Inflammatory Tattoo Reaction

Are You Confident of the Diagnosis?

• What you should be alert for in the history

Most tattoos are the result of intentional placement of exogenous insoluble pigments into the dermis via repeated needle punctures for the purposes of decoration or on the basis of one’s culture.

Other less commonly encountered tattoo forms include cosmetic enhancement such as permanent lip liner or eyeliner, reconstructive surgery such as breast reconstruction, accidental or traumatic tattoos and iatrogenic. Traumatic tattoos can be abrasive in nature from dirt or gravel (Figure 1, Figure 2), or explosive such as shrapnel or gunpowder. Iatrogenic tattoos can be unintentional like those following the use of ferrous subsulfate (Monsel’s solution) for hemostasis, or intentionally placed for the purpose of medical treatments, such as radiation.

Figure 1.

Figure 2.

Tattoo reactions can occur at any time following initial placement and can occasionally even arise following placement of additional tattoos several years after the first.

Acutely, scaling, crusting and tenderness are seen almost universally secondary to the mechanical injury sustained by the skin during the application of the tattoo and are expected to resolve within weeks as the skin heals.

Patients may present with various signs and symptoms such as intense pruritus, erythema, induration, edema and tenderness.

The more recent trend of henna tattoos can result in a significant allergic contact dermatitis occurring anywhere from 24 hours to 2 weeks after the “holiday tattoo.” The responsible allergen is typically paraphenylenediamine.

Delayed type hypersensitivity reactions can occur from weeks to years later. The presenting complaint is most commonly either erythematous nodules/plaques, a lichenoid reaction or eczematous eruption at the site of the tattoo. Patients may also present with asymptomatic nodules and concerns regarding cosmesis and scarring.

Less commonly reported symptoms include intense pruritus and erythema associated with or following UV/sun exposure. In most of these cases, tattoos contain either red and/or yellow pigments, which account for the photosensitive or photoallergic reaction.

Lymph nodes can also become inflamed due to the migration of tattoo pigments to the node via lymphatic drainage.

• Characteristic findings on physical examination

Tattoo reactions can present in a wide range of clinical patterns. Often erythema, pruritus, indurated papules or nodules are characteristically seen within certain areas or borders of the tattoo graphic. Scaling, crusting and ulceration may be present as well (Figure 3, Figure 4, Figure 5, Figure 6). Other reaction patterns include granulomatous, lichenoid, photoallergic, eczematous, urticarial or keratoacanthoma type verrucoid papules. Rarely transient focal hyperkeratosis has occurred following temporary henna tattoos. Not uncommonly, patients may also have a concomitant generalized eruption related to id type auto-sensitization.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Certain clinical patterns provide clues to underlying basis for the reaction. In reported cases of atypical mycobacterial inoculation, asymptomatic or pruritic papules, notably with pustules, developed 10 to 21 days following tattoo application. In these cases, lesions were confined to specific areas of the tattoo, generally identical pigment sections or areas utilizing a specific pigment as part of a mixed compound. In both reports, infections were associated with pigment made from a grey wash compounded from diluting black pigment with non-sterile water, the presumed source.

When evaluating tattoo reactions, it is also important to consider coincidental lesions, including sarcoidosis, infectious processes such as verruca, fungal and atypical mycobacteria as well as malignancies such as B-cell lymphoma, melanoma, basal cell carcinoma, non-Hodgkin’s lymphoma or squamous cell carcinoma.

• Expected results of diagnostic studies

Given the wide range of clinical reaction patterns, it is not unexpected that there is also a wide range of histologic patterns with tattoo reactions.

A granulomatous pattern is perhaps the most common reaction noted histologically. It can be classified as either foreign body or sarcoidal, however, the distinction can be difficult. The predominant feature in foreign body reaction is the presence of abundant giant cells compared with sarcoidal lesions, which are marked by clusters of epithelioid histiocytes. Most tattoo pigments appear black on hematoxylin and eosin stain despite the true pigment color.

Another pattern noted has been massive pseudoepitheliomatous hyperplasia. One report noted pruritic nodules, which developed 2 months after tattoo placement. Verrucoid papules were appreciated clinically, and an initial biopsy demonstrated epidermal hyperplasia suggestive of a regressing keratoacanthoma. Repeated sampling showed marked epidermal hyperplasia, focal cystic keratin dilations, mild reactive keratinocyte atypia as well as dense chronic inflammation, fibrosis and red pigmented granules in the surrounding dermis.

Similarly, eruptive keratoacanthomas have also been noted histologically. In one case, four nodules arose in a single tattoo 3 weeks following application. Pathology from each distinct nodule showed invasive areas of atypical glassy keratinocytes extending into the dermis along with both free and histiocyte-laden pigment.

A rarely reported pattern is a morphea-like tattoo reaction. In one case, the clinical presentation demonstrated typical symptoms of pruritus, inflammation and induration, but notably, the reaction affected multiple different pigments. Biopsy demonstrated lymphoid infiltrate, plasma cells, free and bound tattoo pigment as well as thickened, hyalinized collagen, loss of peri-eccrine fat in addition to proliferation of interstitial fibroblasts. Additional stains showed reduced elastic tissue, suggesting a nonspecific sclerosing response to the foreign material.

In some cases, multiple reaction patterns may be present as a result of distinct immunologic responses to the different pigment compounds. In one instance, a patient developed simultaneous reactions to multiple pigments following re-tattooing over unwanted tattoos. In this case, biopsy from the reactive red pigment area demonstrated a mild lymphocytic infiltrate along with lichenoid changes at the dermal-epidermal junction and was classified as a lichenoid reaction.

Another biopsy taken from a nodular area of light blue pigment in a separate reactive tattoo demonstrated an intense inflammatory infiltrate of large lymphocytes and pigment-laden macrophages filling the upper dermis consistent with a pseudolymphomatous tattoo reaction. Notably the sample lacked germinal center or lymphoid follicule formation, and additional studies using immunohistochemical markers demonstrated a mixed infiltrate with T-cell predominance. T-cell gene rearrangement showed polyclonal expansion, suggesting that the process was reactive.

• Diagnosis confirmation

Sarcoidosis, a chronic granulomatous disease of uncertain etiology, can confound the evaluation of tattoo reactions. Granulomatous inflammation is one of the more common reaction patterns noted with tattoo reactions, yet as many as 25% of patients with sarcoidosis may present with cutaneous manifestations, namely cutaneous granulomas that can preferentially appear within tattoos. Given that the clinical presentation can be nearly identical, a screening workup should be considered to rule out systematic sarcoidosis in these patients.

Cutaneous or extra-nodal lymphoma can also pose a diagnostic challenge. Clinically these lesions will appear as erythematous, plum colored or violaceous nodules. Histologically, pseudolymphomatous reaction patterns can be difficult to distinguish from lymphoma. It is important to consider additional immunohistochemical tests and clonal gene rearrangement studies to avoid misdiagnosis in these cases.

Infectious agents including certain bacterial, fungal, tuberculosis or atypical mycobacterial organisms may also present in a similar manner to tattoo reactions. Inoculation of infectious organisms can be due to the mechanics of tattooing, such as the use of inappropriately sterilized equipment, use of non-sterile water sources for dilution of inks, or by contamination of freshly tattooed skin from poor wound care.

The clinical appearance of pustules or purulent drainage may be indicative of an underlying infectious process. Histologically, pseudoepitheliomatous hyperplasia or granulomas may be present, which can also be seen in tattoo reactions. Special stains such as GMS along with appropriate tissue cultures are indicated to ensure proper diagnosis.

Who is at Risk for Developing this Disease?

Tattoo reactions are possible following any type of tattoo: graphic/intentional, temporary henna, iatrogenic, cosmetic and even traumatic tattoos.

Frequently patients who develop tattoo reactions are later found to have an underlying allergy or sensitization to metallic substrates in the pigment compound. This can on occasion be determined with use of patch testing, which is helpful when it demonstrates a positive result. It is important to note that a negative patch test does not necessarily rule out the possibility of allergy due to the immunologic differences between intradermal pigment deposition and the transdermal application of the compounds with patch tests.

Patients with a known history of sarcoidosis may be at higher risk of developing a tattoo reaction, however, it is not uncommon for the onset of the systemic form to occur many years following tattoo placement.

What is the Cause of the Disease?

• Etiology

Many cases of lichenoid reactions have been associated with mercury-based red pigments. However, mercury sulphide (cinnabar) content is now restricted to much lower concentrations, which may help reduce the number of reactions to some degree. Importantly, substitute compounds such as cadmium red or yellow can also lead to allergic as well as photoallergic reactions. Other organic-based dyes have also been used in place of mercuric pigments, and typically patch testing to these substances will be negative, further complicating evaluation.

In general, metallic substrates used in the pigment compounds are felt to be at the root of most reactions, and occasionally patch testing with corresponding metal may help demonstrate causality.

Commonly associated compounds and pigments include mercury with red, cobalt with blue, cadmium with both yellow and red, chromium with green, and manganese with purple. Carbon (india ink) and iron oxide are common in black pigment.

The principle agent responsible for type IV hypersensitivity reactions from black henna tattoos is not the henna itself, but paraphenylendiamine (PPD), which is added to create darker coloring and shorter drying time.

PPD is known to cross-react with a number of substances including para-amino benzoic acid, sulfonamides, sulfonylureas, dapsone, azo dyes and benzocaine. It is important for patents with known allergy to any of these substances to avoid temporary tattoos, especially those marketed as “black henna,” which generally contain PPD.

• Pathophysiology

Delayed type hypersensitivity reactions mediated by a T-cell response likely account for the majority of tattoo reactions, generally leading to either granulomatous or lichenoid processes.

Other suggested pathophysiologic mechanisms include B-cell mediated responses yielding pseudolymphomatous changes as well as photoallergic/ photosensitive reactions, which lead to chronic eczematous dermatitis, both clinically and pathologically. Koebner phenomenon has also been demonstrated.

Given the wide range of distinct clinical and histopathologic findings, it seems likely that a complex interplay of pigment substrates and immunologic processes is responsible for the reactions.

Systemic Implications and Complications

Sarcoidal granulomas occurring within tattoo reactions present a diagnostic challenge as this reaction pattern may be a cutaneous manifestation of systemic sarcoidosis, sarcoid limited only to the skin (so-called cutaneous sarcoidosis) or purely a local reactive granulomatous response.

It is therefore considered prudent to rule out systemic sarcoidosis. This chronic granulomatous disease is defined by presence of certain clinical symptoms, radiographic findings and histologic changes (specifically noncaseating epithelioid-cell granulomas) affecting two or more organ systems in the absence of any other possible cause for a systemic granulomatous reaction.

Symptoms associated with systemic sarcoidosis include fever, malaise, weight loss, pulmonary issues such as dyspnea, dry cough, chest discomfort, lymphadenopathy, and ocular complications such as anterior uveitis.

Less commonly noted signs and symptoms include neuropathy, cranial nerve palsy (seventh notably) or mental status changes related to central nervous system involvement. Other systems affected less commonly include cardiac, hepatic, osseus or bony changes, muscular weakness, hematologic, rheumatologic, endocrine and renal.

A well rounded screening evaluation for systemic sarcoidosis should include a chest X-ray along with basic labs such as CBC with differential, liver function tests and a basic metabolic panel. Additional screening labs might also include serum calcium levels (assessing for hypercalcemia), erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA) levels. PPD placement is also recommended.

Serum angiotensin-converting enzyme (ACE) is not a sensitive screening tool as this can be elevated in the absence of sarcoidosis. However, once the diagnosis of sarcoidosis has been confirmed serum ACE levels can be monitored as a reflection of disease activity.

Another diagnostic dilemma with regard to tattoo reactions is the distinction between pseudolymphoma versus lymphoma. Pseudolymphomatous reactions can appear very similar to lymphoma. Clinically, pseudolymphomatous reactions are characterized by plum to violet hued firm nodules and are often solitary or localized. However, in the case of tattoo reactions, multiple lesions can occur. Histologically, pseudolymphomas characteristically demonstrate a mixed inflammatory infiltrate higher in the dermis than seen with lymphomas, accompanied by germinal center formation and macrophages.

Distinguishing pseudolymphoma from lymphoma often necessitates special stains and clonal rearrangement studies to characterize the infiltrate. A polyclonal pattern tends to favor pseudolymphoma whereas light chain restriction for either kappa or lambda are more suggestive of lymphoma.

Treatment Options

Medical options

Topical therapies

Potent corticosteriods

Intralesional corticosteroids

Systemic therapies

Steroid taper

Hydroxyzine

Destructive options

Surgical removal

Excision followed by split thickness skin graft

Mechanical removal

Dermabrasion

Laser ablation

Optimal Therapeutic Approach for this Disease

In most cases, the initial therapeutic approach should be conservative management. Superpotent topical steroids, such as clobetasol propionate 0.05%, can be applied twice daily. Improvement should occur within 2 to 4 weeks of treatment. It is difficult to predict which patients may respond, but in general overall effectiveness is considered low.

The next step in management is often dictated by the patient’s desire for preservation of his or her tattoo. Should the patient desire to preserve the tattoo, intralesional kenalog (5 to 10mg/mL dose) may be injected into the affected areas. Patients should be aware that injections will likely need to be repeated about every 8 to 12 weeks to prevent recurrence of the underlying reaction. Additional risks include steroid atrophy due to use of intralesional steroid. This risk can be reduced by using the lowest potency concentration to achieve clearance.

For allergic contact dermatitis reactions to temporary henna tattoos, a short systemic steroid taper is highly effective. This can be combined with oral hydroxyzine and topical corticosteroids for optimal relief.

While some reports have documented effective removal of inflamed or reactive tattoos using lasers, the process does not have widespread acceptance due to the risk of a disseminated cutaneous reaction as well as the potential risk of anaphylaxis. Careful examination of the literature should be done prior to proceeding with laser ablation with special attention to the type of laser used in the report, the location of the tattoo and the presence of additional tattoos (in as much as laser treatment of a single tattoo may incite reaction in uninvolved tattoos).

The definitive treatment for severe persistent tattoo reactions is surgical excision, which based on size and location, may require skin grafting.

Patient Management

Patients will generally guide follow-up on the basis of clinical symptoms or from the desire to preserve the affected tattoo. With topical therapies, clinical response should be evident within 2 to 4 weeks, making 4 weeks a reasonable time for follow-up visit, unless the presentation was very severe or complicated, in which case a 2-week follow-up would be indicated. Maintenance therapy is dependent upon the treatment modality, with intralesional steroids requiring ongoing treatment for suppression of the reaction.

Failure of conservative therapies may necessitate the discussion of surgical excision.

Patients who present with allergic contact dermatitis to a temporary henna tattoo should be educated about the risk of sensitization to PPD and cautioned to avoid henna-based tattoos in the future and hair dyes that might also contain PPD.

Unusual Clinical Scenarios to Consider in Patient Management

Sarcoidal type granulomas can be associated with tattoo reactions. Additionally, patients with tattoos are at an increased risk of acquiring chronic hepatitis C. A unique clinical scenario has been noted in patients with chronic hepatitis C following initiation of interferon alpha, which has become a mainstay medication used to suppress viral proliferation.

While it has been well known that interferon alpha could induce immune-mediated diseases such as sarcoidosis, recent reports have detailed the appearance of sarcoidal granulomas in tattoos following the use of interferon alpha even 4 to 8 weeks after cessation of treatment. In these cases, it remains critical to complete a full systemic screening examination for signs or symptoms of systemic sarcoidosis.

Another challenging clinical scenario regarding tattoo reactions involves patients who are found later to have malignant melanoma. In one report, a 25-year-old patient was diagnosed with a 1mm thick melanoma involving the chest. Given the depth, sentinal lymph node biopsy was undertaken. Radiotracer uptake was noted in the bilateral axillae, and subsequent surgical excision revealed deeply pigmented lymph nodes in each axillae grossly suggestive of metastatic disease.

Given the young age of the patient, intraoperative frozen sections were carried out prior to completion dissection. Careful microscopic evaluation demonstrated reactive follicular hyperplasia with extracellular black coarse granules throughout the sinuses. Findings were correlated with hematoxylin and eosin stains along with special stains including S-100, cytoplasmic homatropine methylbromide (HMB-45) and Fontana-Masson, which were all negative for metastatic disease.

This case serves as a reminder that even with strong clinical suspicion, histologic confirmation of metastatic disease should be fully confirmed prior to proceeding with what could be an unnecessary completion lymphadenectomy, especially given the well known morbidities associated with completion dissection.

What is the Evidence?

(Excellent FDA consumer update summary regarding the risks of tattoos.)

Kennedy, BS, Bedard, B, Younge, M, Tuttle, D, Ammerman, E, Ricci, J, Doniger, AS, Escuyer, VE, Mitchell, K, Noble-Wang, JA, O’Connell, HA, Lanier, WA, Katz, LM, Betts, RF, Mercurio, MG, Scott, GA, Lewis, MA, Goldgeier, MH. “Outbreak of Mycobacterium chelonae infection associated with tattoo ink”. N Engl J Med. vol. 367. 2012. pp. 1020-4. (Study showing the development of M. Chelonae infection after using contaminated premixed grey tattoo ink. The manufacturer has subsequently recalled this ink.)

Kluger, N, Muller, C, Gral, N. “Atypical mycobacteria infection following tattooing: Review of an outbreak in 8 patients in a French tattoo parlor”. Arch Dermatol. vol. 144. 2008. pp. 941-2. (A case series from France detailing 8 patients who all received tattoos from a single artist at a single tattoo parlor, each presenting within a 5-month period with asymptomatic erythematous papules and pustules strictly confined to the grey areas of the tattoos. Subsequent assessment revealed a positive acid-fast bacilli staining sample from the tattoo ink, which had been made using non-sterile tap water to dilute black ink to grey. The outbreak was presumed to be an atypical mycobacterial infection despite negative cultures given histopathology as well as clinical response to routine antibiotics effective against atypical mycobacterial infections, namely minocycline, clarithromycin or topical bacitracin/neomycin.)

Drage, L, Ecker, P, Orenstein, R, Phillips, K, Edson, R. “An outbreak of Mycobacterium chelonae infections in tattoos”. J Am Acad Dermatol. vol. 62. 2009. pp. 501-6. (A case series of six patients who developed M chelonae infections after receiving tattoos at a single tattoo parlor from a single tattoo artist. Clinical findings appeared 1 to 2 weeks following tattoo placement in all patients, and symptoms included pink, red or purple papules, papules with scales, pustules, granulomatous papules, and lichenoid papules and plaques. Cultures were positive in three patients. The diagnosis was made by histopathology in two cases and by clinical association in one remaining case. All isolates were clarithromycin sensitive.)

Balfour, E, Olhoffer, I, Leffell, D, Handerson, T. “Massive pseudoepitheliomatous hyperplasia: an unusual reaction to a tattoo”. Am J Dermatopathol. vol. 25. 2003. pp. 338-40. (A case report of pruritic, verrucous plaques arising 2 months following tattoo placement. Superficial shave biopsy initially revealed epidermal hyperplasia suggestive of a regressing keratoacanthoma. Repeat shave biopsy demonstrated marked epidermal hyperplasia with focal keratin-filled cystic dilations, reactive keratinocyte atypia, dense chronic inflammation, fibrosis and granules of dark red pigment suggesting pseudoepitheliomatous hyperplasia secondary to the tattoo.)

Chorny, J, Stephens, F, Cohen, J. “Eruptive keratoacanthomas in a new tattoo”. Arch Dermatol. vol. 143. 2007. pp. 1457-8. (A case report of multiple crusted nodules arising 3 weeks following tattoo placement. Histopathology showed invasive broad tongues of atypical glassy keratinocytes extending into the dermis. The sample was also notable for tattoo pigment free within the dermis as well as contained within scattered histiocytes. No recurrence of tumors were noted within 6 months following surgical excision.)

Mahalingam, M, Kim, E, Bhawan, J. “Morphea-like tattoo reaction”. Am J Dermatopathol. vol. 24. 2002. pp. 392-5. (A case report of tattoo reaction developing 1 year after tattoo placement characterized by pruritus, inflammation and induration. A punch biopsy sample demonstrated superficial and deep perivascular and periappendageal lymphoid cell infiltrate within scattered plasma cells, both intra- and extracellular depostition of tattoo pigment, thickening and hyalinization of collagen, interstitial fibroblast proliferation and loss of perieccrine adipocytes. Large amounts of hemosiderin deposition was noted in the mid-dermis, and Verhoeff von Gieson stain revealed fragmented, markedly reduced elastic fibers suggesting the diagnosis of morphea-like tattoo reaction. Full skin examination showed no additional clinical lesions suggestive of morphea.)

Chave, T, Mortimer, N, Johnston, G. “Simultaneous pseudoepitheliomatous and lichenoid tattoo reactions triggered by re-tattooing”. Clin Exp Dermatol. vol. 29. 2004. pp. 197-9. (A case report of asymptomatic nodules arising in several tattoos 6 months after re-tattooing over two unwanted longstanding prior tattoos. One re-tattooed area demonstrated an indurated plaque involving several multicolored areas of the newest tattoo, but was limited to the red pigmented areas of the original underlying tattoo. Biopsy from this area showed a lichenoid reaction to red tattoo pigment.A separate tattoo on the back was found to have multifocal nodular reaction to newly applied light blue pigment, and older longstanding tattoos on the forearms also developed multiple small focal areas of nodular reaction within the longstanding blue pigment. Biopsy of the re-tattooed lesion on the back demonstrated pseudolymphomatus tattoo reaction. Patch testing to undiluted pigments was negative. Clinical improvement was noted following several months of using clobetasol propionate 0.05% cream twice daily.)

Arroyo, M. “Black henna tattoo reaction in a person with sulfonamide and benzocaine drug allergies”. J Am Acad Dermatol. vol. 48. 2003. pp. 301-2. (A case report of significant allergic contact dermatitis arising 24 hours following the placement of two black henna temporary tattoos in a man with a history of sulfonamide and benzocaine allergy, highlighting the significance of parapheylenediamine allergy and the high cross reactivity risk with substances such as sulfonamides, sulfonylureas, dapsone, azo dyes and benzocaine.)

Morales-Callaghan, A, Aguilar-Bernier, M, Martinez-Garcia, G, Miranda-Romero, A. “Sarcoid granuloma on black tattoo”. J Am Acad Dermatol. vol. 55. 2006. pp. S71-3. (A case report of tattoo reaction arising 10 months following tattoo placement. Histopathologically, sarcoid granulomas were noted in the areas of black pigment. Patch testing showed type IV sensitization reaction to nickel and cobalt. Both metallographic reflection microscopy and flame atomic absorption spectrophotometry highlighted metals confined to black pigmented areas.)

Nawras, A, Alsolaiman, M, Mehboob, S, Bartholomew, C, Maliakkal, B. “Systemic sarcoidosis presenting as a granulomatous tattoo reaction secondary to interferon-alpha treatment for chronic hepatitis C and review of the literature”. Dig Dis Sci. vol. 47. 2002. pp. 1627-31. (A case report of tattoo reaction occuring 1 month following a 4-week course of recombinant interferon-α 2b for chronic hepatitis C. The interferon-α 2b had been discontinued due to progressive malaise and dyspnea. Biopsy of subcutaneous nodules involving a longstanding tattoo showed noncaseating granulomatous inflammation in proximity to pigment fragments. Given pulmonary symptoms, systemic workup was undertaken revealing bulky scattered lymphadenopathy, which was confirmed on biopsy as noncaseating granuloma and lymphocytic infiltration leading to diagnosis of both cutaneous and systemic sarcoidosis.)

Friedman, T, Westrich, M, Mozes, S, Dorenbaum, A, Herman, O. “Tattoo pigment in lymph nodes mimicking metastatic malignant melanoma”. Plast Reconstr Surg. vol. 111. 2003. pp. 2120-2. (A case report of a 25-year-old male undergoing sentinal lymph node biopsy of bilateral axillae following diagnosis of a 1mm malignant melanoma arising on the chest. The patient had multiple decorative tattoos over both arms. Sentinal lymph node dissection from each axillae was concerning for macroscopic deep, dark gray pigmentation, which was suspected to be metastatic melanoma.Intraoperative frozen section analysis along with multiple staining protocols were done prior to completion dissection, and was found to be negative for metastatic melanoma, revealing instead benign tattoo pigment deposition and sparing the patient unnecessary surgical morbidity.)

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