Tattoo Ink Accumulation in the Lymphatic System: A Review of Literature

Samantha Triplett, Pharm.D., Genevieve Lynn Ness, Pharm.D., BCMAS

Christy Houston Foundation Drug Information Center, Belmont University College of Pharmacy

Introduction Preliminary Results Continued

 Tattoo inks are defined as cosmetics by the Food, Drug, and Cosmetic Act.1
o However, the only components of tattoo inks that are subject to regulation by the Food and Drug
Administration (FDA) are the pigments that are used as color additives.
o Color additives are not approved for injection into the skin. Several of the pigments are not approved
for skin contact, with some classified as industrial pigments used more commonly in interior/exterior
paints, coatings, plastics, glazes, printer inks, or automobile paints.1,2
 Due to the lack of regulation of tattoo inks, there are safety issues and concerns with the injection of these
components into the dermal layers of the skin.1,3,4
o Potential risks associated with tattoos include infections, allergic reactions, granulomas, keloid
formations, and MRI complications.1,3,5,6,7
o The components of tattoo inks are not standardized and can vary depending on the intended color and
manufacturer of the ink.1 Additionally, there have been reports of counterfeit tattoo inks, where the
labeling does not adequately represent the contents of the ink.2,8
o In general, tattoo ink formulations will contain metals, including but not limited to titanium, barium,
aluminum, copper, cinnabar, mercury, strontium, manganese, lead, vanadium, antimony, arsenic,
cadmium, chromium, cobalt, and nickel.2,4,8,9,10 In the tattooing process, the needle can become worn
with the repeated entry into the skin and has the potential to deposit metal particles into the dermal
skin layers.11
 At this time, tattoos are not associated with the development of cancer and the mechanism of tattoo ink
degradation or the effects over time are not well understood.8,12,13
o However, if the tattoo pigments degrade within the skin and its products are carcinogenic, malignant
skin tumors may develop within the tattoo.13
o Potential carcinogens that have been found in tattoo inks include polycyclic aromatic hydrocarbons
(PAHs) and aromatic amines.2,4,8,14
Purpose
 The purpose of this systematic review is to determine the prevalence and health risks of tattoo ink
accumulation in the lymphatic system.
 The migration of tattoo ink to regional lymph nodes is uncommon but has a well documented occurrence in published literature.4-11,13,15-25
 The concern with tattoo ink presence in the lymph nodes is variable and based upon the following:
o Differentiating tattoo ink from potential metastasis is nearly impossible upon imaging, usually resulting in repeat imaging and potentially
unnecessary biopsy of the impacted lymph nodes.5,13,16-21 Tattoo ink accumulation in the lymph nodes can cause lymphadenopathy,
appearing as high-density foci on imaging.5,6,9,13,15-19
o The presence of tattoo ink in the lymph nodes may influence the function of the immune system, either decreasing the immune surveillance
and impacting the transport of foreign materials to the lymph nodes or if the recognition of tattoo ink is deemed as foreign by the immune
system it can initiate the recruitment of the immune cells leading to adverse reactions.7,15
o Due to the permanence of tattoos, the presence of chemicals and carcinogens have a lifelong exposure within the dermal layers of the
skin.2,4,8,10
 The Occupational Safety and Health Administration (OSHA) has a permissible exposure limit (PEL) for PAHs in the workplace air of 0.2 mg/m3 in
an 8-hour time-weighted average.26
o In Lehner K, et al. a biokinetic study of donated cadaver tattoo skin and regional lymph node samples, 12/16 skin samples had PAH
concentrations ranging from 0.1 to 0.6 µg/cm2 (OSHA PEL 0.002 µg/cm2), and 11/16 lymph node samples had PAH concentrations ranging
from 0.1 to 11.8 µg/g (OSHA PEL 0.00002 µg/g).4
 Of the case reports included for analysis, the following was discovered:
o All case reports described the presence of tattoo ink within lymph nodes that were regional to tattoo placement on the body.5-7,9,13,15-27
o A total of 14 cases describe inconclusive imaging that was later determined to be due to the presence of tattoo ink in regional lymph nodes
to tattoos of various ages.5,9,13,15,16,20,22,23,25
o Four cases describe an allergic type immune reaction to a tattoo accompanied by the accumulation of tattoo ink in regional lymph nodes
relative to tattoo placement.7,24,27,28
o Four other cases reported the removal and histological analysis of biopsied lymph nodes due to suspected metastasizes but were
determined to contain tattoo ink regional to the patient’s tattoos.6,18,19,21
o In one case report, a kidney transplant was delayed due to the presence of a dark brown/black lymph node that was present at the donor’s
renal hilum.17 The color of the lymph node was due to the presence of tattoo ink from a recent tattoo on the donor’s back. The transplant
was completed since the lymph node was not found to be cancerous.
o Another case report describes the removal and biopsy of sentinel lymph nodes after melanoma discovery only to find tattoo ink within the
affect lymph nodes.23 However, the patient had the tattoo removed 3 years prior to melanoma development.

Methods
 A comprehensive literature search of Medline Ultimate and Embase was conducted: References
o Keywords: “tattoo,” “tattoos” 1. Tattoos & permanent makeup: fact sheet. FDA. Updated March 15, 2022. Accessed June 29, 2022. https://www.fda.gov/cosmetics/cosmetic-products/tattoos-permanent-makeup-fact-sheet
o MeSH and Emtree terms: “Lymph Nodes,” “Body Modification, Non-Therapeutic,” “Tattooing,” 2.
3.
Rubio L, Guerra E, Garcia-Jares C, Lores M. Body-decorating products: ingredients of permanent and temporary tattoos from analytical and European regulatory perspectives. Anal Chim Acta. 2019;1079:59-72. doi:10.1016/j.aca.2019.06.052
Tattoos and body piercings. Patient Education - Disease and Procedure. Lexicomp. UpToDate, Inc.; 2022. Updated June 8, 2022. Accessed June 9, 2022. https://online.lexi.com
“polycyclic aromatic hydrocarbons.” 4. Lehner K, Santarelli F, Vasold R, et al. Black tattoos entail substantial uptake of genotoxicpolycyclic aromatic hydrocarbons (PAH) in human skin and regional lymph nodes. PloS one. 2014;9(3):e92787. doi:10.1371/journal.pone.0092787
5. Lane EG, Eisen CS, Ginter PS, Drotman MB. Ink on the move: tattoo pigment resembling axillary lymph node calcifications. Clinical Imaging. 2021;79:154-157. doi:10.1016/j.clinimag.2021.04.036
 Randomized controlled trials and observational studies, including case series and case reports were 6. Tamura D, Maeda D, Terada Y, Goto A. Distribution of tattoo pigment in lymph nodes dissected for gynecological malignancy. Int J Surg Pathol. 2019;27(7):773-777. doi:10.1177/1066896919846395
included for analysis. 7.
8.
Deeken A, Jefferson J, Hawkinson D, Fraga GR. Localized chronic fibrosing vasculitis in a tattoo: a unique adverse tattoo reaction. Am J Dermatopathol. 2014;36(4):e81-e83. doi:10.1097/DAD.0b013e3182a27a99
Negi S, Bala L, Shukla S, Chopra D. Tattoo inks are toxicological risks to human health: a systematic review of their ingredients, fate inside skin, toxicity due to polycyclic aromatic hydrocarbons, primary aromatic amines, metals, and overview of regulatory
 Trials and studies regarding clinical tattooing for imaging/diagnosis of lymph nodes and studies frameworks. Toxicol Ind Health. 2022;38(7):417-434. doi:10.1177/07482337221100870
9. Aguillar VLN, de Mello Tucunduva TC, Carvalho FM, et al. Tattoo pigment mimicking calcifications in axillary lymph nodes: a pitfall in mammographic imaging evaluation. Breast J. 2020;26(4):764-766. doi:10.1111/tbj.133653
conducted in animals were excluded from analysis. 10. Schreiver I, Hesse B, Seim C, et al. Synchrotron-based 𝒗-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin. Sci Rep. 2017;7(1):11395. doi:10.1038/s41598-017-11721-z
11. Schreiver I, Hesse B, Seim C, et al. Distribution of nickel and chromium containing particles from tattoo needle wear in humans and its possible impact on allergic reactions. Part Fibre Toxicol. 2019;16(1):33. doi:10.1186/s12989-019-0317-1
Preliminary Results 12.
13.
Kohler C, Foiato T, Marnitz S, et al. Potential surgical and oncologic consequences related to skin tattoos in the treatment of cervical cancer. J Minim Invasive Gynecol. 2016;23(7):1083-1087. doi:10.1016/j.jimg.2016.07.016
Pena Arce C, Vazquez-Gomez O, Carretero RG, Hernandez CD. Elusive diagnosis of lymphadenopathy in a young woman. BMJ case rep. 2019;12(6):e230909. doi:10.1136/bcr-2019-230909
 The results of this study may be used to determine the importance of documenting tattoo presence and 14.
15.
Petersen H, Lewe D. Chemical purity and toxicology of pigments used in tattoo inks. Curr Probl Dermatol. 2015;48:136-141. doi:10.1159/000369647
Bose R, Sibley C, Fahim S. Granulomatous and systemic inflammatory reactions from tattoo ink: case report and concise review. SAGE open med case rep. 2020;8:2050313X20936036. doi:10.1177/2050313X20936036
history in a patient’s medical health record. 16. Heaney RM, Sweeney L, Smith C, O’Brien A. Much ‘tattoo’ about nothing: tattoo pigment mimicking breast microcalcifications on mammography. Radiol case rep. 2021;16(7):1833-1835. doi:10.1016/j.radcr.2021.04.044

 A total of 27 articles were included in this analysis (Figure 1).

Literature Reviews
Biokinetic Studies
Prospective Cohorts 1 24.
Case Series
Case Reports
17. Everson L, Bernstein BS, Chatterjee D, et al. ThINK before living donor transplantation. Kidney Int. 2018;95:237. doi:10.1016/j.kint.2018.07.015
18. Cabalag MS, Christie M, Miller JA. Pigmented lymphadenopathy secondary to tattoo ink: a potential masquerader. Surgery. 2015;157(5):959-960. doi:10.1016/j.surg.2014.02.017
Figure 1: Analyzed Resources by Type 19. Beavis A, Amneus M, Aoyama C, Holschneider CH. Tattoo pigment lymphadenopathy mimicking metastasis in vulvar cancer. Obstet Gynecol. 2012;120(2 Pt 2):442-444. doi:10.1097/AOG.0b013e3182583be2
20. Melnick N, Pierce B. Lymphadenopathy secondary to tattoo ink in a patient with a history of Hodgkin lymphoma. JAAPA. 2022;35(1):29-32. doi:10.1097/01.JAA.000076724.89266.43
2 21. Peterson SL, Lee LA, Ozer K, Fitzpatrick JE. Tattoo pigment interpreted as lymph node metastasis in a case of subungual melanoma. Hand (N Y). 2008;3(3):282-285. doi:10.1007/s11552-008-9107-1
22. Hayakawa A, Sano R, Takei H, et al. Tattoo image composed of radiopaque deposits demonstrated by postmortem computed tomography. Legal med (Tokyo). 2018;35:9-11. doi:10.1016/j.legalmed.2018.09.002
6 23. Dujmovic A, Jurisic N, Mance M, Bulic K, Vrbanovic Mijatovic V, Mijatovic D. Tattoo pigment within regional lymph nodes mimicking cutaneous melanoma metastasis. Acta dermatovenerologica Croatica : ADC. 2020;28(1):47-48. Accessed June 13, 2022.
https://search.ebscohost.com/login/aspx?direct=true&db=mdc&AN=32650854&site=ehost-live
Othman J, Robbins E, Lau EM, Mak C, Bryant C. Tattoo pigment-induced granulomatous lymphadenopathy mimicking lymphoma. Annals of Internal Med Clin Cases. 2017;167(11):830-831. doi:10.7326/L17-0424
25. Blasco-Morente G, Perez-Lopez I, Martinez-Lopez A, et al. Pigmented lymph nodes in a patient with melanoma: tattoos. J Eur Acad Dermatol Venereol. 2016;30:e109-e174. doi:10.1111/jvd.13387
2
26. Gehle K. Polycyclic aromatic hydrocarbons (PAHs) standards, regulations. Agency for toxic substances and disease registry. July 1, 2009. Updated December 10, 2013. Accessed June 29, 2022. https://www.atsdr.cdc.gov/csem/polycyclic-aromatic-hydrocarbons
27. Naeini FF, Pourazizi M, Abtahi-Naeini B, Saffaei A, Bagheri F. Looking beyond the cosmetic tattoo lesion near the eyebrow: screening the lungs. J Postgrad Med. 2017;63(2):132-134. doi:10.4103/0022-3859.201421
16
28. Carter MD, Trites J, McNeil SA, Walsh NNM, Bullock MJ. Florid granuloma annulare-like reaction in regional lymph nodes after “regression” of red pigment in tattoos. Am J Dermatopathol. 2018;40(5):383-385. doi:10.1097/DAD.0000000000001043

0 2 4 6 8 10 12 14 16 18
Acknowledgments: This project was inspired by a drug information query from Matthew Sherman, Pharm.D., MBA.