Accepted Article

Title: Multiple oral granulomatous nodules to hyaluronic acid filler

Carmen Caldas Pozuelo1, MD, Julia Domínguez De Dios2, MD, Xenia Mota Rojas1, MD, MCs

1Department of Otolaryngology, Hospital Álvaro Cunqueiro, Vigo, Spain.

2Department of Pathology, Hospital Álvaro Cunqueiro, Vigo, Spain.

Correspondence to Xenia Mota Rojas, Servicio de Otorrinolaringología. Complejo Hospitalario

Universitario de Vigo, Hospital Álvaro Cunqueiro. Estrada de Clara Campoamor, 341 Spain.
Phone number +34 647107153. Email: xenia.iraisa.mota.rojas@sergas.es

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/JOCD.13734
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Accepted Article
DR. XENIA MOTA ROJAS (Orcid ID : 0000-0001-9369-3309)

Article type : Letter to the Editor

1 Keywords: foreign body granulomas, dermal fillers, hyaluronic acid, lip

2 augmentation, hyaluronidase.

3 Running head: Oral granulomatous reaction to hyaluronic acid

5 Abstract/summary:

6 Case: A 74-years-old Caucasian woman presented with a 2-weeks history of

7 multiple nodules in both lips and perioral region, that caused her mild discomfort
8 while eating. The patient reported hyaluronic acid infiltration on both lips 5-months
9 prior to presentation. The examination revealed multiple, well-defined, millimetric
10 and firm nodules on both lips and oral mucosa. An excisional biopsy of one of the
11 nodules was performed under local anesthesia. Histopathological analysis
12 demonstrated acute eosinophilic inflammation, fibrosis and granulomas on mucoid
13 material, positive for Colloidal Iron stain and Alcian blue stain, alongside a minor
14 salivary gland showed mild atrophy, fibrosis and fat infiltration.

15 Discussion: Enhancement of the aged lip using hyaluronic acid, to restore the
16 bulkiness and elasticitythat have been lost with age, is very common. Nevertheless,
17 soft tissue fillers are used in a wide age range. Hyaluronic acid represents 78% of
18 the dermal filler injections in the United States, been the second most popular
19 nonsurgical cosmetic procedure after botulinum toxin injection. Foreign body
20 granulomatous reaction is a rare delayed complication that has been well
21 documented elsewhere and it has been associated with poor injection technique.
22 Although, it also has been related to hypersensitivity reactions that may be

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 23 caused by impurities developed during the bacterial fermentation process.
Accepted Article
24 Treatment of granulomatous reactions with hyaluronidase is recommended.

25

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 26 Dear editor,
Accepted Article
27

28 Case
29 A 74-years-old Caucasian woman presented with a 2-weeks history of multiple
30 nodules in both lips and perioral region, that caused her mild discomfort while
31 eating. She reported no other symptoms. The patient medical history was
32 remarkable for a superficial Basal Cell Carcinoma on the Neck treated with
33 Imiquimob 2-years prior to presentation. She also reported hyaluronic acid
34 infiltration (Perfectha ® subskin) on both lips 5-months prior to presentation. The
35 examination revealed multiple, well-defined, millimetric, firm nodules on both lips
36 and oral mucosa (Figures 1A and 1B), tender to touch. No other lesions were found
37 elsewhere neither lymphadenopathies. An excisional biopsy of one of the nodules
38 was performed under local anesthesia. Histopathological analysis demonstrated
39 acute eosinophilic inflammation, fibrosis and granulomas on mucoid material
40 (Figure 2), positive for Colloidal Iron stain and Alcian blue stain (Figure 3),
41 alongside a minor salivary gland showed mild atrophy, fibrosis and fat infiltration.

42

43

44 Discussion
45 Enhancement of the aged lip using hyaluronic acid is common. It is used to restore
46 bulkiness and elasticity that have been lost with age1. Nevertheless, soft tissue
47 fillers are used in a wide age range2. Hyaluronic acid represents 78% of the dermal
48 filler injections in the United States3, been the second most popular nonsurgical
49 cosmetic procedure after botulinum toxin injection4. This popularity may be due to
50 the fact that hyaluronic acid is a naturally occurring glycosaminoglycan present in
51 many tissues within the human body5, while the polysaccharide used as a dermal
52 filler is derived from fermented bacteria, it is cross-linked to assure biocompatibility
53 and stabilization6, which makes it minimally immunogenic.

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 54 Foreign body granulomatous reaction is a rare delayed complication that has been
Accepted Article
55 well documented elsewhere2,5,6. Also, migration of these inflammatory nodules have
56 been described6. It has been associated with poor injection technique7, and to
57 hypersensitivity reactions that may be caused by bacterial contamination during
58 injection, or impurities developed during the biofermentation process when
59 production4,6. Other authors have concluded that non-cohesive fillers have less
60 homogenous distribution and integration within the tissue, especially in patients
61 older than 70 years of age8. Nonetheless, hyaluronic acid fillers of high quality have
62 been proven not to induce an inflammatory response8.

63 The histopathological exam of the nodules shows amorphous crystalloid material

64 stained with Alcian Blue and Colloidal iron5, surrounded by a foreign body
65 granulomatous reaction, in which multinucleated cells and histiocytes are present.
66 Alcian Blue and Colloidal iron stains are characteristically good to confirm the
67 presence of mucopolysaccharides9.

68 In 2014 a multidisciplinary panel of experts formed the Global Aesthetic Consensus

69 Group, to make recommendations for early and late complications associated with
70 hyaluronic acid fillers4. These recommendations included the treatment of
71 granulomatous reactions and nodules with hyaluronidase. This is based on the fact
72 that several studies have shown that hyaluronidase is effective treating nodule
73 formation10.

74 In this particular case, the patient received an infiltration of a hyaluronic acid filler
75 that is not approved by the FDA, so it´s safety and effectiveness is not guaranteed.
76 She was treated with a short cycle of oral corticosteroids and hyaluronidase
77 injections on the nodules. The patient was reevaluated 15 days after the emergency
78 visit, showing reduction of the size of the nodules and improvement of the
79 tenderness.

80 On the other hand, other complications associated with soft tissue fillers injection
81 include local infection, such as cellulitis and erysipelas, in which case empiric
82 antibiotics treatment should be initiated. Clarithromycin plus Moxifloxacin,
83 Ciprofloxacin or Minocycline are the recommended drugs4.

84

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 85 Figures legend
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86

87  Figure 1A
88 Clinical image showing multiple nodules on the lower lip

89  Figure 1B
90 Clinical image showing multiple nodules on the right inner side of the upper lip
91
92  Figure 2
93 Amorphous crystalloid material surrounded by an acute eosinophilic inflammatory
94 reaction
95
96  Figure 3
97 To the left mucoid material stained with Colloidal Iron (original magnification ×20)
98 To the right mucoid material stained with Alcian blue (original magnification ×10)
99

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 100 References
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101 1. Florin W, Mandel L. Foreign Body Reaction to Facial Dermal Fillers: Case Report.
102 J Oral Maxillofac Surg. 2012;70(10):2352-2355.

103 2. Tamiolakis P, Piperi E, Christopoulos P, Sklavounou-Andrikopoulou A. Oral

104 foreign body granuloma to soft tissue fillers. Report of two cases and review of the
105 literature. J Clin Exp Dent. 2018;10(2):e177-e184.

106 3. Woodward J, Khan T, Martin J. Facial Filler Complications. Facial Plast Surg Clin
107 N Am. 2015;23(4):447-458.

108 4. Signorini M, Liew S, Sundaram H, et al. Global Aesthetics Consensus: Avoidance

109 and Management of Complications from Hyaluronic Acid Fillers—Evidence- and Opinion-
110 Based Review and Consensus Recommendations. Plast Reconstr Surg. 2016;137(6):961-
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112 5. Alcântara CEP, Noronha MS, Cunha JF, Flores IL, Mesquita RA. Granulomatous
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114 review of literature. J Cosmet Dermatol. 2018;17(4):578-583.

115 6. Cecchi R, Spota A, Frati P, Muciaccia B. Migrating Granulomatous Chronic

116 Reaction from Hyaluronic Acid Skin Filler (Restylane): Review and Histopathological
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118 7. Snozzi P, van Loghem JAJ. Complication Management following Rejuvenation

119 Procedures with Hyaluronic Acid Fillers—an Algorithm-based Approach: Plast Reconstr
120 Surg - Glob Open. 2018;6(12):e2061.

121 8. Tran C, Carraux P, Micheels P, Kaya G, Salomon D. In vivo Bio-Integration of

122 Three Hyaluronic Acid Fillers in Human Skin: A Histological Study. Dermatology.
123 2013;228(1):47-54.

124 9. Shahrabi Farahani S, Sexton J, Stone JD, Quinn K, Woo S-B. Lip Nodules Caused
125 by Hyaluronic Acid Filler Injection: Report of Three Cases. Head Neck Pathol.
126 2011;6(1):16-20.

127 10. Rzany B, Becker-Wegerich P, Bachmann F, Erdmann R, Wollina U. Hyaluronidase

128 in the correction of hyaluronic acid-based fillers: a review and a recommendation for use. J
129 Cosmet Dermatol. 2009;8(4):317-323.

130

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