplasms in the following order: basal cell carcinoma (BCC)/melanoma, keratoacanthoma (KA)/pseudoepitheliomatous hyperplasia (PEH), and squamous cell carcinoma (SCC). Isolated cases of leiomyosarcoma, dermatofibrosarcoma protuberans (DFSP), cutaneous lymphoma, and dermatofibroma (DF) will be reviewed as well.

 Basal Cell Carcinoma and Melanoma



There are limited data to link tattoo creation with BCC or melanoma,[119],[202],[203],[204],[205],[206],[207],[214],[216],[217],[218],[219],[220],[221],[222],[223],[224],[225],[226],[227],[228],[229] with no evidence of linkage between said cancers and tattoos.[217] The presenting lesions tend to be typical for the type of cancer, generally do not follow the contours of the tattoo, and are only present on part of the tattoo. The time between tattooing and presentation varies from months to many years.[230] Thus, the occurrence of BCC/melanoma on a tattoo is usually considered to be coincidental.[202],[207],[208],[210],[218],[223],[227] The occurrence of skin cancer in locations that are not exposed to the sun[203],[217] and the occurrence in younger patients[203] does increase suspicion, but certainly does not prove causation. In one case, a patient presented with four melanomatous lesions on his chest, all within the red ink of a tattoo.[214] Biopsies showed a primary melanoma and three metastases, which the authors suggest could be due to seeding of the red ink after the tattoo artist tattooed over what was to become the primary tumor and dipped the needle back into the ink.

Independent of causality, tattoos certainly present a challenge in terms of early detection of melanoma.[57],[119],[220],[222],[223],[226],[228] The tattoo pattern and design distract from the possible presence of a lesion, and dark ink may make detection of changes difficult.[206],[208],[210] Dark ink may also confound the histopathology or clinical appearance of a lymph node that has been biopsied to evaluate for the presence of melanoma[222],[226],[231],[232],[233],[234],[235],[236],[237],[238] or other cancers.[239],[240],[241] Of note, confounding of mammography due to tattoo pigment has also occurred.[240],[242]

 Keratoacanthoma and Pseudoepitheliomatous Hyperplasia



Due to a lack of consensus on distinguishing criteria of PEH [KA, [Figure 4]] and SCC,[243] there is a variety of ways to break these entities up for review. Since SCC is the one that is generally agreed to be malignant, we have chosen to review it separately from KA and PEH. KA is being reviewed with PEH because the two behave very similarly to each other,[211] both clinically[244] and histologically.[132],[200],[212],[243],[244],[245],[246],[247],[248],[249] Differentiating KA and PEH from each other can be difficult.[132],[200],[212],[245],[250] They both present within a few months of tattoo placement as a papule,[118],[198],[245],[251] nodule,[199],[200],[212],[213],[249],[251],[252],[253] or plaque,[212],[244],[246],[247],[248],[251] that is, sometimes scaly[213],[246],[251] or verrucous.[198],[200],[212],[244],[250],[252],[254] Ulceration[200] and tenderness[200],[244],[246],[247] have been noted in PEH. Pruritus has been noted in KA and PEH.[200],[212],[213],[246],[247],[248],[250],[251],[252] The lesion generally follows the contours of the tattoo[212],[244] or a certain color.[132],[200],[201],[212],[243],[246],[247],[248],[250],[251],[254] Since these lesions are symptomatically and clinically nonspecific, biopsy is required to make a diagnosis.{Figure 4}

KA/PEH can appear histologically[132],[200],[212],[213],[244],[247],[249] and clinically[132],[200],[201],[212],[213] similar to SCC and other pathologies such as lichen planus,[212] mycobacterial,[244] or fungal[213] infection. In fact, KA and PEH are histologically similar to the point that it has been hypothesized that they are a single entity or exist on a spectrum of reactive squamous proliferation.[255] Thus, differentiating them is beyond the scope of this review. Clinically, KA[110],[211] and PEH tend to occur within a year of tattoo placement,[110] while SCC tends to occur years later.[256] The strong tendency for KA/PEH to follow the contour of or stay within the border of a tattoo suggest a causal relationship.[199] In summary, the pathogenesis of KA/PEH is not fully understood, although hypotheses include hypersensitivity,[198] viral involvement,[118],[132],[199],[247],[253] and immunosuppression.[132],[199] Chronic wounds[253] and inflammation[253],[255] have been implicated in the pathogenesis of PEH.

 Squamous Cell Carcinoma



There are several cases of SCC that present similarly to KA/PEH, following the contours[256] or presenting with multiple lesions in the same tattoo.[94],[215],[257] However, there are also cases that present in a manner similar to BCC/melanoma,[215],[258] without clear preference for the contours or border of the tattoo. The SCCs that presented similarly to KA/PEH also presented in a similar time frame,[256],[257] months as opposed to years as for SCCs that are dissimilar from KA/PEH.[110],[215] Schmitz et al.[259] proposed a relationship between KA, PEH, and some forms of SCC. We hypothesize that some forms of SCC share common causative factors and pathological traits with KA/PEH, explaining the cases of SCC that present in the manner of KA/PEH. Two cases of SCC and KA developing in the same tattoo[94],[215] support the theory that there may be a common developmental pathway. The cases of SCC that presented differently from KA/PEH were likely forms of SCC that developed via a different pathway than KA/PEH.[110]

 Cutaneous Leiomyosarcoma



Only one case of cutaneous leiomyosarcoma associated with a tattoo has been described.[209] It involved a 41-year-old male who had a lump under a 10-year-old, black-and-red tattoo removed by his family physician, with subsequent pathological determination of cutaneous leiomyosarcoma. Wide excision with clean margins was performed.

 Dermatofibrosarcoma Protuberans



The only case of DFSP occurring on a tattoo involved a 35-year-old male who presented after a 7-year history of a slowly enlarging mass under a tattoo which had been placed a year before he noticed the mass.[260] Local excision of the mass was carried out, with subsequent re-excision featuring 4-cm margins performed after the pathology report indicated DFSP.[260] Given the rarity of DFSP, causation is not provable.

 Primary Cutaneous Non-Hodgkin Lymphoma



In an interesting case, a 32-year-old male reported a 2-year history of intermittent bumps under the red part of a tattoo that had been placed 17 years earlier.[261] There was improvement with topical steroids, but one bump persisted and grew, prompting surgical excision. Subsequent histological evaluation showed “histiocytic lymphoma.” The authors of the report hypothesized that chronic dermatitis may have played a role in the development of the tumor.[261] Mercury was sometimes used in red pigments at this time, which is known to cause chronic dermatitis. Given very limited evidence, any causation is questionable at best.[56]

 Dermatofibroma



DF is a benign scar-like proliferative lesion of unknown etiology.[262] DFs have been known to occur on tattoos, usually within 2 years of placement. DF tends to be nodular and may be asymptomatic[263] or tender.[262],[264] The lesions can be red in color,[262],[264] with some being mobile.[262],[264] The pathogenesis of DF is controversial, and the two prevailing theories are that it is a fibrosing postinflammatory reactive change, or that it is a benign neoplasm.[263] It has been associated with trauma.[262],[264] DFs are considered benign, although metastases have rarely occurred.[263] Histology is important to rule out malignancy, as the differential includes DFSP and BCC.[265] Surgical excision is usually curative[265] and has been shown to be effective in cases of DF on tattoo.[264]

 Tinea and Other Fungal Infections



Tinea on tattoo presents as a scaly erythematous plaque with vesiculopustular borders and central clearing that is usually pruritic. Literature reports suggest the occurrence of this fungal infection within a month of tattoo placement.[2],[266] Immunosuppression may be associated with the appearance of tinea over a longer time frame (e.g., several years).[267] Tinea is known to be spread by direct contact, and a likely source of infection can usually be identified.[266] In all cases, the vulnerability of the skin from barrier disruption or immunosuppression likely allowed these fungi to spread from nearby sources and infect the skin of the tattoo. Microscopic examination of scrapings from the lesion or a fungal culture is used to make the diagnosis. The causative organisms have been identified as Microsporum canis[266] or Trichophyton tonsurans.[2] Treatment involves discontinuation of any immunosuppressants (when possible) and administration of either or both topical and oral antifungals such as ketoconazole cream and oral terbinafine.[266],[267]

Fungal infections at tattoo sites have been described,[268],[269],[270] including a case of fungal eye infection thought to be related to a tattoo.[271] One instance of a “homemade” tattoo involved the appearance of necrotic Aspergillus fumigatus papules within a month of placement.[268] In another case, a ritual Samoan tattoo developed nodular lesions containing Sporothrix schenckii within 3 weeks of placement.[270] A third patient developed an ulcerative lesion 7 years after tattoo placement (zygomycosis from Saksenaea vasiformis).[269] Finally, another patient developed candida endophthalmitis presenting with decreased visual acuity within a week of tattooing.[271] Of note, the latter case (candida endophthalmitis) occurred 4 days after a tattoo was placed in an asplenic patient.

All patients in the aforementioned cases were able to clear their infections. The A. fumigatus was treated uneventfully with oral voriconazole and local terbinafine,[268] while the Sporothrix was treated successfully with itraconazole.[270] The zygomycosis showed improvement with potassium iodide. Amphotericin B given as an outpatient three times a week for several months was curative.[269] The patient with candida endophthalmitis responded well to amphotericin B after diagnostic vitrectomy.

In summary, it is reasonable to suggest that proper aseptic technique during tattooing and proper wound care would significantly lower the risk of these infections. In the asplenic patient, antimicrobial prophylaxis could be considered, although this would require that a detailed medical history be taken before embarking on tattoo placement. Education of asplenic patients and other key stakeholders to this possible occurrence could prevent a delay in diagnosis and treatment of a sight-threatening infection. Finally, aspergillosis infection associated with LTR has been described,[38] with the hypothetical mechanism involving the creation of microscopic skin defects that served as a portal of entry for the fungus.

 Viral Infections



Hepatitis B

Hepatitis B (HB) has been referred to as “serum hepatitis,” long-incubation hepatitis, or Australia/hepatitis-associated antigen hepatitis.[272] The incubation time is around 50–150 days,[273] and presentation involves jaundice and malaise typical of this disease. Although local tattoo reactions were not reported, evidence of causality includes biological plausibility,[274] case series,[273],[274],[275],[276] and epidemiologic studies.[274],[277] HB is known to be transmissible by very small amounts of blood[274],[278] and tattoo shops in the mid-20th century were known to share needles and ink between clients.[273],[274],[278],[279] Outbreaks of HB have been associated with single tattoo shops[273],[275],[276],[278],[279],[280],[281] making the diagnosis challenging or even a single tattoo shop on a single day.[278],[280],[282] Given the parenteral nature of HB transmission, tattoo transmission seems the most likely explanation for this correlation.[283]

In one report, an outbreak of HB was traced to an acupuncture facility, supporting the hypothesis that small amounts of blood on needles can transmit the virus.[284] Several epidemiologic studies supported a correlation between tattooing and HB.[274],[277] However, the propensity for some individuals who get tattoos to engage in other high-risk activities may be a confounder[285] that was only occasionally accounted for.[274],[277],[286] One case–control series suggesting no increased risk of chronic viral hepatitis[287] excluded patients with a known history of viral hepatitis or liver disease, weakening the study.[285]

The vast majority of patients survive symptomatic HB infection,[280] and there is no treatment specific to tattoo-acquired HB. With prevention being the best approach, the parenteral nature of transmission suggests that using sterile, patient-specific tattoo needles and ink would prevent transmission via tattooing. Options for ensuring sterility include using disposable equipment[283] or intense sterilization.[280] Given that HB is difficult to destroy,[273],[278] disposable materials would likely be the safer option.

Hepatitis C

Hepatitis C (HC) was formally known as non-A non-B hepatitis,[288] and the presentation tends to be similar to HB, although the symptoms may present sooner.[289] HC is more frequently asymptomatic than HB,[289] and its transmission by tattoo may be more likely to result in subclinical or occult infection compared to IV drug use (IVDU) transmission.[290] Tattoo reactions were not noted in cases of HC that were thought to be acquired via tattooing.

The transmission of HC is parenteral[291] and can theoretically be transmitted via the same mechanism as HB. However, likely due to the greater tendency to remain asymptomatic and result in chronic infection, case reports linked to a single tattoo shop are less common.[292] HC from tattoos is thought to be less likely to result in acute hepatitis due to the presumably lower viral load than HC acquired via IVDU.[290] Isolated case reports linking unsafe tattooing to HC do suggest causality.[293] Most of the evidence connecting tattooing to HC is epidemiological,[168],[185],[288],[291],[294],[295],[296] however, often relying on sample testing and not clinical presentation to discover cases. The improvements in the hygiene of tattooing[291] would apply only to regulated legitimate tattooing studios, which explains why receiving a tattoo in prison or by a nonprofessional may confer a higher risk for HC.[168],[291],[297],[298] This also explains the low number of case reports, as tracing the source of an outbreak to an illegitimate tattoo artist would be challenging. Tattooing was often shown to be a risk factor even when a history of IVDU was excluded.[294],[295],[297]

Although treatments exist for HC, prevention is preferable. Given that HC contributes to significant overall infectious disease mortality,[299] improvement must be made on slowing the spread of this disease. At a population level, enforcement of proper hygiene and improving screening for populations at risk could be beneficial.[297] Educational initiatives aimed at individuals should discourage being tattooed by anyone other than a professional tattooist.

Human immunodeficiency virus infection

It is theoretically possible to transmit HIV via tattooing from infected needles or ink.[4],[6],[300] Epidemiologic studies disagree over whether tattooing is a risk factor for HIV, although most suggest that it is not.[4],[300],[301],[302] It is difficult to determine if tattooing acts as a surrogate for high-risk activity as there are many confounders.[301] Looking at case reports of prisoners who allegedly contracted HIV due to tattooing, the evidence is largely circumstantial and does not fully consider other risk behaviors.[197] A case report of HIV transmission by acupuncture suggests that tattooing is a plausible mechanism.[195],[303] The paucity of case reports describing HIV transmission is likely due to increased tattoo safety in professional parlors. Unregulated tattooists are unlikely to submit reports of complication or infection. Furthermore, HIV's lower infectivity relative to HC may explain the lack of epidemiologic support for this method of transmission.[6] In summary, while HIV transmission via tattooing is theoretically possible and may rarely occur, it is likely not an epidemiologically significant mode of transmission.

Herpes

Herpes simplex virus (HSV) has been identified in tattoos, both clinically[304] and with PCR.[305],[306] The symptoms start 2–3 days after tattooing as a painful erythematous rash.[304],[305],[306] One case was not limited to the tattoo in a patient whose history of herpes is unknown.[305] A patient with a known history of herpes labialis experienced an attack of herpes labialis much more severe than usual after cosmetic lip tattooing.[304] Another patient with no previous HSV history presented with herpes confined to the tattoo.[306]

There is disagreement over the mechanism behind HSV infection of a fresh tattoo[305] and given the different presentations, different mechanisms could explain different cases. Possible mechanisms include contamination of the tattooing needle,[304],[306] superinfection of a fresh wound,[305],[306] and a local altered immune response.[307] Regarding a case of a tattoo with no previous herpes history, needle contamination from herpetic whitlow or an unnoticed herpetic lesion on the patient that was tattooed over could help explain the distribution of lesions. Superinfection could also explain this, but only if the entire area was exposed. Of note, all of the above cases experienced resolution of their symptoms with valaciclovir[305] or famciclovir.[306] In addition to reiterating the importance of sterile technique, these case reports highlight the possibility of tattooing as a potential trigger in patients with a history of HSV, raising the possibility of potential benefit to preprocedure prophylaxis.

Molluscum contagiosum

Molluscum contagiosum (MC) is a viral infection caused by a poxvirus that is transmitted by direct contact.[308] It presents similarly to verrucae; both often present as multiple asymptomatic papules restricted to a tattoo. The symptomatic presentation has occurred.[309] Unlike verrucae, MC is often umbilicated.[309],[310],[311],[312] Presentation occurs weeks[308],[313],[314] to months[310],[311],[315] after tattooing, and diagnosis is confirmed by biopsy.

Possible mechanisms of transmission include contamination of the instruments used for tattooing[308],[309],[313],[314],[316] or the ink,[308],[309],[311],[313] or reduction in immunity from the ink.[309] A Koebner[316] or pseudo-Koebner[309] response may be involved in the development of these lesions. As with verrucae, the presence of lesions on only one of several colors in a tattoo[310],[311],[315] suggests an effect of that specific ink and not just an effect of trauma, which would affect multiple colors. One case involved a patient whose tattoo had been applied in stages, with the MC-affected color being done all at once, separately from the rest of the tattoo.[311] In this case, it was possible that inoculation occurred due to contamination that was only present on that occasion.

Treatments for MC include destructive (most common), immunomodulatory, and antiviral interventions,[314] although most MC papules will resolve without treatment.[310] Specifically referring to tattoo-associated MC, curettage has been effective.[309],[314],[316]

Verrucae

Verrucae have been reported in association with tattoos in various patterns. The presentation usually consists of papules[317],[318],[319],[320],[321],[322],[323],[324],[325] that are often asymptomatic[317],[320],[326] and stay within the borders of a tattoo.[317],[327] In some cases, involvement is limited to a single color within the tattoo,[319],[321],[325],[328],[329],[330] or follows a line of the tattoo.[324],[331] Incubation time can be months[320],[323],[324],[325],[329] to years.[224],[317],[319],[321],[324],[327],[328] Presentations include both verrucae plana[224],[320],[322] and verrucae vulgaris.[317],[318],[319],[321],[323],[324],[325],[330] Diagnosis is clinical, with the support of histology if necessary. It can be challenging to differentiate HPV verrucae from seborrheic keratosis [SK, [Figure 5]] clinically.[329] PCR to characterize/confirm the type of HPV is performed less commonly.{Figure 5}

Possible mechanisms for this include contamination of the tattooing equipment or ink;[317],[318],[319],[320],[322],[324],[325],[330] contamination via the artist's saliva;[224],[322],[324],[325] direct inoculation of viruses already present on the skin or in a hair follicle;[224],[318],[322],[323],[324],[329],[330] reactivation of latent virus;[327],[329] or immune modulation that lowers the local ability to fight infection.[326],[328],[332] Similarly, a Koebner[317],[320] or pseudo-Koebner[326] response has been proposed. Cases of warts appearing within one tattoo color but not others suggest contamination or an immunomodulatory effect specific to that ink, while warts on multiple colors support the theory of traumatic induction/immunomodulation. Delayed onset has occurred after sunburn, thought to be due to immune modulation by UV light,[327] as well as postpartum from pregnancy-associated immunosuppression.[319] One case appeared in a patient with known discoid lupus erythematosus.[323] Causative agents include HPV 27,[317] 47,[224] and 6B.[328]

Treatments include curettage,[325],[328] topical imiquimod alone[317],[318],[322] or with tretinoin,[320] cryotherapy,[321],[323],[324] local treatment such as retinoid[329] or fluorouracil,[329] and electrocautery.[326] Primary prevention consists of ensuring that the tattooing materials and skin are both free of contamination.[326] This includes not tattooing over any lesions which could lead to more widespread viral verrucae throughout the tattoo.

 Bacterial Infections: Syphilis



Syphilis can be transmitted in association with tattoo placement in one of two ways – with the tattoo being the primary inoculation site or as a localization site for the lesions of secondary syphilis.[4] Syphilis can be transmitted through the saliva of the tattooist.[8],[333],[334] This was prevalent in the 19th century, when artists frequently exposed the tattoo and/or the needle to their saliva,[303] such as to mix with dried pigments to create ink or to wipe away blood or excess ink.[335] Affected patients would develop one or more chancres typical of primary syphilis at the tattoo site within days to months before progressing to systemic signs/symptoms of syphilis.[4],[336] Patients with tattoos and syphilis (even if tattooing was not the inoculation site) can develop lesions characteristic of secondary syphilis[112] or even gumma localized to their tattoos.[4],[333]

Syphilis is inoculated via tattooing by breaking the skin barrier and providing Treponema access. Epidemiologically, several outbreaks of syphilis in the past have been traced to individual tattoo artists who used saliva during the tattooing process.[336],[337],[338] The lesions of secondary syphilis are thought to localize to tattoos due to a decreased immune response,[336],[339] perhaps as a result of chronic inflammation or injury.[4] This could be the result of a Koebner response which is thought to be associated with other TRCs. Of interest, the lesions on tattoos may spare the red areas, likely due to the antisyphilitic properties of mercury[4],[7],[333],[336],[339] which was a commonly used pigment in red tattoo ink before its concentration was limited to 3 ppm by the U.S. Food and Drug Administration.[76] Due to increased awareness and the adoption of aseptic techniques, transmission of syphilis by tattooing is much less frequent today.[233],[234],[302],[334] In the exceedingly rare event of syphilis inoculation via tattooing, prompt antibacterial therapy is indicated. In the event of a secondary syphilis-like lesion appearing in a tattoo, clinicians should be aware of this possibility and test the patient for syphilis.

 Uncomplicated Superficial Bacterial Infections



Although the incidence of tattoo-related infection (TRI) has been reported as high as 3.2%,[335] there are relatively few reported cases of uncomplicated superficial skin infections aside from Mycobacterium. Such superficial infections tend to present as erythematous,[235],[236],[340],[341] swollen,[235],[236],[340] painful,[340] hot,[340],[341] edematous[340],[341] areas over tattoos sometimes accompanied by fever.[236],[340] Some of the reported causative organisms include Serratia marcescens;[340]Streptococcus pyogenes, and Staphylococcus aureus.[236] A case of staphylococcal-scalded skin syndrome involving a homemade tattoo presenting with generalized erythema, purulent fissures, and areas of dry crusting of the skin.[341] Other reports of TRIs may warrant mention, but granular details are beyond the scope of this review.[199],[238],[340],[341],[342]

It is likely that uncomplicated skin infections are far more common than published case reports would indicate. Although tattoo inks are not always sterile, even sterile ink and equipment will not protect a patient from commensal/environmental organisms that survive on the skin after improper sterilization or enter the wound later due to improper aftercare.[233] Treatment consists of prompt recognition and appropriate antimicrobial therapy – initially broad, but preferably narrowed based on subsequent culture/sensitivity results.[235],[236],[340],[341]

 Necrotizing Fasciitis



Cases of necrotizing fasciitis following tattoo placement have been reported, with presentations typical of necrotizing soft-tissue infections with localized pain,[198],[343] erythema,[198],[343] swelling,[343] cellulitis,[198],[249],[343] skin breakdown/necrosis,[198],[249],[343] purulent discharge,[197],[249] fevers,[198],[249],[343] shortness of breath,[198] rigors,[198],[249],[343] hypotension,[198],[343] and decreased urine output.[198],[343] Majority of infections originated between the lower trunk and thighs, and all patients required surgical debridement and IV antibiotics. Risk of mortality is significant.

Causative organisms include S. aureus,[198],[249],[343] Group C Streptococcus,[198]S. pyogenes,[198],[249],[343]Pseudomonas aeruginosa,[198],[249],[343]Corynebacterium species,[343] and Klebsiella oxytoca.[249],[343] Infections are usually polymicrobial, and the unsanitary conditions of the traditional tattooing may play a role in their development.[198],[249],[343] Patients are treated with surgical debridement plus broad-spectrum antibiotic regimen. Many patients require subsequent skin graft placement. Since necrotizing soft-tissue infections require prompt recognition and treatment post tattoo education is essential. Tattoo artists must inform their customers of the signs and symptoms that should prompt urgent medical attention.

 Toxic Shock Syndrome



Toxic shock syndrome (TSS) posttattooing has been reported,[251],[344],[345] although the connection is somewhat speculative.[251],[345] Presenting complaints may include fever,[251],[342],[345] rigors,[251],[344] syncope,[251] headache,[251],[344] abdominal pain,[345] anorexia,[345] nausea,[345] diarrhea,[344],[345] vomiting,[345] with potential for progression to necrotizing infections.[251] Additional reported complaints included orthostasis, syncope,[345] acute confusion,[344] and cutaneous rashes.[344],[345] The associated rash may subsequently desquamate.[344] The contribution of the tattoo may be obvious,[344] but one should not assume this in the absence of overt findings.[251],[345]

TSS is caused by a soft-tissue infection with exotoxin-producing S. aureus or S. pyogenes.[346] These exotoxins are also sometimes referred to as superantigens, and clinically, TSS can be difficult to distinguish from staphylococcal septic shock. In one case, a tattoo had been placed on the anterior abdominal wall 2 weeks earlier, and a computed tomography scan showed subcutaneous inflammation in the area of the tattoo.[345] In another case, a patient was admitted for nonspecific signs of sepsis and severe groin pain which turned out to be necrotizing iliopsoas myositis.[251] She quickly died of Streptococcal TSS. Hematogenous spread of bacteria from the tattoo was suspected when postmortem examination revealed punctate hemorrhages of the parietal pleura and a purulent empyema deep to the tattoo site. Blood cultures were eventually positive for group A Streptococcus.[251] The third case presented with nonspecific systemic symptoms and an erythematous rash featuring greenish papules on the tattoo which made the diagnosis of a soft-tissue infection somewhat easier.[344] Desquamation of the patient's fingers and tattoo site on the back several days after his condition had stabilized supported the diagnosis of TSS. However, this was after he had been treated for TSS, as desquamation may occur after the onset of symptoms and thus should not be relied upon for diagnosis.[346] Methicillin-sensitive S. aureus (MSSA) grew from a skin culture of the tattoo site, but blood cultures remained negative. This is typical of staphylococcal TSS,[347] with streptococcal TSS being more likely to produce positive blood cultures.[248]

Management of TSS requires prompt administration of broad-spectrum IV antibiotics, including robust Gram-positive coverage, plus hemodynamic/vasopressor support in the intensive care unit (ICU) as indicated.[251],[345] Antibiotics can subsequently be narrowed once culture (and sensitivity) confirmation of the microorganism is finalized.[344] In summary, it is important to consider the possibility of TSS in the setting of a patient with a sepsis-like picture even if the tattoo itself does not appear infected. Finally, in addition to antibiotics, surgical consultation is important due to the likely need for operative debridement.

 Bacteremia



Bacteremia has been reported in association with tattooing, with the primary infection usually involving the tattoo site, up to and including necrotizing fasciitis.[199],[200],[249],[254] At times, the trauma of tattooing may introduce a metastatic infection such as endocarditis,[213],[244],[247],[348] pyelonephritis,[349] septic arthritis,[213] or a distant soft-tissue infection[208],[228],[350] that may further propagate the bacteremia. The presentation is typical of a septic patient, including complaints/findings of malaise,[228],[244],[247] fevers,[200],[213],[229],[247],[249],[254],[348],[349] rigors,[244],[249],[254] nausea and vomiting[249],[350] plus specific symptoms related to the site of infection such as blisters,[200],[249] erythema,[200],[247],[254],[349] purulence,[208],[249],[254] abdominal pain,[349] muscle pain,[228] back pain,[208],[350] paresthesias,[208] lower extremity weakness,[208] dysuria,[350] dyspnea,[247],[348] and fatigue.[213],[247]

Bacteremia may result from a primary tattoo infection,[349] the mechanism of which consists of the introduction of bacteria into the wound from improper aseptic technique,[199] contaminated ink or instruments, as well as poor aftercare.[200],[254] Similar mechanism is thought to cause a transient bacteremia with infection spread to distant sites. This, in turn, can fuel an ongoing bacteremia, with or without a clinical tattoo infection being apparent. Among risk factors for tattoo-related bacteremia is neutropenia, and providers should be aware of this potential association.[200] Causative organisms vary, but include MSSA,[208],[213],[254] MRSA,[199],[249],[350]Staphylococcus lugdunensis,[347]Hemophilus influenzae,[228] Group A Streptococcus[254]/S. pyogenes,[249]P. aeruginosa,[200],[249] and Moraxella lacunata.[348]

Management depends on the site of infection, but fundamentally after blood cultures are taken, empiric broad-spectrum antibiotics should be immediately started.[200],[228],[249],[254],[349] Antibiotic regimen can then be tailored once sensitivities become available,[228],[249],[254] and appropriate surgical or interventional treatment is undertaken.[208],[213],[228],[244],[247],[249],[254],[348],[349],[350] As with other tattoo infections, proper sanitation is critical to preventing these occurrences. Of note, a delay in treatment can have serious consequences.[254] Educating patients about the signs and symptoms of infection and– perhaps more importantly – sepsis, as well as the importance of prompt medical care could mitigate the risk of morbidity or mortality.[254]

 Endocarditis



Among several reported cases of bacterial endocarditis (BE) following tattooing, three cases had known prior valvular disease,[244],[247],[351] one case showed myxoid degeneration of one of the two valves affected,[213] with others demonstrating no evidence of other heart disease.[348],[352] The presenting complaints included fever,[213],[247],[348],[351] rigors/night sweats,[244] malaise,[244] fatigue,[213],[247] and dyspnea[247],[348] usually starting within a week of tattooing. However, presentation as late as 2 months after tattooing was reported.[353] Heart failure[244],[247],[348] and embolic events[244],[247],[351] were noted. Signs of tattoo infection were only present in approximately 20% of cases,[247] and the link between the tattoo and BE was presumed in the other cases. The causative organisms identified were S. lugdunensis,[247]S. aureus,[213],[244],[351] and M. lacunata.[348]

Superficial skin infections are common with tattoos,[247] likely due to disruption of the epidermis which acts as a microbial barrier. These infections are usually from commensals,[247] although infected ink[233] is a possible route of infection even if the skin is properly sterilized. The frequency of infections suggests that bacteria are frequently introduced to the body, although tattoo infection is not a prerequisite for BE. Once inside the body, it is possible that transient bacteremia may lead to colonization of damaged heart valves. Although the bacteria at the tattoo site may be successfully eliminated by the immune system, BE is already occurring.[353],[354] This explains the occurrence of tattoo endocarditis in patients with valvular damage, but not the patient without valvular abnormalities.

Tattoo-related BE should be treated like any other BE, with sustained course of antibiotic therapy directed against the organism identified from blood cultures, and surgery when indicated. All five patients with detailed reports required surgical valve replacement, with one having an abscess at the base of the coronary sinus noted at the time of surgery[247] and another developing a prosthetic valve abscess prompting a redo valve replacement.[244] All five patients recovered well, although one required a pacemaker due to complete heart block.[247] Antibiotic prophylaxis for patients with cardiac defects receiving a tattoo is not universally recommended,[348] although insufficient data exist to make any definitive statements in this context. Educating patients and tattoo artists of the potential dangers is important,[355] especially because the awareness of BE following tattoo creation is low.[352]

 Metastatic Infections



While localized tattoo infections are quite common, it is possible for TRIs to become a source of metastatic infections to other parts of the body. Clinical presentations tend to be diverse, including sepsis-like symptoms, pain localized to the involved area,[208],[251],[349],[350] weakness, and paresthesias.[208] Specific reported anatomic locations include epidural abscess,[208],[350] xanthogranulomatous pyelonephritis,[349] iliopsoas myositis/abscess,[251],[350] and streptococcal empyema.[251]

Most cases in the literature had some evidence of infection or the potential for contamination, including localized irritation and drainage,[208] the use of contaminated ink or after-care materials,[251],[349] repeated equipment/ink use without sterilization,[350] and one had an erythematous tattoo that was reported to have been placed with unsterile equipment.[349] It is proposed that bacterial spread is hematogenous,[251],[349],[350] involving the appearance of transient bacteremia.[350] Even without evidence of an overt tattoo infection, bacteria could be introduced into the bloodstream via tattoo placement, similar to the mechanism involved in IVDU.[353],[354]

Treatment depends on the location of the remote infection, and with general management strategies being outside of the scope of the current review, the reader is referred to definitive sources on the topic.[208],[349],[350] In aggregate, reported cases on this topic highlight the importance of proper sterilization of the skin and equipment before tattooing, as well as education of patients to seek medical attention if the tattoo shows signs of infection. Clinicians should be aware of recent tattoo placement or infection as a risk factor for distant infections when building their differential.

 Leishmaniasis



Leishmaniasis is a disease caused by the parasite Leishmania which is endemic to parts of the tropics, subtropics, and southern Europe, the most common forms of which are cutaneous and visceral.[356] It is transmitted by the phlebotomine sand fly[356] and transmission specifically via tattooing has not been reported. However, much like secondary syphilis, cutaneous manifestations of the infection appear to have a predilection for tattoos. Cutaneous leishmaniasis (CL) tends to present as a painless nodular or ulcerated lesion which may be indurated[211] and all reported cases of tattoo-associated CL (TACL) fit that description. In addition, there may be an association between TACL- and HIV-positive status in the context of preexisting cutaneous and visceral leishmaniasis.[240],[357],[358] Much remains to be learned about the above factors, and the temporal relationship between leishmaniasis infection, tattoo placement, and TACL is poorly understood.

It is known that Leishmania parasites are found in the blood and that CL lesions tend to develop at the site of even minor trauma.[359] The mechanism is thought to involve infected dendritic cells or macrophages that carry Leishmania to new areas of the body,[360] especially skin regions affected by active inflammation. There is a documented tendency for leishmaniasis to occur in areas of trauma or antigen-specific hypersensitivity reaction.[359] Given that tattoos are traumatic and cause inflammation, this is likely the mechanism observed in tattoo leishmaniasis. Moreover, the high prevalence of macrophages (which Leishmania utilize for reproduction) within tattooed skin may predispose a patient to TACL.[357]

Leishmaniasis should be included on the differential list for suspicious tattoo lesions in patients with a history of travel to an endemic area or history of leishmaniasis, especially if the patient has failed antibiotics and other treatments or is immunocompromised. Among other recent developments, it was proposed that tattoo-based interventions may help treat CL by enhancing local drug delivery.[360]

 Tattoo-Associated Lymphadenopathy



Tattoos can be associated with localized lymphadenopathy, at least in the acute phase.[263] This may confound clinical decision-making in the context of infection[361] or malignancy.[93],[263],[362] Usually, the patient presents with a lump or swelling that may or may not be painful or tender.[93],[264],[361],[362],[363],[364] On physical examination, the node may be described as mobile.[93],[263],[364] It may be firm[263],[363] or rubbery.[93] The lag time between tattoo placement and finding/symptoms may be as short as 5 months[361] or as long as years.[263] While the tattoo may be visible, tattoos are common enough that the presence of a tattoo that is not obviously infected or inflamed may not necessarily raise suspicion, or there may be repeated episodes of low-grade inflammation.[93],[364] When excised, the lymph node may appear dark in color which is suspicious for malignancy, especially melanoma.[263],[348],[363],[364] Furthermore, the presence of tattoo pigment in a lymph node can make evaluation for melanoma difficult.[232] Biopsy, however, generally shows benign lymph nodes, suggestive of reactive lymphadenopathy.[363] Tattoo lymphadenopathy may also be discovered on radiography,[240],[242] perioperatively,[348] or on sentinel lymph node biopsy.[233],[234],[235],[236],[237],[238],[348]

The mechanism of tattoo-associated lymphadenopathy (TAL) involves macrophages taking up tattoo pigment that migrates to lymph nodes via lymph channels,[363],[364] similar to the process used to identify a sentinel lymph node for biopsy.[263] Autopsy studies suggest that patients with upper extremity tattoos have pigmentation of the axillary lymph nodes,[361] with most being asymptomatic.

The majority of patients did not require treatment after biopsy ruled out malignancy.[362] One patient was initially diagnosed with reactive lymphadenitis and was treated for an ingrown toenail, the presumptive cause.[361] Biopsy showing tattoo lymphadenopathy was only performed after the Zadek's procedure[365] failed to resolve the painful swelling at the site of the lymph nodes. TAL should be considered on the differential for a palpable or tender mass proximal to a tattoo. The decision to consider lymph node biopsy/dissection should be based on the overall clinical context and situation-specific risks.

 Eczematous Reactions



Eczematous tattoo reactions (ETRs) have been reported in association with trauma,[366] immune reconstitution,[367],[368] and implantation of an implant,[369] as well as both short- and long-term interval after tattoo placement.[72],[73],[74],[269],[270],[285],[366],[367],[368],[370] The patient tends to present with pruritic,[73],[74],[269],[270],[285],[368],[369],[370] erythematous,[74],[269],[270],[367],[368] or eczematous[72],[366],[370] lesions that are sometimes described as plaques[367],[369],[370] and tend to be confined to, or prominent on a certain color of a tattoo.[74],[285],[367],[368],[369],[370] Lesions have been known to occur outside the tattoo,[269],[270] including generalized reactions.[72],[366],[368],[369] Conjunctivitis after eyelash tattooing has been observed.[269] Diagnosis is generally clinical, but biopsy can help rule out other conditions such as sarcoidosis or infection (e.g., mycobacteria). Such course of action is important in a patient who fails initial therapy and an alternative diagnosis is sought.

Many of these reactions are labeled as allergies,[269],[270],[285],[368],[370] implying a type 1 hypersensitivity reaction. However, delayed-type hypersensitivity (including systemic contact dermatitis) has also been proposed as a mechanism.[369] It is difficult to argue against the hypothesis that the tattoos are the cause of the reactions given the temporality and/or geography of lesions. However, patch tests are generally not considered useful,[368] and it is thought that haptenization or dissociation plays a role in the pathology.[366] In one study of 90 patients with a variety of tattoo reactions, the authors suggested the importance of haptens in the genesis of said reactions.[282] Among other features, histological characteristics include lymphocytic infiltration,[366],[368] spongiotic dermatitis[368],[369] and granulomatous[72],[73],[74] patterns. In the setting of trauma, it is thought that the injury releases mercury into circulation and causes rapid sensitization.[366] In cases of immune reconstitution (e.g., bone marrow transplant), the immune system is “seeing” pigment for the first time and reacting as if the tattoo had just been placed.[367],[368] Another proposed mechanism involves immune cross-reactivity between various materials, including implants and the tattoo ink.[269],[369]

The mainstay of treatment for ETRs includes either topical,[73],[269],[285],[368],[369] intralesional,[368],[369] or systemic steroids.[366],[368] Effectiveness may vary from complete response[73],[269] to partial or no response.[270],[285],[369] LTR may also be effective,[285],[370] although adverse reactions have been reported.[13],[35] In refractory cases, excision has been effective in ETRs.[72],[366],[368] Removal of the implant associated with the ETR may help but is usually difficult or not possible.[369] Spontaneous remission has been reported.[367]

 Photosensitivity Reaction



Occasionally, tattoos will react to sunlight, with presentations such as localized swelling,[280] inflammation,[278] bullae formation,[341] and eczema.[275] The time between tattoo placement and reaction varies from months[275] to years.[278] The mechanism is unclear, and it is not known if these reactions are photoallergic or phototoxic.[278] Cadmium sulfate is thought to be contributory;[280] however, there have been reactions to tattoos without cadmium sulfate.[278] Histologic appearance includes lichenoid,[278] granulomatous,[278] and acanthosis with spongiosis.[275] Treatment consists of systemic prednisone plus topical cortisone cream for photoreaction, with other therapeutic options considered on an as-needed basis.[275],[341]

 Lichenoid Reaction



The lichenoid tattoo reaction is thought to be the most common tattoo reaction,[81],[281],[283],[371] and tends to present as raised,[273],[276],[371] pruritic,[272],[274],[276],[277],[279],[281],[283],[284],[286],[287],[371],[372] and possibly erythematous lesions that may be described as papules or plaques.[55],[272],[277],[279],[281],[283],[284],[286],[372] Often the lesions will be confined to the tattoo[274] or a certain color of a tattoo (most commonly red).[272],[273],[276],[279],[287],[371],[372] There are reports of generalized reactions, some of which started in, or have a preference for a tattoo.[273],[277],[281],[283],[284],[286] One report describes lichenoid reaction on lower extremity tattoos just after superficial trauma involving other tattoos.[287] Attributed lag time between tattoo placement and onset of symptoms can be as little as 2 days or as long as years, with most reactions occurring within a year.[273],[272],[276],[277] Exposure to sunlight may aggravate the pruritus.[276]

Histology is generally consistent with a lichenoid reaction, although not necessarily specific for it.[272],[273],[274],[277],[281],[283],[286],[372] However, nodular and granulomatous patterns were also noted on lesions that were grossly considered lichenoid.[272] The presence of eosinophils may favor a hypersensitivity rather than lichenoid etiology,[281] with one source using the term “lichenoid tattoo hypersensitivity.”[273]

Diagnostically, patch tests are considered unreliable and are often negative in this specific setting.[272],[276],[277],[371] The mechanism for the lichenoid reaction is unknown, but one theory is delayed type hypersensitivity simulating graft versus host reaction.[273],[277] The mechanism for the generalized nature of some of the reactions is thought to be dissemination of the tattoo pigment through the body or a local reaction that leads to similar reactions at distant sites.[281],[283],[286] A Koebner or pseudo-Koebner phenomenon has been proposed mechanistically, although the more generalized response is still poorly understood.[277] The occurrence of lichenoid reactions (localized to the red areas of tattoos) among patients tattooed by the same artist within 6 months of each other also raises the possibility that a contaminant (including possibly a microorganism) could be contributory.[273] Finally, the presence of lesions localized to the tattoo points away from true lichen planus.[273]

Management includes local steroids, oral nonsteroid pharmacotherapy, LTR, surgical excision, and combinations of the above. Reported local pharmacotherapy of various effectiveness includes fluorinated topical steroid cream,[371] topical clobetasol propionate,[272],[274],[276] halobetasol propionate,[277] intradermal triamcinolone acetonide,[276] other intralesional steroids,[55] and tacrolimus.[287] Intralesional steroids plus oral antihistamines were partially effective in one case.[279] Nd:YAG[371] and Erbium-doped yittrium aluminium garnet laser[276] LTR approaches were shown to be effective, including Nd:YAG LTR in combination with clobetasol propionate in a patient who did not respond to clobetasol propionate alone.[272] Although it has shown to be effective in treating lichenoid reactions, LTR has been associated with generalized reactions.[281],[283] An approach consisting of excision using a skin knife to only remove the elevated portions of the tattoo was successful and preserved the tattoo with an overall good cosmetic result.[279] Finally, spontaneous resolution of lichenoid reaction was described.[286]

 Psoriatic Reactions



The localization of psoriasis to tattoos was described by Heinrich Koebner as early as 1876.[292],[373] The so-called Koebner phenomenon features well-defined,[288],[293],[295],[296] scaly,[288],[295],[374],[375] erythematous,[288],[291],[293],[195],[296],[374],[376] and occasionally pruritic[288],[291] plaques associated with tattoos. The plaques usually appear within a few weeks of tattoo placement (although in unusual circumstances this may happen several months after placement of the tattoo).[377] Although most cases are localized to the tattoo,[375] there are examples that are clearly associated with the tattoo that extends beyond its border[373] or start in the tattoo and progress to involve other areas.[291],[296],[376] Generalized reactions have occurred,[288],[295] including instances where there was documented preference for the tattoo.[374],[377] Psoriatic arthritis has occurred parallel to new-onset psoriasis.[296] The association between tattoos and psoriasis has occurred in patients with and without a known history of psoriasis.[288],[292],[293],[295],[374],[375],[377] Diagnosis is usually clinical although biopsies can be confirmatory.[293],[295],[296],[375],[376]

Despite significant advances in Heinrich Koebner's original paper, the mechanism of the Koebner phenomenon, which occurs in about 25% of psoriasis patients, is still unclear.[293],[295],[373] Hypotheses include trauma,[296],[375] hypersensitivity to tattoo pigment,[296],[375] a cutaneous manifestation of immune compromise,[378] increased vasoactivity,[377] and increased cytokine/CD4 lymphocytes/adhesion molecular synthesis.[373] The term “isotattootopic” has been proposed to refer to an isomorphic or isotopic skin reaction at a tattoo site.[378] In one report, a patient developed guttate psoriasis after starting penicillin for strep throat, which persisted despite two courses of amoxicillin.[377] This mechanism was hypothesized to involve T-cell activation against endogenous keratin isotopes that mimic streptococcal antigens.[377] Subclinical inflammation of the tattoo was thought to explain the reaction in a tattoo that had been asymptomatic since placement 7 months earlier.[377] It is important to note that the appearance of Koebner reaction (e.g., “Koebnerization”) may merely be revealing otherwise subclinical psoriasis or a predisposition to psoriasis.[296],[375] As it can be difficult to establish causality in some cases,[292] the possibility of coincidence is worth considering in patients whose reaction did not start in a tattoo or show a preference for it. Interestingly, one patient with a previously known history of psoriasis was re-tattooed a month after his tattoo-associated outbreak started but did not develop another outbreak.[288] In another paradoxical case, a reaction occurred while a patient was taking methotrexate.[292] Taken together, the above peculiarities highlight the need for better understanding of the Koebner phenomenon, as well as factors that modulate this as yet nebulous entity.

Koebnerization of psoriasis on a tattoo should be treated as one usually treats psoriasis. Treatments outlined in the literature include systemic methotrexate for a systemic reaction,[295] over-the-counter 1% topical hydrocortisone,[288] topical fluticasone propionate,[288] triamcinolone acetonide,[288] topical mometasone,[291] topical clobetasol,[374] topical clobetasol propionate and salicylic acid,[375] and calcipotriene.[293] One patient with streptococcal-induced guttate psoriasis had improvement with hydroxyzine and topical alclometasone and mometasone but noticed flares after discontinuing amoxicillin therapy.[377] Ultimately, calcipotriene resulted in satisfactory improvement without reoccurrence.[377]

Although not well described in the English literature, a survey of psoriasis patients suggests that a relationship between psoriasis and tattoos may not be that uncommon.[379] In fact, approximately 4.5% of surveyed psoriasis patients with tattoos reported developing psoriasis within weeks of tattooing. Within this group, 75% had a history of Koebner phenomenon.[379] Accordingly, clinicians should counsel psoriasis patients about the risks associated with tattooing.[292] Patients with a history of Koebner phenomenon and those with active psoriasis at the time of tattooing may be at increased risk of developing tattoo psoriasis.[292],[379] If the patient decides to proceed with tattooing, they should be encouraged to follow-up for treatment of any flare-ups.

 Vitiligo



Vitiligo has been reported in association with tattoos.[289] In one case, a patient presented 2 months after cosmetic eyebrow tattooing with depigmentation of the eyebrows, forehead, and left lower extremity.[289] She was diagnosed clinically with nonsegmental vitiligo, presumably induced by tattooing.[289] The temporal relationship, as well as the fact that most of the lesions appeared over the tattoos, suggests causal association. This is supported by the fact that the Koebner phenomenon (e.g., the formation of psoriatic lesions in uninvolved skin of psoriatic patients after trauma) can be seen in vitiligo.[380] The simultaneous appearance of lesions outside the boundaries of the tattoo as well as distant from the tattoo suggests that a systemic reaction may be involved, possibly similar to lichenoid reactions, sclerosing reactions, or reactions to LTR. The most likely explanation is the presence of a multifactorial response which includes local effects of tattoo pigment and/or trauma as well as a systemic immune/inflammatory response in a predisposed patient. In effect, it may be that the tattoo actually “reveals” the vitiligo rather than “inducing” it.[380] The treatment and outcome were not specified for the above-mentioned case.[289] Of note, micropigmentation (a procedure similar to tattooing) can be used to cover patches of vitiligo and is well-tolerated.[380]

 Keloid Scar Formation



Keloids are rare in tattoos,[45] although isolated cases have been reported.[45],[317] These lesions extend beyond the site of injury (e.g., the affected tattoo area), which helps differentiate keloids from hypertrophic scars (which generally do not extend beyond the tattoo). An example of such esthetically pronounced scars is provided in [Figure 6]. In one case, a keloid appeared after the patient was burned at the tattoo site during a laser procedure for hair removal.[45] Causation is not assumed in this instance, and the keloid is more likely to be a complication of the burn, as opposed to a direct consequence of the tattoo. The other case developed after tattooing, with the keloid pattern appearing to follow the design of the tattoo.[317]{Figure 6}

 Epidermal Cysts



Milia, or small superficial epidermal cysts,[381] are common and have occasionally been reported to occur on tattoos.[381] Presentation may include a pruritic[381] or asymptomatic rash[310] over a tattoo that occurs within a few months of tattoo placement.[381] Physical examination shows small (1 mm) papules distributed throughout a tattoo[310],[381] or throughout a single tattoo color.[382]

These milia can be primary or may occur due to traumatic implantation of epithelium or disrupted follicular structures.[381] As milia have been reported to occur following trauma and needle biopsy,[381] it can be hypothesized that a similar mechanism causes tattoo milia. The presence of milia throughout multiple colors of two out of the three tattoos[310],[381] supports the traumatic etiology, but the preference for red areas of one tattoo invites speculation as to a possible role for the specific ink.[310] While one patient had milia strictly limited to the red areas of the tattoo, it seems likely that the primary lichenoid reaction was limited to the red areas and the lichenoid reaction gave rise to the milia (a recognized phenomenon). Given this association between milia and lichenoid reactions,[382] it has been proposed that a lichenoid or other reactive process could be involved in the development of milia in patients without an overt lichenoid reaction.[30]

Treatments for tattoo milia include urea cream plus salicylic acid.[381] Spontaneous resolution may occur.[310] Other treatments of milia that were not specifically used on tattoo milia include electrodesiccation,[381] laser ablation,[381] or topical retinoid therapy.[381]

 Sclerosing Reactions



Sclerosing tattoo reactions have been reported.[308],[313],[383] As with many tattoo reactions, the presentation tends to be nonspecific and included pruritus[308],[313],[383] and inflammation[308],[313],[383] over the entirety of a multicolored tattoo[383] or just over the red areas.[308],[313] One patient failed antibiotic therapy for presumed cellulitis before a biopsy revealed the true nature of the lesion.[313] All three patients lacked examination findings suggestive of systemic scleroderma,[308],[313],[383] and no history of scleroderma was given for any patient. Given the lack of evidence of systemic disease, these lesions were referred to as “morphea-like”[383] or “scleroderma-like.”[308],[313]

The sclerosis is thought to be a response to chronic inflammation induced by the tattoo pigment.[308],[383] Histologic findings of decreased/fragmented elastic fibers in the lesion of one patient support the nonspecific sclerosing response over a systemic disease.[383] Of interest, parallel to one patient's main sclerosing tattoo reaction, a distant tattoo that had been performed previously to the sclerosing tattoo became pruritic.[308] This suggests that local hypersensitivity can provoke a systemic reaction, such as lichenoid tattoo reactions, vitiligous tattoo reactions, or reactions to LTR. One patient's biopsy suggested features of lupus erythematosus.[313] Treatments included betamethasone dipropionate ointment,[308] intralesional triamcinolone acetonide, and topical clobetasol.[313]

 Seborrheic Keratosis



SK has been reported following tattooing.[315],[329] Small, uniform papules appear over multiple colors of a tattoo several months or years after the tattoo is placed.[315],[329] Diagnosis is confirmed via biopsy,[329] likely because SK can be difficult to differentiate from HPV.[329] The mechanism for SK in tattoos is not well understood, although it has been proposed that SK and HPV lesions exist on a spectrum,[329] or that HPV may play a role in the development of nongenital SK.[384] One patient improved with CO2 laser treatment,[315] and treatment was not discussed for the other patient.

 Chronic Fibrosing Vasculitis



Chronic fibrosing vasculitis on a tattoo has been reported once in the medical literature that we could find. A patient presented with hyperkeratotic, verrucous plaques localized to red areas of a tattoo that occurred a month after the tattoo was placed.[385] The patient had several prior tattoos using the same red ink without a reaction, and the patient's friend received a tattoo with the same ink on the same day as the patient without a reaction. Biopsies showed chronic fibrosing vasculitis and Candida parapsilosis, the latter of which was considered to be a secondary infection.[385] This reaction was theorized to be due to a futile attempt by the immune system to clear an antigen (the tattoo pigment) involving a type 4 hypersensitivity reaction.[385] Treatment was not indicated beyond “an excisional biopsy of the plaques was performed”[385] and the further outcome is unknown.

 Leukocytoclastic Vasculitis



Leukocytoclastic vasculitis (LCV) has been reported in association with tattooing several times, presenting several weeks after placement or touch-up of a tattoo in one of two ways: either as an erythematous excoriated rash,[386] or as a multitude of red/purple purpuric[321],[332] lesions. Either presentation may be pruritic.[332],[386] The excoriated, erythematous rash was limited to the red ink of the multicolored tattoo,[386] while other two patients had more widespread/generalized lesions and constitutional symptoms.[332] One of the generalized cases had a clear preference for the tattoo,[321] while the other did not[332] and was likely assumed to be related to the tattoo due to temporality. In all cases, the diagnosis was made via biopsy.[321],[332],[386]

The mechanism of LCV is not completely understood, and the etiology of tattoo-associated LCV is an area of active debate,[387],[388] but hypotheses include hypersensitivity to ink [Figure 7][321],[332],[387] and infection.[388] The case of generalized LCV without a preference for the tattoo had cellulitis over some of the lesions,[332] but it is unclear whether the LCV or the infection came first. The preference of one case for the red tattoo ink[386] supports a local role for specific inks, while the more generalized reactions that occurred with constitutional symptoms point toward a more generalized systemic response. It seems possible that tattoos could cause LCV via two distinct mechanisms resulting in two distinct clinical presentations.{Figure 7}

Treatment and outcome were not specified for the localized case.[386] The generalized case that showed a preference for the tattoo was treated with IV corticosteroids transitioned to prednisone and colchicine with the improvement of skin lesions and arthralgias at 4 weeks.[321] However, the previously healthy patient still required crutches for ambulation at 4 weeks.[321] The generalized case without a preference for the tattoo was treated with oral cephalexin and prednisone, antiseptic baths, and topical mupirocin which showed improvement in all lesions within a month.[332]

 Tattoo “blow-Out”



Tattoo blow-out is a phenomenon that is likely underreported.[322] Patients will present with tattoo ink that has formed a “blurry halo”[322],[323],[389],[390] outside of the desired image.[390] The process starts within days of having the tattoo placed,[323],[390] and most patients do not report symptoms.[322],[323],[389],[390]

The mechanism is thought to be migration of tattoo ink that has been accidentally injected too deeply, beyond the dermis.[322],[389],[390] Once in the hypodermis, it migrates via an unknown mechanism that could be wicking,[390] fascial spread,[390] lymphatic spread,[390] or vascular spread.[390] This mechanism would explain the predominance for female patients (whose skin tends to have a thinner dermis than men[389]) and locations on the body with thinner skin,[389] such as the dorsum of the foot[323],[390] and inner surface of the upper arm.[322] The chemical properties of the ink,[322],[389] gravity,[389] and excessive ink[389] may also affect the extent of the “blow-out.” Biopsies, when performed, show no vascular or lymph involvement,[323] and may show the ink deeper than expected.[390]

QS-Nd:YAG laser therapy has been used successfully, with good cosmetic result.[323],[390] One patient failed laser therapy,[322] although he only underwent one session, as opposed to nine[390] and two.[323] Four years after the one session of laser therapy, the blow-out persisted but had not changed significantly.[322]

 Edema



Although edema following tattooing was reported as a TRC in a large multi-national survey (n = 3,411 participants),[324] there was only one report of two patients available in the English medical literature.[330] Both patients presented with localized edema, one of which was erythematous and painful, while the other was painless.[330] One patient presented 10 days after tattooing and the exact timeline was not reported for the other patient.[330] One patient had been tattooed many times before (including on the contralateral leg) but had not had an edematous reaction before.[330] Both were initially diagnosed with cellulitis, which was thought to be incorrect due to delayed onset and absence of fever/chills/cutaneous inflammation in the asymptomatic patient, and absence of fever/lymphangitis/local lymphadenopathy with normal white blood cell/C-reactive protein, erythrocyte sedimentation rate, and blood cultures in the patient with painful erythema.[330] The ultimate diagnosis was “sterile inflammatory edema.”[330]

The edema is thought to be due to the acute inflammatory reaction that occurs at the time of the procedure, and resolves as the wound heals within several weeks.[330] A plane ride 48 h after the patient without prior tattoo reactions was tattooed could have contributed to the edema.

Both were initially misdiagnosed with cellulitis, and one was given antibiotics.[330] The antibiotics were discontinued, the other patient was given paracetamol, and both patients recovered with no further treatment beyond a recommendation to rest and avoid sitting/standing.[330] Clinicians should be aware of this phenomenon in order to avoid misdiagnosing the reactions as cellulitis and/or ordering unnecessary antibiotics and tests.

 Sparing



Much of this paper has been spent discussing diseases and reactions surrounding tattoos, but it is also important to mention an uncommon “sparing phenomenon” that has occurred with tattoos. Also called the “reverse Koebner phenomenon,” skin diseases have been known to spare sites of injury,[319] including tattoos. Interestingly, both cases of this phenomenon were related to palpable, reddish/purple purpuric lesions mostly on the lower extremities. One patient developed the lesions on day 5 of a hospital admission for multifocal pneumonia but was unable to comment on symptoms as he was intubated in the ICU due to respiratory failure.[391] The tattooed areas as well as a well-defined 2–3 cm halo around each of the two separate tattoos was spared.[391] A biopsy was consistent with LCV.[391] The other patient presented to the ED with the skin lesions and constitutional symptoms.[392] Although some of the lesions overlapped the tattoo slightly, none of the lesions were centered on the tattoo.[392] A quantitative analysis showed that this was unlikely to have occurred by chance.[392] The lesions were thought to be LCV but no biopsy was performed.[392]

The reverse Koebner phenomenon is poorly understood,[266],[319] likely in part because it is so uncommon.[266] The mechanism for the first patient's response was hypothesized to be related to the presence of toothpaste in his homemade tattoos, as fluoride has been shown to have an effect on immune function.[391] Similarly, the second patient's response was thought to be due to hamamelitannin, a potentially anti-inflammatory chemical found in a type of witch hazel used to create the tattoo ink.[392] Dissimilar from tattooing, the reverse Koebner had also occurred when psoriasis[319] or LCV[266] spared an area that pressure had been applied to, possibly due to decreased blood flow and subsequently decreased deposition of immune complexes. Although the pressure-related sparing phenomenon is also identified as a reverse Koebner phenomenon, it is possible that multiple, distinct mechanisms can all result in a common clinical presentation. As the reverse Koebner phenomenon is neutral or if anything, beneficial, the patients with tattoo-related reverse Koebner phenomenon did not require any treatment for it.

 Magnetic Resonance Imaging-Associated Tattoo Burns



Burns associated with tattoos and MRI are fortunately very rare, with fewer than 20 documented cases. Untoward effects range from a slight tingling sensation[393] to burning pain.[394],[395] In more severe cases, first-[396] and second-[397] degree burns have been described. Although permanent sequalae secondary to the burns have not been reported, completion of an MRI examination can be challenging or impossible.

Mechanistically, the magnetic field is thought to induce an electrical current within the heavy metals of the tattoo pigment,[398] giving off heat in a manner similar to an induction stove. Tattoos with loop patterns and ink containing iron oxide are considered “high risk” for this occurrence.[394] Of note, this effect is rare even in such “high-risk” tattoos. Nevertheless, there has been a reported case of a burn in a tattoo that did not contain iron oxide and likely did not feature a loop.[396]

The current guidelines recommend screening patients for tattoos, including permanent makeup and instructing the patient to inform the technologist immediately if they notice a tingling or burning sensation during the MRI examination.[399] If alternative imaging modalities are not appropriate, applying a cold compress or wet towel may prevent the rise in temperature and alleviate pain to a tolerable level, thus facilitating the completion of the MRI with no permanent sequelae.[394] Resection of the tattoo can also be considered to allow MRI completion,[398] but this option is very aggressive and impractical (especially for larger tattoos).

 Miscellaneous Topics



The domain of TRCs, as evidenced in previous sections of this review, is both vast and complex. Additional topics that are beyond the scope of the current review but may warrant a brief mention include pyoderma gangrenosum following tattoo placement,[400],[401] less commonly reported TRCs of laser therapy,[40] as well as psychosocial and financial aspects of tattoo placement, including TRCs.[402]

 Conclusion



The many complications of tattooing are fascinating and require a significant amount of expertise spanning various specialties including infectious disease, dermatology, immunology, rheumatology, pathology, surgery, and epidemiology. The overarching theme of this review is the need for better awareness of TRCs, coupled with appropriate education of patients, health-care providers, and tattoo artists. Primary prevention of TRCs should be the ultimate goal; however, excellent knowledge of management approaches specific to each TRC should be emphasized given the significant heterogeneity of clinical presentations and treatments alike. More systematic study of TRCs will improve the care afforded to tattooed patients and provide an excellent opportunity for specialists from different fields to work with and learn from each other. Of importance, TRCs often constitute unique presentations of known diseases and researching them may help elucidate their mechanisms, many of which are incompletely understood. Finally, the authors would like to emphasize the need for a centralized reporting mechanism for TRCs. Such infrastructure will be instrumental in improving the safety of tattooing, an important aspect of managing the continuous growth of this increasingly socially accepted phenomenon.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

This manuscript represents a literature review. Consequently, institutional board review was not required before conducting/publishing our findings.

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